Recent Advances in Pediatrics (Special Volume 24): Respiratory Diseases Suraj Gupte
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Obstetric Vasculopathies
First Edition: 2013
9789350903674
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Acute Respiratory Infections in Under 5S1

Bratati Banerjee
 
INTRODUCTION
Infections of the respiratory tract are the most common illnesses in humans, particularly among children. Though these are not very alarming in adults other than causing discomfort, in the extremes of age and in those with low respiratory reserve they cause considerable morbidity and mortality. Childhood acute respiratory infections, including pneumonia, is a significant public health problem in India.
Acute respiratory infections (ARIs) may cause inflammation of the respiratory tract anywhere from the nose to the alveoli, with a wide range of combination of symptoms and signs. Depending on the site of infection, ARIs are classified as acute upper respiratory tract infections (AURIs) or acute lower respiratory tract infections (ALRIs). The upper respiratory tract consists of the airways from the nostrils to the vocal cords in the larynx, including the paranasal sinuses and the middle ear. The lower respiratory tract covers the continuation of the airways from the trachea and bronchi to the bronchioles and the alveoli. The commonly occurring AURIs are common cold, pharyngitis, otitis media and sinusitis. The common ALRIs include epiglottitis, laryngitis, laryngotracheitis, bronchitis, bronchiolitis and pneumonia.1-7
Acute respiratory infections are not confined to the respiratory tract only, but have systemic effects because of possible extension of infection or microbial toxins, inflammation and reduced lung function. Diphtheria, pertussis (whooping cough) and measles are vaccine-preventable diseases that may have a respiratory tract component, but also affect other systems.1,2
 
PROBLEM STATEMENT
Acute respiratory infections in children under 5 years of age are a cause of concern all over the globe, particularly in developing countries. Except during the neonatal period, ARIs are the most common causes of both illness and mortality in children under five, who average 3 to 6 episodes of ARIs annually, regardless of where they live or what their economic situation is. Pneumonia alone is responsible for about one-fifth of the estimated 10.6 million deaths per year in this age group. The World Health Organization (WHO) estimates that 2 million children under 5 years of age 2die of pneumonia each year. It is estimated that Bangladesh, India, Indonesia and Nepal together account for 40% of the global ARI mortality.1,2,8
In India, the infant mortality rate (IMR) has declined from 139/1,000 live births in 1972 to 42/1,000 live births in 2009. There are wide inter and intra state variations in infant and child mortality. There are also variations between rural and urban India. For example, rural IMR is 55/1,000 live births as opposed to an urban IMR of 34/1,000 live births. A significant proportion of child deaths (over 50% of under-five mortality and 66% of infant mortality) occur in the neonatal period. Neonatal mortality rate is 35/1,000 live births and under five mortality rate is 74. A significant proportion of child deaths (over 50% of under-five mortality and 66% of infant mortality) occur in the neonatal period. According to WHO about 20% of all deaths in children under 5 years of age are due to ALRIs—pneumonia, bronchiolitis and bronchitis, 90% of which occur due to pneumonia.9-11
Acute respiratory infections is also an important cause of morbidity in children in India. Common illnesses in children under 3 years of age include fever (27%), acute respiratory infections (17%), diarrhea (13%) and malnutrition (43%). National Family Health Survey (NFHS) III carried out in 2005 to 2006, reported 5.8% children less than 5 years of age suffered from ARI, as diagnosed by cough and short, rapid breathing, in the preceding 2 weeks before the survey. The burden of disease in terms of episodes per child per year has been found to range from 0.03 to 0.52.12-14
 
ETIOLOGY
The vast majority of AURIs have a viral etiology. Rhinoviruses account for 25 to 30% of AURIs; respiratory syncytial viruses (RSVs), para influenza and influenza viruses, human metapneumovirus, and adenoviruses for 25 to 35%; corona viruses for 10%; and unidentified viruses for the remainder. Contrary to the general belief that RSV infection is a problem of the West, WHO has shown that even in the developing countries RSV is the main cause of respiratory infection, killing around 6 lakhs children annually. Among bacteria, group A streptococci take the lead, though Corynebacterium diphtheriae, N. meningitidis may also cause AURI. H. influenzae, pneumococcus and Staphylococcus aureus are responsible for superimposed infections, leading to complications related to ears, sinuses, mastoids, lymph nodes and lungs. Acute pharyngitis, in conjunction with the development of a membrane on the throat, is nearly always caused by Corynebacterium diphtheriae in developing countries.1,3,15
Both bacteria and viruses can cause pneumonia. Bacterial pneumonia is often caused by Streptococcus pneumoniae (pneumococcus) or Haemophilus influenzae, mostly type B (Hib) and occasionally by Staphylococcus aureus or other streptococci. Just 8 to 12 of the many types of pneumococcus cause most cases of bacterial pneumonia, although the specific types may vary between adults and children and between geographic locations. Other pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, cause atypical pneumonias. Their role as a cause of severe disease in children under five in developing countries is unclear. The most common causes of viral LRIs are RSVs, followed by parainfluenza 3viruses. Before the effective use of measles vaccine, the measles virus was the most important viral cause of respiratory tract-related morbidity and mortality in children in developing countries.1,12
According to a systematic review, childhood pneumonia in India is caused by bacteria, viruses, atypical organisms like Chlamydia and Mycoplasma, although the precise proportions in community and hospital-based studies is not clear. However, it appears that about 10 to 15% of childhood pneumonias are caused by H. influenzae and RSV each; and 12 to 35% by pneumococcus. Other important causes include S. aureus, Gram negative organisms (especially in younger infants), Mycoplasma and Chlamydia. Serotypes of S. pneumoniae causing childhood pneumonia are also not well identified. However, it is not possible to differentiate between bacterial and viral ARIs based on clinical signs or radiology.11,14
Box 1.1 lists the various organisms contributing to occurrence of ARIs.1,2,4,11,14
Table 1.1 lists pathogens responsible for pneumonia in the different age groups.7
 
RISK FACTORS
The community-based NFHS-III survey reported that ARI affects all children, irrespective of socioeconomic status; however certain risk factors likely to be associated with occurrence of and death from ARI have emerged from various studies.13-15
 
Demographic and Socioeconomic Factors
Prevalence is higher in young age particularly during infancy, slightly higher among boys, in rural areas, among scheduled-tribe children and those with poor economic status. However, case fatality rate is higher in girls. The prevalence is lower with high parental education particularly among children of mothers who have at least completed high school.13,14,16-18
 
Environmental Factors
The prevalence is higher among those residing in lower standard of living households with presence of environmental pollution. Those using biomass or solid fuel and those exposed to environmental tobacco smoke, i.e. passive smoking show higher prevalence than those without such exposure or using cleaner fuels. Prevalence is also high in children of households keeping large animals. Living in overcrowded conditions and sharing of bedroom are likely to result in increased occurrence of ARI. Prevalence is lower in those living in households that use piped drinking water and water filter for the purification of water.11,13,14,17-19
 
Nutritional Factors
Low birth weight, malnutrition and hypovitaminosis A have been found to be risk factors of ARI. Non-breastfed children or those with discontinuation of breastfeeding in early infancy or delayed weaning are at higher risk of getting pneumonia. These children are also at a higher risk of death from pneumonia.11,184
 
Illness and Treatment Factors
Probable risk factors that have emerged as being significant are lack of immunization particularly measles, previous history of severe ARI and asthma, unresponsiveness to earlier treatment and use of non-allopathic medicine. Correction of these factors can probably reduce mortality due to ARI.17,18 5
Table 1.1   Pathogens responsible for pneumonia in the different age groups
Age
Bacteria
Viruses
Others
Neonates
Group B streptococci
CMV, herpes
Chlamydia
1–3 months
S. pneumoniae
CMV, RSV
Chlamydia
S. aureus
Influenza
H. influenzae
Parainfluenza
4 months–5 years
S. pneumoniae
RSV
Mycoplasma
S. aureus
Adenovirus
H. influenzae
Influenza
Group A Streptococcus
Klebsiella
Pseudomonas species
M. tuberculosis
Over 5 years
S. pneumoniae
Influenza
Mycoplasma
S. aureus
Varicella
Legionella species
H. influenzae
M. catarrhalis
M. tuberculosis
The WHO 2008 report cited and categorized all these risk factors into three groups as:20
  1. Definite risk factors: Malnutrition (weight-for-age z-score <–2), low birth weight, lack of exclusive breastfeeding during first 4 months, lack of measles immunization, indoor air pollution, crowding.
  2. Likely risk factors: Parental smoking, zinc deficiency, maternal inexperience, co-morbidities.
  3. Possible risk factors: Maternal illiteracy, day-care attendance, rainfall (humidity), high altitude (cold air), vitamin A deficiency, higher birth order, outdoor air pollution.
 
INTERVENTIONS
Interventions to control ARIs can be divided into four basic categories: immunization against specific pathogens, early diagnosis and treatment of disease, improvement in nutrition and safer environment. The first two fall within the purview of the health system and will be discussed here, whereas the last two fall under public health and require multisectoral involvement.1
 
Immunization
Widespread use of vaccines against measles, diphtheria, pertussis, Hib, pneumococcus and influenza have the potential to substantially reduce the 6incidence of ARIs in children in developing countries. Of these three vaccines contribute the most to the reduction of deaths from pneumonia. These are measles, Haemophilus influenzae B and pneumococcus.
Measles immunization leads to significant decline in child mortality, at least partly mediated by its impact on reduction of complications, including pneumonia. The exact burden of Hib pneumonia in India is not clear. The vaccine is efficacious in reducing invasive Hib disease and Hib pneumonia and meningitis in research trials. However the overall effectiveness depends on the proportion of childhood pneumonia caused by Hib. Similarly for pneumococcal pneumonia the exact burden and the serotypes responsible for invasive disease in India are not known. Polymerase conjugate vaccine are efficacious in reducing disease caused by vaccine-serotypes, so the overall effectiveness against childhood pneumonia is dependent on the relative burden of pneumococcal pneumonia and the serotype coverage of the vaccine.14
 
Measles Vaccine2
Tissue culture vaccines, either chick embryo or human diploid cell line vaccines, presented as a freeze dried product are given at 9 months of age as recommended by WHO—expanded program on immunization. However, seroconversion may be poor due to presence of maternal antibodies. A second dose is therefore given a year later in many countries. The reconstituted vaccine is administered subcutaneously as a single dose of 0.5 mL. Measles vaccine can also be combined with other live-attenuated vaccines such as mumps and rubella (MMR) vaccine, measles and rubella (MR) vaccine and measles mumps, rubella and varicella vaccine (MMRV).
 
Hib Vaccine1,21
Currently three Hib conjugate vaccines are available for use in infants and young children.
Polysaccharide vaccine : The first Hib vaccine licensed was a pure polysaccharide vaccine. Similar to other polysaccharide vaccines, immune response to the vaccine was highly age-dependent. Children under 18 months of age did not produce a positive response for this vaccine. As a result, the age group with the highest incidence of Hib disease was unprotected, limiting the usefulness of the vaccine.
Conjugate vaccine : The shortcomings of the polysaccharide vaccine led to the production of the Hib polysaccharide-protein conjugate vaccine. Attaching Hib polysaccharide to a protein carrier greatly increased the ability of the immune system of young children to recognize the polysaccharide and develop immunity. There are currently three types of conjugate vaccine utilizing different proteins in the conjugation process, all of which are highly effective: tetanospasmin (also called tetanus toxin), mutant diphtheria protein and meningococcal group B outer membrane protein.
7Combination vaccines : Multiple combinations of Hib and other vaccines have been licensed, reducing the number of shots necessary to vaccinate a child. Hib vaccine is often given as a combined preparation with DPT vaccine. WHO has certified several Hib vaccine combinations, including a pentavalent diphtheria-pertussis-tetanus-hepatitis B-Hib, for use in developing countries. Three or four doses are given intramuscularly, depending on the manufacturer and type of vaccine. The vaccine schedule is at 6, 10 and 14 weeks of age. For children more than 12 months of age who have not received their primary immunization, a single dose is sufficient for protection.
 
Pneumococcal Pneumonia Vaccine1,2,22
Two kinds of vaccines are currently available against pneumococci: a 23-valent polysaccharide vaccine—pneumococcal pneumonia vaccine (PPV23), which is more appropriate for adults than children and a 7-valent protein-conjugated polysaccharide vaccine—pneumonia conjugate vaccine (PCV7). A 9-valent vaccine (9-PCV) has undergone clinical trials in The Gambia and South Africa, and an 11-valent vaccine (11-PCV) is being tried in the Philippines.
Polysaccharide vaccine: PPV23 is a polysaccharide non-conjugate vaccine containing capsular antigens. A dose of 0.5 mL of the vaccine contains 25 mg of purified capsular polysaccharide from each 23 serotype. It is administered to adults and children over 2 years of age, as a single intramuscular dose preferably in the deltoid muscle or may even be given subcutaneously. The vaccine should not be mixed in the syringe with other vaccines, but may be administered at the same time by separate injection in the other arm.
Conjugate vaccine: PCV7 or pneumococcal conjugate vaccine is suitable for infants and toddlers. This contains 7 selected polysaccharides bound to protein carriers and induces a T cell dependent immune response. These are 2 μg of capsular polysaccharides of serotypes 4, 9V, 14, 19F and 23F; 2 μg of oligosaccharide from 18C; and 4 μg of polysaccharide of serotype 6B in a 0.5 mL dose; each serotype is conjugated to the non-toxic diphtheria CRM 197 protein and adsorbed onto aluminium salt to enhance the antibody response. Unlike the polysaccharide, vaccine the conjugate vaccine decreases nasopharyngeal colonization of bacteria, which produces herd immunity, thereby resulting in less transmission of disease to non-immunized children and adults. The primary series is given as 3 intramuscular doses to infants at 6, 10 and 14 weeks. A booster dose administered after 12 months of age may improve the immune response. The other schedule is at 2, 4 and 6 months of age and a booster at 12 to 15 months.
 
Availability of Vaccines in India
Hib vaccines are available in several formulations: monovalent, tetravalent (DTwP-Hib), pentavalent (DTwP-HepB/Hib) and in similar combinations with acellular pertussis vaccine. All three types of Hib vaccines from Indian manufacturers are licensed in the country. The vaccines are available in a variety of vial sizes. Prequalified pentavalent vaccines are available in single, two and 8ten-dose presentations. Indian manufacturers currently produce 4 million doses of Hib-containing vaccines each year for the private market. Pentavalent vaccine supply offered to The Global Alliance for Vaccines and Immunization (GAVI)—eligible countries from two multinational suppliers is currently 66 million doses per year. Supplier capacity is sufficient to meet the present and future demand for India, if given sufficient lead time to increase production. GAVI has been instrumental in funding of Hib vaccine for children in urban slums, promotion of safe injection practices and inclusion of auto-disabled syringes for childhood immunizations in India.23,24
Wyeth Pharmaceuticals produces a PCV-7, which is the only commercially available pneumococcal conjugate (protein linked to polysaccharide) vaccine. It protects against pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, 23F. The vaccine is licensed in more than 70 countries for use in children of less than 5 years of age and has been introduced into immunization program in more than a dozen high-income countries. PCV-7 in developing countries is not expected to confer the same level of immunity because the distribution of serotypes in most developing countries differs from that in the high-income countries. It does not provide protection against serotypes 1 and 5 that, together with serotype 14, are the most frequent isolates in GAVI-eligible countries. Nevertheless, in March 2007, WHO issued guidance calling for the introduction of pneumococcal conjugate vaccines into immunization program in developing countries, beginning with the currently licensed PCV-7.31. Other pneumococcal conjugate vaccines that expand the serotypes coverage of PCV-7 are in late stages of development. GAVI provides vaccines at heavily subsidized rate to developing countries and has approached the Government of India asking for non-binding expressions of interest in introducing pneumococcal vaccines.22,25
 
Vaccination Recommendations in India
Currently other than measles, diphtheria and pertussis, no other vaccine has been included in the primary immunization schedule of India. Hib vaccine is being given in some districts.
 
Hib Vaccine
The Hib and pneumococcal subcommittee of National Technical Advisory Group on Immunization (NTAGI) in India met in April 2008 and reviewed the available published and unpublished literature as well as consulted prominent Hib experts to make an informed decision regarding the introduction of Hib vaccine into the routine Universal Immunization Program (UIP) in India.23
The committee noted that Hib diseases burden is sufficiently high in India to warrant prevention by vaccination. Hib vaccines have been demonstrated to be safe, both globally and in India, and extremely efficacious in all settings where they have been used. Hib vaccine fits into the UIP immunization schedule. Several Indian manufacturers are currently producing Hib vaccines and a detailed analysis showed that supplier capacity would be sufficient to meet the present and future 9demand for India if given sufficient lead time to increase production. Recognizing that it is the poorest children that are most at risk, the Indian Academy of Pediatrics (IAP) has already recommended this vaccine for routine use in India. The NTAGI subcommittee also strongly recommended that Hib vaccine should immediately be introduced in India's UIP.23
 
Pneumococcal Vaccine
WHO considers the inclusion of this vaccine in National Immunization Programs as particularly high priority in countries with under 5 mortality > 50 per 1,000 live births or greater than 50,000 child deaths annually. With an infant mortality rate of 50 per 1,000 live births and under five mortality of 74, India meets the WHO's criteria for countries where pneumococcal vaccination should be a priority for introduction. However, there have been considerable debate over this issue and pneumococcal vaccine has not been considered a priority in India.22,26-28
 
CASE MANAGEMENT
 
Background
Reduction of infant and child mortality has been an important consideration of the health policy of Government of India and it has tried to address the issue right from the early stages of planned development.
The ARI Control Program was started in India in 1990. It sought to introduce scientific protocols for case management of pneumonia with co-trimoxazole. Initially 14 pilot districts were selected and later on 10 new districts were included in 1991. A review of the health facility done in 1992 revealed that although 87% of personnel were trained and the drug supply was regular yet there were problems in correct case classification and treatment.29
Since 1992, the Program was implemented as part of Child Survival and Safe Motherhood (CSSM) Program and later with Reproductive and Child Health (RCH) Program in 1997. Cotrimoxazole tablets are supplied as part of drug kit for use by different category of workers at subcenters and above, for managing cases of Pneumonia. Under RCH-II, activities have been implemented in an integrated way with other child health interventions. The Rapid Household Survey done in 2002, showed that utilization of government facilities for children with ARI was very low at 14%, whilst NFHS II data suggests that the proportion of children with ARI taken to a facility or provider was 64%.29,30
Subsequently in 2005, The National Rural Health Mission (NRHM) was launched that incorporated a complete restructuring of current strategies to achieve the goal of improved public health services. NRHM brought all the major national health program under one umbrella.31
Integrated Management of Neonatal and Childhood Illnesses (IMNCI) strategy is one of the main interventions under RCH II/NRHM. It is the Indian adaptation of the WHO-UNICEF generic Integrated Management of Childhood Illness (IMCI) strategy and is the centerpiece of newborn and child health strategy under Reproductive and Child Health II Program and National Rural Health 10Mission. IMNCI adopts a syndromic approach to case management according to algorithms provided. The strategy encompasses a range of interventions to prevent and manage the commonest major childhood illnesses, which cause death, i.e. neonatal illnesses, ARI, diarrhea, measles, malaria and malnutrition. The package of services is implemented at the level of household, subcenters and primary health centers.12
F-IMNCI is the integration of the facility based care package with the IMNCI package, to empower the health personnel with the skills to manage new born and childhood illness at the referral health facility like Community Health Centers, First Referral Units, District Hospitals and Medical College Hospitals. It helps to build capacities to handle referrals taking place from the community.32
IMNCI Plus indicates wider, comprehensive range of interlinked interventions that form the newborn and child health component of RCH II Program. It includes skilled care at birth, IMNCI including in patient care and immunization.12
 
Categorizations12
Depending on the age of the child various signs and symptoms differ in their degree of reliability, diagnostic value and importance. Therefore for management children are divided into two age groups:
  1. Young infant up to 2 months
  2. Children 2 months up to 5 years.
 
History Taking12
Proper history should be taken to note the age of the child, for how long the child is coughing, whether the child is able to drink, (if the child is aged 2 months up to 5 years), has the young infant stopped feeding well (child less than 2 months of age), has there been any antecedent illness such as measles, does the child have fever, is the child excessively drowsy or difficult to wake (if yes, for how long), did the child have convulsions, is there irregular breathing, short periods of not breathing or the child turning blue, any history of treatment taken during illness.
 
Physical Examination12
Look and listen for the following:
Count the breaths in one minute: To decide if the child has fast breathing. The child must be quiet and calm when you look and listen to his breathing. To count the number of breaths in one minute, use a watch with a second hand or a digital watch. Look for breathing movement anywhere on the child's chest or abdomen, which should be exposed for counting. Young infants usually breathe faster than older children do. The cut-off rate to identify fast breathing therefore depends on the age group.
Fast breathing is present when the respiratory rate is:
  • 60 breaths per minute or more in a child less than 2 months of age
  • 50 breaths per minute or more in a child aged 2 months up to 12 months
  • 40 breaths per minute or more in a child aged 12 months up to 5 years.
11In a young infant, if the count is 60 breaths or more, the count should be repeated, because the breathing rate of a young infant is often irregular and erratic. The young infant may occasionally stop breathing for a few seconds, followed by a period of faster breathing. If the second count is also 60 breaths or more, the young infant has fast breathing.
Look for chest indrawing: Look for chest indrawing when the child breathes IN. Look at the lower chest wall (lower ribs). The young infant has chest indrawing if the lower chest wall goes IN when the infant breathes IN. Chest indrawing occurs when the effort the young infant needs to breathe in is much greater than normal. In normal breathing, the whole chest wall (upper and lower) and the abdomen move OUT when the young infant breathes IN.
Look and listen for stridor: A child with stridor makes a harsh noise, while breathing IN. Stridor occurs when there is narrowing of the larynx, trachea or epiglottis, which interferes with air entering the lungs. These conditions are often called croup.
Look for nasal flaring: Nasal flaring is widening of the nostrils when the young infant breathes IN.
Listen for grunting: Grunting is the soft, short sounds a young infant makes when breathing OUT. Grunting occurs when an infant is having difficulty in breathing.
Listen for wheeze: A child with wheezing makes a soft whistling noise or shows signs indicating breathing OUT is difficult. Wheezing is caused by narrowing of the air passage in the lungs.
Look and feel the child: See if the child is abnormally sleepy or difficult to wake, feel for fever or low body temperature, check for severe malnutrition or cyanosis.
 
Classification and Management of Illness12
The children are classified into three groups and color coded accordingly. The first group with very sick children, falling under the pink classification, needs urgent referral to higher level health facility. The second group, in the yellow classification, is treated at the outpatient department. The third group is coded green and these children can be managed at home.
Table 1.2 presents the salient features of the classification and management of the illness.
 
Treatment12
A. Young infant aged up to 2 months (Tables 1.3 and 1.4)
Referral is the best option for a young infant with possible serious bacterial infection. However, if referral is not possible, give oral amoxicillin every 8 hours and intramuscular gentamycin once daily.12
Table 1.2   Classification and management of illness
Signs
Classify as
Identify treatment
Young infant aged up to 2 months
  • Convulsions
  • Fast breathing (60 breaths per minute or more)
  • Severe chest indrawing
  • Nasal flaring
  • Grunting
  • Bulging fontanalle
  • If axillary temperature 37.5°C or above (or feels hot to touch) or temperature less than 35.5°C (or feels cold to touch)
  • Lethargic or unconscious
  • Less than normal movements
Possible
serious
bacterial infection
  • Give first dose of intramuscular ampicillin and gentamycin
  • Treat to prevent low blood sugar
  • Warm the young infant by skin to skin contact if temperature less than (or feels cold to touch), while arranging referral
  • Advise mother on how to keep the young infant warm on the way to the hospital
  • Refer urgently to hospital
• Pus discharge from ear
Local
bacterial infection
  • Give oral cotrimoxazole or amoxicillin for 5 days
  • Teach mother to treat local infections at home
  • Follow up in 2 days
Child aged 2 months up to 5 years (Cough or difficult breathing)
  • Any general danger sign (not able to drink, vomits everything, had convulsions) or
  • Chest indrawing or
  • Stridor in calm child
Severe
pneumonia or
very severe
disease
  • Give first dose of injectable chloramphenicol (if not possible give oral amoxicillin)
  • Refer URGENTLY to hospital
• Fast breathing
Pneumonia
  • Give cotrimoxazole for 5 days
  • Soothe the throat and relieve the cough with a safe remedy if child is 6 months or older
  • Advise mother when to return immediately
  • Follow up in 2 days
• No signs of pneumonia or very severe disease
No pneumonia: cough or cold
  • If coughing is more than 30 days, refer for assessment
  • Soothe the throat and relieve the cough with a safe remedy if child is 6 months or older
  • Advise mother when to return immediately
  • Follow up in 5 days if not improving
Ear problem13
• Tender swelling behind the ear
Mastoiditis
  • Give first dose of injectable chloramphenicol (if not possible give oral amoxicillin)
  • Give first dose of paracetamol for pain
  • Refer urgently to hospital
  • Pus is seen draining from the ear and discharge is reported for less than 14 days, or
  • Ear pain
Acute ear infection
  • Give cotrimoxazole for 5 days
  • Give paracetamol for pain
  • Dry the ear by wicking
  • Follow-up in 5 days
• Pus is seen draining from the ear and discharge is reported for 14 days or more
Chronic ear infection
• Dry the ear by wicking
• Follow up in 5 days
• No ear pain and
• No pus is seen draining from ear
No ear infection
• No additional treatment
Table 1.3   Intramuscular antibiotics (Birth – 2 months)
Weight
Gentamicin
Dose: 5 mg/kg
Ampicillin
Dose: 100 mg/kg
Undiluted 2 mL vial containing
20 mg = 2 mL at 10 mg/mL
OR
Add 6 mL sterile water to 2 mL vial containing 80 mg = 8 mL at 10 mg/mL
Vial of 500 mg mixed with 2.1 mL of sterile water for injection to give 500 mg/2.5 mL or 200 mg/mL
1kg
0.5 mL
0.5 mL
2 kg
1.0 mL
1.0 mL
3 kg
1.5 mL
1.5 mL
4 kg
2.0 mL
2.0 mL
5 kg
2.5 mL
2.5 mL
 
Prevention of Low Blood Sugar
 
B. Child aged 2 months up to 5 years (Tables 1.5 and 1.6)
If referral is not possible:
  • Repeat chloramphenicol injection every 12 hours for 5 days
  • Then change to an appropriate oral antibiotic to complete 10 days of treatment.
 
Soothing the Throat
  • Safe remedies to recommend
    • Continue breastfeeding
    • Honey, tulsi, ginger, herbal tea and other safe local home remedies
  • Harmful remedies to discourage
    • Preparations containing opiates, codeine, ephedrine and atropine.
 
SUMMARY AND CONCLUSION
Acute respiratory infections are deadly diseases that claim the lives of many infants and children under 5 years of age. These include the Acute Upper Respiratory Infections (AURIs), and the Acute Lower Respiratory Infections (ALRIs). The most common bacteria involved are Streptococcus pneumoniae (pneumococcus) or Haemophilus influenzae, mostly type B (Hib), and occasionally 15by Staphylococcus aureus or other streptococci.
Table 1.5   Intramuscular antibiotic (2 months up to 5 years)
Age or Weight
Chloramphenicol
Dose: 40 mg per kg
Add 5.0 mL sterile water to vial containing 1,000 mg = 5.6 mL at 180 mg/mL
2 months up to 4 months (4 - < 6 kg)
4 months up to 9 months (6 - < 8 kg)
9 months up to 12 months (8 - < 10 kg)
12 months up to 3 years (10 - < 14 kg)
3 years up to 5 years (14 - < 19 kg)
1.0 mL = 180 mg
1.5 mL = 270 mg
2.0 mL = 360 mg
2.5 mL = 450 mg
3.5 mL = 630 mg
Table 1.6   Oral antibiotics (2 months up to 5 years)
Cotrimoxazole
(trimethoprim + sulfamethoxazole)
Give 2 times daily for 5 days
Amoxycillin
Give 3 times daily for 5 days
Age or weight
Adult tablet Single strength
(80 mg trimethoprim + 400 mg sulfamethoxazole)
Pediatric tablet
(20 mg trimethoprim + 100 mg sulfamethoxazole)
Syrup
(40 mg trimethoprim + 200 mg sulfamethoxazole per 5 mL)
Tablet 250 mg
Syrup 125 mg in 5 mL
2 months up to 12 months (4 - < 10 kg)
1/2
2
5.0 mL
1/2
5 mL
12 months up to 5 years (10 - 19 kg)
1
3
7.5 mL
1
10 mL
Viruses commonly responsible are respiratory syncytial viruses (RSVs), parainfluenza and influenza viruses. Atypical organisms like Chlamydia and Mycoplasma also sometimes cause pneumonia. Various socio-economic, demographic, environmental, nutritional and illness and treatment factors make the children of developing countries more vulnerable to these infections. Prevention of ARI is possible by immunizing the children at the appropriate age. The current immunization strategy protects against diphtheria, pertussis and measles. There has been strong recommendation for inclusion of vaccine for Hib in the immunization schedule. Pneumococcal pneumonia vaccine, in spite of fulfilling the criteria for recommendation as proposed by WHO, is under a lot of debate. Integrated Management of Neonatal and Childhood Illnesses, is 16a simple tool to bring down the morbidity and mortality due to ARI, through syndromic approach for identification of problems and their management.
REFERENCES
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  1. Park K. Epidemiology of communicable diseases. In: Park's Textbook of Preventive and Social Medicine, 21st edn. Jabalpur: Banarsidas Bhanot  2011.
  1. Chourjit K, Gupte S. Pediatric viral infections. In: Gupte S (Ed): The Short Textbook of Pediatrics, 11th edn. New Delhi: Jaypee  2009:247–269
  1. Singh D, Gupte S. Pediatric pulmonology. In: Gupte S (Ed): The Short Textbook of Pediatrics, 11th edn. New Delhi: Jaypee  2009:321–352.
  1. Kabra SK. Upper respiratory tract infections. In: Parthasarthy A (Ed): IAP Textbook of Pediatrics, 3rd edn. New Delhi: Jaypee  2007:447–449.
  1. Lahiri K. Infections of larynx, trachea and bronchi. In: Parthasarthy A (Eds): IAP Textbook of Pediatrics, 3rd edn. New Delhi: Jaypee  2007:449–450.
  1. Balachandran A, Shivbalan SO. Pneumonia in children. In: Parthasarthy A (Eds): IAP Textbook of Pediatrics, 3rd edn. New Delhi: Jaypee  2007:451–455.
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  1. Government of India. SRS Bulletin January 2011. Sample Registration system, Registrar General of India 2011;45:1.
  1. Gvernment of India. Child Health Programs. Annual report 2009-2010. New Delhi: Department of Health & Family welfare, Ministry of Health & Family welfare 2009.
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  1. Government of India. Students' Handbook for Integrated Management of Neonatal & Childhood Illnesses. New Delhi: WHO & MOHFW  2003.
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  1. Mathew JL, Patwari AK, Gupta P, et al. Acute Respiratory Infection and Pneumonia in India: A Systematic Review of Literature for Advocacy and Action: UNICEF-PHFI Series on Newborn and Child Health, India. Available at http://www.traveldoctoronline.net/acute-respiratory-infection-and-pneumonia-in-india--a-systematic-review-of-literature-for-advocacy-and-action--unicef-phfi-series-on-newborn-and-child-health--india-MjE0Nzg1NTU=.htm Accessed 2 October 2011.
  1. Denny FW Jr. The clinical impact of human respiratory virus infections. Am J Respir Critl Care Med 1995; 152(4, part 2):S4–12.
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  1. Atkinson W, Hamborsky J, McIntyre L, Wolfe S. Centers for Disease Control and Prevention (CDC): Epidemiology and Prevention of Vaccine-Preventable Diseases, 9th edn. Washigton: Public Health Foundation  2006.
  1. Levine OS, Cherian T. Pneumococcal vaccination for Indian children. Indian Pediatrics 2007;44:491–496.
  1. NTAGI Subcommittee. Recommendations on Haemophilus influenzae Type b (Hib) Vaccine Introduction in India Subcommittee on Introduction of Hib Vaccine in Universal Immunization Program, National Technical Advisory Group on Immunization. Indian Pediatrics 2009;46:945–954.
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Respiratory Manifestations of Systemic Disease2

Amar Taksande, Krishna Vilhekar, Satish Tiwari
 
INTRODUCTION
The lung is a common site of disease in several disorders that primarily affect other organs. The common signs and symptoms are cough, chest pain, tachypnea, dyspnea or cyanosis. Cough most commonly arises from upper or lower respiratory tract disorders, but it can originate from the central nervous system and it can be a prominent symptom in children with gastroesophageal reflux disease. Chest pain does not commonly arise from pulmonary processes in otherwise healthy children, but more often has a neuromuscular or inflammatory etiology. Kussmaul breathing or hyperpnea, are deep, rapid respirations and indicate the body is trying to compensate for severe metabolic acidosis. Cheyne-Stokes respiration is an abnormal pattern of breathing characterized by when periods of hyperventilation with waxing and waning tidal volume alternate with periods of central apnea. It results from any condition that slows the blood flow to the brain stem, because it slows impulses sending information to the respiratory center of the brain stem. Imaging often plays a central part when lung involvement is suspected clinically and this role has increased with the advent of high-resolution computed tomography (HRCT). The chest radiograph may provide diagnostic information and be useful in follow-up, but it is relatively insensitive. In evaluating a child or adolescent with respiratory symptoms, it is important to obtain a detailed past medical history, family history and review of systems to evaluate the possibility of extrapulmonary origin. However, lung involvement has a profound effect on prognosis and may be challenging to accurately diagnose.1-3
 
PROFILE
Disorders that commonly have respiratory complications are connective tissue disease, vasculitis, central nervous system disease, liver disease, hematological disease, neuromuscular disease, obesity, etc.20
 
Connective Tissue Diseases
 
Juvenile Rheumatoid Arthritis
Juvenile rheumatoid arthritis (JRA) is a common, rheumatic disease of children and a major cause of chronic disability. The pulmonary complications are rheumatoid pleural effusion; diffuse rheumatoid lung disease is similar to that of cryptogenic fibrosing alveolitis. Other uncommon associations include eosinophilic pneumonia, bronchiolitis obliterans with organizing pneumonia (BOOP), ‘shrinking lungs’ and upper lobe fibrosis with cavitation. The prevalence of acute bronchitis, pneumonia, pulmonary tuberculosis, bronchiectasis and empyema is increased in patients with rheumatoid arthritis. Laboratory investigation reveals hematologic abnormalities often reflect the degree of systemic or articular inflammation, with elevated white blood cell and platelet counts and decreased hemoglobin concentration and mean corpuscular volume. Elevated antinuclear antibody (ANA) titers are present in at least 40 to 85% of children with oligoarticular or polyarticular JRA, but are unusual in children with systemic-onset disease.4,5
 
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by inflammation of blood vessels and connective tissues resulting in multisystem involvement. The hallmark of lupus is autoantibody production against many self- antigens and other nuclear antigens, such as ribosome, small nuclear (anti-Sm) and cytoplasmic (anti-Ro, anti-La) ribonuclear proteins, platelets, coagulation factors, immunoglobulin (Ig), erythrocytes, and leukocytes. Respiratory manifestations include acute pulmonary hemorrhage, pulmonary infiltrates and chronic fibrosis. Pulmonary infarction or embolism may also occur in SLE patients with circulating anticardiolipin antibodies.6,7 Pleuritis, manifesting as pleuritic chest pain with or without pleural effusion, is common and may be unilateral or bilateral. Pericarditis may lead to central chest pain, worse when leaning forward. ‘Shrinking lungs’ is an uncommon feature caused by diaphragmatic weakness rather than parenchymal involvement in SLE. Such patients are breathless and orthopneic and show paradoxical abdominal movements with respiration. Chest radiography shows small lungs with a high diaphragm and lower zone linear atelectasis.7,8
 
Sjögren Syndrome
Sjögren syndrome (SS) is an autoimmune disease characterized by progressive lymphocytic and plasma cell infiltration of the salivary and lacrimal glands. It is uncommon in pediatric age group. Pulmonary abnormalities include desiccation of the trachea and bronchial tree, leading to recurrent infections, airflow limitation and bronchiectasis, fibrosing alveolitis and lymphoid interstitial lung disease, which may develop into non-Hodgkin lymphoma of the lung positive ANA, hypergammaglobulinemia and presence of IgM rheumatoid factor (RF) levels.9-11 Corticosteroids, non-steroidal anti-inflammatory drug and hydroxychloroquine 21are commonly used drugs. Immunosuppressive agents such as cyclosporine and cyclophosphamide are reserved for severe functional disorders and life-threatening complications.
 
Juvenile Dermatomyositis
Juvenile dermatomyositis (JDM) characterized by proximal symmetrical muscle weakness, skin rash and vasculitis. It is caused by complement-mediated vascular inflammation and associated with human leukocyte antigen (HLA) types (e.g. DQA1, DRB). Auto-antibodies to nuclear antigens and cytoplasmic (i.e. anti-transfer RNA synthetases) antigens may be present. There is a decrease in ventilatory capacity in the absence of respiratory complaints. Pulmonary fibrosis can occur, but is more common with children who have antibodies to Jo-1. Dysphonia often manifests as a higher pitch (bird-like) voice. Aspiration pneumonia and respiratory muscle weakness may occur as life-threatening complications for which ventilation may be required. Juvenile dermatomyositis (JDM) with vasculopathy is the most severe form. It is associated with classic nailfold capillary changes showing damaged and blocked small arteries, veins and capillaries. Pulmonary vasculitis leads to spontaneous pneumothorax and rarely, myocarditis can occur.12,13 Corticosteroids are the mainstay of therapy for children with JDM.
 
Scleroderma
Scleroderma (Sd) is characterized by fibrosis affecting the dermis and arteries of the lungs, kidneys and gastrointestinal tract. It may be localized (morphea, linear scleroderma) or generalized (systemic scleroderma). The more common is interstitial lung disease. This begins as an inflammatory alveolitis, which evolves to interstitial fibrosis. The other form of pulmonary disease is pulmonary hypertension, which can occur in isolation as part of the vasculopathy of scleroderma or secondary to the interstitial lung disease. This can usually be detected by echocardiography. Finally, pleuritis with or without pleural effusion may also occur. On examination, dry rales are common and may be associated with reduced chest expansion.14 Repeated chest infections from aspiration as a consequence of esophageal dysmotility are the most common pulmonary manifestation of systemic sclerosis. Pulmonary hypertension can also cause shortness of breath and difficulty getting an adequate breath with activity. Pericardial effusion is usually asymptomatic and may develop in up to one-third of patients with systemic sclerosis. Investigation shows presence of anti-nuclear antibodies and anticentromere antibody. Anti-Scl 70 antibody (anti-topoisomerase I antibody) is seen diffuse scleroderma patient. Basilar pulmonary fibrosis includes reticular pattern or lineonodular densities in basilar portions of the lungs on chest X-ray. High resolution, thin-section computed tomography (CT) scan of the lungs, is critically important in the evaluation of patients. There is no direct cure for scleroderma.14,15 Skin thickening can be treated with D-penicillamine and other drugs or interventions ([IFN-4] 22Interferon-gamma, Mycophenolate mofetil, cyclophosphamide, photopheresis, allogeneic bone marrow transplantation).
 
Ankylosing Spondylitis
Juvenile ankylosing spondylitis occurs most frequently in older boys, adolescents, and young adults. This seronegative arthropathy may have extra-articular manifestations including ocular, cardiac and pulmonary disease. The most common pulmonary manifestation is chest wall restriction caused by fusion of the costovertebral joints. This usually causes minimal impairment of lung function, but predisposes to chest infections because of the difficulties in expectoration.16,17 Upper lobe fibrotic disease occurs rarely and is usually asymptomatic, unless cavitation and mycetomas supervene.
 
Amyloidosis
Amyloidosis is a group of diseases characterized by deposition of insoluble fibrous amyloid protein in various body tissues. Pulmonary involvement may be localized or part of systemic amyloidosis. Primary systemic amyloidosis is rare, but involves the lungs more commonly than in secondary disease (due to chronic infection or monoclonal gammopathy), in which pulmonary involvement is unusual. Patients present with cough, dyspnea or hemoptysis with trachea-bronchial involvement. Untreated disease may be stable or progress to respiratory failure.18,19 The chest radiograph is usually normal with diffuse disease, but may demonstrate a diffuse reticulonodular pattern, which may be associated with calcifications. There may be honeycombing. Localized disease may involve the lung parenchyma or airways. Pulmonary nodules may be solitary or multiple, may cavitate and calcify. Airways involvement is usually indolent, but may cause bronchial stenosis with distal atelectasis. Submucosal deposits may be multifocal, plaque-like or polypoid. Lymphadenopathy may be massive and coarsely calcified.19,20 There is no specific treatment for primary systemic amyloidosis. Autologous stem cell transplantation is another possible treatment.
 
Sarcoidosis
Sarcoidosis is systemic granulomatous disease that primarily affects the lungs and lymphatic systems of the body. It is less common in children than in adults. The etiology of sarcoidosis is unknown. The non-caseating epitheloid granulomatous lesions of sarcoidosis can occur in almost any part of the body mainly lungs.21,22
Lung is the most frequently affected organ in the children and presents with coughing, shortness of breath, chest pain, dyspnea on exertion and hemoptysis. Parenchymal lung disease may lead to airway obstruction and bronchiectasis, airway hyperactivity. Chest radiography is used in staging the disease:
Stage I disease—shows bilateral hilar lymphadenopathy (BHL).
Stage II disease—shows BHL plus pulmonary infiltrates.
Stage III disease—shows pulmonary infiltrates without BHL.
Stage IV disease—shows pulmonary fibrosis.
23Definitive diagnosis requires demonstration of the non-caseating granulomatous lesions in a biopsy of tissue, usually taken from the most readily available affected organ. CT scan of the thorax may demonstrate lymphadenopathy or granulomatous infiltration. Broncho-alveolar lavage fluid reveals excessive lymphocytes with an increased cluster of differentiation 4 (CD4)/CD8 ratio of 2:1 to 13:1. Oral corticosteroids are usually the treatment of choice.21,23 Other agents include tumor necrosis factor blockers, chloroquine, azathioprine, cyclophosphamide, thalidomide and infliximab have been frequently used in adults with active sarcoidosis.
 
Vasculitis
Vasculitis is an inflammatory and often destructive process of the blood vessels. It is difficult to diagnose because of presenting symptoms can be non-specific and multiple organs are involved. Pulmonary vasculitis may occur in the context of a primary vasculitis or may be associated with an underlying disease. Pulmonary involvement is frequent in the anti-neutrophil cytoplasmic antibodies (ANCA) positive small vessel vasculitides and Goodpasture syndrome, but is less common in the immune complex vasculitides.24,25 Pulmonary involvement as part of a systemic vasculitis occurs in:
 
Wegener Granulomatosis
Wegener granulomatosis (WG) is a necrotizing granulomatous vasculitis of small size vessels characterized by the upper and lower respiratory tracts involvement and glomerulonephritis. The disease is rare in children, but it may present as early as two weeks of age. There is a female predominance of 3:1. The etiology is unknown. Three of the six criteria should be present for diagnosing childhood WG.
  1. Abnormal urinary sediment (microscopic hematuria with or without red cell casts).
  2. Granulomatous inflammation on biopsy of an artery or perivascular area.
  3. Nasal sinus inflammation.
  4. Subglottic, tracheal or endobronchial stenosis.
  5. Abnormal chest radiograph showing nodules, fixed infiltrates or cavities or CT scan.
  6. Positive c-ANA staining.
The initial complaints are nonspecific constitutional symptoms of fever, malaise, weight loss, myalgia and arthralgia, which are associated with upper airway illness (cough, nasal discharge sinusitis, mucosal ulceration) in 75 to 90% cases. Pulmonary manifestation includes infiltrate, nodules, hemoptysis and dyspnea. Saddle nose deformity and subglottic stenosis are common in children.26,27 Respiratory complications include pulmonary hemorrhage and upper airway obstruction due to subglottic stenosis. Infectious complications include pneumonia and sinusitis, typically complicating granulomatous lesions and obstruction. Chest radiography typically shows pulmonary nodules, 1 to 9 cm in diameter, with poorly defined or well-circumscribed borders. Central necrosis 24may lead to formation of thick-walled or thin-walled cavities. Confirmation of the disease is established by the detection of the granulomatous inflammation on biopsy of the upper airway, lung, kidney or skin.27,28 Corticosteroids and cyclophosphamide have been effective in WG.
 
Churg-Strauss Syndrome
Churg-Strauss Syndrome (CSS) is rare in children. It consists of a small and medium-sized vessel vasculitis, with skin and peripheral nerve involvement. It is characterized by eosinophilia, extravascular necrotizing granuloma and eosinophilic infiltration of multiple organs particularly the lungs, but may also involve the gastrointestinal tract, the heart and the kidneys. The condition is usually associated with a preceding history of asthma or allergic sinusitis. It has rarely been reported in children, where most of the cases had pre-existing asthma, allergic rhinitis or atopic disease. Pulmonary involvement, includes asthma, pleural effusions (which may be eosinophilic), eosinophilic infiltrations and diffuse alveolar hemorrhage. Chest radiography abnormalities are transient patchy air space opacities, multiple non-segmental consolidations, which may be nodular and rarely cavitate and diffuse interstitial opacities. Diffuse miliary nodules and large nodules with cavitation are unusual. The characteristic pathologic changes include tissue infiltration with eosinophils, necrotizing or non-necrotizing granulomas as well as vasculitis involving small- or medium-sized vessels.29,30 The treatment is corticosteroid therapy. Major organ involvement may require aggressive approach with pulse doses of intravenous corticosteroids combined with other immunosuppressive agents, such as cyclophosphamide, azathioprine and methotrexate.
 
Henoch-Schönlein Purpura
Henoch-Schönlein purpura (HSP), also known as anaphylactoid or allergic purpura is most frequent in children between 2 and 8 years and has a 2:1 male preponderance. This may develop after upper respiratory tract infection. Many organisms have been implicated, including streptococci. Pulmonary involvement is unusual and most will have decreased diffusion capacity and rarely, hemoptysis or even pulmonary infarction. Diffuse alveolar hemorrhage may occur secondary to a diffuse alveolitis/capillaritis. Chest radiograph demonstrates patchy multifocal consolidations or transient ill-defined infiltrations or effusions.31,32 The prognosis is good, with supportive care usually being sufficient.
 
Behçet Disease
Behçet disease (BD) is a small blood vessel vasculitis of unknown origin characterized by painful recurrent oral and genital ulcerations and uveitis. The disease is uncommon in children with most cases reported from the eastern Mediterranean. As a systemic disease, it also involves visceral organs such as the gastrointestinal tract, pulmonary, musculoskeletal and neurological systems. This syndrome can be fatal; death can be caused by complicated rupture of the vascular 25aneurysms, or severe neurological complications, and therefore immediate medical treatment is necessary. Lung involvement is typically in the form of hemoptysis, pleuritis, cough or fever and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm, which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary hypertension and right heart failure may develop.33,34 Laboratory tests are not diagnostic, although the finding of HLA-B51 supports the diagnosis. Corticosteroids oral or topical represent the initial therapy. Other drugs, including colchicine, chlorambucil, azathioprine, cyclosporine, thalidomide and tacrolimus, have been used. Anti-tumor necrosis factor-α (TNF-α) therapy or IFN-α-2a in severe or intractable cases may be tried.
 
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is also called Kussmaul disease represents the classic form of focal segmental necrotizing vasculitis. The PAN has been described in all age groups and rarely found in children. Boys and girls appear to be equally affected, with a mean age of 9-year of age. The cause is unknown, although the occurrence of PAN after drug exposure and infection due to hepatitis B virus or Streptococcus species has implicated immune complexes. The presence of circulating antineutrophil cytoplasmic antibodies is diagnostic.35 Treatment with corticosteroid and immunosuppressive drug has increased the survival rate. Plasma exchange is useful as a second-line treatment in PAN to conventional therapy.
 
Takayasu Arteritis
Takayasu arteritis (TA) (or pulseless disease), is a chronic vasculitic disease of the aorta, the proximal portions of its major branches, and the pulmonary artery. It leads to progressive wall fibrosis and lumen stenosis or rarely aneurysm formation. It is most common in women (90%) of Asian descent between the ages of 15 and 45 years, but also occurs in children and infants. The etiology of TA is unknown, but an association with tuberculosis has been reported. In Japan, it is associated with human leukocyte antigens HLA-A10, B5, Bw52, DR2 and DR4. Pulmonary involvement is rare. Pulmonary artery thrombosis, stenosis and post-stenotic dilatation have been reported in Takayasu arteritis.36-38 Recent studies suggest that noninvasive imaging modalities such as magnetic resonance imaging (MRI), color Doppler ultrasonography (CDU) and positron emission tomography (PET) scanning with radioactive-labeled 18-fluorodeoxyglucose (FDG) allow diagnosis of Takayasu arteritis earlier in the disease course than standard angiography.
 
Goodpasture Disease
Goodpasture disease is a rare immunological disease with formation of pathognomonic antibodies against renal and pulmonary basement membranes. It is characterized by pulmonary hemorrhage and glomerulonephritis associated with antibodies commonly directed against specific epitopes of type IV collagen within the alveolar basement membrane of the lung and glomerular basement membrane (GBM) of the glomerulus. Goodpasture disease is rare in childhood. 26Lung symptoms may present as dry cough and minor breathlessness. In severe cases, lung damage may cause severe impairment of oxygenation so that intensive care is required. Patients usually present with hemoptysis associated with pulmonary hemorrhage that can be life-threatening. The patient may be anemic due to loss of blood through lung hemorrhaging over a long period.39,40 Rates of survival and recovery of renal function have improved with pulse methylprednisolone, oral cyclophosphamide and plasmapheresis therapy.
 
Neurological Disorders
Severe respiratory disorders can arise indirectly from disordered ventilatory control by the brain stem (e.g. Cheyne–Stokes respiration) or from weakness of the respiratory muscles. Respiratory infections are the terminal event of many neurological conditions, particularly those with bulbar involvement.
 
Neurofibromatosis
Neurofibromatosis is an autosomal dominant genetic disorder that usually appears in childhood and adolescence. Interstitial pulmonary fibrosis has been reported in patients with neurofibromatosis. Compromises to the spinal column can weaken associated movement of the rib muscles and diaphragm that diminish pulmonary function. Chest radiography characteristics are of diffuse linear interstitial densities and large bullae distributed predominantly in the upper lobes or apical segments of the lower lobes.41-43 Other manifestations include thoracic kyphoscoliosis, neurofibromas and obstructive sleep apnea.
 
Pulmonary Lymphangioleiomyomatosis
Tuberous sclerosis is an autosomal dominant disorder characterized by the formation of hamartomatous lesions in multiple organs. The disease results from mutations in one of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin), which have an important role in the regulation of cell proliferation and differentiation. Facial angiofibromas, renal angiomyolipomas, and pulmonary LAM are some of the major features of this disease. Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive disease probably affects 1 to 3% of patients with tuberous sclerosis. It is characterized by overgrowth of smooth muscle cells in the pulmonary lymphatics, blood vessels, and airways results in obstruction of the small airways with cyst formation and pneumothorax, chylothorax and hemoptysis. Some of the manifestations are shortness of breath, coughing, chest pain, pneumothorax, chylous pleural effusions, hemoptysis and eventually respiratory failure, but asymptomatic cases may occur.44,45 Early findings on chest radiography are diffuse linear densities, which become more nodular and widespread over time, leading to a generalized cystic and honeycomb appearance. Pulmonary function tests can show an obstructive or restrictive pattern. Classical CT findings (diffuse, homogeneous, small thin-walled cysts) and compatible clinical history can be highly suggestive of LAM. It is extremely difficult to treat and the long-term prognosis is poor with the average duration of survival from the 27time of diagnosis to 10 years.45,46 Treatment consists of supportive management; hormonal therapy has been tried, but without consistent success.
 
Hematological Disorders
Hematological disorders may be associated with disorders of the thoracic cage, mediastinum, lung, pleura or pulmonary vessels. Thoracic skeleton lesion present with local pain, deformity or fracture and in some cases with soft tissue swelling. Up to 60% of patients with myeloma have lytic lesions in the ribs, sternum and clavicle at presentation. Lymphadenopathy present in up to 66% of patients with Hodgkin's disease has enlarged mediastinal lymph nodes. Typically, the lymph node involvement is bilateral and asymmetrical and both hilar and mediastinal lymphadenopathy occur. Direct extension from these lymph nodes is thought to occur along the lymphatics of the bronchial sheaths, resulting in consolidation on chest radiography. The lesions can coalesce to form discrete masses, which may cavitate or appear as discrete pulmonary nodules in advance cases. Such involvement is usually in the distant bronchioles, but may occur within the bronchi and trachea. Pulmonary infiltrates on chest radiography leukemia patients are more likely to be caused by infection, cardiac failure or pulmonary hemorrhage. Pulmonary nodules may occur in patients in whom leukemia relapses. Pleural effusions occur in Hodgkin or non-Hodgkin lymphoma, usually in association with intrathoracic lymphadenopathy. Effusions may also occur in leukemia, as a consequence of the disease or of infection.47-49
Lung disease in children with sickle cell anemia is the common cause of death. Sickle cell disease patients may develop a sickle crisis affecting the chest. This is an acute pneumonia-like illness characterized by fever, chest pain, tachypnea, dyspnea, hypoxemia and fatigue. Etiological factor include infection (Mycoplasma pneumoniae, Chlamydia), pulmonary fat embolism and pulmonary infarction from vaso-occlusive crisis. Acute chest syndrome (ACS) is a constellation of findings including a new radiodensity on chest radiograph, fever, respiratory distress, and pain that often occurs in the chest, but may include only the back and/or the abdomen. Radiographs may show patchy shadowing with single-lobe involvement, most often the left lower lobe and when multiple lobes are involved, usually both lower lobes are affected. Pleural effusions, either unilateral or bilateral, may not be present initially, but may progress rapidly to a total whiteout.50 Treatment of ACS includes oxygen administration, empirical antibiotics (cephalosporin and macrolide) and simple or exchange blood transfusion therapy.
 
Gastrointestinal Disorders
 
Gastroesophageal Reflux
Gastroesophageal reflux (GER) is the common esophageal disorder and occurs when stomach contents reflux into the esophagus during or after a meal. There is a high prevalence of GER in children with chronic cough and asthma. Patients frequently experience complications, including strictures, malnutrition, respiratory disorders, esophagitis, bleeding and changes in the normal epithelial lining of the 28lower esophagus. When the refluxed material passes into the back of the mouth or enters the airways, the child may have a raspy voice or a chronic cough. Other symptoms include recurrent pneumonia, wheezing, difficult or painful swallowing, vomiting, sore throat, weight loss, heartburn (in older children).51,52 Biopsies can be obtained at the time of endoscopy to determine whether there is inflammation due to GERD or whether there are other problems such as allergic esophagitis that are causing the symptoms. Esophageal pH probe monitoring records the amount of stomach acid coming back-up into the esophagus and indicates whether acid is in the esophagus when the child has symptoms such as crying, coughing or arching her back. Radionucleotide scintiography using technetium may demonstrate aspiration and delayed gastric emptying when these are suspected. Esophageal manometry permits evaluation for dysmotility.
 
Hepatopulmonary Syndrome
Hepatopulmonary syndrome (HPS) is the one of the complication of liver53 cirrhosis with portal hypertension, irrespective of etiology, age and sex. It has also been observed in non-cirrhotic portal hypertension and in acute hepatic conditions. The HPS is characterized by the typical triad of hypoxemia, intrapulmonary vascular dilations and liver disease. There is intrapulmonic right-to-left shunting of blood, which results in systemic desaturation. It should be suspected and investigated in the child with chronic liver disease with history of shortness of breath or exercise intolerance and clinical examination findings of cyanosis, digital clubbing and oxygen saturations <96%, particularly in the upright position. Contrast echocardiography and standard cardiopulmonary testing are generally sufficient to make the diagnosis of HPS.54,55 The presence of HPS independently worsens prognosis of cirrhosis. Liver transplantation is the choice of treatment though mortality is comparatively high.
 
Pancreatic Disorders
The most common pancreatic disorder in children is acute pancreatitis presents with acute respiratory insufficiency. Pleural effusion occurs in up to 15% of patients and is typically on the left side and painless. The effusion is often hemorrhagic with raised amylase levels. Severe acute pancreatitis is rare in children. In this life-threatening condition, the patient is acutely ill with severe nausea, vomiting, and abdominal pain. Shock, high fever, jaundice, ascites, hypocalcemia and pleural effusions can occur. A bluish discoloration may be seen around the umbilicus (Cullen sign) or in the flanks (Grey Turner sign). The mortality rate, which is ≍ 25%, is related to the systemic inflammatory response syndrome with multiple organ dysfunctions (MODs). The chest roentgenogram may demonstrate atelectasis, basilar infiltrates, elevation of the hemidiaphragm, left (rarely right) sided pleural effusions, pericardial effusion and pulmonary edema. Endoscopic retrograde cholangiopancreatography (ERCP) or more often magnetic resonance cholangiopancreatography (MRCP) are essential in the investigation of recurrent pancreatiti.56-58 Disease is generally self-limiting and supportive treatment is 29necessary. Surgical treatment is reserved for pancreatic abscess and necrotic pancreatitis.
 
Congenital Heart Disease
Congenital heart lesions may produce different degrees of circulatory dysfunction and a wide spectrum of clinical manifestations. After general assessment of the patient, specific attention is directed toward the presence of cyanosis, abnormalities in growth and any evidence of respiratory distress. Tachypnea, along with tachycardia, is the earliest sign of left-sided heart failure. If the child has dyspnea or retraction, it may be a sign of a more severe degree of left-sided heart failure or significant lung pathology. Pulmonary complications of congenital heart disease (CHD) can be structural due to compression causing airway malacia or atelectasis of the lung. Surgical repair of CHD can also result in structural trauma to the respiratory system, e.g. chylothorax, subglottic stenosis or diaphragmatic paralysis. Disruption of the Starling forces in the pulmonary vascular system in certain types of CHD lead to alveolar-capillary membrane damage and pulmonary edema. Direct pulmonary complications of CHD are either by structural impact on the airways, abnormal pathophysiological mechanisms leading to increased lung water and/or significant pulmonary disease. Many children with CHD are at greater risk of infection including respiratory tract infections, which can cause prolonged hospitalization and delay of definitive cardiac repair. These lesions that permit communication between the systemic and pulmonary circulation and cause a large left-to-right shunt are the most frequent congenital cardiac anomalies. Long-term complications then include left ventricular diastolic dysfunction and dilated cardiomyopathy causing airway compression. Enlargement of the left atrium, which lies just below the carina can result in, widening of the angle of tracheal bifurcation with or without compression of the main stem bronchi. The aortic arch, pulmonary artery slings, anomalous innominate artery and congenital absence of the pulmonary valve. These lesions lead to compression of the airway by a pulsatile artery and subsequent malacia of that airway. The vascular abnormalities that can cause respiratory difficulty from airway compression are virtually unlimited. Respiratory tract infection in children with CHD is an important cause of morbidity and mortality including respiratory failure, prolonged mechanical ventilation and hospitalization. Atelectasis in patients with CHD can be attributed to extrinsic compression from vascular malformation, restrictive defects from pulmonary edema or from underlying respiratory tract infection. CHD leading to Eisenmenger's syndrome or PH is associated with a paradoxical state of coexisting thrombotic and bleeding diathesis.59-61 A broad spectrum of cardiac and pulmonary diseases can lead to the development of pulmonary hypertension. Restrictive lung function appears to be a prominent finding in many types of CHD both pre and postsurgical repair. In addition, both obstructive and diffusion defect scan also be seen depending on the underlying pathophysiology. Chest X-ray and electrocardiography should be performed in all patients as part of the initial work-up. For additional diagnostic screening and anatomic definition, echocardiography, two-dimensional color flow Doppler and cardiac catheterization should be performed.30
 
Miscellaneous
 
Neuromuscular Disorder
A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria:
  1. It is a primary myopathy
  2. It has a genetic basis
  3. The course is progressive
  4. Degeneration and death of muscle fibers occur at some stage in the disease.
Respiratory muscle involvement is expressed as a weak and ineffective cough, frequent pulmonary infections and decreasing respiratory reserve. Pharyngeal weakness may lead to episodes of aspiration, nasal regurgitation of liquids and an airy or nasal voice quality. The thoracic deformity further compromises pulmonary capacity and compresses the heart. There is no definitive treatment. In neuromuscular disease the main respiratory complication are hypoventilation, atelectasis and pneumonia.62,63 The diagnostic tests are spirometry, lung volume determination and respiratory muscle force measurements. Pulmonary infections should be promptly treated.
 
Obesity
Obesity is a chronic medical problem that requires management. Obstructive sleep apnea is more common and may contribute to problems such as hypertension, daytime fatigue and pulmonary hypertension. Snoring, episodes of night-time coughing fits or excessive daytime sleepiness can be due to obstructive sleep apnea, which warrants further investigation with referral to a sleep laboratory for polysomnography.64-66 Management consists of dietary counseling, exercise therapy and behavioral management. The uses of pharmacologic agents are sibutramine, Orlistat, Topiramate, Metformin or Rimonabant.
 
Lysosomal Storage Diseases
Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders, usually autosomal recessive and most prevalent in Ashkenazi Jews. The majority of LSDs result from defective lysosomal acid hydrolysis of endogenous macromolecules and their consequent accumulation. They tend to be multisystemic and are always progressive, although the rate of progression may vary. Gaucher's disease is the most common, in which a deficiency of glucocerebrosidase activity results in accumulation and deposition of glucosyl ceramide in the reticuloendothelial system. Pulmonary involvement, seen in type 1, leads to dyspnea and recurrent infections, culminating in respiratory failure. In Niemann-Pick disease, the enzyme defect is sphingomyelinase, with accumulation of sphingomyelin. Presentation is in infancy or childhood. Symptoms are related to the organs in which they accumulate. Lung involvement is variable, depending on the subtype of the disease, but may cause death in infancy. Chest radiography may demonstrate alveolar opacities, a reticulonodular pattern or bronchial wall thickening. Miliary 31shadowing has been reported.67-70 High-resolution computed tomography (HRCT) findings include interlobular septal thickening, nodules, alveolar opacities and focal air trapping. Infiltrative disease may lead to pulmonary hypertension.
 
SUMMARY AND CONCLUSION
Lung in systemic disease may be a manifestation of the underlying pathological process, complication of the disease. Imaging plays a central part when lung involvement is suspected clinically and this role has increased with the advent of high resolution computed tomography. There is a high prevalence of gastro-esophageal reflux in children with chronic cough and asthma. Obstructive sleep apnea is more common and may contribute to problems such as hypertension, daytime fatigue and pulmonary hypertension in obese children. Pulmonary complications of congenital heart disease can be structural structural impact on the airways, abnormal pathophysiological mechanisms and/or significant pulmonary disease. The common respiratory manifestations in connective tissue disease include acute pulmonary hemorrhage, pleural effusion, infiltration and chronic fibrosis. In vasculitis, the pulmonary manifestation includes infiltrate, nodules, hemoptysis and dyspnea, pleural effusions and diffuses alveolar hemorrhage.
32
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A-Z Pneumonias3

Suraj Gupte, K Gowrinath, Utpal Kant Singh
 
INTRODUCTION
According to conservative estimates duly projected in World Health Organization (WHO) documents, globally, acute respiratory infections continue to be a leading cause of under-5 childhood morbidity.1,2 An overwhelming proportion of such infections pertain to the upper airway. However, a proportion of the afflicted children may suffer from lower respiratory tract infections (LRTIs) involving lung parenchyma usually from a viral or bacterial infecting agent, leading to respiratory distress. These may well become severe enough and life-threatening if early treatment is not instituted.3
 
DISEASE BURDEN/PROBLEM STATEMENT
Pneumonia, inflammation of the lung parenchyma usually from infecting agents, is a leading cause of morbidity and mortality worldwide with predominance in the resource-limited countries. Worldwide, pneumonia is responsible for 20% deaths in childhood.4 Notably, 70% of these deaths occur in children of Africa and S-E Asia.2 It kills more children in under-5 year age group than any other disease. For every single child death in a developed country, more than 200 children die of pneumonia in the developing countries.3 Furthermore, every year, pneumonia is responsible for more than 4 million deaths among children. Half of these occur in under-5s.4 Only about 50% children with pneumonia have access to medical care. Only less than 20% are treated with antibiotics.7,8
A striking feature of childhood pneumonia epidemiology is that 75% of global cases are limited to 15 countries. India stands out with the highest incidence (44 millions) in under-5s. Close on the heels, comes China (21 millions), and Pakistan (10 millions).9
According to another estimate, 150 million new cases of childhood pneumonia occur annually in under-5s, accounting for 10 to 20 million hospitalizations. Pneumonia is the single most common cause of under-5 mortality, contributing 19% of all under-5 deaths globally. Nearly 2 million under-5 deaths occur due to pneumonia; 50% of these are due to the pathogen, Streptococcus pneumoniae. Out 36of the 156 million episodes of clinical pneumonia, 43 million occur in India alone, 8.7% these being severe and life-threatening.
In low or middle income countries, pneumonia is responsible for 20% deaths compared to only 4.3% deaths in prosperous countries.5
According to the WHO's Global Burden of Disease 2000 Project, lower respiratory infections are the second leading cause of death in children younger than 5 years {about 2.1 million (19.6%)}, accounting for about one in 5 under-5 deaths.7 This number is far more than the combined mortality from acquired immunodeficiency syndrome (AIDS), measles and malaria. It is a matter of concern that about 40 to 50% of the global mortality is contributed by the Indian subcontinent.
The WHO Child Health Epidemiology Reference Group estimated the median global incidence of clinical pneumonia to be 0.28 episodes per child-year.1 This equates to an annual incidence of 150.7 million new cases, of which 11 to 20 million (7–13%) are severe enough to require hospital admission. Ninety-five percent of all episodes of clinical pneumonia in young children worldwide occur in developing countries.
Approximately, 50 million new cases of pneumonia occur annually among children younger than 5 years, accounting for 10 to 20 million hospitalizations, as per other estimates.
 
PATHOPHYSIOLOGY10-13
In pneumonia secondary to infection, usual mode of transmission of pneumonic infection is through the droplet spread directly from close personal contact and, occasionally, through inhalation of pathogens colonized in the upper airway.14
Why pneumonia? Factors that bypass or inactivate local defenses (e.g. tracheostomy tubes, immotile cilia syndrome) predispose the child to pneumonia. The result is loss of surfactant activity with local collapse and consolidation.
Pneumonia is primarily an inflammation and consolidation of the alveoli with involvement of remaining lung tissue. As a result, air exchange is significantly compromised. Poor lung compliance, functional residual capacity and vital capacity, ventilation perfusion mismatch and intrapulmonary shunting join hands to produce hypoxemia.
In lobar pneumonia (consolidation), one or more lobes of the lung are involved. Box 3.1 presents salient pathological features of the four classical stages (often overlapping) of lobar pneumonia (consolidation).
Bronchopneumonia denotes crowding of patchy consolidations, usually involving all lobes and predominantly the dependent lower and posterior parts of lungs. The neutrophilic exudate is centered in bronchi and bronchioles, with centrifugal spread to the adjacent alveoli.
Interstitial pneumonia, usually of viral etiology, is characterized by patchy or diffuse inflammation involving the interstitium.There is infiltration with lymphocytes and macrophages. Instead of a significant exudate, alveoli contain protein-rich hyaline membranes {similar to those found in adult respiratory distress syndrome (ARDS)} lining the alveolar walls which become thickened. The lymphocytes, macrophages and plasma cells infiltrate the alveolar septa.37
Bacterial superinfection of viral pneumonia may produce a mixed picture of interstitial and alveolar airspace inflammation.
Miliary pneumonia refers to multiple, discrete lesions resulting from the spread of the pathogen to the lungs via the bloodstream. The varying degrees of immunocompromise in miliary tuberculosis, histoplasmosis, and coccidioidomycosis may manifest as granulomas with caseous necrosis to foci of necrosis. Miliary herpesvirus, cytomegalovirus, or varicella-zoster virus infection in severely immunocompromised children results in numerous acute necrotizing hemorrhagic lesions.
 
CLASSIFICATIONS10-19
Various classifications of pneumonia are listed in Box 3.2.
 
OVERVIEW OF MAJOR CATEGORIES OF PNEUMONIA
 
Community-acquired Pneumonia
A pneumonia caused by pathogens acquired outside the hospital setting, i.e. in the community.
Most cases are secondary to viruses (RSV, adenoviruses, influenza virus, parainfluenza virus, metapneumovirus), especially in children > 5 years of age.
After this age, bacterial infections (Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus pneumoniae, Haemophilus pneumoniae, Bordetella pertussis) become more frequent than viral infections.
In 1/3rd – ½ cases, etiology may be mixed.38
Clinically as well as investigatively, it is difficult to distinguish between viral and bacterial pneumonias. High fever with a toxic look, especially when accompanied by some pleural effusion, certainly support the probability of bacterial pneumonia. 39
Fig. 3.1: Bronchopneumonia. Note the diffuse patchy opacities spread all over the lung field (bilateral) in the chest X-ray
Fig. 3.2: Lobar pneumonia. Note the consolidation on right side
Community-acquired pneumonia (CAP) is more responsive to medication than the hospital-acquired pneumonia where the pathogens are usually not responsive to routinely recommended antibiotics.
 
Hospital-acquired Pneumonia/Nosocomial Pneumonia
A pneumonia that develops in the hospital, at least after 48 hours after admission and not incubating at the time of admission to the ward, should be considered HAP.40
Fig. 3.3: Left lower lobe pneumonia
Figs 3.4A and B: Radiologic appearance in lobar pneumonia (left) and bronchopneumonia (right). Note the large patch involving a lobe in lobar pneumonia/consolidation and patchy, diffuse involvement of most of the lung in bronchopneumonia. The lobar pneumonia is primarily the result of exudation in the alveoli of a lobe. The bronchopneumonia begins as an inflammation of bronchioles and bronchi spreading to involve the alveoli
The causative pathogens are usually gram-negative bacilli though gram-positive cocci are being increasingly incriminated in its etiology.
Viruses, especially respiratory syncytial virus (RSV), may also cause human papillomavirus (HPV).41
 
HAP May be of the Following Types
  • Ventilator-associated pneumonia (VAP)
  • Postoperative pneumonia (POP), and
  • Health-care-associated pneumonia (HCAP).
Just as in CAP, aspiration is the most important route for acquiring infection in HAP.
Box lists the clinical criteria for defining HAP as per Center for Disease Control and Prevention (CDC), Atlanta.20
Hospital-acquired pneumonia (HAP) is best prevented. Therapy revolves around prompt broad-spectrum antibiotic administration, ensuring coverage of medical device reporting (MDR) strains, especially Pseudomonas aeruginosa as described later.
 
Congenital Pneumonia and Other Neonatal Pneumonias
In true congenital pneumonia, the newborn presents with signs of pneumonia right at birth. Routes of infection to the newborn are hematogenous, ascending or aspiration.
Intrapartum pneumonia is acquired during passage through the birth canal and infrequently via hematogenous or ascending transmission or aspiration of septic maternal fluids.
Postnatal pneumonia may occur via invasive therapies such as IV line, central venous access, ventilation and other iatrogenic maneuvers and may be both CAP and HAP. Predisposing risk factors include prematurity, early rupture of membranes, maternal fever, etc.
Neonatal pneumonia may be early-onset (<48 hrs) or late-onset (>7 days). In the first week gram-negative pathogens dominate the etiologic pattern. In the second week, gram-positive pathogens take over.
 
Persistent Pneumonia and Recurrent Pneumonia
The term, persistent pneumonia, refers to a chronic nonresolving pneumonias in which radiologic findings persist for>one month in spite of an adequate treatment.9 Box 3.3 lists the predisposing factors for persistent pneumonia.
Also termed “chronic” or “nonresolving” pneumonia, it should be considered when clinical and radiologic evidence of pneumonia continues to be present in spite of appropriate therapy spread for at least a month.
The term, recurrent pneumonia, denotes at least two attacks of pneumonia in one year or more than three attacks at any time in life, the rider being radiologic clearance in between the episodes. Box 3.4 lists the predisposing factors for persistent pneumonia.
Most factors are related to host defenses or lung defenses. One should always look for evidence of infection at various sites, especially skin and GIT, in case a systemic immunodeficiency is on the card.
In Indian settings, underlying bronchial asthma and tuberculosis must always be borne in mind while investigating these children. Quite a proportion of these children may be suffering from bronchiectasis, usually post-tuberculosis.42
 
ETIOLOGIC CONSIDERATIONS16-19
Experience has shown that a number of factors have a bearing on the etiology of pneumonia with special reference to the etiologic pathogens Box 3.5.
Some pneumonia-causing organisms show predilection for certain age groups. Table 3.1 provides a list of these pathogens.
 
CLINICAL ASPECTS18-21
The WHO has simplified the diagnosis of ARI based on manifestations as per Box 3.6. Here, the chance of missing pneumonia is nullified though some nonpneumonia cases may be included.
 
Presenting Complaints
Etiologic agent, age, and underlying illnesses all affect the clinical manifestations of pneumonia Box 3.6.
 
Physical Signs
Commonly-encountered difficulties in examination of the chest in infants and young children are presented in Box 3.7.43
Table 3.1   Age-wise pathogens causing pneumonia
Age group
Pathogens
Neonates
Bacteria: GBS, Escherichia coli, Klebsiella, Staphylococcus aureus, Listeria monocytogenes
Viruses: CMV, Herpes
Other pathogens: Chlamydia
1–3 months
Bacteria: Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae
Viruses: CMV, RSV, influenza, parainfluenza
Other pathogens: Chlamydia
4–12 months
Bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus
Viruses: RSV, influenza, adenovirus
Other pathogens: Mycoplasma
1–5 years
Bacteria: Streptococcus pneumoniae, H. influenzae, S. aureus, Klebsiella, Pseudomonas sp, Mycobacterium tuberculosis
Viruses: RSV, influenza, adenovirus
5 years
Bacteria: Streptococcus pneumoniae, S. aureus, Mycobacterium tuberculosis
Viruses: Influenza, varicella
Other pathogens: Mycoplasma, Legionella sp, Moraxella catarrhalis
 
Crying Child
Babies and young children often cry during the physical examination making auscultation difficult. The best chance of success lies in prewarming hands and instruments and in using a pacifier to calm down the infant. The opportunity to listen to a sleeping infant should never be lost.
Older infants and toddlers may cry because they are ill or uncomfortable, but, most often, they have stranger anxiety. For these children, it is best to spend a few minutes with the parents in the child's presence. Occasionally, if the child is allowed to hold the stethoscope for a few minutes, it becomes less frightening.
Even under the best of circumstances, examining a toddler is difficult. If the child is asleep when the physician begins the evaluation, auscultation should be performed early.
In many cases, the sounds created by upper airway secretions can almost obscure true breath sounds and lead to erroneous diagnoses. If doubt exists as to the etiology of sounds heard through the stethoscope, the examiner should listen to the lung fields and then hold the stethoscope near the child's nose. If the sounds from both locations are approximately the same, the likely source of the abnormal breath sounds is the upper airway.
Normal physiology: Babies take many shallow breaths as opposed to a few deep ones. Therefore, a subtle finding, particularly one at the pulmonary bases, can be missed.44
Generally, it is possible to make a diagnosis of bronchopneumonia or lobar pneumonia from a careful examination of the chest, especially auscultation.
Pneumonia may occur as a part or complication of another generalized process or illness, say influenza, measles, pertussis, etc.21 Therefore, signs and symptoms 45suggestive of other disease processes, such as rashes and pharyngitis, should also be sought during the examination.
Coinfection of pneumonia with malaria, is a frequent observation in malaria endemic belts, leading to a considerable overlap of clinical manifestation.22
Occult pneumonia (i.e. radiographic pneumonia in a child without lower respiratory tract findings) in young febrile children may sometime occur.
 
COMPLICATIONS
Pneumonia, especially staphylococcal pneumonia if not treated timely and appropriately, may cause complications such as:
  • Pleural effusion/empyema
  • Pneumothorax
  • Collapse
  • Pneumatocele
  • Lung abscess
  • Bronchiectasis
  • Subcutaneous emphysema
  • Metastatic spread: Meningitis, septic arthritis, osteomyelitis.
 
SPECIAL FEATURES OF PNEUMONIA IN VARIOUS AGE GROUPS
 
Newborns
In the neonate, pathogens that may infect the infant via the maternal genital tract include group B streptococci, Escherichia coli and other fecal coliforms, and Chlamydia trachomatis. Group B streptococci most often is transmitted to the fetus in utero, usually as a result of colonization of the mother's vagina and cervix by the organism. Affected infants commonly present within the first few hours 46after birth, but if infection is acquired during the delivery, the presentation may be delayed.
The usual presenting symptoms include tachypnea, hypoxemia, and signs of respiratory distress. Physical examination may reveal diffuse fine crackles, and the chest radiograph may demonstrate a ground-glass appearance and air bronchograms.
Newborns may be affected by the bacteria and viruses that cause infections in older infants and children. Risk factors for infection include older siblings, group daycare, and lack of immunization, particularly against pertussis.47
Fig. 3.5: Development of complications in staphylococcal pneumonia.Source: Singh D, Gupte S. Pediatric pulmonology. In: Gupte S (Ed): The Short Textbook of Pediatrics , 11th edn. New Delhi: Jaypee 2009:321-352
Some peculiar features of neonatal pneumonia are:
  • Absence of fever
  • Absence of cough
  • Apneic spells, grunting and periodic breathing
  • Cyanosis
  • Air hunger
  • Sepsis
  • Frequency of bronchopneumonia predominant48
Fig. 3.6: Pneumatocele complicating staphylococcal pneumonia
  • Speedy clinical worsening in general condition
  • High mortality despite timely treatment.
 
Infant (1–3 Months)
In the young infant, aged 1 to 3 months, continued concern about perinatally acquired pathogens mentioned above as well as the unusual Listeria monocytogenes remains. However, most pneumonias in this age group are community-acquired due to Staphylococcus aureus, and sometimes non-typeable Haemophilus influenzae.
 
Infant (3–12 Months)
Although the young unimmunized or incompletely immunized infant remains at theoretical risk for Haemophilus influenzae and pneumococcal disease, herd immunity gained from widespread immunization of the population has been generally protective.
Most lower respiratory disease in the young infant occurs during the respiratory virus season and is viral in origin, particularly in the patient with clinical bronchiolitis. The most common agents include parainfluenza viruses, influenza virus, adenovirus, metapneumovirus, and respiratory syncytial virus (RSV). Morbidity and mortality from RSV and other viral infections is higher among premature infants and infants with underlying lung disease.
Streptococcus pneumoniae is by far the most common bacterial pathogen in this age group.
Infection with Staphylococcus aureus may be complicated by lung abscess, parapneumonic effusions, and empyema.
Atypical organisms may also cause infection in infants. Of these, C. trachomatis, Ureaplasma urealyticum, cytomegalovirus, and Pneumocystis carinii 49(PCP) are the most common. Pneumocystis pneumonia is generally limited to immunocompromised infants.
Bordetella pertussis may affect infants. Only 80% of fully immunized children are protected against pertussis and immunity to this disease wanes in late adolescence. Since infants have not completed the vaccination series and because adults are a potential reservoir for infection, both groups are at risk.
 
Young Children (1–5 Years)
Viruses are a common cause of pneumonia among toddlers and preschoolers. The usual culprits are those previously discussed.
Streptococcus pneumoniae is by far the most common bacterial cause of pneumonia. Among hospitalized children, Streptococcus pneumoniae accounts for 21 to 44% of disease.6,21,22 Children in this age group are also at risk for infection by Mycoplasma pneumoniae.
 
Older Children (> 5 Years) and Adolescents
Bacterial pneumonia in this age group most often is caused by Streptococcus pneumoniae. M. pneumoniae is a frequent cause of pneumonia among older children and adolescents. Mycoplasma accounts for 14 to 35% of pneumonia hospitalizations in this age group.6,20,24
Chlamydia pneumoniae can cause pneumonia in this age group.
Older adolescents may have lost their immunity to pertussis and may become infected by this organism. Unlike the whooping cough in infants, pertussis in older patients usually causes a paroxysmal cough, which persists for more than 3 weeks and may last up to 3 months.
Factors predisposing a child to staphylococcal pneumonia are listed in Box 3.9.
 
DIAGNOSIS27-32
Diagnosis is by and large clinical with support from investigations:
  • History and physical examination
  • Investigations.
Since history and physical examinations stand discussed under “Clinical Manifestations”, we shall restrict here to investigations. These are:
  • Complete blood count (CBC)
  • Nasopharyngeal aspirate, especially for viral antigen
  • Chest X-ray.
50High TLC often occurs in pneumocioccal pneumonia and, at times, in occult pneumonia.
Viral cause is often diagnosed by clinical assessment alone. However, rapid diagnosis is possible with antigen detection techniques like direct fluorescent antibody staining, ELISA, polymerase chain reaction (PCR) and viral culture available in selected research centers only.
Clinical diagnosis of pneumonia is sufficient in ambulatory child. No further diagnostic testing like chest X-ray is required routinely. But, further diagnostic modalities are recommended in hospitalized children shoeing no response to antibiotic therapy and those with possible complications like empyema.
Diagnostic yield from cultures of respiratory secretions in community-acquired pneumonia among children is low: 24% for specific pathogen and 0.3% for mixed infections.17
Microbiologic investigations are not routinely advisable in community-acquired pneumonia but in hospitalized infants under 18 months of age, a nasopharyngeal aspirate should be sent for viral antigen detection such as immunofluorescence with or without viral culture.22
Chest X-ray (CXR), usually a PA view, is the most important diagnostic tool to detect the presence, site, type and extent of pneumonia. Radiographic findings are accepted as a reference standard for defining pneumonia. However, its role in altering the outcome of pneumonia remains unclear.
It is useful to confirm the diagnosis and identify complicated pneumonia in the form of lung abscess/pneumatoceles or empyema in children requiring hospitalization.
X-ray findings suggesting bronchopneumonia include diffuse, patchy consolidations, usually involving the whole lung and often in both lungs.
X-ray finding suggestive of lobar pneumonia (consolidation) include a large homogenous opacity occupying the anatomic area of the lobe without mediastinal shift, usually involving only one lung.
X-ray findings in viral pneumonia show predominantly interstitial pneumonia (pneumonitis).
Additionally, X-ray may give a clue to the likely pathogen or type of pneumonia.
 
Post-therapy X-ray: Yes or No?
Traditionally, diagnosis is made on the basis of clinical findings and chest X-ray findings in hospital settings. In resource-limited countries, the World Health Organization (WHO) has simplified detection of pneumonias for the benefit of the community health providers solely on the basis of clinical findings obtained by visual inspection and timing of the respiratory rate.1-3
This might mean erroneous inclusion of some cases of LRTIs (say, bronchiolitis) and croup. However, the benefit lies in not missing pneumonia cases and offering them reasonable therapy fairly early in the disease.
As a rule, a routine post-therapy follow-up chest X-ray is usually not required in children, the exceptions being presence of:51
  • Collapse
  • Round pneumonia
  • Poor clinical response to therapy.
An invasive diagnostic procedure like needle aspiration or lung biopsy is only rarely required.
Neonatal pneumonia: Diagnosis of pneumonia in a newborn is usually presumptive, most cases showing bilateral alveolar densities followed by extensive, dense bilateral changes with numerous air bronchograms.
Persistent/recurrent/chronic pneumonia: Chest X-ray showing infiltrates in a particular area on two or more occasions points to a foreign body, congenital anomaly or a tumor as the obstructive condition. Infiltrates in changing localities suggest cystic fibrosis or immunodeficiency. In aspiration pneumonia, infiltrates usually restrict themselves to right middle lobe, lower lobe or lingual. Additional investigations may be in the form of CT (including high-resolution CT), MRI and bronchgraphy, bronchscopy, pulmonary function tests, bronchalveolar lavage (BAL), sweat chloride, etc.
For GERD, barium swallow, cine esophagogram, radionuclide scans and esophageal pH monitoring may be in order.
In chronic sinobronchial disease or bronchiectasis, electron microscopic morphologic studies on nasal mucosal scrapings/biopsy may well be useful.
In case of immunodeficiency, in addition to routine blood counts (complete and differential), evaluation for HIV, quantitative serum immunoglobulins and skin tests for delayed hypersensitivity should be done.
The need for identifying a widely accepted gold standard for diagnosis of pneumonia in children is indeed being felt.28
Infectious Diseases Society of America and the Pediatric Infectious Diseases Society are currently collaborating to create evidence-based recommendations for the guidelines for diagnosis of pneumonia in children that is likely be released in 2011.
 
DIFFERENTIAL DIAGNOSIS
  • Other causes of LRTI (bronchiolitis, bronchitis).
  • Nonradiopaque foreign bodies which may produce multiple abscesses or pneumatoceles, resulting in a radiologic picture simulating that seen in staphylococcal pneumonia, miliary mottling of hematogenous tuberculosis and tropical eosinophilia.
  • Rarely, histoplasmosis and sarcoidosis may also be confused with radiographic picture of staphylococcal pneumonia.33
 
MANAGEMENT34-37
Once the diagnosis of pneumonia is arrived at, it becomes important to decide whether the child needs outpatient treatment or hospitalization.
Most children with viral pneumonia are not quite sick. They may be treated as outpatients with cotrimoxazole or amoxicillin together with supportive care.
52Hospitalization is indicated in the following circumstances:
  • Child is sick enough, manifesting features of hypoxia such as cyanosis, respiratory difficulty, restlessness, seizures, etc.
  • High-risk factor(s)
  • Poor response to treatment provided as outpatient.
 
Specific Antimicrobials
Community-acquired pneumonia: The choice of antibiotic(s) depends on the anticipated pathogen(s) in a given case rather than the anatomic type of pneumonia (Table 3.2).
Hospital-acquired pneumonias: Here, the recommended antimicrobials again vary with the likely pathogens (Table 3.3).
Response to appropriate antibiotics is, as a rule gratifying (Fig. 3.8). Poor response should arose the possibility of an underlying pathology that may be congenital (Figs 3.9 and 3.10) or acquired (Fig. 3.11).
Table 3.2   Recommended antibiotics for etiologic pathogens in community-acquired pneumonia (CAP)
Suspected pathogen
Antimicrobial
Streptococcus pneumoniae
Penicillin G, ampicillin, amoxicillin.
If penicillin hypersensitivity: Cephalosporins (e.g. cefazolin)
Streptococcus pneumoniae MDRS
Amoxycllin + clauvulic acid (amoxi-clav)
Ampicillin + sublactam
Staphylococcus aureus
Ampicillin + cloxacillin
Vancomycin
Clindamycin
H. influenzae
Ampicillin as such or in combination with
Chloramphenicol
Ceftriaxone
Klebsiella
Penicilli + gentamicin
Pseudomonas
Ticarcillin + gentamicin
Pneumocystis carinii (new name P. jirevici)
Cotrimoxazole
Thrush
Amphotericin B, 5-fluorocytosine
Mycobacterium tuberculosis
ATT
Respiratrory syncytial virus
Ribavirin
Influenza type A
Ostelmavir, peramivir
Mycoplasma pneumoniae
Erythromicin
Aspiration pneumonia
Prophylaxis recommended
Loeffler's pneumonia
Symptomatic treatment
53
Table 3.3   Antimicrobials in hospital-acquired pneumonia (HAP)
Pathogen
Antimicrobial
Gram-negative bacilli
Aminoglycosides (gentamicin, amikacin, netilmicin)
Klebsiella
3rd generation cephalosporins
P. aeroginosa
Ticarcuillin + clavulinic acid, Ceftazidine, Quinolones
Staphylococcus aureus
Vancomycin, Cloxacillin, Quinolones, Cefazolin
Fig. 3.7: Lobar pneumonis. Note right upper lobe consolidation in an adolescent. Subsequently, it turned out to be of bacterial etiology
Neonatal pneumonia: Generally speaking, pneumonia in the first week of life is best treated with ampicillin plus an aminoglycosie or cefatoximine, pneumonia after first week may well be nosocomial with vancomycin or a third generation cephalosporin. In case of Pseudomonas aeruginosa, ceftazidime or ticarcillin plus an aminoglycoside is a good choice.
Persistent/recurrent/chronic pneumonia: Therapy is addressed to treatment of superimposed infection plus correction of the underlying condition.
 
General Measures
These comprise:
  • Good nursing care
  • Bed rest
  • Suction
  • Oxygen54
Fig. 3.8: Resolving lobar pneumonia. Note the resolution of consolidation after 10-day course of antibiotics
Fig. 3.9: Lobar pneumonia. Note the axial CT of thorax showing pneumonic consolidation with multiple cystic lesions containing air and fluid levels in the left posteromedial segment
  • Symptomatic treatment for cough, fever and pain
  • Adequate fluid and dietary intake
  • Treatment of CCF, if present
  • Physiotherapy, especially breathing exercise during convalescence
  • Surgical intervention in such children who develop complications like emphysema, tension pneumothorax, (common in Staphylococcus pneumonia), etc.55
Fig. 3.10: Recurrent lobar pneumonia. The axial CT of thorax of the same subject as in Figure 3.7 showing consolidation that recurred in the same segmental area. Later, it proved to be intralobar sequestration with aspergilloma
Fig. 3.11: Right parahilar pneumonia in an immunocompromised adolescent female. Later, it proved to be due to nocardiosis. She was treated with cotrimoxazole
 
PROGNOSIS
Generally speaking, if appropriate and timely treatment becomes available, prognosis is good.
Poor prognostic signs include:
  • Poor nutritional status
  • Young age
  • Bilateral disease.56
Fig. 3.12: Chest X-ray of the same case as in Figure 3.8, showing resolution of pneumonia after two weeks’ of cotrimoxazole therapy
  • Such underlying diseases as cystic fibrosis, immunodeficiency, asthma, and malignancy
  • Complications like CCF and respiratory failure.
Very young children who develop pneumonia and survive are at risk for developing lung problems in adulthood, including chronic obstructive pulmonary disease (COPD).
 
PREVENTION
 
General Measures
Good nutritional status, better living conditions and environmental factors (say, reduction of smoke pollution indoors as well as outdoors) are important factors in prevention of pneumonia; in fact, for the whole spectrum of acute respiratory infection (ARI) as such.
In prosperous countries, effective steps pertaining to the above-said factors at the beginning of 21st century had resulted in significant reduction in mortality from pneumonia even before antibiotics appeared on the scene.38,39
Breastfed infants have better immunity against respiratory infections. Unfortunately, less than 40% infants receive exclusive breastfeeding for first six month son a global scale despite the recommendation by the WHO, UNICEF and other international and national agencies.40
Zinc supplementation has also been advocated as another preventive measure against pneumonia and other LRTs.41 57
 
Vaccination
Immunization is important to cut down incidence of pneumonia as a complication of vaccine-preventable diseases. Immunization against measles, Streptococcus pneumoniae, pertussis, H. influenzae type b influenza, etc. is the most effective way to prevent pneumonia.
In the developed world, pneumonia has been effectively controlled with the use of Haemophilus influenzae type b (Hib) and pneumococcal vaccines which form a part and parcel of the immunization schedule. Currently, these vaccines (especially, pneumococcal) are not available on a large scale in resource-limited countries known for high fatality from pneumonia.
Children prone to pneumococcal pneumonia (autosplenectomy, asplenemia, nephrotic syndrome) must be given pneumococcal vaccine, preferably conjugate type, which is safe even < 2 years of age and has widely demonstrated its efficacy. In fact, based on data from various efficacy studies, WHO has recommended inclusion of conjugated pneumococcal vaccine (PCV) with high priority in developing countries with under-5 mortality rates > 50/1000 live births or burden of under-5 deaths > 50,000/year.38 India with under-5 mortality of 69 and death burden in <under-5s of 2.02 million qualifies for such an inclusion.
The vaccine is now available in India. However, its exorbitant cost is a roadblock. Unless, the price is brought down by some kind of subsidy, it appears to be unaffordable in the resource-limited countries.39-41 The Global Alliance for Vaccines and Immunization (GAVI), known for providing extensive support for immunization activities, has already offered to supply PCV-7 to India at a highly subsidized and affordable cost for an extended period up to 2015 in the first instance. If the Government of India accepts this generous offer, this shall prove a boon in controlling pneumococcal disease, particularly pneumonia, a major cause of morbidity and mortality in childhood.
58Box 3.11 gives the salient details of pneumococcal vaccination as per recommendations of the IAPCOI 2007-2008.46
Finally, improved MCH care, other health promotional activities in vulnerable areas, health education to sensitize young parents for early recognition of pneumonia and need to consult health providers, are critical for cutting down morbidity and mortality from pneumonia. Ever since 2009, 12th November is being observed as World Pneumonia Day. The goal is to save the lives of millions of children around the world through public education measures about the illness, raising awareness about it among healthcare providers and advocacy for more funding.
59
 
SUMMARY AND CONCLUSION
Pneumonia is a leading cause of hospitalization and death, especially in the resource-limited countries. Most pneumonias are of viral etiology with subtle manifestations and may be treated in the outpatient. WHO recommends detection of cases of pneumonias through sheer clinical work-up based on respiratory rate and chest retractions for the benefit of the larger section of the community. Sick children with pneumonia, especially with hypoxic manifestations, need hospitalization. Choice of antibiotic(s) in bacterial pneumonia is dictated by the likely etiologic pathogen which vary in different age groups and also whether the pneumonia is community-acquired or hospital-acquired. A large majority of the bacterial pneumonias after 6 months of age are secondary to Streptococcus pneumoniae infection but a pneumonia in a neonate is most likely to be due to gram-negative pathogens, GBS or Staphylococcus aureus. A pneumonia that persists, despite adequate therapy, after month should be labeled “persistent pneumonia”; a radiologiclly-proved pneumonia occurring 2 in one year or > 3 times at any time in life should be considered “recurerent pneumonia”. These need detailed investigations bearing in mind the predisposing conditions. Exclusive breastfeeding for a minimum of 6 months considerably protects the infant from pneumonia and several other infections. Over and above the routine vaccination, immunization with conjugate pneumococcal vaccine can go a long way in preventing pneumococcal pneumonia and reduce the incidence of pneumonias to a large extent across the board.
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Pneumonia: Select Issues and Concerns4

H Paramesh
 
INTRODUCTION
Pneumonia is an inflammation of the lung parenchyma where oxygen and carbon-dioxide gas exchange takes place.
Pneumonia kills more children than any other illness. More than measles, malaria and AIDS combined. One in five under-five deaths globally is due to pneumonia. Hence, the need for urgent attention to recognize treat and create awareness to mitigate the problem by preventive measures. The millennium development goal of WHO and UNICEF is to reduce the under-five mortality by two-thirds between 1990 and 2015.1
Although most cases of pneumonia are caused by microorganisms the noninfectious causes can also contribute fairly, which include aspiration of meconium in neonatal period, food, gastric acid, foreign bodies, lipid substances, chemicals like kerosene, hypersensitivity reaction, drugs and radiation-induced pneumonitis. The microorganisms vary in community-acquired, hospital-acquired and ventilator-acquired pneumonias.
 
HARD FACTS ABOUT PNEUMONIAS
  • Ten percent of inpatient admissions are due to pneumonias.2
  • Eight percent pneumonias do not have any risk factors.
  • Thirteen percent are invasive pneumonias as per invasive bacterial infections surveillance (IBIS).3
  • Only 50% of children with pneumonia receive proper treatment; one of five caregivers knows the danger signs of pneumonia, only 20% of children receive recommended antibiotics. 36% of acute respiratory infections (ARIs) children are taken to health facility.
  • Rural and children of uneducated mother often lack appropriate care.
Data from the National Commission of Macro Economics and Health, Government of India 2005, shows that mortality from pneumonia is higher in children of scheduled cast, scheduled tribes and other backward class.64
 
RISK FACTORS
The risk factors that influence pneumonia include, host and environmental factors as listed in the Table 4.1.
 
MECHANISM OF DEVELOPMENT OF PNEUMONIA
Pneumonia develops in a child through five basic mechanisms:
  1. By inhalation of a single virulent agent from upper airways.
  2. By inhalation of contaminated droplets from any patients in the crowd when that child coughs or sneezes.
  3. Contiguous spread from the neighboring bronchi or bronchioles.
  4. Secondary invasion by germs when the defence of the lower respiratory tract is low.
  5. By hematogenous spread.
 
DIAGNOSIS
The diagnosis of pneumonia is purely on clinical ground based on the pathophysiologic changes in the lung4,5 as listed in the Table 4.2.
Dullness to percussion in young children always means pleural effusion.
The important clinical clues to recognize pneumonia for the health providers in the community are:
  • Rapid breathing (Trachypnea): In children less than 2 months the respiratory rate is more than 60/minute; 2 months to 12 months more than 50/minute; 12 months to 5 years more than 40/minute and above 5 years more than 30/ minute is utilized to diagnose pneumonia.
  • Indrawing of lower chest wall (Retractions): Along with tachypnea is diagnostic of severe pneumonia. Please note that retractions are the features of airway obstruction. Since young infants have soft pliable rib cage, one can see the retractions even in restrictive lung disease.
Table 4.1   Risk factors for pneumonia
Host factors
Environment factors
  • Young age
  • Sex, male > female
  • Low birth weight
  • Under nutrition
  • Zinc deficiency, lack of breastfeeding
  • Immune compromise
  • CHD*/previous pneumonia
  • Measles/pertussis
  • Family size
  • Crowding
  • Air pollution (Indoor)
  • Parental smoking
  • Young uneducated mother
  • Child care practices, blowing oil in the nostrils after bath
  • Poor sanitation
  • Birth order
* CHD-Coronary heart disease
65
Table 4.2   Clinical features in relation to pathophysiologic changes
Pathophysiology
Clinical features
Constitutional aberration of respiratory system
Fever, cold, cough, biphasic fever, cough is late onset in hematogenous spread
Decrease compliance (stiff lung)
Tachypnea, shallow breathing
(Retractions in infants with soft pliable rib cage)
VAQ abnormality
Grunting, moaning, flaring of nostrils
Hypoxia
Tachycardia, exertional dyspnea, mood changes and coma
Pleural involvement
Pleuretic sharp pain, splinting of chest, trepopnea
Diaphragmatic involvement
Acute abdominal pain, referred pain to shoulder
Consolidation of lobe
Bronchial breathing, dulllness
 
CAUSES FOR COMMUNITY-ACQUIRED PNEUMONIA
Information regarding pathogen-specific causes of pneumonia are limited and available information is often difficult to interpret. Lung puncture and bronchoalveolar lavage (BAL) is neither practical nor ethical. In the IBIS study in Vellore conducted between 1999 and 2002 on 285 cases of pneumonia, S. pneumoniae was isolated in 15 out of 285 (5.5%) and Haemophilus influenzae in 4 out of 285 (1.4%) in children under five year of age.6 Lung puncture studies of Sinha et al in 1966 and Jayanth Prakash et al in 1996 in children under 5 years showed 6% and 17%; 11.4% and 2.9% yield of S. pneumoniae and H. influenzae respectively.7,8 Kabra's study in 2003 showed 5% S. pneumoniae but no growth of H. influenzae and serologic test showing 24% of mycoplasma and 11% of Chlamydia.9 Our observation in Bangalore (between 2000 and 2004) shows a blood culture yield is only 44/554 (7.2%). The organisms are S. pneumoniae in 4.77% S. aureus was the main organism 47.6%; Pseudomonas 19%; Klebsiella 4.77%; no growth of H. influenzae serological test for mycoplasma is 24.19%. Studies in USA by Ian C Michelow et al on 154 hospitalized pneumoniae patients by doing PCR test identified the pathogen by 60% (of which 73% S. pneumoniae, 45% virus, 14% Mycoplasma, 9% Chlamydia and 23% mixed bacteria and virus).10 In general the most common organisms for community- acquired pneumonia in children are:
  • S. pneumoniae
  • H.influenzae type b
  • Mycoplasma
  • S. aureus.
In hospital-acquired pneumonia the most common organisms are drug resistant S. aureus and enterococci. In ventilator acquired pneumonia it is enterococci, E. coli, Klebsiella, Pseudomonas and drug resistant Streptococcus are the common organisms.
The diagnosis of etiologic agent is only a clinical judgment some of the clinical clues may help in the diagnosis as given in Table 4.3.66
Table 4.3   Pneumonias: specific features (HP)
Pathogen
Features
Staphylococci
Young children, rapid spread, pneumatocele formation, empyema, pyopneumothorax are common
Pneumococci
Right upper lobe, transient albuminuria, mucocele on gums, utricaria. Common with sickle cell, splenectomy children
H. influenzae
Prolonged pertussis type of coughing leukocytosis—18,000–70,000/cmm
Streptococci
Post, Hilar adenopathy, pneumatocele, empyema
Klebsiella
Debiliated children—who receive nebulization or humidified oxygen. Pneumonic lobe is bigger
Mycoplasma
Observed in young age also, dry hacky cough, myalgia, conjunctivitis
Viral
Perihilar, peribronchial infiltrates hyperaeration, hilar adenopathy, segmental atelectesis
 
APPROACH TO PNEUMONIA IN THE COMMUNITY
  • Non-severe pneumonia: Where child has only tachypnea:
    • Paracetamol for fever and bronchodilator for wheeze
    • Antibiotics–penicillin/ampicillin/amoxacillin
    • Home care, but reassess in 2 days or earlier if there are symptoms of severe pneumonia
    • Oral hydration.
  • Severe pneumonia: Where child has tachypnea with retractions:
    • Refer to the hospital for further management.
  • Very severe pneumonia: Where child is having absent social smile, poor feeding, stridor in a quite child, severe malnutrition along with tachypnea and retractions
    • Manage fever and wheeze
    • Give first dose of antibiotic
    • Refer urgently to the hospital for proper management.
Selection of antibiotics:11,12 The earlier recommendation of cotrimoxazole for community-acquired pneumonia by WHO is not applicable now because only 15.7% of pneumococci are sensitive. So the suggested antibiotics are as per Table 4.4.
The duration of treatment ranger between 7 and 14 days, but this is not based on any empirical evidence. Shorter duration of therapy, if found to be effective, could be particularly important in resource-poor settings where there is a high risk of death.13
 
Barriers for Injectable Antibiotics in Severe Pneumonia
The barriers for parenteral antibiotics in severe pneumonia are:
  • Non-availability of injectable antibiotics in the health facility
  • Lack of trained staff to administer67
Table 4.4   Antibiotics for community-acquired pneumonia
Clinical situation
Antibiotic(s)
Nonsevere pneumonia
Penicillin/Ampicillin/Amoxacillin
Severe pneumonia
Parenteral penicillin/Chloramphenicol
Very severe pneumonia
Chloramphenicol
Less than 2 months of age
Parenteral ampicillin and gentamycin
  • Risk of non-complianced/risk of needle borne infection
  • Administrative cost
  • Constraints of regimes like hospitalization and referral.
According to Amoxicillin Penicillin Pneumonia International Study (APPIS) the efficacy of oral amoxicillin vs injectable penicillin is the same. It is only the degree of hypoxia increases the risk of treatment failure. High dose of amoxicillin at home is equaled to parenteral ampicillin without any complication.
 
Management Issue in the Rural Health Care
The absenteeism among doctors and staffs in primary health centers is high. We need the need based services at public health centers not like government office timings. The agriculture farm workers in the villages go to work in the morning and come only in the evening. They cannot afford to waste a days earning. The MBBS doctors needs with training in skills of providing services in the rural area in addition they deserve the provision for better financial and nonfinancial incentives for their stay with their family. In addition there is a need for increasing paramedicalization of the primary health care services with better incentives.
Cost of reducing pneumonia deaths: Nearly 85% of deaths from pneumonia in children occurs in under 5 years of age. The appropriate course of antibiotics for treatment of pneumonia costs about US$ 0.27, which includes cost of scaling up treatment coverage, training of staff, hospitalization cost of severe pneumonia. The cost effectiveness of vaccines against pneumococci and H. influenzae versus the disease burden in the community is debatable. Hence, it is essential that we focus our economics on strengthening of our staff on broader health system. According to a recent observation, there is no drop in prevelence of pneumonia in US after using vaccine for pneumocci since 2000.14,15
 
SUMMARY AND CONCLUSION
Pneumonia, an inflammation of the lung parenchyma where oxygen and carbon dioxide gas exchange takes place, kills more children than any other illness.
The diagnosis and etiology of pneumonia is more of a clinical suspicion than investigations. Blood culture for respiratory infection is not only difficult to interpret, but also not fruitful since only 7.2% of them are positive.
Selection of antibiotics is more an experience than experiment. Duration of therapy is a matter of enlightened practice than applied science. Judicious and 68limited use of antibiotics is important to successfully reduce the antimicrobial resistance which, otherwise, is assuming an unmanageable proportion.
The prevention of pneumonia in the community includes:
  1. Hand washing.
  2. Avoidance of indoor air pollution and tobacco smoke.
  3. Adequate nutrition, encourage breastfeeds and zinc supplementation.
  4. Immunizations for communicable diseases like measles and pertussis.
  5. Lastly and most importantly education of health professionals and society.
The cost effectiveness of vaccines against pneumococci and H. influenzae versus the disease burden in the community is debatable. Hence, it is essential that we focus our economics on strengthening of our staff on broader health system.
REFERENCES
  1. UNICEF/WHO. Pneumonia: The forgotten Killer of Children. Geneva:WHO  2006.
  1. Paramesh H. Childhood pneumonia recognition and management. IAP J Pract Pediatr 1994;2:49–54.
  1. Brahmadathan KN. Acute bacterial infection of the lower respiratory tract. In: Trends in Respiratory Diseases. New Delhi: Tata McGraw-Hill;  2003.pp.85-92.
  1. Paramesh H, Shenoi A. Evaluation of respiratory distress. In: Gupte S (Ed): Recent Advances in Pediatrics (Special Vol 13: Pulmonology); 2003.pp.77-85.
  1. Jain M, Paramesh H. The importance of clinical findings and lab parameters in the diagnosis of pneumonia. Karnataka Pediatr J 2000;14:44–45.
  1. Brahmadathan KN, Lalith MK. Acute bacterial infection of the lower respiratory tract. Status of respiratory diseases in India In: The Environment and the Infection. New Delhi: Tata McGraw-Hill  2003;70:33–36.
  1. Sinha DP, Hughes JR. Lung tap in lower respiratory tract infections in children. Indian Pediatr 1966;3:385–392.
  1. Prakash J, Agarwal D, Agarwal KN, Gulati AK. Etiologic diagnosis of pneumonia in under five children. Indian Pediatr 1996;33:329–331.
  1. Kabra SK. Etiology of acute lower respiratory tract infection. Indian J Pediatr 2003;70:33–36.
  1. Michelow IC. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004;113:701–707.
  1. Paramesh H. Rational use of antibiotics in respiratory disease. In: Gupte S (Ed): Recent Advances in Pediatrics - 17: Hot Topics. New Delhi: Jaypee  2007:160–168.
  1. Kabra SK, Lodha R, Pandey RM. Antibiotics for community-acquired pneumonia in children (Review). Cochrane Datab System Rev 2010:CD 004874.
  1. Haider BA, Lassi ZS, Bhutta ZA. Short course versus long course antibiotic therapy for severe community-acquired pneumonia in children aged 2 months to 59 months. Cochrane Datab System Rev 2008:CD005979.
  1. Gupte S, Gowrinath. Pneumonia. In: Gupte S, Gupte N (Eds): Pediatric Infectious Diseases. Gurgaon: Macmillan  2011:362-392.
  1. White A. Reflections on management of pneumonia. Commun Doctor 2009;3:12–19.

Ventilator-Associated Pneumonia5

B Vishnu Bhat, Bahubali D Gane
 
INTRODUCTION
Ventilator-associated pneumonia (VAP) is one of the most important causes of nosocomial infections in pediatric intensive care units (PICUs). The VAP is defined as an inflammation of the lung parenchyma caused by infectious agents not present or in incubation at the initiation of mechanical ventilation (MV).1 It is labeled as early onset when the infection develops less than 4 days and late onset if it develops after 4 days of mechanical ventilation.
 
INCIDENCE
It is estimated that the incidence of VAP in adults is greater than 10%.2 The incidence in children, estimated by the CDC's National Nosocomial Infections Surveillance (NNIS) study is 20%.3-5
In the majority of reports, VAP frequencies varied between 8 and 28%.6-10 A prospective investigation of VAP in 23 Italian intensive care units (ICUs) that included 724 critically ill patients, who had received prolonged (more than 24 hours) ventilatory assistance after admission found a mean rate of 23%. The frequency rose from 5% for patients receiving MV for 1 day to 69% for those receiving MV for more than 30 days.6 The risk of pneumonia in intubated patient is 6 to 21 times higher than in other patients; the risk increases between 1 and 3% for each day requiring endotracheal intubation and mechanical ventilation.11,12
Three recent studies have examined the incidence and prevalence of VAP in pediatric ICUs. First study done by NNIS program sponsored by the Center for Disease Control and Prevention (CDC) showed that the pooled mean VAP rate was 6/1,000 ventilator days for PICU patients.13 VAP was the second most common cause of nosocomial infection, representing 20% of nosocomial infections in this population. The highest age-specific rates of ventilator-associated pneumonia occurred in the 2 to 12 months age group and the most common causative organism was P. aeruginosa, which accounted for 22% of cases.13
A second study of 20 PICUs in 8 countries performed by the European multicenter study group found that the incidence of nosocomial infection was 7123.6% and the most frequent nosocomial infection was pneumonia (53%). P. aerugnosa caused 44% of ventilator-associated pneumonia.14
A large prospective cohort study was conducted in 16 Canadian ICUs: of the 1,014 mechanically ventilated patients included, 177 (18%) developed VAP, as assessed by bronchoscopic sampling with bronchoalveolar lavage (BAL) or protected specimen brush (PSB) in 131.15
 
ETIOLOGIC AGENTS
Microorganisms responsible for VAP may differ according to the population of patients in the ICU, the durations of hospital and ICU stay and the specific diagnostic methods used. Most of the cases of VAP are caused by aerobic gram- negative bacteria (GNB). More recently, however, some investigators have reported that gram-positive bacteria have become increasingly more common, S. aureus being the predominant gram-positive isolate. The predominant GNB associated with VAP were P. aeruginosa and Acinetobacter spp., followed by Proteus spp., Escherichia coli, Klebsiella spp and H. influenzae. The high rate of polymicrobial infection in VAP has been emphasized repeatedly, when the protected specimen brush (PSB) technique was used to identify the causative agents in 52 consecutive cases of VAP and a 40% polymicrobial infection rate.7 Underlying diseases may predispose patients to infection with specific organisms. Cystic fibrosis increases the risk of P. aeruginosa and/or S. aureus infections, whereas trauma and neurological patients are at increased risk for S.aureus infection.16,17 High rate of H. influenzae, S. pneumoniae, methicillin-sensitive S. aureus (MSSA), or susceptible Enterobacteriaceae were constantly found in early-onset VAP, whereas P. aeruginosa, Acinetobacter spp., MRSA and multiersistant GNB were significantly more frequent in late-onset VAP.16,18 This different distribution pattern of etiologic agents between early-and late-onset VAP is also linked to the frequent administration of prior antimicrobial therapy in many patients with late-onset VAP. The exposure to antibiotics initially at the onset of MV decreased the rate of pneumonia caused by gram-positive cocci or H.influenzae (p < 0.05), whereas the rate of pneumonia caused by P. aeruginosa was significantly higher.19
Isolation of fungi, most frequently Candida species, at significant concentrations poses interpretative problems. Invasive disease has been reported in VAP, but more frequently, yeasts are isolated from respiratory tract specimens in the apparent absence of disease. The use of the commonly available respiratory sampling methods (bronchoscopic or nonbronchoscopic) in mechanically ventilated patients appears insufficient for the diagnosis of Candida pneumonia. At present, the only method to establish Candida as the primary lung pathogen is to demonstrate yeast or pseudohyphae in a lung biopsy. However, the significance of Candida isolation from the respiratory samples of mechanically ventilated patients is being investigated in greater depth (Table 5.1).72
Table 5.1   Microorganisms causing ventilator-associated pneumonia20
Early-onset pneumonia
Late-onset pneumonia
Others
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Aerobic gram-negative bacilli
Pseudomonas aeurginosa Enterobacter spp.
Acinetobacter spp.
Klebsiella pneumoniae
Serratia marcescens
Escherichia coli
Other gram-negative bacilli
Staphylococcus aureus
Anaerobic bacteria
Legionella pneumophila
Influenza A and B
Respiratory syncitial virus
fungi
 
RISK FACTORS
Risk factors provide information about the probability of lung infection developing in individuals and populations. Thus, they may contribute to the elaboration of effective preventive strategies by indicating, which patients might be most likely to benefit from prophylaxis against pneumonia.The risk factors for VAP can be divided into three categories: host related, device related and personnel related.
Host-related risk factors include pre-existing conditions such as immune-suppression, chronic obstructive lung disease and acute respiratory distress syndrome. Other host related factors include patients body positioning, level of consciousness, number of intubations and medications, including sedative agents and antibiotics. Bacterial contamination of endotracheal secretions was higher in patients in the supine position than in patients in the semi recumbent position in some studies.21 Whether due to a pathophysiological process, medication or injury, decreased level of consciousness resulting in the loss of cough and gag reflexes contributes to the risk of aspiration and therefore increased risk for VAP.22 Reintubation and subsequent aspiration can increase the likelihood of VAP 6-fold.23
Device-related risk factors include endotracheal tube, ventilator circuit and presence of a nasogastric or an orogastric tube. Secretions pool above the cuff of an endotracheal tube and low cuff pressures can lead to microaspiration and/or leakage of bacteria around the cuff into the trachea.24 Nasogastric and orogastric tubes disrupt the gastroesophageal sphincter, leading to reflux and increased risk for VAP.
Improper handwashing resulting in the cross-contamination of patients is the biggest personnel-related risk factor for VAP. Patients, who are intubated and receiving mechanical ventilation often need interventions such as suctioning or manipulation of the ventilator circuit. These interventions increase the likelihood of cross-contamination between patients if healthcare staff do not use proper handwashing techniques. Failure to wash hands and change gloves between contaminated patients have been associated with an increased incidence of VAP.5 In addition, failure to wear proper personal protective equipment when antibiotic resistant organisms have been identified increases the risk of cross-contamination 73between patients. Other known risk factors for development of VAP in children include genetic syndromes, immune deficiency, transport out of the PICU, surgery, continuous enteral feedings, bronchoscopy and medications, specifically steroids, H2 receptor antagonists, immunosuppressants, neuromuscular blocking agents25-29 (Flow chart 5.1).
 
PATHOGENESIS
Pneumonia results from microbial invasion of the normally sterile lower respiratory tract and lung parenchyma caused by either a defect in host defenses, challenge by a particularly virulent microorganism or an overwhelming inoculum. The normal human respiratory tract possesses a variety of defense mechanisms that protect the lung from infection, for example; anatomic barriers, such as the glottis and larynx, cough reflex, tracheobronchial secretion, mucociliary lining, cell-mediated and humoral immunity and a dual phagocytic system that involves both alveolar macrophages and neutrophils. When these coordinated components function properly, invading microbes are eliminated and clinical disease is avoided, but when these defenses are impaired or if they are overcome by virtue of a high inoculum of organisms of unusual virulence, pneumonitis results.
As suggested by the infrequent association of VAP with bacteremia, the majority of these infections appear to result from aspiration of potential pathogens that have colonized the mucosal surfaces of the oropharyngeal airways. Intubation of the patient not only compromises the natural barrier between the oropharynx and trachea, but may also facilitate the entry of bacteria into the lung by pooling and leakage of contaminated secretions around the endotracheal tube cuff.30 This phenomenon occurs in most intubated patients. Supine position may facilitate its occurrence.
Flow chart 5.1: Routes of infection in VAP34
74In previously healthy, newly hospitalized patients, normal mouth flora or pathogens associated with community-acquired pneumonia may predominate. In sick patients who have been hospitalized for more than 5 days, GNB and S. aureus frequently colonize the upper airway.30
Uncommonly, VAP may arise in other ways. Macroaspirations of gastric material initiate the process in some patients. Allowing condensation in ventilator tubing to drain into the patient's airway may have the same effect. Tracheal suctioning or manual ventilation with contaminated equipment may also bring pathogens to the lower respiratory tract. More recently, concerns have focused on the potential role of contaminated in line medication nebulizers and these devices are infrequently associated with VAP.
Although, tracheal colonization by potentially pathogenic microorganisms occurs before lung infection in a majority of ventilated patients, its relationship with VAP development remains controversial. Upper airway colonization is a frequent occurrence in ventilated patients and that it can act as a harbinger of nosocomial pneumonia in this setting. The tracheobronchial tree, as well as the oropharynx of mechanically ventilated patients are frequently colonized by enteric GNB.31 Bacterial adhesions and prior antimicrobial therapy appear to facilitate the process of colonization. Interestingly, Enterobacteriaceae usually appear in the oropharynx first, whereas P. aeruginosa more often appears first in the trachea.32
Other sources of pathogens causing VAP include the paranasal sinuses, dental plaque and the subglottic area between the true vocal cords and the endotracheal tube cuff. Whether bacteria ascend from the intestines or descend from the oropharynx, the stomach may act as a reservoir in which pathogens can multiply and attain high concentrations.33 Alkalinization of the normally acidic gastric environment seems to be a prerequisite for this mechanism to be operational.
 
DIAGNOSIS
The diagnosis of VAP is usually based on clinical, microbiologic and radiologic criteria.
Clinical criteria for diagnosing VAP include fever, leukocytosis or leukopenia, purulent secretions, new or worsening cough, dyspnea, tachypnea, crackles or bronchial breath sounds and worsening gas exchange. These criteria are nonspecific and their sensitivity and specificity relative to pathology is poor.35-37 The clinical criteria for VAP are in many cases indistinguishable from those for generalized sepsis or systemic inflammatory response syndrome.38,39 Consequently, clinical findings are generally considered in conjunction with radiology and microbiologic findings. Chest roentgenogram remains an important component in the evaluation of hospitalized patients with suspected pneumonia. It is most helpful when it is normal and rules out pneumonia.
Radiologic criteria include the presence of new or progressive pulmonary infiltrates, cavitation, air bronchogram or pneumatocele on chest radiograph. Air bronchograms have the highest correlation with pneumonia with a sensitivity of 58 to 83%. In comparison, “evolving infiltrates” has a sensitivity of 50 to 78%.40,41 Chest X-ray findings have only limited specificity (33%–42%), when infiltrates are evident, the particular pattern is of limited value for differentiating among 75cardiogenic or noncardiogenic pulmonary edema, pulmonary contusion, atelectasis (or collapse), and pneumonia. Because atelectasis is common among patients in the ICU, the contribution of repeating the chest X-ray after vigorous pulmonary physiotherapy was emphasized to differentiate infiltrates caused by atelectasis from those due to infection.42
Microscopy evaluation and culture of tracheal secretions and/or expectorated sputum are also frequently inconclusive for patients clinically suspected of having pneumonia, because the upper respiratory tract of most patients in the ICU is colonized with potential pulmonary pathogens, whether or not parenchymal pulmonary infection is present.43-45 For patients with histologically documented pneumonia, endotracheal aspirate sensitivity was 82%, but its specificity was only 27%. Microscope examination of tracheal aspirates may, however, be of some potential value in the diagnosis of patients with VAP. Indeed, specimens from intubated patients with pneumonia showed higher semiquantitative grading of neutrophils and bacteria including intracellular organisms than did those from patients without pneumonia.45
Combinations of various criteria to establish a diagnosis in patients with VAP have been suggested and validated. The National Nosocomial Infection Surveillance system was developed by the CDC as a tool to describe the epidemiology of hospital acquired infections and to produce aggregated rates of infection suitable for inter-hospital comparison. The clinical criteria for the diagnosis of VAP have been established by the NNIS and the CDC3 (Box 5.1). More recently, the Clinical Pulmonary Infection Score (CPIS) was proposed by Pugin et al47 based on six variables, namely fever, leukocytosis, tracheal aspirates, oxygenation, radiographic infiltrates and semiquantitative cultures of tracheal aspirates with gram stain (Tables 5.2 and 5.3).
 
TREATMENT
Once VAP develops, treatment is usually supportive along with the administration of antibiotics.
Early antibiotic therapy is important in the management of patients with clinically suspected VAP and patients, who are initially treated inadequately have poorer outcome than those receiving adequate therapy at the beginning. Clinicians are faced with the following options; first, to treat all patients with suspected VAP early, preferably with a combination of broad-spectrum antibiotics at high doses, in order to cover the most likely causative microorganisms and overcome potential resistance problems.
76
Table 5.2   Clinical pulmonary infection score47
Sign
Point(s)
Temperature, °C
36.5–38.4
0
38.5–38.9
1
< 36 or ≥ 39
2
Blood leukocytes, cells/μL
4000–110000
0
< 4000 or > 11000
1
Band forms ≥ 50%
2
Oxygenation, PaO2/FiO2 (mm Hg)
> 240 or ARDS
0
< 240 and no evidence of ARDS
2
Pulmonary radiography
No infiltrate
0
Diffuse (or patchy) infiltrates
1
Localized infiltrate
2
Tracheal secretions
Absence of tracheal secretions
0
Presence of non-purulent sputum
1
Purulent secretions
2
Culture of tracheal aspirate
Pathogenic bacteria cultured, minimal or no growth
0
Pathogenic bacteria cultured, moderate or more growth
1
Moderate or greater growth of pathogenic bacteria
consistent with that seen on original gram stain
2
Note: Total score of > 6 points suggests ventilator-associated pneumonia
Alternatively, a more conservative policy can be followed at the risk of exposing some ICU patients to delay in therapy or inadequate treatment. There are actually two challenges for intensivists; first, to decide when and which patient should be treated and second to select, which antibiotics to prescribe empirically. For the first challenge, Singh et al proposed a strategy by which all patients with suspected VAP are treated empirically with one antibiotic (e.g. ciprofloxacin).48 After 3 days of therapy, it is withdrawn in all patients with a low likelihood of pneumonia, as assessed by the clinical pulmonary infection score (score < 6). This approach, while treating all patients with suspected VAP has the merit of limiting the administration of unnecessary antibiotic therapy.77
Table 5.3   CDC criteria for VAP3
Radiology
Signs/Symptoms/Laboratory
Two or more serial chest radiographs with at least one of the following New or progressive and persistent infiltrate Consolidation Cavitation Pneumatoceles, in infants ≤ 1 year old
NOTE: In patients without underlying pulmonary or cardiac disease (e.g. respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary edema or chronic obstructive pulmonary disease), one definitive chest radiograph is acceptable.
For any patient, at least one of the following:
  • Fever (>38°C or >100.4°F) with no other recognized cause
  • Leukopenia (<4000 WBC/mm) or leukocytosis (>12,000 WBC/mm)
  • For adults >70 years old, altered mental status with no other recognized cause
and
at least two of the following:
  • New onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements
  • New onset or worsening cough, or dyspnea, or tachypnea
  • Worsening gas exchange (e.g. O2 desaturations (e.g. PaO2/FiO2 < 240), increased oxygen requirements, or increased ventilator demand)
Alternate criteria, for infants <1 year old:
Worsening gas exchange (e.g. O2 desaturations, increased oxygen requirements, or increased ventilator demand)
and
at least three of the following:
  • Temperature instability with no other recognized cause
  • Leukopenia (<4000 WBC/mm) or leukocytosis (>15,000 WBC/mm) and left shift (>10% band forms)
  • New onset of purulent sputum or change in character of sputum, or increased respiratory secretions or increased suctioning requirements
  • Apnea, tachypnea, nasal flaring with retraction of chest wall or grunting
  • Wheezing, rales, or ronchi
  • Cough
  • Bradycardia (<100 beats/min) or tachycardia (>170 beats/min)
Alternate criteria, for child >1 year old or ≤ 12 years old, at least three of the following:78
  • Fever (>38.4°C or >101.1°F) or hypothermia (<36.5°C or <97.7°F) with no other recognized cause
  • Leukopenia (<4000 WBC/mm) or leukocytosis (≥15,000 WBC/mm)
  • New onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements
  • New onset or worsening cough, or dyspnea, apnea, or tachypnea.
  • Rales or bronchial breath sounds.
  • Worsening gas exchange (e.g. O2 desaturations, increased oxygen requirements, or increased ventilator demand)
For the second challenge, the selection of initial appropriate antibiotic therapy appears to be an important determinant of clinical outcome. However, there is a critical question: how should the selection of empiric antibiotic therapy proceed? Although ciprofloxacin is usually effective against Enterobacteriaceae. Haemophilus influenzae and some Staphylococcus spp., it is ineffective against streptococci, P. aeruginosa and Acinetobacter. In a recent study, Fowler et al suggested that Piperacillin-tazobactam could be the most appropriate empiric therapy for suspected VAP. The favorable results associated with piperacillin-tazobactam (possibly in combination with an aminoglycoside), especially in patients with suspected late-onset pneumonia, have been due to its broad spectrum of activity, or to a lower level of resistance emergence and super infection during or after therapy. However, the authors did not demonstrate improved outcome associated with appropriate vs. inappropriate therapy or with combination therapy vs. monotherapy.49 Evidence-based guidelines suggest that Piperacillin-tazobactam may be the most effective single agent for the empiric treatment of VAP.50 Several clinical trial compared Piperacillin-tazobatam with Ceftazidime (both in combination with an aminoglycoside) and found that the former was at least, as effective as the latter.51 According to the guideline of the American Thoracic Society, the initial antibiotic therapy should be based on specific risk factor that influence the spectrum of causative microorganisms in patients with VAP.30 In patients with a high probability of infection due to multiresistant bacteria, such as in late-onset pneumonia, in those who have received prior antibiotic treatment, or in those, who have had prolonged ICU stay before developing VAP, a combination antimicrobial therapy is recommended with antibiotics active against Pseudomonas aeruginosa, Acinetobacter spp. and possibly methicillin-resistant Staphylococcus aureus (MRSA). Some patients may be changed to monotherapy, based on clinical response and the results of patients cultures available at days 2 and 3. Several other approaches have been proposed, mainly based on the use of specific diagnostic techniques, resulting in the treatment of fewer patients with clinically suspected VAP.7 The selection of antibiotic regimen is mainly based on the timing of VAP 79onset in reference to the start of mechanical ventilation, prior antibiotic use during the current hospitalization, results of appropriate diagnostic tests, as well as the most common bacterial pathogens isolated and the antimicrobial resistance pattern of the specific ICU.
Prescribing an initial broad spectrum antibiotic regimen in order to cover all likely pathogens may result in improved clinical outcome. Initial combinational antimicrobial therapy, particularly aimed against antibiotic resistant gram-negative bacteria (e.g. Pseudomonas aeruginosa and Acinetobacter spp.) and MRSA, offers the greatest likehood of providing adequate initial treatment. However, unless supported by appropriate cultures, such broad-spectrum antibiotic regimens should not be administered unnecessarily for a prolonged period in order to avoid the emergence of antibiotic resistant infection. Some authorities suggest that it is necessary to keep unit specific microbiological data to guide the empiric therapy of suspected VAP. The use of unit specific microbiology information can potentially influence antibiotic prescriptions in order to reduce the administration of inadequate or ineffective antimicrobial treatment. Thorough knowledge of ICU antibiotic resistance patterns should be available and apply, when choosing empiric therapy and awaiting culture results. If initial broad spectrum therapy is to be instituted, its de-escalation is also imperative once microbiological and clinical response data become available.52 If empiric therapy is administered by mean of highly effective bacteriocidal agents, the emergence of resistance could theoretically be minimized. The center for disease control and prevention suggested that the optimization of antibiotic use can be enhanced by education about appropriate antibiotic use and by providing data to physicians about the resistant organisms seen in their own ICU, as part of an ongoing surveillance program, aimed to minimize the risk of antibiotic resistance.
 
PREVENTION
Ventilation-associated pneumonia (VAP) has been associated with increased morbidity and mortality and greater costs and hence prevention remains an important goal for all intensivists. Preventive strategies can be divided into four main categories:53
  1. Identification and “Control” of risk factors
  2. Classic infection control measures
  3. Strategies aiming to limit airway colonization
  4. Other methods.
 
Identification and “Control” of Risk Factor
Various risk factors for VAP have been identified. They include old age, severity of injury or illness, length of hospital stay prior to ICU admission, duration of mechanical ventilation or length of ICU stay, supine body position and type of comorbidity. Underlying chronic cardiorespiratory disease, neurological injury and trauma as well as prior administration of corticosteroids and prior inappropriate antibiotic treatment also predispose patients to VAP.54 Identification 80of potentially modifiable risk factors for VAP at the institutional level and development of strategies to modify or prevent the occurrence of these risk factors is a significant preventive measure. Although risk factors for acquiring VAP have been well-defined, diagnosis of VAP remains controversial. As a result, patients are often treated empirically with antibiotic regimens based on suspected pathogens.
 
Classic Infection Control Measures
Prevention of VAP relies on basic infection control practices. General infection control measures remain the cornerstone of infection prevention in intensive care units. Furthermore, handwashing remains the cornerstone of ICU—acquired infection prevention and it is simple but very effective preventive measure. In addition, infection control programs employing combinations of interventions aimed at preventing both colonization of the aerodigestive tract with pathogenic bacteria and aspiration have been shown to be successful and cost-effective.53
 
Strategies Limiting Airway Colonization
Colonization of the oropharynx with pathogens and ongoing aspiration seem to be required for the development of VAP. Oropharyngeal colonization is pivotal in the pathogenesis of VAP, while gastric and intestinal colonization appear to be less important than previously believed. Oropharyngeal colonization with several pathogens and microaspiration of colonized oropharyngeal secretions is a major cause of early-onset VAP. Prolonged mechanical ventilation (>5 days) and administration of broad-spectrum antibiotics increase the risk for late-onset VAP, which is more likely to be related to gram-negative bacteria. Realization that the pathogenesis of VAP requires aspiration of contaminated secretions, originating from the aerodigestive tract and ventilator circuit, helps highlight the role of cross-infection and the importance of standard infection control procedures. Many specific strategies interfering with colonization have been studied. Topical non-absorable antibiotics, either of the whole digestive tract or the oropharynx have been used to decrease the incidence of VAP, but there is risk of selecting antibiotic-resistant bacteria. For these reasons, the widespread use of these strategies is limited.53
The strategies that have been found to be of use are:
  • Subglottic secretion drainage
  • Pharmacologic strategies aiming to reduce colonization of the aerodigestive tract with pathogenic bacteria using aerosolized antibiotics53
  • Chest physiotherapy.
 
Other Preventive Measures
  • Closed suctioning system
  • Strategies attempting to decrease the occurrence of aspiration: Positioning of patients in a semirecumbent position, patients receiving ventilation should be positioned at a 45 head-up angle to decrease the risk of the aspiration of gastric contents.81
  • Kinetic beds
  • Changing circuits and humidifiers
  • Selective digestive decontamination (SDD)
  • Noninvasive ventilation.
 
MORBIDITY AND COST
With respect to morbidity measures, the prolonged hospital stay, as a direct consequence of VAP has been estimated in several studies.55-58 In one study, VAP prolonged the duration of MV from 10 to 32 days.59 In another, the median length of stay in the ICU for the patients, who developed VAP was 21 days versus a median of 15 days for paired control subjects.60 Reported mean durations of MV, ICU stay and hospital stay were, respectively, 12.0, 20.5 and 43.0 days for trauma patients with pneumonia compared with 8.0, 15.0 and 34.0 days for their matched control subjects.61 Analyzing the same variables, others found, 27.3, 32.9 and 52.5 days for case patients versus 19.7, 24.5 and 43.2 days respectively for patients without VAP.62 Similarly, it was demonstrated that the mean hospital stay after ICU admission was longer for surgical ICU patients (30.0 versus 22.3 days for control subjects) and medical and respiratory ICU patients, who developed nosocomial pneumonia (40.9 versus 23.1 days for control subjects).58 Thus, summarizing available data, VAP likely to extend the ICU stay by at least 4 days. These prolonged hospitalizations underscore considerable financial burden imposed by the development of VAP. However, a precise and universal evaluation of such overcosts is difficult. The average excess cost of nosocomial pneumonia was estimated to be US$1,255 in 1982.63 In 1985, the average extracost was US$2,863. More recently, the extrahospital charges attributed to nosocomial pneumonia occurring in trauma patients were evaluated to be US$ 40,000 in USA.64
 
MORTALITY
In ICU ventilated patients with VAP appear to have a 2 to 10 fold higher risk of death compared with patients without pneumonia. In 1974, fatality rates of 50% for ICU patients with pneumonia versus 4% for patients without pneumonia were reported.65 The results of several studies conducted between 1986 and 2001 have confirmed that observation: Despite variations among studies that partly reflect the populations considered, overall mortality rates for patients with or without VAP varied from 19 to 33% to 25 to 44% respectively in various studies.6,7,66,67 These rates correspond to increased risk ratios of mortality for VAP patients from 1.7 to 2.5 in these studies.
European Prevalence of Infection in Intensive Care (EPIC) Study's stepwise logistic regression analyses demonstrated that ICU-acquired pneumonia increased the risk of death with an odds ratio of 1.91 (95% CI, 1.6 to 2.3), independently of clinical sepsis and bloodstream infection.68 Another study based on 1,978 patients in the ICU, including 1,118 patients receiving MV, demonstrated that, in addition to the severity of illness, the presence of dysfunctional organ(s) and nosocomial bacteremia and nosocomial pneumonia independently contributed to the deaths 82of ventilated patients.36 Using the Cox model in a series of 387 patients, it was demonstrated that patients with clinically suspected pneumonia had an increased risk of mortality.
 
SUMMARY AND CONCLUSION
Ventilator associated pneumonia is one of the most important causes of nosocomial infections in pediatric intensive care units. VAP is an inflammation of the lung parenchyma caused by infectious agents not present or in incubation at the initiation of mechanical ventilation. It is early onset when the infection develops less than 4 days and late onset when develops 4 days after mechanical ventilation. Incidence in children, estimated by the CDC's National Nosocomial Infections Surveillance study is 20%. Most of the cases of VAP are caused by aerobic gram-negative bacteria, predominant being P. aeruginosa and Acinetobacter spp. Risk factors include immunosuppression, acute respiratory distress syndrome, level of consciousness, number of intubations and medications like sedatives. The majority of these infections appear to result from aspiration of potential pathogens that have colonized the mucosal surfaces of the oropharyngeal airways. The diagnosis of VAP is usually based on clinical, microbiologic and radiologic criteria. Early antibiotic therapy is important in the management of patients with clinically suspected VAP. Initial broad spectrum therapy is to be instituted and de-escalated once microbiological and clinical response data is available. Some of the measures beneficial in prevention of VAP are changes of ventilator circuits, use of closed endotracheal suction systems, weekly changes of heat and moisture exchangers, semirecumbent position and kinetic beds. Ventilated patients with VAP appear to have 2 to 10 fold higher risk of death compared with patients without pneumonia.
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Acute Bronchiolitis6

Suraj Gupte, Sahil Pandita, Mary Stanton
 
INTRODUCTION
Acute respiratory infections, especially of viral origin, are the most common ailment in infants and children both in the prosperous and resource-limited world. Though most such infections pertain to the upper airway, a proportion of these children suffer from lower respiratory tract infections (LRTIs) involving lung parenchyma usually from an infecting agent, leading to respiratory distress. These may well be severe enough and life-threatening if early treatment is not instituted.
Amongst the LRTIs, in infants and young children, bronchiolitis is by and large the most common. During winter in particular, it is the most frequent cause of hospitalization of infants.1
 
DEFINITION
Bronchiolitis is defined as a condition characterized by inflammation of bronchioles (often along with bronchi), resulting in nasal discharge, mild fever, wheezy cough and dyspnea, usually in infants and from a viral infection.1-3 The severity varies from mild to severe. The cases with severe illness are vulnerable to significant morbidity and mortality.1,4
Coexistence of such conditions as cardiopulmonary disease (congenital heart diseases, chronic lung disease such as asthma or cystic fibrosis), or immunodeficiency is accompanied by enhanced risk of severe and prolonged bronchiolitis which, if not timely treated, may prove fatal.
 
DISEASE BURDEN
Clinical burden of bronchiolitis is huge though exact figures, in resource-limited countries in particular, are not available in view of the frequent tagging of the condition with pneumonia and mild disease remaining unrecorded. In USA, bronchiolitis seemingly is responsible for hospitalization of 75,000 to 125,000 infants every year.188
 
EPIDEMIOLOGY
Bronchiolitis, occurring in both epidemic and sporadic forms, develops following spread of infection by direct contact with respiratory secretions.
Globally, most cases of bronchiolitis occur during winter followed by autumn and spring in temperate climates and rainy season in tropical climates.5 Sporadic cases continue to occur throughout the year as is the experience in India.
It occurs primarily in the first 2 years of life with peak incidence around 6 months of age.
 
RISK FACTORS
Bronchiolitis occurs more frequently in:
  • Boys than in girls
  • Artificially-fed infants
  • Poor socioeconomic status
  • Overcrowded environments
  • Infants of mothers who smoked during pregnancy
  • Infants of relatively younger mothers.
 
ETIOLOGY
Most often, bronchiolitis is the result of a viral infection, usually by respiratory syncytial virus (RSV). The viruses incriminated include:
  • Respiratory syncytial virus
  • Adenoviruses
  • Influenza viruses (A and B)
  • Parainfluenza viruses
  • Mycoplasma
  • Herpes virus
  • Enteroviruses.
Respiratory syncytial virus, the most common causative virus, has been isolated from over 50% of children, younger than 2 years of age, hospitalized with bronchiolitis.
Emerging viruses like rhinovirus,7 human bocavirus or human metapneumovirus a new paramyxovirus) may well be the primary cause or they may coexist along with RSV as the cause of bronchiolitis. There is evidence that RSV–metapneumovirus coinfection may be more severe than monoinfection.2
Certain bacteria (M. pneumoniae, Pneumococcus, Streptococcus, H. influenzae, H. pertussis) and even allergy have been incriminated though convincing evidence in support of this observation is yet to be available.
 
PATHOLOGY AND PATHOPHYSIOLOGY
Bronchiolitis is characterized by:
  • Acute inflammation, edema, and necrosis of epithelial cells lining the bronchioles89
  • Increased mucus production
  • Bronchospasm.
All of them contribute to obstruction of the small airways.
As a rule, smaller airways are involved. Infection of bronchiolar respiratory and ciliated epithelial cells produces increased mucus secretion, cell death, and sloughing, followed by a peribronchiolar lymphocytic infiltrate and submucosal edema. The combination of debris and edema produces critical narrowing and obstruction of small airways.
Hypoxia results from decreased ventilation of portions of the lung, the so-called “ventilation-perfusion mismatch”. During the expiratory phase of respiration, further dynamic narrowing of the airways produces disproportionate airflow decrease and resultant air trapping. Work of breathing is increased due to increased end-expiratory lung volume and decreased lung compliance. Once the obstruction becomes severe and respiratory efforts get exhausted, hypercapnia occurs.
Notably, recovery of pulmonary epithelial cells occurs after 3 to 4 days. The cilia, however, take a couple of weeks or more to regenerate. Macrophages clear the debris.
Duration of illness is approximately 2 weeks. Nearly 20% of patients may have symptoms lasting longer than 3 weeks.
 
CLINICAL FEATURES
Invariably, clinical manifestations of bronchiolitis follow exposure to a family member suffering from a respiratory infection.
About 4 to 6 days after the initial onset of symptoms of a URI with sneezing, clear rhinorrhea, slight fever and diminished appetite, the infant develops dyspnea (rapid, shallow breathing), wheezy cough, irritability, feeding difficulty and prostration. Cough, if present, is usually mild. Fever may be mild to moderate. If dyspnea is marked, air hunger, flaring of alae nasi, chest retractions and cyanosis may be present. Dehydration and respiratory acidosis may complicate the clinical picture.
Initially, apnea rather than wheezing may be encountered in:
  • Infants < 2 months, and
  • Former premature infants.
Chest signs include:
  • Tachypnea
  • Intercostals retractions (subcostal and sprasternal)
  • Hyperresonant percussion note from emphysema
  • Diminished breath sounds (very poorly audible breath sounds point to a nearly complete bronchiolar obstruction suggestive of a very severe disease) and
  • Widespread wheeze with prolonged expiratory phase and fine crepitations.
Liver and spleen may become palpable from visceroptosis secondary to hyperinflation of the lungs.90
Fig. 6.1: Acute bronchiolitis. The infant was hospitalized for slight fever, cough, shortness of breath, wheeze and feeding difficulty. In addition to the intercostal retractions, the infant was quite tachypneic but did not look that sick. Note that the subject with pneumonia usually looks sick and toxic
 
DIFFERENTIAL DIAGNOSIS
Brochiolitis needs to be differentiated from:
  • Asthma: Usually, frequent exacerbations are its important feature
  • Bronchopneumonia: Wheeze, if present, only mild; crepitations predominant. Child looks sick
  • Foreign body in the airway: History of inhalation, localized wheeze, signs of collapse/emphysema
  • Congestive cardiac failure
  • Gastroesophageal reflux
  • Congenital anomalies, such as a vascular ring or congenital heart disease.
 
APPROACH TO DIAGNOSIS
A good history and physical examination are most important for suspecting bronchiolitis in a given child.
 
History
Manifestations take off as a viral upper respiratory tract infection with slight rhinorrhea, cough, and low-grade fever. In a proportions of these subjects URI may descend down to involve the lower airway, manifesting as paroxysmal cough, dyspnea, wheezing, cyanosis, vomiting and irritability in a day or two. 91
 
Physical Examination
The positive findings include tachypnea, tachycardia, fever (usually in the range of 38.5–39°C), cyanosis, otitis media, nasal flaring, intercostal retractions. Auscultation shows diffuse expiratory wheezing, inspiratory crackles, apnea (especially in infants younger than 6 weeks), palpable liver and spleen (visceroptosis secondary to hyperinflation of the lungs and consequent depression of the diaphragm). Flow chart 6.1 outlines the sequence of events in the development of bronchiolitis.
In order to assess the severity of the disease, Distress Assessment Instrument (Table 6.1), among other clinical scoring systems, is available.4
This system has undergone validation and reliability measurements, showing good inter-observer reliability.
 
Investigations
 
X-ray of Chest
Though the diagnosis is usually clinical, it is advisable to have a chest X-ray to exclude bronchopneumonia in which diffuse patchy involvement of the lung(s) is conspicuous. The bronchiolitis X-ray, on the other hand, shows hyperinflated lungs with low lying diaphragm and widened intercostals spaces, patchy infiltrates, focal atelectasis, reticular nodular pattern and fullness of the perihilar region.
Flow chart 6.1: Algorithmic representation of sequence of events in a case of bronchiolitis4
92It needs to be stressed that all chest X-rays may show is nonspecific change(s) rather than classical findings. Hence, the importance of clinical diagnosis remains supreme. Table 6.2 shows the X-ray findings in hundreds of brochiolitis cases encountered in two studies-1993 to 2002 in North India and 2007 to 2012 in South India.
Fig. 6.2: X-ray of chest in brochiolitis. Note evidence of hyperinflation (low lying diaphragm, widening of intercostal spaces), patches of atelectasis and fullness of perihilar region on both sides
Table 6.1   Respiratory distress assessment instrument (RDAI)
Points
Maximum
points
0
1
2
3
4
Wheezing
Expiration
None
End
½
¾
All
4
Inspiration
None
Part
All
2
Location
None
Segmental:
>2 of 4 lung
fields
Diffuse
>3 of 4
lung fields
2
Retractions
Supraclavicular
None
Mild
Moderate
Marked
3
Intercostal
None
Mild
Moderate
Marked
3
Subcostal
None
Mild
Moderate
Marked
3
Note : A score of 7 to 15 indicates mild , 16 to 30 moderate, and over 30 severe bronchiolitis
93
Table 6.2   Frequency of radiologic findings in the chest X-ray in two series5,6
X-ray finding
North Indian Study (n=210)5
South Indian study (n=456)6
Hyperinflation/emphysema
60%
75%
Patchy infiltrates/focal atelectasis
42%
50%
Reticular nodular pattern
29%
25%
Low lying diaphragm
56%
60%
Perihilar fullness
20%
42%
Widening of intercostal spaces
82%
78%
Note: Only 20 to 27% films in the two series, respectively, showed more than three findings
 
Oxygen Saturation
Pulse oximetry is most useful in measuring the oxygen saturation and thereby assessing the severity of bronchiolitis.
 
Serum Electrolytes
In case of coexisting dehydration and suspected dyselectrolytemia, it is good to have serum electrolytes.
 
Arterial Blood Gas
Arterial blood gas (ABG) is useful in detecting hypoxia and hypercapnias in severe bronchiolitis warranting mechanical ventilation.
 
Viral Testing
Viral testing by polymerase chain reaction (PCR), rapid immunofluorescence or culture is of value only for epidemiologic purpose or in difficult cases.
 
Treatment
No doubt, cases suffering from mild-moderate bronchiolitis can be managed in the outpatient. However, severe bronchiolitis is an emergency warranting hospitalization. Saturation on pulse-oximetry <92% is a definitive indication for hospitalization (Box 6.1).
The mainstay of management is mostly symptomatic and supportive. The measures include:
  • Humidified oxygen inhalation through face mask or head box
  • Atmosphere well saturated with water vapors
  • IV fluids to combat dehydration
  • Optimal nutrition
  • Maintenance of patent airway (clearing nasal passages, suctioning, positioning)
  • Postural drainage.94
 
Humidified Oxygen
Moderately ill infants often require supplemental humidified oxygen. It is said to be the drug of choice. Its use is indicated when oxygen saturation is < 94% as such or in combination with clinically significant respiratory distress.
 
IV Fluids
These are needed to maintain hydration in moderate to severe respiratory distress.
 
Bronchodilators
Bronchodilators are better avoided since rather than doing any good, they may increase the cardiac output and restlessness. If opted for, preferred drug is salbutamol or racemic or levo epinephrine by nebulization.
Salbutamol (albuterol) is a selective beta-2 agonists that acts by relaxing the pulmonary smooth muscle and, thereby, decreasing airway resistance.
Other purative mechanisms are suppression of inflammatory mediators from mast cells, decreased microvascular permeability, and enhanced mucociliary function. Since infants have a paucity of smooth muscle, there is less likely to be benefit from albuterol inhalation.
 
Nebulized Epinephrine
It has been shown to achieve a short-term improvement in mild cases of bronchiolitis in the outpatient but not in severe cases admitted to the hospital. The beneficial effect of nebulized epinephrine appears to be secondary to its vasoconstriction property that reduces the airway edema.9
 
Steroids
In the past, the issue of steroid therapy in bronchiolitis remained quite controversial. Now the consensus is that steroids have no role and should no longer be prescribed in bronchiolitis as a routine.1,8 In subjects with severe disease (on artificial ventilation), steroids may be given a chance for a possible beneficial outcome.1095
 
Hypertonic Saline Nebulization
Hypertonic saline (3%) nebulization has been shown to be beneficial in bronchiolitis by reducing the length of hospital stay and improving the clinical severity score.11-13
 
Antimicrobial Therapy
Since exact etiologic diagnosis is practically impossible in clinical practice, an antibiotic may be given on the presumption of a causative or superimposed bacterial infection. Else, antibiotic therapy has no role.
 
Antiviral Drug
Role of antiviral therapy in bronchiolitis remains limited.
Severe bronchiolitis resulting from RSV, especially in immunocompromised subjects, CF, CLD, CHD and extreme preterm/VLBW infants may be treated with ribavirin available as sterilized lympholyzed powder to be reconstituted for aerosol therapy (Box 6.2). Treatment is carried out using a small particle aerosol generator (SPAG) for 12 to 18 h/day for at least 3 days but not more than 7 days. A careful and constant monitoring of both patient and equipment is important, especially if the patient is in need of assisted ventilation.
Therapy with ribavirin is expensive, one 6 g vial costing approximately US$ 250 (Indian ₹ 13000). The drug is teratogenic and expensive.
96Respiratory syncytial virus is the most common cause of bronchiolitis. However, specific antiviral therapy of symptomatic infants has been of limited value. Aerosolized ribavirin treatment of mild-to-moderately ill infants with laboratory-confirmed RSV bronchiolitis does not prevent the need for mechanical ventilation or reduce the length of hospital stay.
The American Academy of Pediatrics does not recommend the routine use of ribavirin but suggests that ribavirin might be administered based on specific clinical circumstances and physician experience. Patients who are at risk of persistent viral replication might benefit from ribavirin therapy; some experts recommend that ribavirin be considered when caring for severely immunocompromised patients who develop laboratory confirmed RSV-associated bronchiolitis, such as children undergoing bone marrow transplantation. Experts debate the role of ribavirin therapy for severely ill infants who require mechanical ventilation. In a single placebo-controlled study, investigators found that infants treated with aerosolized ribavirin had a shorter duration of ventilation and of hospital stay.
 
Experimental Therapies
Therapies such as interferon, surfactant, vitamin A, mist therapy, or anticholinergics remain to convincingly establish their role in bronchiolitis treatment.
All in all, the key take-home message is not to routinely prescribe bronchodilators, antibiotics or steroids in bronchiolitis.
 
PROGNOSIS AND OUTCOME
An overwhelming proportion of infants with bronchiolitis recover fully though they may continue to have cough for several days ahead.
The case fatality rate for bronchiolitis is highest among young infants between 1 and 3 months of age. Former preterm/very low birth weight infants have a bronchiolitis mortality rate of 30 per 1000 live births.12
The presence of underlying medical conditions, say congenital heart disease or chronic lung disease, is too is an important predictor of poor outcome. In these high-risk children, the case fatality rate may be as high as 5%.
Recurrence of bronchiolitis is unusual. In fact, in the event of recurrences, the probability of asthma should be seriously considered.
 
COMPLICATIONS
 
Short-term
  • Rapidly progressive exhaustion, anoxia and death
  • Dehydration, electrolyte imbalance and acid-base imbalance, especially respiratory acidosis
  • Congestive cardiac failure (CCF)
  • Bacterial superinfection: Bronchopneumonia, acute otitis media (AOM).97
 
Long-term
  • Bronchiolitis obliterans: Obliteration of bronchioles and even brochi by nodular masses consisting of granulation and fibrotic tissue. Over and above insult to the small airways by viruses (RSV, influenza, parainfluenza, Mycoplasma and bacteria (H. pertussis), it may be seen in such inflammatory conditions as juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE), scleroderma, Stevens-Johnson syndrome (SJS) and inhalation of toxic fumes (NO2, NH3) and following lung and bone marrow transplantation. In a proportion of cases of bronchiolitis obliterans, bronchiectasis may be associated.
  • Hyperlucent lung syndrome (Swyer-James syndrome, Macleod syndrome): Diminished perfusion and vascular marking of the affected lung, usually following injury to the lung. The most common physical finding is hyperresonance and small lung with mediastinal shift to the affected side.
 
PREVENTION
The following measures may contribute to safeguarding from RSV infection, thereby providing some protection against bronchiolitis:1,2,13-16
  • Meticulous hand and aerosol hygiene as an integral part of childcare
  • Breastfeeding promotion
  • Discouragement for parental smoking
  • Hyperimmune RSV intravenous hyperimmune globulins in high-risk children before onset of RSV season
  • Palivizumab (IM monoclonalk antibody), especially in infants with cardiopulmonary disease or immunocompromised status, and very preterm infants.
 
SUMMARY AND CONCLUSION
Bronchiolitis is a common acute respiratory illness of infants and toddlers characterized by necrotizing inflammation of the lower airway, primarily bronchioles. Respiratory snycytial virus is the causative pathogen in most of the cases. Clinical manifestations include cough, mild fever, dyspnea, tachypnea, wheezing, chest retractions, etc. Feeding difficulties are common. Diagnosis is usually clinical but can be confirmed by antigen testing of nasal or nasopharyngeal aspirates, viral immunofluorescence or polymerase chain reaction. Therapy is principally supportive, revolving around humidified oxygen, maintenance of hydrations and fluid and electrolyte balance and provision of optimal nutrition. Bronchodilators, steroids and antiviral drugs (ribavarin) are not recommended routinely but may be considered in select cases. Hypertonic saline (3%) nebulization may be beneficial by reducing the length of hospital stay and improving the clinical severity score. Experience has shown that such measures are designed to safeguard from RSV infection may provide some protection against bronchiolitis. 98
References
  1. Egan M. Cystic fibrosis. In: Kliegman RM, Santon BF, St Geme JW, Shor NF, Behrman RE (Eds): Nelson Textbook of Pediatrics, 19th edn. Philadelphia: Saunders/Elsevier  2012:1481-1497.
  1. Singh UK, Prasad R, Ram S. Acute bronchiolitis. In: Gupte S, Gupte SB (Eds). Recent Advances in Pediatrics (Special Vol 21: Neonatal and Pediatric Intensive Care). New Delhi: Jaypee  2011:385–395.
  1. Singh D, Gupte S. Pediatric pulmonology. In: Gupte S (Ed). The Short Textbook of Pediatrics, 11th edn. New Delhi: Jaypee  2009:321–351.
  1. Kalappanaver NK, Sanjay S. Bronchiolitis. In: Gupte S, Gupte N (Eds). Pediatric Infectious Diseases. New Delhi: Macmillan  2011:393–407.
  1. Gupte S. Pal M. Acute bronchiolitis: A neglected entity. Proceedings, 2nd Asian Conference Respiratory Diseases, Singapore 2002. Abstract No. ACRD/Ped/09.
  1. Gupte S. Acute bronchiolitis and pneumonia: Five-year experience in South India. S Afr Bull Trop Subtrop Dis 2012;12:67-
  1. Van Woensel JBM, van Aalderen WMC, Kimpen JLL. Viral lower respiratory tract infection in infants and young children. BMJ 2003;327:36–40.
  1. Wong JW, Moon S, Beardsmore C, et al. No objective benefit from steroids inhaled via a spacer in infants recovering from bronchiolitis. Eur Respir J 2000;15:388–394.
  1. Hartling L, Wiebe N, Russel K, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev 2004:CD003123.
  1. Code A. Brownlee KG, Conway SP, et al. Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Arch Dis Child 2000;82:126–130.
  1. Mandelberg A, TRej G, Witlzing M, et al. Nebulized 3% hypertonic saline solution in hospitalized infants with viral bronchiolitis. Chest 2003;123:481–487.
  1. Tal G, Cesar K, Oron A, et al. Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2-year experience. Isr Med Assoc J 2006;8:169–173.
  1. Gupta N, Puliyel A, Manchanda A, Puliyel J. Nebulized hypertonic saline vs epinephrine for bronchiolitis: Proof of concept study of cumulative sum (CUSUM) analysis. Indian Pediatr 2012;49:543–547.
  1. Holman RC, Shay DK, Curns AT, et al. Risk factors for bronchiolitis-associated deaths among infants in the United States. Pediatr Infect Dis J 2003;22:483–490.
  1. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:543–546.
  1. Grimaldi M, Gouyon B, Michaut F, et al. Severe respiratory syncytial virus bronchiolitis: epidemiologic variations associated with the initiation of palivizumab in severely premature infants with bronchopulmonary dysplasia. Pediatr Infect Dis J 2004;23:1081–1085.

Status Asthmaticus7

Zahid-ul-Kareem, Anjul Dayal, VSV Prasad
 
INTRODUCTION
Bronchial asthma has a wide clinical spectrum ranging from a mild, intermittent disease to one that is severe, persistent and difficult to treat, which in some instances can also be fatal.1-4 More than 100,000 deaths are estimated yearly throughout the world.1-2 Patients at greater risk for fatal asthma attacks are mainly those with severe, unstable disease, although death can occur to anyone, if the asthma attack is intense enough.2-4 Most deaths from asthma are preventable. Morbidity in asthma is a considerable problem and is mainly related to the more severe phenotypes of the disease.
Status asthmaticus is a condition of progressively worsening bronchospasm and respiratory dysfunction due to asthma, which is unresponsive to standard conventional therapy and may progress to respiratory failure and the need for mechanical ventilation.5 In some patients who present with asthmatic crisis, repeated peak expiratory flow (PEF) measurements, when available may document subacute worsening of expiratory flow over several days before the appearance of severe symptoms, the so-called ‘slow onset asthma exacerbation’. In others, however, lung function may deteriorate severely in less than 1 hour, the so-called ‘sudden onset asthma exacerbation’.6,7 Slow onset asthma exacerbations are mainly related to faults in management (inadequate treatment, low compliance, inappropriate control, coexisting psychological factors) that should be investigated and corrected in every patient in advance. On the other hand, massive exposure to common allergens are mainly considered the triggers in sudden asthma exacerbations.
 
PATIENTS AT RISK OF DEVELOPING NEAR-FATAL OR FATAL ASTHMA8
A combination of severe asthma is recognized by one or more of:
  • Previous near-fatal asthma, e.g. previous ventilation or respiratory acidosis
  • Previous admission for asthma, especially if in the last year
  • Requiring three or more classes of asthma medication
  • Heavy use of β2-agonist101
  • Repeated attendances at emergency department (ED) for asthma care especially, if in the last year
  • “Brittle” asthma.
Adverse behavioral or psychosocial features recognized by one or more of:
  • Noncompliance with treatment or monitoring
  • Failure to attend appointments
  • Fewer general practitioner (GP) contacts
  • Frequent home visits
  • Self-discharge from hospital
  • Psychosis, depression, other psychiatric illness or deliberate self-harm
  • Current or recent major tranquillizer use
  • Denial, alcohol or drug abuse, obesity, learning difficulties, employment problems, income problems, social isolation, childhood abuse, severe domestic, marital or legal stress.
 
PATHOPHYSIOLOGY
Asthma is an inflammatory disease of the airways that appears to involve a broad range of cellular and cytokine-mediated mechanisms of tissue injury.1 The most consistently linked regions have been on chromosomes 2q, 5q, 6p, 12q and 13q.9 The cascade of inflammation begins with degranulation of mast cells, usually in response to allergen exposure. Peripheral airways occlusion forms the pathologic basis of the gas exchange abnormalities observed in acute, severe asthma. The differentiation between early and delayed bronchospasm is important because early bronchospasm may be more sensitive to bronchodilating agents, while late bronchospasm is refractory to bronchodilation and more sensitive to anti-inflammatory therapy. Widespread occlusion of the airways lead to the development of extensive areas of alveolar units in which ventilation (V) is severely reduced, but perfusion (Q) is maintained (i.e. areas with very low V/Q ratios, frequently lower than 0.1).10 The autonomic nervous system also contributes to bronchoconstriction.
 
PULMONARY MECHANICS AND GAS EXCHANGE ABNORMALITIES
 
Dynamic Hyperinflation
In asthmatic crisis, remarkably high volumes of functional residual capacity (FRC), total lung capacity and residual volume can be observed. Lung hyperinflation that develops as a result of acute airflow obstruction, however, can also be beneficial since it improves gas exchange. The increase in lung volume tends to increase airway caliber and consequently reduce the resistive work of breathing. This is accomplished, however, at the expense of increased mechanical load and elastic work of breathing. Inspiration, therefore, begins at a volume in which the respiratory system exhibits a positive recoil pressure. This pressure is called intrinsic positive-end expiratory pressure (PEEPi) or auto-PEEP. This 102phenomenon is called dynamic hyperinflation. Dynamic hyperinflation shifts tidal breathing to a less compliant part of the respiratory system pressure–volume curve leading to an increased pressure–volume work of breathing. Second, it flattens the diaphragm and reduces the generation of force. Third, dynamic hyperinflation increases dead space, thus increasing the minute volume required to maintain adequate ventilation. Conceivably, asthma increases all the three components of respiratory system load, namely resistance, elastance and minute volume. Finally, in acute severe asthma, the diaphragmatic blood flow may also be reduced. Under these overwhelming conditions, in the case of persistence of the severe asthma attack, ventilatory muscles cannot sustain adequate tidal volumes and respiratory failure ensues.
 
EFFECTS OF ASTHMA ON THE CARDIOVASCULAR SYSTEM
In expiration, because of the effects of dynamic hyperinflation, the systemic venous return decreases significantly and again rapidly increases in the next respiratory phase. Rapid right ventricular filling in inspiration, by shifting the interventricular septum toward the left ventricle, may lead to left ventricular diastolic dysfunction and incomplete filling. The large negative intrathoracic pressure generated during inspiration increases left ventricular afterload. Pulmonary artery pressure may also be increased due to lung hyperinflation, thereby resulting in increased right ventricular afterload. These events in acute, severe asthma may lead to pulsus paradoxus. In advanced stages, when ventilatory muscle fatigue ensues, pulsus paradoxus will decrease or disappear as force generation declines. Such status harbingers impeding respiratory arrest.
 
CLINICAL AND LABORATORY ASSESSMENT
Patients with acute, severe asthma appear seriously dyspneic at rest, are unable to talk with sentences or phrases, are agitated and sit upright.1 Drowsiness or confusion are always ominous signs and denote imminent respiratory arrest. Vital signs in acute, severe asthma are: tachycardia, tachypnea, wheezing throughout both the inspiration and the expiration; use of accessory respiratory muscles; evidence of suprasternal retractions and pulsus paradoxus. Accurate measurement of saturation of peripheral oxygen (SPO2) is mandatory.
A Becker score > 4 is considered moderate status asthmaticus. Pulsus paradoxus can be a valuable sign of asthma severity, but its detection should not delay prompt treatment. Paradoxical thoracoabdominal movement and the absence of pulsus paradoxus suggest ventilatory muscle fatigue and together with the disappearance of wheeze and the transition from tachycardia to bradycardia, represent signs of imminent respiratory arrest. The usual cardiac rhythm in acute, severe asthma is sinus tachycardia, although supraventricular arrhythmias are not uncommon.
 
Blood Gas Analysis
As the severity of airflow obstruction increases, arterial partial pressure of carbon dioxide (PaCO2) first normalizes and subsequently increases. The transition from 103hypocapnia to normocapnia is an important sign of severe clinical deterioration and the appearance of hypercapnia probably indicates the need for mechanical ventilation.5 Hypercapnia per se is not an indication for intubation and such patients may respond successfully to the application of aggressive medical therapy.1 Metabolic acidosis denotes impeding respiratory arrest. Lactic acidosis is often present in status asthmaticus and usually reflects a combination of dehydration and excess lactate production from overuse of the respiratory musculature.
Excessive use of β2-agonists may decrease serum levels of potassium, magnesium and phosphate.
The presence of leukocytosis on complete blood count may suggest respiratory infection as the source of wheezing, though it can also represent a stress response to steroid administration or a response to β2-agonist therapy.
 
Chest Radiography
Chest radiographs in the majority of patients with an acute asthma will be normal,9 but chest radiographic examination is a valuable tool to exclude complications. Chest radiographic examination, however, should never be permitted to delay initiation of treatment.
 
MANAGEMENT
Early home management of asthma exacerbations is of paramount importance, since it avoids treatment delay and prevents clinical deterioration.
Clinical parameters that suggest the need for pediatric intensive care unit (PICU) admission are ill defined; however, children with past PICU admissions or a history of rapid clinical deterioration, children with severe distress (inspiratory and expiratory wheezing, limited air entry, air hunger and inability to phonate) despite initial bronchodilator therapy or those with a Becker asthma score > 7 should be considered for PICU admission.
Emergency-department management of a child with severe status asthmaticus should focus upon the assessment of impending respiratory failure, followed by therapeutic interventions, including, but not limited to, obtaining intravenous (IV) access, providing supplemental O2 and continuous inhaled β2-agonists and administering IV steroids.
 
Fluids
Critically ill children with status asthmaticus are often dehydrated as a result of decreased oral intake prior to admission and increased insensible fluid losses from increased minute ventilation. Providing appropriate fluid resuscitation and ongoing maintenance fluid is essential; however, overhydration should be avoided because these children are at risk for pulmonary edema due to microvascular permeability, increased left ventricular afterload and alveolar fluid migration associated with the inflammatory lung process in asthma.104
 
Oxygen
Treatment with inhaled β2-agonists may induce generalized pulmonary vasodilatation and as a result, exacerbate V/Q mismatch and worsen hypoxemia. Oxygen treatment is recommended for most patients, who present with severe exacerbation in order to maintain oxygen saturation > 90%.
 
Corticosteroid Treatment
Systemic corticosteroids are recommended for most patients in the emergency department, especially those with moderate-to-severe exacerbation and patients, who do not respond completely to initial β2-agonist therapy.1,11,12 Corticosteroids in the emergency department may also help to reduce mortality from asthma.3 Since benefits from corticosteroid treatment are not usually seen before 6 to 12 hours, early administration is necessary.
Methylprednisolone is the most common agent used in the PICU and is preferred because of its limited mineralocorticoid effects. The initial dose is 2 mg/kg, followed by 0.5 to 1 mg/kg/dose administered IV every 6 hours. Treatment duration depends upon the severity of illness, but generally continues until the asthma exacerbation is resolved. In addition to common and well-known side effects of corticosteroid administration (hyperglycemia, hypertension, hypokalemia, psychosis, susceptibility to infections), myopathy should be considered seriously in the intubated and mechanically ventilated patient.
 
Inhaled β2-agonists
In the treatment of status asthmaticus, inhaled β2-agonists are a bridge to support ventilation and oxygenation until the anti-inflammatory effects of corticosteroids take effect. Continuous rather than repetitive nebulization of short-acting β2-agonists is the most effective means of reversing airflow obstruction. Salbutamol (albuterol) is the most frequently used agent. The usual dose of continuous albuterol nebulization is 0.15 to 0.5 mg/kg/h or 10 to 20 mg/h. Hypokalemia and hyperglycemia are the most common metabolic derangements associated with albuterol use. Periodic serum potassium levels should be monitored during inhaled β2-agonist treatment.
 
Intravenous and Subcutaneous β2-agonists
Intravenous and subcutaneous β2-agonists are most beneficial in children with severe status asthmaticus and limited respiratory air flow, when distribution of inhaled medications may be significantly reduced. Subcutaneous administration of β2-agonists is primarily used for children with no IV access subcutaneous dosing for terbutaline is 0.01 mg/kg/dose, with a maximum dose of 0.3 mg. The dose may be repeated every 15 to 20 minutes for up to three doses. IV terbutaline therapy starts with a loading dose of 10 mcg/kg over 10 minutes, followed by continuous infusion at 0.1 to 10 mcg/kg/min.105
 
Methylxanthines
Methylxanthines, such as theophylline, in the emergency department are of debated efficacy and not generally recommended.1 Theophylline therapy may be helpful in those critically ill children who are not responsive to steroids, inhaled and IV β2-agonists and O2. Its nonbronchodilating properties, including its action on the diaphragm and its anti-inflammatory effects, may warrant the use of theophylline in the emergency care of acute, severe asthma.13
 
Anticholinergics
Anticholinergics, such as ipratropium bromide, may be considered in the emergency treatment of asthma, but there is controversy on their ability to offer additional bronchodilation.14-16
 
Magnesium Sulfate
Magnesium acts as a bronchodilator, primarily through its activity as a calcium channel blocker and its role in activation of adenylate cyclase in smooth muscle cells. As result of these mechanisms, magnesium inhibits calcium-mediated smooth muscle contraction and facilitates bronchodilation. The value of magnesium administration in the treatment of status asthmaticus remains controversial. The usual dose of magnesium is 25 to 50 mg/kg/dose over 30 minutes, administered every 4 hours. Magnesium can also be given by continuous infusion at a rate of 10 to 20 mg/kg/h. With either dosing regimen, some have suggested a target magnesium level of 4 mg/dL to achieve maximal effect. Side effects of magnesium administration include hypotension, CNS depression, muscle weakness and flushing. Severe complications, such as cardiac arrhythmia including complete heart block, respiratory failure due to severe muscle weakness and sudden cardiopulmonary arrest, may occur in the setting of very high serum magnesium levels (usually >10–12 mg/dL). Serum magnesium levels should be regularly monitored. Magnesium sulfate as an adjunct to standard therapy in patients with severe exacerbation of asthma could cause improvement in pulmonary function and decrease in hospital admission.17,18
 
Helium-Oxygen
Helium is a biologically inert, low-density gas that, when administered by inhalation in a mixture with O2, reduces airflow resistance in small airways by reducing turbulent flow and enhancing laminar gas flow. These characteristics may also enhance particle deposition of aerosolized medications in distal lung segments. A recent Cochrane review concluded that Heliox was not beneficial in asthma, though most of the studies cited were in adults. In contrast, some small studies in nonintubated children with moderately severe asthma have shown improvement in lung function and clinical asthma score with Heliox therapy. Most recently, Kim et al. demonstrated that the use of Heliox to drive continuous albuterol nebulization treatments for children in the emergency department with moderately severe status asthmaticus was associated with significantly improved clinical asthma scores.16 106
 
Antibiotics
Empiric antibiotic treatment for children with status asthmaticus is not indicated.
 
Noninvasive Mechanical Ventilation
Mortality rates in mechanically ventilated children with status asthmaticus increase compared to those children, who do not require mechanical ventilation. Noninvasive positive-pressure ventilation (NIPPV) is an alternative to conventional mechanical ventilation in these patients. A systematic review that examined data in these patients concluded that insufficient quality data are available to make recommendations about the use of NIPPV in patients with asthma; however, it is relatively easy to institute and a trial may be warranted prior to the institution of conventional mechanical ventilation. At present, the recommendation is a trial of NIPPV before intubation and mechanical ventilation should be considered in selected patients with acute asthma and respiratory failure (Evidence Category B).19,20
 
Mechanical Ventilation
In status asthmaticus, tracheal intubation is indicated for children following cardiorespiratory arrest, those with refractory hypoxemia or those with significant respiratory acidosis unresponsive to pharmacotherapy. The exact time to intubate is based mainly on clinical judgment, but it should not be delayed once it is deemed necessary. It should be performed by the most skilled individual. Hypotension should be anticipated. Ketamine is an excellent anesthetic agent for induction because of its relatively long half-life, bronchodilating properties and relative preservation of hemodynamic stability. A cuffed endotracheal tube with the largest diameter appropriate for the age of the child should be used, as high ventilatory pressures are typical, when treating mechanically ventilated children in status asthmaticus. Ventilatory support in status asthmaticus should maintain adequate oxygenation, allow for permissive hypercarbia (moderate respiratory acidosis) and adjust minute ventilation (peak pressure, tidal volume and rate) to maintain an arterial pH of > 7.2. Slow ventilation rates with prolonged expiratory phase, minimal end-expiratory pressure and short inspiratory time should be employed. The ideal mode of mechanical ventilation has not been established for asthmatic children with respiratory failure. Pressure-regulated volume control is a relatively new mode of mechanical ventilation. Although experience is limited with this mode of ventilation in patients with asthma, the decelerating flow pattern combined with the option to independently adjust pressure with a preset tidal volume is appealing to enhance the gas distribution and minimize risk of barotrauma.
The use of high-frequency ventilation has been described in a few case reports. Some authors suggest using pressure-support ventilation without any preset rate and allowing the patient to breathe spontaneously. This strategy avoids complications associated with continuous or frequent use of muscle relaxants and has the further advantage of allowing the child to maintain forced exhalation, 107while receiving support for inspiration. Tracheal gas insufflation has also been used to facilitate expiratory gas flow and reduce severe hypercarbia.
Tracheal extubation should occur as soon as possible. Rapid weaning from the ventilator should take place “declare them well and pull the tube.”
Chest physiotherapy (CPT) may augment airway clearance and encourage resolution of mucous plugging; however, it should only be considered in children with clear segmental or lobar atelectasis. In all other populations of children with status asthmaticus, CPT has no therapeutic benefit. Some suggest that CPT is irritating to the severe asthmatic and may actually worsen clinical symptoms. CPT is not recommended as part of routine management in the critically ill patient with status asthmaticus.
 
Sedation During Ventilation
Mechanically ventilated children require sedation and often, muscle relaxants to prevent patient-ventilator asynchrony and to reduce the risk of sudden cough-induced pulmonary barotrauma. Ketamine by continuous infusion is the first choice for sedation, usually combined with intermittent or continuous administration of benzodiazepines. Usual ketamine dosing is 1 mg/kg/h and is adjusted to achieve sufficient sedation. When opiates are used, fentanyl is preferred because morphine causes histamine release, which may exacerbate bronchospasm. Neuromuscular blocking agents are frequently required to facilitate mechanical ventilatory support. Vecuronium is a commonly used agent. The starting dose is 0.1 mg/kg/h, which should be titrated to train-of-four monitoring usually one to two twitches. Drug holidays can be used to reduce the risk of overdose, prolonged paresis and myopathy that are sometimes observed in children, who receive continuous infusions of the nondepolarizing neuromuscular blocking agents.
 
Extracorporeal Membrane Oxygenation Support
When maximal medical therapy is failing, extracorporeal membrane oxygenation (ECMO) should be considered. Numerous case reports demonstrate high survival rates, even in a gravely ill patient population. The survival for children with refractory status asthmaticus, who are placed on ECMO is ~90%.
 
Prognosis of Patients in Status Asthmaticus
Mortality rates for children with severe status asthmaticus, who arrive at the hospital intact are nearly zero. Nearly all asthma deaths occur in those children, who suffer a cardiopulmonary arrest prior to arrival for emergency hospital care. Improved outpatient management strategies are necessary to eliminate these deaths.
 
Prevention of Relapse
Prevention of subsequent asthma attacks is imperative. Patients should be discharged only after they have been provided with the necessary medications (and educated how to use them), instructions in self-assessment (PEF, symptoms score), a follow-up appointment and instructions for an action plan.108
 
SUMMARY AND CONCLUSION
Asthma is a major worldwide health care problem, which has received increased attention in recent years due to alarm over reports of rising mortality and hospitalization rates. Recognition of risk factors for developiong near fatal asthma attack is important. Status asthmaticus is the more or less rapid, but severe asthmatic exacerbation that may not respond to the usual medical treatment. Treatment for acute, severe asthma includes the administration of oxygen, β2-agonists and systemic corticosteroids. Continous infusion of aminophylline, terbutaline and ketamine are other options there is increasing evidence for the use of magnesium sulfate in status asthamaticus. The exact time to intubate a patient in status asthmaticus is based mainly on clinical judgment. Permissive hypercapnia, increase in expiratory time and promotion of patient-ventilator synchronism are the mainstay in mechanical ventilation of status asthmaticus. A trial of noninvasive ventilation before intubation and mechanical ventilation should be considered. Finally, after successful treatment and prior to discharge, a careful strategy for prevention of subsequent asthma attacks is imperative, e.g. recurrence of airflow obstruction.
REFERENCES
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  1. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma. A meta analysis. Am J Emerg Med 1992;10:301–310.
  1. Aubier M, De Troyer A, Sampson M, Macklem P, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249–252.
  1. O'Driscoll BR, Kaira S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet 1993;341:324–327.
  1. Crave D, Kercsmar CM, Myers TR, et al. Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma. J Pediatr 2001;138:51–58.
  1. Kim IK, Phrampus E, Venkataraman S, et al. Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations. A randomized, controlled trial. Pediatrics 2005;116:1127–1133.
  1. Singh AK. A randomized controlled trial of intravenous magnesium sulphate as an adjunct to standard therapy in acute severe asthma. Iran J Allergy Asthma Immunol 2008;7:221–229.
  1. Mohammed S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J 2007;24:823–830.
  1. Ram FSF, Wellington SR, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Datab System Rev 2005;3: CD004360.
  1. Nowak R, Corbridge T, Brenner B. Noninvasive ventilation. J Allergy Clin Immunol 2009;124:S15–S18.

Aerosol Therapy8

K Gowrinath
 
INTRODUCTION
An aerosol is a suspension of solid particles or liquid droplets of different density or size in a gaseous medium. Historically, treatment through inhalation of burning vegetation and chemicals for lung diseases was practiced by Hippocrates and Galen.1 Aerosol therapy in children is used mostly for treating asthma. Antimicrobial drugs2 or mucolytics3 have been administered through inhalation route, e.g. cystic fibrosis (CF). Other recent advances in inhaled therapy include administration of insulin4, surfactant or gene vector.5 Aerosol therapy is superior and safer when compared to systemic administration of same drug.6 Inhalation therapy is painless and often convenient. The main advantage of aerosol therapy is faster optimal therapeutic response compared to other routes of administration and selective treatment of lung diseases by achieving high drug concentrations in the airway with therapeutic dose without significant systemic side effects.7 Nasal passages are additional common targets of inhaled drug therapy. Pump inhalers are used for spraying decongestants, antihistaminics or steroids into the nose8. The main disadvantage of aerosol therapy is that specific inhalation techniques are necessary for the proper use of each of the available types of inhaled device and suboptimal technique can result in decreased drug delivery and reduced efficacy.9 In very young children, anatomical, physiological and emotional factors may pose significant challenges and problems.10 Another problem with aerosol therapy is that the time required for administration of drug is longer than oral route and some devices are less portable. Some drugs are active only when administered through inhalation route, e.g. cromolyn sodium, ciclosonide.
 
AEROSOL DELIVERY
The optimal delivery of aerosol to the lung in a child depends upon the inhalation technique and the breathing pattern. In children, important inhaled drug delivery issues include lower tidal volume and inspiratory flow rates, determination of appropriate dosages and reducing local and systemic adverse effects.11 In infants and children, rapid respiratory rate, uneven distribution of ventilation, anxiety 111and crying may lead to higher oropharyngeal deposition and lesser deposition in lower airways.12 For proper airway deposition of aerosol, the size and physical characterestics of aerosol and amount of aerosol are also important. The mean mass aerodynamic diameter (MMAD) defines the distribution of aerosol particles generated. The MMAD is the particle diameter around, which the mass of the particles equally divided between bigger and smaller particles. The geometric standard deviation (GSD) is a measure of the variability of the particle diameter within the aerosol. As the GSD increases, the MMAD increases because larger particles carry more mass. During inhalation therapy, aerosol particles of less than 5 microns are deposited in the lung and smaller than 1 micron size will be exhaled.13 The mechanisms of airway deposition of drug include inertial impaction (particle size of at least 3 microns), which is highly dependent on inspiratory flow rate, gravitational sedimentation (average particle size of 2 microns and breath holding of 5 to 15 seconds enhances drug deposition) and diffusion (smaller than 2 microns).14 Around 70% of inhaled drug is deposited within oropharynx and larynx due to impaction without any therapeutic action and effective therapeutic response is achieved only when the inhaled drug get deposited in appropriate receptors in the large and small airways.15,16 Deposition of aerosol in the alveoli is followed by rapid absorption into the circulation and may result in systemic side effects.17 In infants, airway drug deposition is only 1.5 to 2.0%.18 The airway drug deposition is about 5.4% in 2 to 4 years age and 11.1% at 5 to 7 years age.19
 
FACTORS INFLOWING AEROSOL THERAPY
Aerosols for medical use are basically generated by jet of compressed air (jet nebulizer), ultra high frequency sound (ultrasonic nebulizer), using a small quantity of propellant with drug (pressurized metered dose inhaler) or rotating discs (dried powder inhaler). The advantages and disadvantages of using different aerosol devices are given in Table 8.1. Nebulizers; compressed air nebulizers (atomizers) were the only devices available for administration of aerosol drugs until jet nebulizer was introduced in 1956. The nebulized drug is delivered in fine mist in high dose and can be used at any age and for any disease severity. Conventional jet nebulizers are highly inefficient as only 8 to 10% of the drug reaches the lung and most drug remains in the apparatus or wasted during expiration.20 Small volume nebulizers are most frequently used for treating asthma. Large volume nebulizer (> 100 cc) is used for administering high dose of bronchodilators in severe airway obstruction and for humidification. The nebulizer performance may be influenced by the brand used, fill volume of drug along with flow and humidity of driving gas.21 Aerosol output from a nebulizer is affected by multiple factors including nebulizer design, drug formulation, patient's tidal volume and breathing pattern.22 In children particularly infants if the airflow of the nebulizer exceeds the maximum inspiratory flow, medication will be lost to the atmosphere during inspiration. Up to 50% of 3 mL solution filled usually remain trapped in the nebulizer body (dead volume), on the walls of the baffle and in the tubing.23 Most nebulizers deliver aerosol continuously whereas patient inhales approximately 30 to 50% of the respiratory cycle and as a result the dose available to be inhaled 112is approximately 50% or less.
Table 8.1   Advantages and disadvantages of various aerosol devices
Advantages
Disadvantages
Nebulizers
Patient's coordination is not required
Expensive and bulky
Effective with tidal breathing
Electrical power source is required
Administration of high dose is possible
Pressurized gas source is required
Can be given in acute attacks
Regular maintenance is required
Dose modification possible
Dose delivery not accurate
Can be used with supplemental oxygen
Lengthy treatment time
Propellant free
Risk of contamination if not cleaned or sterilized properly
Can deliver combination therapy
High doses of drug may lead to toxicity
Not all drugs are available in solution form
Does not aerosolize the suspensions well
Performance variability with jet nebulizers
Possible drug inactivation due to higher temperature as in ultrasonic nebulizers
Pressurized metered dose inhalers (pMDI)
Portable and compact
Coordination of breathing and actuation is needed
Quick administration of desired dose of drug
Device actuation is required
No drug preparation is required
Cold Freon effect
No contamination possible
High pharyngeal deposition
Multidose convenience and dose to dose reproducibility is high
Potential to abuse
Not all medications are available
Remaining doses difficult to determine
Dry powder inhaler (DPI)
Easy to handle and portable
Device has to be assembled before use
Quick to use
Requires moderate to high inspiratory flow for pulmonary deposition of drug; no deposition if inspiratory flow rate is less113
Breath actuated
Bitter taste of the drug is more evident
Less patient coordination is required
Cannot be used in acute attacks
Propellant free
High pharyngeal deposition
Higher drug deposition in target area than pMDI
Not all medications are available
Most DPIs are moist sensitive and high humidity may lead to clumping of drug
To overcome this problem, inexpensive, disposable breath actuated nebulizers24 that mechanically generate aerosol during inspiration only have been introduced. Breath enhanced nebulizers25 have an inspiratory valve that allow the patient to inhale additional air during inhalation and prevents drug loss during expiration and are more efficient, but time consuming. Vibrating mesh and adaptive aerosol delivery (AAD)26 devices does not have compressor like jet nebulizer. These devices release medication during first 50 to 80% of respiration and reduces the amount of drug wasted. Ultrasonic nebulizer (USN) generate aerosol particles by means of vibrations in a piezoelectric crystal. The USN can deliver large volume of aerosol over a reasonably short period of time, but are inefficient in nebulizing suspensions or viscous solutions.27 Another problem with USN is that the crystal may break and proteins in the medication become inactive due to relatively high temperature generated during nebulization.28 Nebulizers are more expensive, requires a power source with regular maintenance and potential cause of cross infection.29 Nebulizers can be used only when other aerosol devices can not be used.
 
SOME AEROSOL DEVICES
 
Pressurized Metered Dose Inhaler
Pressurized metered dose inhaler (pMDI) was introduced in 1956 and proved to be invaluable in treating diseases like asthma.30 Among all inhaled drug delivery systems used in asthma, MDI has been found to be the most efficient, portable, cheap and easy to handle. Different types of pMDI available in the market (Fig. 8.1). pMDI consists of a canister with pressure of about 3.5 atmospheres containing a drug in the micronized form mixed with a propellant along with a dispersal agent. The dispersal agent or surfactant is added to prevent clumping of drug in the canister and to lubricate the valve mechanism. The surfactants commonly used are soya lecithin, sorbitan trioleate and oleic acid. Chloroflourocarbons (CFCs) used as propellant in pMDI were implicated in the depletion of the ozone layer with harmful effects of increased ultraviolet radiation reaching the earth and are being replaced by hydrofluoroalkanes(HFA), HFA134 and HFA227, which were found to be safe.31 Temperature within the canister is very important, as only at temperature 114higher than 20°C, aerosol particles are small and respirable.
Fig. 8.1: Different types of pMDIs available in the market
The technique of inhalation is important as even with best inhalation technique only 10 to 15% of the aerosol reaches at the site of action in the lungs.32 All the advantages of using MDI will be nullified if patients do not use them properly.33 Children under the age of 4 years, the most common errors were not shaking the pMDI before use (48%) and taking two consecutive puffs (28%).34 One of the recommended techniques of using MDI involves 7 steps.35 Medical personnel responsible for teaching the proper technique regarding the use of MDI themselves are not aware of proper inhalation technique as Kelling et al. showed that only 40% physicians correctly performed four or more steps involved in a recommended inhalation maneuver.36 The major difficulty in using MDI is the inability to coordinate actuation of aerosol with inhalation.37 The maximal deposition of aerosols in the lungs depends upon the combination of slow deep inhalation followed by breath-holding for at least 10 seconds.38 Firing the canister at a distance of 4 cm from the open mouth was reported to yield higher drug deposition in the lungs but aerosol may be sprayed away from the mouth due to accidental tilting of the MDI and this technique did not show any advantage over the technique of using the MDI held between the lips.39 A high level of CFC containing pMDI has been reported to cause adverse reactions mainly in children. Once delivered from the pMDI, the cold Freon effect of CFC on the pharyngeal wall (Freon effect) may cause momentary stoppage of inhalation in some children.40 Routine substitution of MDI for nebulization can be done successfully and results in considerable cost savings.41
 
Breath Actuated Meter Dose Inhaler42
Actuation of the inhaler must coincide with inhaled air stream to carry out the drug into the lungs. Breath actuated inhalers have been introduced to remove the 115need for patient cooperation. Breath activated metered dose inhaler (autohaler) has been designed to release the drug at the onset of inspiration resulting in synchronization of inhalation with delivery of the drug. The main advantage with the autohaler is low inspiratory flow (30 L min) is sufficient to trigger the device. The disadvantage with this form of inhalation device is that higher oropharyngeal deposition of drug if the inspiratory flow is high. Most breath actuated MDI are not suitable for children under 5 years age, but new device (easy breathe) holds promise.43
Auxillary spacing devices (Holding chambers, Spacers): Spacer devices (Fig. 8.2) are tubular attachments (volume 20–750 mL) to the pMDI mouthpiece and can overcome the corohation problem or cold Freon effect with the use of pMDI alone.44 Spacer holds the medication in a chamber after it has been released from the pMDI. The inhalation from spacer should be done within 30 seconds of actuating the inhaler. First, open-tube spacer devices were introduced for use with MDIs in 1970s.45 After spacers were introduced, initially their efficacy was questioned,46 but later MDI with holding chamber has been reported to be equal in therapeutic value compared to nebulizer therapy even in acute asthma.47 The advantages of using MDI with spacer include higher drug deposition in the airway and greatly reduced oropharyngeal drug deposition. A spacer with valve reduces the velocity of the particles before they reach the mouth and allows more of the propellants to evaporate and traps excipients such as oleic acid so that the inhaled particle becomes smaller and penetrate further into the lung.48 On using spacer, there is four fold increase in therapeutic efficacy with increase in the deposition of the drug in the peripheral airways.49 The drug output from the spacer is influenced by the size, design, shape, presence or absence of valve, deadspace and mode of inhalation.50
Fig. 8.2: Different types and sizes of spacer devices
116If spacer is used upside down so that valve falls open and mask is attached to the mouth piece, it can be used to give treatment to infants.51 In children who cannot use pMDI by themselves, the aerosol can be delivered by any other person into the holding chamber. Small children and infants who have low tidal volume and lower inspiratory rate, drug deposition through small volume spacer may be more.52 In older children, larger volume (750 mL) spacers do not have any additional clinically relevant benefit compared to 150 mL spacer.53 Spacer with valve holds the medication in its chamber after it has been released from the pMDI allowing the child to breath in and out of mouth piece or face mask. The child often needs to take five or six breaths to inhale all of the medication. Spacers are recommended for all children who use steroids. In case of infants, the valves of the spacer may have high resistance or the chambers may be too large for infants.54 Many young children do not cooperate with spacer treatment or tolerate a mask of any kind. Valved spacer devices with mask designed for use in small children may provide a poor seal with the face leading to reduced dose delivery and better to use a mouth piece at as young age as possible.55 The face mask seal is critical for efficient aerosol drug delivery in infants and young children. Plastic spacers may cause adhesion of airborne drug particles on their walls due to electrostatic charge and this may reduce the drug delivery from such spacers.56 Nonelectrostatic spacers have been developed and recommended in children as their use result in increased deposition.57,58 Spacer therapy will not be effective if medical personnel themselves are not aware of the proper technique of their use.59 Currently, use of nebulizer is being replaced by spacer with pMDI in the management of acute asthma.60 Even children less than 2 years of age with acute wheezing attack respond faster to bronchodilator delivered by pMDI with spacer and facial mask than with nebulizer.61
 
Dried Powder Inhalers
Dried powder inhalers (DPI) were introduced in 1971 by Bell et al for inhalation of cromolyn sodium under the name of spinhale.62 In DPI, micronized drug is contained in a gelatin capsule or blister and is mechanically released after the rotation of inhalation device, the force of patient's inspiratory effort then generates a fine aerosol powder.63 With DPI, 9 to 30% of total drug inhaled may get deposited in the lungs.64 Aerosol generation and delivery through DPI depends on several external factors such as initial size of the respirable particles, ambient humidity, inspiratory pressure and flow rate and airway resistance.65 A patient generating peak inspiratory flow rate of more than 60 min is considered ideal for use of most DPI devices.66 The DPIs tend to work better with rapid and forceful inhalation since this maneuver disperses the powder formulation into small ‘respirable’ particles as efficiently as possible.67 The particle velocity generated by forced inspiration through DPI is lower than that of MDI and so less drug is deposited at the oropharynx but the particle size is not uniform. High humidity and rapid changes in surrounding temperature may clump the drug particles within the DPI and reduce its delivery.68 Main disadvantage of DPI is that only children above 3 years can use them effectively.69 The DPI is not suitable for infants, disabled persons and those with low levels cognitive or lung function.70 Both single dose 117DPI and multidose DPI are available (Fig. 8.3). Unlike single dose DPI, multidose DPI like Discus gives reliable and consistent drug delivery.71 In addition, Discus is easy to teach and found to be acceptable to most of the patients as they found it easy to use. Additional advantages with discus include integrated mouth piece covering, protection from moisture, facility to count the doses and drug delivery independent of any orientation or position.72 Another multidose DPI, Novolizer tends to have higher drug deposition at higher flow rates.73 Battery powered electrically driven DPI, which operate at very low inspiratory flow rate have been developed for use in children.74
Aerosol therapy is challenging when the patient is on mechanical ventilation. Deposition of drug in intubated and ventilated patient is only about 3%.75 Depending upon the humidification within ventilatory circuit and the ventilator duty cycle, there may not be adequate time for the aerosol cloud to develop in the circuit and the geometry of the circuit may hinder the deposition of aerosols in the airway.76
Despite the mechanical and engineering challenges in designing devices for aerosol administration, the clinician's greatest challenge is patient education to use their medication and aerosol devices appropriately.77 While selecting aerosol delivery device, the factors to be considered are device/drug availability, clinical setting, patient's age and the ability to use the device correctly, drug administration time, cost and reimbursement, convenience in both inpatient and outpatient settings, physician and patient's preference.78
 
SUMMARY AND CONCLUSION
Inhalation therapy has emerged as an important breakthrough in the management of airway diseases like asthma. Different aerosol delivery devices have been developed to treat respiratory diseases like asthma. Optimal deposition of inhaled drug in the lung depends upon the inhalation technique and breathing pattern.
Fig. 8.3: Single and multidose DPIs
Use 118of accessory devices like spacers with pMDI can greatly reduce the steroid induced side effects and helps to improve deposition of inhaled drug in lungs. pMDI is the most effective portable and cheap device but requires proper technique for optimal drug deposition. Breath actuated pMDI avoid the need to co-ordinate inhalation with release of drug but not suitable for children under five years age. The DPI does not require breathholding but generating adequate inspiratory pressure for optimal drug release is required. The DPI is not suitable for very young children. Inhalation therapy in very young children like infants is problematic and newer methods are being developed to improve the airway drug deposition in them. Among all inhalation devices available, nebulizers are least efficient but can be used in all age groups and continuous delivery of high concentration of drugs is possible. Unless each inhalation device is used properly, the expected clinical improvement may not occur. The prescribing doctor should know the technique of using the inhalation device well before educating the patient about its use.
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Psychological Aspects of Bronchial Asthma9

GK Vankar, Rachana Pole
 
INTRODUCTION
Asthma, one of the most common respiratory diseases among children, is defined as “a chronic respiratory disease of unclear etiology, characterized by reversible airway obstruction and heightened airway irritability usually accompanied by inflammation of tissues of the airways, mucus congestion, or constriction of airway smooth muscles.”1
The prevalence of bronchial asthma has increased continuously since the 1970s, and now affects an estimated 4 to 7% of the people worldwide. Childhood bronchial asthma varies widely from country to country. At the age of 6 to 7 years, the prevalence ranges from 4 to 32%. Pal et al2 have analyzed 15 Indian studies on prevalence of bronchial asthma in children. They found wide differences in samples, primary outcome variables, lack of consistency in age category, rural-urban variation, and criteria for positive diagnosis. The study instruments confounded the outcome variables. The mean prevalence was 7.24 ± SD 5.42. Childhood asthma incidence among children 13 to 14 years of age was lower than in the younger children (6–7 years of age). Urban and male predominance with wide inter-regional variation in prevalence was observed.
International Study of Asthma and Allergies in Childhood (ISAAC) found prevalence in India relatively low, with a prevalence of wheezing in the last 12 months in 13 to 14 years olds of 6.0% compared with 8.0% in the rest of the Asia-Pacific region, 13.8% globally, 16.8% in Western Europe, and 32.2% in the United Kingdom.3
 
ETIOLOGIC HYPOTHESES
Various hypotheses have been postulated regarding the etiology of asthma as shown in Box 9.1. We discuss psychosomatic hypothesis in this chapter.
Although no definite etiological factor has been found, multiple risk factors predisposing to asthma and also factors acting as triggers of asthmatic attack are known (Boxes 9.2 and 9.3).124
125Psychological factors may predispose to asthma and may also act as a trigger of asthmatic attack. These observations support the etiological hypothesis of psychosomatic origin of asthma.
 
PSYCHOSOMATIC THEORY OF ASTHMA
Franz Alexander, a classical psychoanalyst, began his studies on psychological aspects of bronchial asthma.4 He considered the symptoms of acute attack of bronchial asthma were “a cry for mother.” Though psychoanalysis has not been popular at this juncture as a treatment, it heralded era of ‘biopsychosocial’ approach to all disorders, medical and psychiatric.
Psychological stress and asthma can be linked in many ways.
Possible mechanisms by which psychological stress can induce or exacerbate asthmatic changes include:
 
Stress and Autonomic Dysregulation5
Experimental studies in which asthmatic patients are exposed to stressful situations have focused on stress induced vagal reactivity as a mediator of emotionally induced bronchoconstriction. Adrenoceptors are regulated by noradrenaline which is released locally from sympathetic nerves, and by adrenaline and noradrenaline secreted by the adrenal medulla. The regulatory effects of adrenaline and noradrenaline on adrenoceptors suggest a plausible mechanism by which stress induced activation of the sympathetic nervous system might influence bronchomotor tone. It seems paradoxical that activation of the sympathetic nervous system by stress, resulting in release of mediators with a agonist effect, should relax airway smooth muscle and that acute psychological stress, which is accompanied by a rapid increase in circulating catecholamines should consequently cause bronchodilation. However, the stress induced response of the autonomic nervous system is more complex and variable. Once the acute stressor is terminated, levels of adrenaline and noradrenaline quickly return to normal or below normal. The relative strength of sympathetic versus parasympathetic control in response to certain forms of stress differs with the individual, with some showing a predominantly parasympathetic response. Such individuals may be particularly susceptible to stress induced bronchoconstriction. It is possible that sympathetic activation itself might contribute to asthma symptoms. For example, increases in circulating levels of adrenaline and noradrenaline are known to alter a number of immune parameters that might contribute to inflammation of the airways. Some evidence suggests long term increases or potentiation of the catecholamine response with chronic stress. Prolonged increases in catecholamine levels under chronic stress may also contribute to asthma severity. Chronic daily use of agonists by mild to moderate asthmatics with a specific genetic predisposition may increase severity by down regulating â receptors and it is possible that chronically increased stress induced catecholamines do the same among genetically susceptible subgroups. In addition, in those with chronic life stress the physiological response to acute stressors may result in more sustained effects on the immune system, even following sympathetic recovery.126
Flow chart 9.1: Mechanism in acute and chronic stress
 
Stress and Endocrinal Imbalance6
Psychological stressors have been associated with the activation of the sympathetic and adrenomedullary system and the hypothalamicpituitary-adrenocortical (HPA) axis.
 
Stress and Immunomodulations7
Psychological stress can influence cell trafficking, cell function including mitogen stimulated blastogenesis and natural killer cell cytotoxicity, and lymphocyte production of cytokines. Stress can modulate immune response through nerve pathways connecting the autonomic nervous and immune systems, by triggering the release of hormones and neuropeptides that interact with immune cells, and through the impact on behaviors such as smoking and drinking alcohol that are adopted as ways of coping with stress. Subjects exposed to cognitive or social laboratory stressor tasks lasting only a few minutes show suppression of T cell mitogenesis and increased numbers of circulating T suppressor/cytotoxic (CD8) cells and natural killer cells. This phenomenon includes stress elicited alteration of the production of the cytokines IL-1â, IL-2, and IFNã. As highlighted previously, airway inflammation and hyperresponsiveness are thought to be orchestrated by activated T lymphocytes and the cytokines they produce. The T helper cell Th2 cytokine phenotype promotes IgE production with subsequent recruitment of inflammatory cells that may initiate and/or potentiate allergic inflammation.
 
Stress and Infections8
A potential consequence of stress induced changes in immune response is suppression of host resistance to infectious agents, particularly agents that cause upper respiratory disease. The primary evidence for such effects comes from 127studies of psychological stress as a risk factor for respiratory infections. Increased incidence of upper respiratory infections under stress in these epidemiological studies may be attributable either to stress induced increases in exposure to infectious agents or to stress induced changes in host resistance.
 
Stress and other Associations9
Stress arising from lack of social relationships or social connectedness can be linked to adverse health outcomes and physiological effects including altered immunological functioning. For children the family is primary source of support in face of challenges of chronic disease. Many of the psychosocial factors thought to be important in the increase asthma morbidity and mortality in form of childhood anxiety and depression, noncompliance, family conflict are dependent on family structure and function. Social support/networks may facilitate asthma management and general coping which, in turn, may enhance the asthma status and reduce disruptive effects of environmental stressors.
Chronic stress in low socioeconomic status includes poverty, minority ethnicity, the real or perceived threat of crime and violence, and poor transportation. Exposure to violence is associated with the occurrence of asthma. Frequency of adverse life events and level of perceived stress show an inverse relationship to socioeconomic status. Discriminatory experiences based on gender, race, religion or caste may also be important life stressors.
 
ASTHMA AND DEPRESSION
The prevalence of depression in asthma ranges from 1 to 45%.10-17 This wide range in the reported rates is problematic but most authors suggest an increased prevalence of depression in patients with asthma.
Various studies have investigated, and several studies have concluded that are individuals with asthma are more likely to be depressed than those without asthma.18-23 Other investigators24,25 have not found such evidence.
In investigations utilizing objective measures of asthma severity (i.e. clinician diagnoses, airway reactivity testing), Mrazek26 found that more severe asthma was associated with increased depressive symptoms; however, studies by Afari et al27 and Janson et al28 did not find this association. However, two studies that used patients’ subjective ratings of their own asthma severity found significant relationships between perceived asthma severity and depressive symptoms.29,30 Thus these subjective measures of asthma severity may be more strongly related to depression than objective severity measures. One potential explanation for this possibility is that the individual's perception of their own asthma severity may be more important than the ‘real’ severity of the individual's asthma in determining whether or not asthma leads to the person becoming depressed.
A population study by Goldney et al31 examined the relationship between depression (as measured by the Prime-MD) and a number of symptoms known to be related to asthma severity, and found that dyspnea, wakening at night, and morning symptoms were particularly strongly associated with depression.128
The finding of Goldney et al relating asthma symptoms to significant decrement in the quality of life also leads to the question of whether experiencing certain specific asthma symptoms might lead to person with asthma becoming depressed, rather than depression resulting from simply ‘having’ asthma.
Box 9.4 shows DSM IV TR criteria for major depression.32 Some adolescents may present with irritability rather than depressed mood as the main manifestation. Other adolescents present with somatic symptoms such as abdominal pain, chest pain, headache, lethargy, weight loss, dizziness and syncope, or other nonspecific symptoms.33 Others present with behavioral problems such as truancy, deterioration in academic performance, running away from home, defiance of authorities, self-destructive behavior, vandalism, alcohol or other drug abuse, sexual acting out, and delinquency.34
 
PANIC DISORDER AND ASTHMA
As shown in Box 9.5 many of the manifestations in panic attack are similar to manifestations of acute attack of asthma.
Approximately one asthma patient in ten has panic disorder whereas asthma and other chronic respiratory diseases are three times more common in patients with panic disorder than among those with other psychiatric disorders or general population. Causal direction between asthma and panic may be bidirectional.
Panic may elicit or exacerbate asthma symptoms by several pathways. As described above, the psychophysiological stress response that accompanies panic may elicit autonomic and inflammatory responses among people with asthma, and dyspnea and other unpleasant body sensations accompanying asthma may trigger panic. Although the poor correlation between asthma severity and panic symptoms35 might argue against the latter pathway, there are reasons to believe that both mild and severe asthma symptoms might trigger panic, but by 129different pathways.
Symptoms of mild asthma might more easily be confused with panic symptoms, whereas symptoms of more severe asthma are more recognizable and lead to a clearer path of coping behavior, thus decreasing the panicogenic effect. The frightening nature of severe dyspnea may evoke panic through classical conditioning. Consistent with the possibility that asthma can be a contributing cause of panic disorder are findings that where panic disorder and asthma are comorbid, the respiratory disorder typically precedes the onset of panic disorder.36,37 During panic attack, hyperventilation can occur and voluntary hyperventilation may bring attach of asthma in a patient.38
The relationship between panic disorder and asthma is not a specific one. There is a higher prevalence of nonrespiratory diseases, such as cardiovascular and cerebrovascular disease, among panic disorder patients than among those with other psychiatric disorders or those with no psychiatric disorder.39 In addition, panic disorder and asthma seem to be independently transmitted in families of those with asthma.40
Another possible bidirectional pathway is shared respiratory dysregulation that may contribute to the pathophysiology of both problems.41 For example, the experience of dyspnea in both disorders may be linked by CO2 sensitivity. Medullary chemoreceptors and the locus coeruleus may be stimulated by bronchoconstriction in asthma, inducing the expression of an underlying vulnerability to panic.42 Repeated stimulation of chemoreceptors may lead to dysfunction of the brain's suffocation alarm system to underlie the development of panic disorder.43 This mechanism may stimulate hyperventilation, thus exacerbating both panic and asthma.44
 
DEPRESSION, ANXIETY, AND LIFE-THREATENING ASTHMA ATTACKS
A high prevalence of denial and anxiety has been found among asthma patients who have experienced a near-fatal attack.45,46 Two studies found that children who 130died from asthma attacks had higher levels of psychosocial problems, including depressive symptoms and family dysfunction47,48 although these latter findings were not replicated in another study.49 Interpretation of psychological factors in near-death asthma has been limited by retrospective assessment because increases in anxiety or denial may be the result, and not the cause, of these severe asthma exacerbations. Strunk et al50 have recommended that prospective studies be done and a national database implemented for tracking characteristics of patients with fatal or near-fatal attacks.
 
How Depression Affects Asthma Outcome?
Depression occurring in asthma is associated with poor asthma control, more acute attacks, more hospitalizations, higher health care costs.
A meta-analysis by DiMatteo et al51 revealed that patients with a chronic disease and depression were three times more likely to be noncompliant with medical treatment than nondepressed patients. Bosley et al52 found that individuals with asthma who were classified as ‘noncompliant’ (took less than 70% of their prescribed doses of inhaled medication) had significantly higher depression scores (measured on the HADS) than those who were compliant, DiMatteo et al51 have also hypothesised the possibility of a ‘feedback loop’, in which depression leads to treatment noncompliance, noncompliance further exacerbates asthma, asthma exacerbations lead to increased depression, and so on, resulting in a cycle of ever-worsening outcomes for the individual.
 
FAMILY AND ASTHMATIC CHILD
Three studies on parental knowledge about bronchial asthma report poor knowledge and stigmatizing negative attitude. This emphasizes the need for pediatrician–parent communication to enable parents to help their children fully.
Beside disease related knowledge, family characteristics like socio-economic disadvantage, gender bias, physical/psychiatric disorders in the family, marital disharmony and burden of care along with living in poor social capital neighborhood may obstruct family to adequately care for the child.
Fig. 9.1: How depression affects asthma outcome negatively
131
 
PSYCHOLOGICAL INTERVENTIONS IN CHILDREN
Psychological therapies are effective at improving various aspects of asthma control or quality of life.52 Psychotherapies like cognitive behavior therapy and relaxation techniques with or without biofeedback assistance reduce the frequency of attacks and severity of symptoms. Family treatments can also be useful in selected cases of asthma especially when adequate pharmacotherapy does not help.
Because psychotherapy approaches are briefly discussed as per their theoretical framework.
  1. Behavioral therapies focus on identifying the processes by which behavior has been learned via association, reward, or observation and modifying behavior using methods such as systematic desensitization, selective reinforcement, and positive modeling. The behavior itself, rather than the underlying motivations, is the focus of behavioral interventions. Dahl found positive results following behavioral therapy when school absenteeism and use of as-needed medications were the outcome measures.53
  2. Cognitive therapies act by identification and constructive management of incorrect and damaging thoughts, such as perceptions of helplessness or inappropriate fear of asthma attack, that can trigger episodes. Information (e.g. about the relationships between anxiety and bronchoconstriction) also targets cognitions.
    Fig. 9.2: Panic cycle: Cognitive behavioral explanation
    132
  3. Cognitive behavior therapy (CBT): The CBT combines the key elements of both behavioral and cognitive models and is currently used more frequently than either cognitive or behavioral therapies alone. As mentioned in the above box in two studies measuring asthma knowledge as an outcome reported benefits of CBT,54 and CBT has been reported to have a positive effect on self-efficacy measures.
  4. Relaxation techniques are generally conducted with or without biofeedback and were the focus of several earlier studies of psychological interventions in asthma. Relaxation techniques control stress and anxiety, which, in asthma, may improve breathing and respiratory function. Such programs generally include progressive relaxation, and hypnosis or deep relaxation, which may be induced using mental imagery. This is often accompanied by autosuggestion to create positive thoughts and feedback of biologic indicators, which the subject must control via relaxation. Alexander and Weingarten measured the effect of relaxation therapy on peak expiratory flow and found effects favoring the treatment group compared with the control group.55,56 In addition, self-hypnosis- assisted relaxation reduced emergency room visits, again in a single study that also found that self-reports of asthma improved in the self-hypnosis.57
  5. Counseling involves talking over problems with a health professional. In supportive counseling, the counselor acts primarily as a good listener who provides emotional support. Supportive therapy sometimes has a problem-solving focus and may be helpful for patients experiencing an acute crisis.58
  6. Educational approaches do not attempt to alter core psychological processes and therefore are not psychological therapies as such. They are already the subject of systematic reviews59 and are routinely included as necessary components of optimal asthma care.60
  7. Breathing retraining exercises include a range of techniques for improving breathing control in asthma (e.g. yoga, and transcendental meditation). These are not regarded as standard psychotherapies, although aspects of breathing retraining may be included in behavioral therapy or CBT. A Cochrane review has previously examined the effectiveness of breathing retraining exercises, suggesting that conclusion must be viewed with caution.61
133
 
BEHAVIORAL ASPECTS OF MEDICATIONS USED IN BRONCHIAL ASTHMA
The behavioral aspects are summarized in Box 9.6.
 
SUMMARY AND CONCLUSION
Bronchial asthma, a chronic disease of childhood and adolescence, is characterized by airway obstruction that is, to a variable degree, reversible, either spontaneously or with treatment, airway inflammation, and increased airway responsiveness to a variety of stimuli. Current biopsychosocial approach emphasizes need to consider biological, psychological and social factors to understand and treat the disease effectively. Stress causes bronchial asthma by complex interplay of autonomic dysregulation, endoctine imbalance, immunomodulation, increased infection either due to greater exposure or reduction of host resistance. A variety of family related factors may precipitate the disorder, may impede treatment seeking or 135contribute to noncompliance with consequent increase in morbidity and mortality. Depression and anxiety disorders are the most common psychiatric comorbidities which are treatable with specific antidepressant and antianxiety medications. Family education about asthma, and Cognitive Behavior Therapy coupled with relaxation exercises can improve overall outcome. Use of corticosteroids in asthma is controversial. Only few patients who have coincident asthma or bronchospastic component may benefit from short or long-term treatment. For some such patients alternate day oral dosing/inhaled steroids may be useful. These measures reduce brain levels of steroids and thereby psychiatric symptoms like mood changes, cognitive disturbance delirium and sleep disturbance. In conclusion, psychological therapies are effective at improving various aspects of asthma control or quality of life. Psychotherapies like cognitive behavior therapy and relaxation techniques with or without biofeedback assistance reduce the frequency of attacks and severity of symptoms.
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Cystic Fibrosis: Past, Present and Future10

Suraj Gupte, Sahil Pandita
 
INTRODUCTION
Cystic fibrosis (CF) is the most common life-limiting genetic disorder amongst the white population though it occurs in other populations, including Indians, as well. A multisystem disorder, it is characterized by involvement of pancreas and lungs together with other exocrine glands, manifesting mainly with maldigestion, malabsorption and recurrent respiratory infections together with the resultant complications.1 The dominant morbidity and mortality is secondary to pulmonary involvement.
With the availability of modern treatment, most children with CF can have a fulfilling and nearly normal school years and, later, reasonable adulthood. The lifespan has now extended to fourth decade and yet better is on the card.
 
HISTORICAL PERSPECTIVES2,3
Though not pointedly named in the ancient medical literature, there has been an inkling of awareness of CF way back in the 1700s, as popularized by the German saying, “a child whose forehead tastes like salt when kissed will soon die.” In all probabilities, potentially CF cases were misdiagnosed as whooping cough, chronic bronchitis or pneumonia. Those with predominant gastrointestinal manifestations were misdiagnosed as celiac disease.
A truly documented history of CF dates back to 1930s, the period of discovery for cystic fibrosis, when the illness was first described to be a disease of its own nature. The earliest paper written on the disease was by Swiss pediatrician, Fanconi, who described CF under the title “celiac syndrome,” which he defined as changes in the pancreas.
The term, cystic fibrosis, was coined by Dorothy Anderson of the Babies’ Hospital, New York. She was the first doctor to give the disease its earliest definitive description. She also theorized that the condition was caused by deficiency in Vitamin A.
Later, the 1940s were marked by changing theories on the nature of cystic fibrosis. Sidney Farber and Harry Shwachman pointed out a link of CF with the 140abnormal secretion of mucus. The idea that Vitamin A is the underlying cause of cystic fibrosis was challenged by a number of researchers, including Dorothy Anderson, the person who proposed it in the first place. The use of antibiotics, particularly penicillin, became part of the treatment for this condition.
The 1950s saw the beginnings of the sweat test, the standard test now used for diagnosing CF. The test was developed as a result of discoveries made by Paul di Sant'Agnese during the heat wave in New York in 1950.
In 1955, Dr Shwachman laid the foundation for the modern way of treating cystic fibrosis, which was early diagnosis, active early treatment and proper nutrition. Also, Dr Archie Norman began studies on high fat diets in treating the disease in London that year.
The cystic fibrosis transmembrane conductance regulator (CFTR) gene was detected in 1989.
To cut the long story short, Dorothy Anderson was the first physician to specifically recognize CF as a disease. Together with her research team, created the first tests to diagnose it. Though earlier believed to be a disease limited to the white race, it is being increasingly reported in Orientals over the past few decades.
 
EPIDEMIOLOGY
The disorder usually occurs amongst white population, i.e. Europeans and Americans. According to a recent conservative estimate, there are around 6,500 CF subjects in UK and 40,000 in the USA.
Fig. 10.1: Dorothy Anderson (center) is credited for pioneering work on CF. Born in 1901, she died in 1963 from cancer. She was the first person to actually identify the CF
141Until a few decades ago, it was believed to be a disorder of sheer Caucasian population and virtually nonexistent in the Indian subcontinent.
Since late 1960s and early 1970s, documentations of the CF from North India, particularly from Chandigarh and Delhi, changed the scenario.4-13
As pointed out in our earlier communication,14 subsequently, more and more cases are being identified from different parts of India, including South India.
 
CYSTIC FIBROSIS GENE
Lap-Chee Tsui and team discovered the gene, cystic fibrosis transmembrane conductance regulator (CFTR), causing CF. Box 10.1 gives the salient information about the CF gene at a glance.
Protein structure: The CFTR is a type of protein classified as an ABC (ATP-binding cassette) transporter or traffic ATPase. These proteins transport molecules such as sugars, peptides, inorganic phosphate, chloride, and metal cations across the cellular membrane. CFTR transports chloride ions (Cl) ions across the membranes of cells in the lungs, liver, pancreas, digestive tract, reproductive tract, and skin.
The structure of the complete CFTR protein has not yet been experimentally determined. This is because membrane proteins, such as CFTR, with substantial hydrophobic (“water-fearing”) regions are extremely difficult to crystallize, and X-ray crystallography can only be carried out on protein crystals.
By comparing the CFTR protein sequence with that of other known ABC transporters, models depicting the structure of CFTR have been proposed.
142
Fig. 10.2: Approximate gene location is based on chromosome 7 map from NCBI Entrez Map Viewer
Fig. 10.3: Diagram depicting the five domains of the CFTR membrane protein (Sheppard 1999)
143The CFTR is made up of five domains: two membrane-spanning domains (MSD1 and MSD2) that form the chloride ion channel, two nucleotide-binding domains (NBD1 and NBD2) that bind and hydrolyze adenosine triphosphate (ATP), and a regulatory (R) domain. Delta F508, the most common CF-causing mutation, occurs in the DNA sequence that codes for the first nucleotide-binding domain (NBD1).
While most ABC transporters consist of four domains (two membrane-spanning and two nucleotide-binding domains), CFTR is the only one known to possess a regulatory domain. Modification of the regulatory domain, either through the addition or removal of chemical phosphate groups, has been shown to regulate the movement of chloride ions across the membrane.
Although there are no structures of the entire CFTR protein in the Protein Data Bank (PDB), an international archive of molecular structure data, a structure for a similar ABC transporter is available from the PDB. In September 2001, the Journal Science published an article on the X-ray structure of a CFTR-related ABC protein (Msba) in E. coli. The PDB ID for this protein is IJSQ. PDB also contains a structure based on the theoretical model of the first nucleotide-binding domain (NBD1). PDB ID for this entry is 1NBD. In addition, PDB contains synthetic peptide structures (25–26 amino acids long) of NBD1's alpha helical region containing the delta F508 mutation. PDB IDs for structures of these peptides are 1CKW, 1CKX, 1CKY, and 1CKZ.
Common disease causing mutation: About 70% of mutations observed in CF patients result from deletion of three base pairs in CFTR's nucleotide sequence.
Fig. 10.4: Theoretical model of NBD1. PDB ID 1NBD as viewed in Protein Explorer (Source: http://proteinexplorer.org)
144This deletion causes loss of the amino acid phenylalanine located at position 508 in the protein; therefore, this mutation is referred to as delta F508 or simple F508.
With normal CFTR, once the protein is synthesized, it is transported to the endoplasmic reticulum (ER) and Golgi apparatus for additional processing before being integrated into the cell membrane. When a CFTR protein with the delta F508 mutation reaches the ER, the quality-control mechanism of this cellular component recognizes that the protein is folded incorrectly and marks the defective protein for degradation. As a result, delta F508 never reaches the cell membrane.
People who are homozygous for delta F508 mutation tend to have the most severe symptoms of cystic fibrosis due to critical loss of chloride ion transport. This upsets the sodium and chloride ion balance needed to maintain the normal, thin mucus layer that is easily removed by cilia lining the lungs and other organs. The sodium and chloride ion imbalance creates a thick, sticky mucus layer that cannot be removed by cilia and traps bacteria, resulting in chronic infections. While the mechanism that leads to lung damage is not fully understood, lung disease is the leading cause of morbidity and mortality among CF patients.
Factors that affect the disease phenotype: Because CF is an autosomal recessive genetic disorder, an individual must have two copies of a mutated CFTR gene to express the disease phenotype. Someone with one normal, functional copy of the CFTR gene and one mutated copy would just be a carrier of the disorder, and would not display typical CF symptoms. It is important to note that just because two people might have the same two copies of the mutated CFTR gene, each may experience very different symptoms. This is because the development of a disorder such as CF is greatly influenced by environmental factors and genetic factors other than CFTR.
Fig. 10.5: The delta F508 deletion is the most common cause of cystic fibrosis. The isoleucine (Ile) at amino acid position 507 remains unchanged because both ATC and ATT code for isoleucine
145According to the Cystic Fibrosis Mutation Database maintained by the Hospital for Sick Children in Toronto, Ontario, more than 900 mutations are known in the CFTR gene. Different CFTR mutations result in different disease phenotypes. Some may have little or no effect on CFTR function, and some may result in milder forms of disease. For example, one study in the Netherlands indicated that CF patients who had one copy of delta F508 deletion and one of A455E mutation generally expressed a milder form of pulmonary disease than those who were homozygous delta F508.
The presence of variant forms of genes other than CFTR can also affect disease phenotype. Meconium ileus (MI), a severe intestinal obstruction, is observed in 15 to 20% of babies born with cystic fibrosis. No CFTR gene mutations have been associated with MI. A 1999 study has shown that cystic fibrosis modifier 1 (CFM1), a modifier gene located on chromosome 19, may determine MI susceptibility.
 
ETIOPATHOGENESIS
 
Genetics
The CF is inherited as an autosomal recessive trait. The CFTR is predominantly expressed in epithelial cells of airways, gut, pancreas, biliary tract, sweat glands and genitourinary system. There is a high frequency of CFTR mutations. To date, over 1340 mutations stand identified by the technique involving gene sequencing. The most common mutation is delta F508.
 
Pathophysiology
The following four defects are noteworthy:
  1. Failure to clear mucus secretions
  2. Paucity of water in mucus secretions, causing airway obstruction and similar changes in pancreatic and biliary ducts
  3. High salt content of sweat and other serous secretions
  4. Chronic/recurrent infections of respiratory tract.
The fundamental defect is the generalized anomaly in secretion of mucus, causing viscid secretions. Nearly all manifestations are the outcome of thick mucus secretions that obstructs the organ passages plus failure of sweat glands to reabsorb chloride and high sweat chloride concentration.
Moreover, airway epithelium fails to secrete chloride into the lumen along with active absorption of sodium.
The outcome is a cocktail of dehydration of luminal mucus, defective mucociliary action and collection of thick viscous secretions. This is the modus operandi of recurrent lower respiratory tract infections (LRTIs) and chronic obstructive pulmonary disease (COPD) in CF.
Gastrointestinal manifestations are the result of viscid eosinophilic material in the lumen of pancreas, intrahepatic bile duct, gallbladder, intestinal glands and submaxillary glands.146
 
Pathology
Box 10.2 lists the pathologic changes in various organs.
 
CLINICAL MANIFESTATIONS
Clinical presentation depends on the involvement of the organ/system as also on age at first diagnosis and intensity of progression of the disease.
Undoubtedly, the respiratory and digestive manifestations are predominant.
Cough, first dry and hacking and later productive with purulent expectorated mucus, usually beginning in early infancy is the most dominant manifestation of CF.
Recurrent attacks of wheezy bronchitis are accompanied by failure-to thrive (FTT). Eventually, (usually after first decade) pulmonary complications such as atelectasis, hemoptysis, pneumothorax, cor pulmonale and respiratory failure complicate the clinical picture.
Rhinorrhea with nasal obstruction and nasal polyps are common. Gastrointestinal manifestations in the form of chronic/recurrent diarrhea with extraintestinal (pancreatogenous) steatorrheic stools (large, voluminous, fatty that stick to the pan) with failure to gain weight despite good appetite and intake are common.
Typically, the child appears malnourished with protuberant abdomen, poor growth, wasted muscle mass and delayed maturation. He is particularly vulnerable to deficiencies of fat-soluble vitamins and other micronutrients.
Causes of malnutrition in CF include:
  • Poor energy intake
  • Enhanced energy loss (steatorrhea, glucosuria from CF-related diabetes)
  • Enhanced energy expenditure.
Experience has demonstrated that the most problematic manifestations with high vulnerability for complications are in relation to the lower respiratory tract. Eventually, it is the progressive pulmonary disease that ends up with respiratory failure and even death. Manifestastions of CF are listed in Box 10.3.
CF and malnutrition: A common denominator in all cases of CF is malnutrition.
But, why? The precise answer is energy imbalance as per Box 10.4.16147
Fig. 10.6: A 10-year-old child with CF. He presented with recurrent chest infections and chronic diarrhea ever since early infancy. Note significant malnutrition despite good dietary intake. Salient investigations showed stool fat 15.5 g/24 h, normal D-xylose absorption, sweat chloride 90 mEq/L, X-ray chest: was consistent with chronic bronchitis with bronchiectasis
 
DIAGNOSIS17
Clinical suspicion, particularly in the presence of recurrent respiratory infections and recurrent diarrhea since early infancy, especially with growth failure despite good dietary intake, is an important step towards detecting cases of CF.149
Confirmation: Generally speaking, demonstration of high sweat chloride (> 60 mEq/L) together with one or more of the following criteria is considered sufficient for the diagnosis:
  • Chronic obstructive pulmonary disease
  • Documented exocrine pancreatic dysfunction
  • Positive family history.
Various causes of high sweat chloride are listed in Box 10.5. Nevertheless, it must be borne in mind that in no other situation the levels ever touch the magnitude encountered in CF.
A level between 40 to 60 mEq/L should be considered suspicious. Generally speaking, levels in this range may be seen in
  • Infants
  • Children with atypical CF
  • Children with CF but retention of exocrine function.
Likewise, in certain conditions, sweat chloride may be false-negative
Box 10.7 presents currently-recommended diagnostic criteria for CF.150
According to the current understanding, identification of 2 CFTR mutations in association with suggestive clinical picture is diagnostic of CF. Nevertheless, the CF must not be considered ruled out if the results of genotype analysis are negative.
 
Newborn Screening
It consists in determination of:
  • Immunoreactive trypsinogen (IRT) on dried blood spots, and
  • Limited DNA testing on blood spots along with sweat chloride estimation.
Once screening gives the clue, diagnosis can be confirmed with sweat test.
With availability of such screening, diagnosis is frequently made much before manifestations of CF (say chronic cough, recurrent respiratory infections/diarrhea FTT) appear. Advantages of newborn screening are:
  • Prevention of nutritional deficiencies, thereby improving long-term growth and cognitive function.
  • Better lung function as a consequence of improved weight for age following early diagnosis and treatment.
  • Genetic counseling for the family.151
 
Prenatal Diagnosis (DNA Testing)
Prenatal diagnosis, by DNA mutation studies in the fetus, is recommended in the following situations:
  • All couples planning to have children
  • Individuals with a family history of CF
  • Partners of CF women.
In view of the improving prognosis with increasing longevity in CF, it may well be advisable to avoid termination of pregnancy.
 
Other Tests
These include pulmonary function, pancreatic function, radiology, microbiologic studies, etc.
 
TREATMENT
Early aggressive treatment is the cornerstone of good prognosis.
Though a life-lasting disease, availability of modern treatment, including good nutrition, better antimicrobials for superimposed infections, and modalities for improving lung function and enhancing digestion and absorption of nutrients have improved life expectancy. Quite a proportion of them are now reaching the fourth decade of life. Life expectancy in 1960s used to be just up to mid teens.
 
Specific Replacement Therapy18,19
Pancreatic enzyme replacement therapy (PERT) forms the cornerstone of management of CF. This may be administered either in the form of generic enzymes or proprietary preparations.
Proprietary PERT is available as:
  • Powder
  • Enteric-coated microsphere capsules
Generally, enteric-coated microsphere capsules are preferred over powders.
Availability is as up to 2,000 units lipase per enteric-coated, pH-sensitive enzyme microsphere capsules. The microsphere capsules should be either mixed in an acidic fruit or taken with a fruit juice. This is important since administration with high pH food/drink is likely to cause activation of the enzyme before it reaches the small intestine which is not desirable.
PERT may be calculated in terms of:
  • Weight of the subject: The recommended dose is a maximum of 2,500 lipase units/kg/meal. A dose exceeding this limit carries the risk of developing fibrosing colonopathy. In most infants, 2,000 to 4,000 units/feed suffice. Childen < 4 years, need 1,000 units/kg/meal and > 4 years 500 units/kg/meal.
  • Dose is 500 to 4000 lipase units/g of fat consumed in case of infants.152
 
Remaining Nutritional Therapy20-22
 
Enhanced Needs
Nutritional needs of the CF child are enhanced on account of:
  • Maldigestion and malabsorption, causing nutritional deficiencies
  • Increased work of breathing
  • Increased metabolic activity related to basic defect
  • Superadded infection(s) eventually causing anorexia and weight loss
  • Restrictive diets often given on account of recurrent respiratory infections, wheezy bronchitis and digestive/absorptive problems.
 
Diet
Energy needs in CF may be 50 to 100% that of the age-matched normal subjects. In addition to the age, factors such as energy level, lung function, and magnitude of steatorrhea and nutritional status play an important role in determining the needs. All these parameters are, therefore, required to be considered in calculating their diets.
On an average, the CF child's target need for calories is 130 Kcal/kg body weight. But, the need may become more (say 150–200 Kcal/kg body weight) in the event of acute severe malnutrition.
Actual diet should be in the form of normal mixed diet with enough of carbohydrates, proteins and fats. The fats are well tolerated, provided that PERT is being adequately given. Rather than focus on a diet in medium-chain fatty acids and discouragement of long-chain fatty acids (a practice boosted in the past), the stress needs to be on a diet that is acceptable and tolerated by the child. The traditional diet is, therefore perfectly all right.
Route (Enteral or Parenteral): Most subjects do well on enteral nutrition. Occasionally, the child may need nasogastric tube feeding, percutaneous enterostomy or short-term parenteral nutrition (intravenous hyperalimentation).
Anticipatory guidance may become necessary as the child grows and develops food likes and dislikes. While taking his preferences into consideration, parents must ensure that his nutritional needs are in no way compromised. Special attention is needed during toddle and adolescent periods when the risk of developing failure to thrive and malnutrition, respectively, is considerable.
Role of appetite stimulants such as cyproheptadine, megestrol acetate hydrazine sulfate and cannabinoids remains controversial. The consensus does not favor this therapy.
Role of anabolic steroids and growth hormone too remains debatable.21
 
Special Diets
Since chances of essential fatty acid deficiency (EFAD) and docosahexonoic acid deficiency (DHAD) in CF are enhanced, food rich in these elements (human milk, fish, marine, walnuts, almonds, etc.) may be added to diet. As a rule, there is no need to add proprietary supplements of these elements.153
 
Diet in Comorbidities
In grown-up subjects (say adolescents and young adults) with CF-related diabetes (CFRD), minor diet modification in the form of a cut on concentrated sweets and beverages may assist in controlling the high blood sugar levels.
 
Supplementation with Vitamins and Micronutrients
Supplements of vitamins, especially fat-soluble vitamins (A, D, E and K), together with iron, zinc and calcium are indicated in most instances. In the presence of overt deficiency signs (e.g xerophthalmia, scurvy, rickets, anemia, acrodermatitis enteropathica), specific micronutrients need to be given in therapeutic doses.
There is enough evidence that nutrition supplements lead to improved calorie intake and weight gain.
 
Fluids and Electrolytes
Since, in hot tropical areas in particular, risk of hyponatremia is high, CF subjects should be given additional fluids and sodium over and above the high sodium diet. The requirement in non-CF subjects is 2 to 4 mEq/L/da.
 
Therapy Targeted at Respiratory System
The lifeline of pulmonary therapy in CF is:
  • To clear secretions from airways (physiotherapy remaining the armamentarium), and
  • To control infection and colonization supported by prompt treatment of acute exacerbation through use of antimicrobial therapy.
 
Inhalation Therapy
The aim is to deliver medications and hydrate the lower respiratory tract.
 
Airway Clearance Therapy
It consists of chest physiotherapy, chest percussion (manual or mechanical), and postural drainage to move out secretions from small airways where expiratory flow rates are slow. It is advisable to continue airway clearance therapy even in the absence of evidence of infection.
 
Endoscopy and Lavage
Tracheobronchial suctioning and lavage is helpful in obstructed airways.
Antibiotics and mucolytic agents can also be directly administered by this method.
 
Antibiotic Therapy23,23
In order to control respiratory infection, antibiotic therapy–intermittent short course to almost continuous–is mandatory. Generally, doses are 2 to 3 times higher. Antibiotics may be administered.154
  • Orally to cover common pathogens S. aureus, nontypable H. influenzae, P. aeruginosa.
  • In aerosolized form in case of P. aeruginosa and other gram-negative pathogens which usually are resistant to oral antibiotics.
  • Intravenously in subjects with progressive or unrelenting infection.
It is advisable to employ a beta-lactamase stable antimicrobial along with a fluoroquinolone (ciprofloxacin, norfloxacin, ofloxacin) or an aminoglycoside gentamicin, amikacin, netilmicin).
 
Mucolytics
In order to lower the viscosity of the mucus secretions/sputum that eventually facilitates its clearance, recombinant deoxyribonuclease (rhDNase) and nebulized hypertonic saline have proved to be of value.
However, more work needs to be done to recommend their acceptability as standard supportive treatment of CF.
 
Bronchodilator Therapy
In the presence of reversible airway obstruction (improvement of >15% in flow rates following bronchodilator inhalation therapy), beta-adrenergic agonist aerosol is indicated.
 
Anti-inflammatory Therapy
In CF, frequent/chronic infection and the resultant inflammatory response contributes to lung destruction..
There is now sufficient evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen, administered in high doses over at least 4 years, leads to slowing down of disease progression. However, the side effects of NSAIDs such as gastrointestinal bleeding and perforation need to be borne in mind.
Chronic steroid therapy (oral), though effective in slowing down the progression of airway disease, is likely to cause serious side effects, including growth retardation.
It has been speculated that rather than low-dose oral steroids, it may well be advisable to use inhaled steroids. Several trials conducted so far support the contention that this therapy prevents pulmonary progression in CF subjects with relatively mild disease. Further clinical trials are, however, warranted before this therapy is accepted as a part of the standard protocol for management of CF.
155
 
Immunization
Full immunization, including HiB and pneumococcal vaccine, is generally indicated for CF patients.
Pseudomonas infection is quite an issue in CF. Infection with RSV might play a role in the initial Pseudomonas colonization and the decline in pulmonary function. RSV vaccine should be adsvisable in CF subjects as and when it becomes available in the near future.
Antibacterial vaccinations protecting directly against Pseudomonas aeruginosa colonization are promising for the future. The potential candidates are currently being assessed in clinical trials. More studies are needed to complete recommendations especially for CF subjects and transplant candidates.
 
Other Therapies
 
Growth Hormone
Administration of recombinant growth hormone, thrice a week, improves nitrogen balance and thereby nutrition, height and weight velocities.
 
Dehydration, Dyselectrolytemia and Salt Depletion
In case of acute gastroenteritis, prompt fluid and electrolyte therapy should be instituted, particularly bearing in mind the risk of hypochloremic alkalosis. Supplements of salt should be available for CF children, especially in summer.
 
Rhinosinusitis
Its antibiotic therapy fail to resolve the problem, an endoscopic sinus surgery may be resorted to.
 
Nasal Polyps
Despite initial response to treatment with local steroids and decongestants, polyps may cause considerable obstruction when surgical removal should be seriously considered.
 
Tracheobronchial Suctioning
For many CF children with a weak cough reflex, gentle suctioning can be very helpful. However, deep suctioning should be avoided as it can be very irritating.
 
Expectorants
Guaifenesin acts by stimulating gastric mucosa and the gastric nerve to stimulate the cough reflex. Furthermore, it also induces a vagally-mediated increase in airway secretion.
 
Surgical Intervention
As far as possible, local anesthesia should be preferred. When a major surgery needs general anesthesia, the surgery should either preceded by 1 to 2 weeks course of intensive antibiotic therapy with increased airway clearance before surgery or prompt intravenous antibiotic therapy.
Duration of anesthesia should be minimal. After a major surgery, early ambulation, airway clearance treatment, and intermittent deep breathing are important.156
 
New Therapies
  • Mutation-specific therapies (PCT 124) that suppress the termination codon, allowing some correction of the defect in CF.
  • Potentiators that activate CFTR mutant (VX-770) or traffic to the plasma membrane (G55ID-CFTR)
  • Therapies that facilitate bypassing of the primary CFTR defect (Demufusol, Moli 1901), thereby organizing the alternative ion channels and normalizing the ion transport properties. The result is correction of the mucociliary abnormality in the airway in CF.
 
PULMONARY COMPLICATIONS AND THEIR TREATMENT
With increasing lifespan, incidence of complications has enhanced. Such complications as atelectasis, hemoptysis, pneumothorax, superadded infections, including nontuberculous mycobacteria (NTB), bone and joint complications, sleep-disordered breathing, acute and chronic respiratory failure and congestive heart failure need prompt recognition and appropriate treatment depending on the merits of the individual situation.
Lung transplantation may be the last resort.
Table 10.1 lists the available guidelines for treatment of fatal complications of CF.
Table 10.1   Treatment of life-threatening complications of CF
Complication
Action
Liver disease
Ursodeoxycholic acid (by and large for prevention of progression of
liver damage)
Liver transplantation
Respiratory failure
Standard line
End-stage lung disease
Lung transplantation (ideal)
Alternatively, supportive and palliative care
157
 
PROGNOSIS24-26
Appropriate treatment and psychosocial support contribute to acceptable coping by infants, children and adolescents. Most of the children reach adulthood despite gradual progression of lung disease with a median cumulative survival exceeding 35 years. Increasing lifespan is accompanied by several psychosocial considerations.
CF, being a long-term chronic disorder, takes a considerable emotional toll.
Not just that, parents of subjects with CF too are quite vulnerable to development of psychologic problem.26,27 Parents of children with CF are expected to discharge responsibility not only for the physical care of their children, but also for dealing with medical, educational, and other service providers; for helping their children to cope with the physical and emotional demands of their illnesses; and for balancing competing family needs. Providing daily care to children with chronic health conditions often presents parents with a variety of burdens and obligations that can increase tension, deplete energy, and be accompanied by symptoms of psychological distress.
The inclusion of a psychologist in the multidisciplinary CF team is, therefore, of enormous benefit not only to the affected child but also to the family. Furthermore, the psychologic support can be of benefit to the other children in the ward in the event of such difficult time as acute respiratory failure that may terminate as death.
158
 
SUMMARY AND CONCLUSION
A multisystem, life-limiting, genetic disease involving the exocrine glands and causing predominantly progressive respiratory and gastrointestinal manifestations, CF is now known to occur in India and should be seriously considered in the differential diagnosis of recurrent/chronic respiratory infection with recurrrent/chronic diarrhea on top of failure to thrive. The CFTR should be considered the most dependable and confirmatory test though high sweat chloride (> 60 mEq/L) nearly confirms the diagnosis. Pancreatic enzyme replacement therapy (PERT) along with good nutrition is the lifeline of treatment of CF. Supportive care and use of appropriate antibiotic for prevention and treatment of superadded infections are mandatory. Inclusion of a psychologist in the multidisciplinary CF team is of enormous benefit not only to the affected child but also to the family. Lifespan has now increased to fourth decade. With increase in life expectancy, CF may be complicated (over and above the airway problems by such comorbidities as diabetes mellitus, liver disease, infertility, osteoporosis and fractures. Lung transplantation may be the only plausible wayout in end-stage CF.
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  1. Cystic Fibrosis Trust. History of cystic fibrosis. Available at: http://www.cftrust.org.uk/aboutcf/whatiscf/cfhistory/. Accessed on: 11 August 2012.
  1. Changing the Face of Medicine. Dorothy Hansine Anderson. Available at: http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_8.html
  1. Mehta S, Wadhwa UN, Perkash A, Chuttani PN. Small bowel function in chronic diarrhea in children. J Assoc Phys India 1968;16:343–347.
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  1. Gupte S, Walia BNS, Mehta S. Tropical malabsorption: Experience in north Indian children. In: Gupte S (Ed). Newer Horizons in Tropical Pediatrics. New Delhi: Jaypee  1977:270–283.
  1. Gupte S, Pal M. Coexistence of cystic fibrosis and celiac disease in two children. Asian Chron Med Sc 1989;4:122–125.
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Pediatric Flu11

Novy Gupte, Suraj Gupte, Sahil Pandita
 
INTRODUCTION
Globally, flu (influenza) accounts for a huge burden on the health and well-being of not only adults but also children. As many as 90 to 100 million children and adolescents are estimated to suffer from seasonal flu annually despite the availability of an effective vaccine.1 Even in flu pandemics, children suffer in a big way as exemplified in the most recent novel H1N1 flu pandemic of 2009 to 10.2
No pediatric age is a bar, including neonates, though flu is infrequent in neonates and early infancy.3
Clinical presentation is somewhat different from that seen in adults. In addition to high fever, chills and shakes, bodily pains, headache and a dry hacking cough, children often have nausea, vomiting and/or epigastric pain. As a result, parents and physician's attention gets distracted towards different diagnoses. In neonates, in particular, presentation is often atypical with feeding difficulty, jitteriness, irritability and vomiting. High index of suspicion is, therefore, essential for detecting cases.4
 
UNIQUE PECULIARITIES
As in most other diseases, influenza in childhood has its own special features.1,5 Some peculiarities of pediatric influenza are listed in Box 11.1.
 
HIGH-RISK CHILDREN
Even amongst children, certain groups of children are at yet increased risk for complications of Box 11.2 lists children at great risk of serious influenza-related complications.6
It may well be pertinent to know why children are at a higher risk for the flu? This is primarily because of the immature immune system.
Children with chronic health conditions are at even higher risk of getting the flu and experiencing complications. According to the CDC, 6 treating children with flu can be costly. Severe complications are most common in children <2 162years.
Figs 11.1A to E: Pediatric flu. Note that it occurs in all age groups, including infants < 6 months in whom, of course, incidence is much less. Even neonates may infrequently suffer from influenza
Children aged 6 months to 5 years are at risk of febrile seizures. Children with chronic health conditions such as asthma and diabetes have an extremely high risk of developing serious influenza related complications.
  • Children 6 months and older should get the flu vaccine.
  • Children younger than 6 months cannot get the flu vaccine. Parents should get vaccinated themselves and follow prevention tips to keep them healthy.163
  • Parents and care-providers of children younger than 5 years or with chronic health conditions should get the vaccine. If the child is younger than 5 or has any chronic health conditions and experiences flu-like illness, the family must contact a health care provider as soon as possible.164
 
ETIOLOGIC VIRUS1,7-9
Flu is caused by one of the three types of flu viruses. Types A and B are responsible for the seasonal epidemics. Type C virus causes sporadic—mild or asymptomatic —illness.
Type A and B are the primary pathogens causing epidemic disease. Type A has the potential for causing global pandemics as well (in addition to seasonal epidemics annually) though pandemics are admittedly the rare phenomena, occurring on an average thrice in a full decade.
Fig. 11.2: Flu virus types
Fig. 11.3: Flu virus. Note the glycoproteins, rod or hammer-like spikes termed hemagglutinins (HA) and knob-like spikes termed neuraminidase (NA), shown as spikes over the surface of the virus antigen
165
Fig. 11. 4: Major surface antigens of flu virus, hemagglutinin and neuraminidase
Type A virus, the predominant virus causing flu, is further divided into different subtypes based on the chemical structure of the virus, i.e. surface proteins hemagglutinin and neuraminidase.
 
Confirmed Serotypes of Influenza Type A Virus
Confirmed serotypes of type A virus are:
  • H1N1: Spanish influenza in 1928, H1N1 influenza in 2009
  • H2N2: Asian influenza
  • H3N2: Hong Kong influenza
  • H5N1: Avian strain—a pandemic threat
  • H7N7: Unusual zoonotic potential
  • H9N2, H7N2, H7N3, and H1 09.
There are two important types of antigenic variations in the HA and NA molecules: “antigenic drift” and “antigenic shift.”
Antigenic drift results from repeated point mutations. Point mutations, caused by inadequate ‘proofreading’ of the proper sequence, lead to amino acid substitutions within the HA and NA molecules. These mutations often affect the ability of antibodies to bind with the virion. This can lead to the virions being invisible to the host antibodies. The direct effect of the drift means that vaccines have to be annually updated.
The second type of antigenic variation, “antigenic shift” results from sharing of genes between different virions, i.e. reassortment. Antigenic shift is responsible for flu pandemics.166
 
EPIDEMIOLOGIC CONSIDERATIONS
Flu is highly contagious, particularly when children share close quarters in school classrooms and residential group facilities.10,11
It spreads when a child either inhales infected droplets in the air (coughed up or sneezed by an infected person) or when the child comes in direct contact with an infected person's secretions.
A person can be contagious one day before onset of symptoms and 5 to 7 days after being sick.
This can happen, for example, when they share pencils at school or play computer games and share the remotes or share utensils such as spoons and forks. Hand to hand contact is also important in transmission and spread of influenza.
 
PATHOGENESIS
Following its entry into the child's airway, the virus attaches to sialic acid.1,9 Then, it residues on cells via hemagglutinin (HA). By endocytosis, it enters the vacuoles. In the vacuoles, with progressive acidification, it fuses with the endosomial membrane. There is also release of the viral RNA into the cytoplasm. Thereafter, RNA is transported to the nucleus and transcribed. RNA that is newly synthesized is returned to the cytoplasm where it gets translated into proteins which are transported to the cell membrane.
Fig. 11.5: Replication of flu virus. Note the various stages, beginning with entry of the virus into the airway and its budding through the cell membrane
167Now the stage is set for budding of the virus through the cell membrane. Viral replication continues for 10 to 14 days.
Influenza virus invasion of the respiratory epithelium causes:
  • Loss of ciliary function
  • Reduced mucus production
  • Desquamation of the epithelial layer.
The net result of these changes is secondary bacterial infection either directly through the epithelium or through obstruction of the normal drainage by the Eustachian tube as happens in case of middle year space.
The exact immune mechanism involved in termination of primary infection and prevention against reinfection remains poorly understood presently. It has been conjectured that it may correspond to the induction of cytokines that inhibit viral replication, e.g. interferon and tumor necrosis factor.1
 
CLINICAL FEATURES
Except in infants and young children, a predominantly respiratory illness is the hallmark of influenza type A and B infections in children and adolescents.12,13 The symptoms are more severe than symptoms of a childhood common cold. Symptoms start abruptly.14,15 Usually, the child feels the “worst” during the first two or three days of onset. The symptoms in children are listed Box 11.3 lists the usual and unusual manifestations in pediatric flu.
Major manifestations may localize anywhere in the airway, producing an isolated upper respiratory tract illness, bronchiolitis or pneumonia.14,15
Many of the symptoms are mediated through cytokine production by the respiratory tract epithelium. There is no systemic spread of the influenza virus.
Typically, flu causes a febrile illness of 2 to 4 days. However, cough and evidence of small airway dysfunction may persis much longer, say few weeks.
High transmissibility of the influenza virus contributes to development of a similar illness by other family members or close contacts.
168
Fig. 11.6: A child with flu. The kinship of high fever with dry cough and bodily pains during the course of an outbreak of flu, is highly suggestive of the diagnosis. In infants and toddlers, manifestations may well be atypical, often contributing to missed or delayed diagnosis
Flu, being a less distinct illness in young children and infants, symptoms may well be localized to any region of the respiratory tract. Often, atypical presentation in the form of refusal of feed, irritability and jitteriness may fail to draw attention to the diagnosis of influenza. This often is the case in infants and toddlers.
 
DIAGNOSIS1-3,16,17
 
Clinical Suspicion
Clinical diagnosis of flu in a child in the course of an outbreak can be made with reasonable certainty in the presence of fever without focus, malaise, cough, coryza, bodily pains, etc.
 
Nonspecific Investigations
Nonspecific findings include a relative leukopenia and evidence of collapse or infiltrate in chest X-ray in 1 in 10 children with influenza.
 
Specific Investigations
Rapid and reliable diagnostic tests for influenza are based on variations of PCR viral genome detection technology or of antigen capture like ELISA.
The confirmation of the diagnosis (made by rapid tests) can be made serologically with acute and convalescent sera drawn around the time of illness and tested by hemagglutination inhibition.
169Isolation of the flu virus from the nasopharynx by inoculation of the specimen into embryonated eggs or a limited number of cell lines that support the growth of influenza virus.
Hemadsorption that depends on the capacity of the HA to bind red cells confirms the presence of the virus in the culture.
 
PREVENTION
 
Flu Vaccines17-19
Annual vaccination is the mainstay in seasonal flu prophylaxis. All children aged 6 months and older need to receive the vaccine to prevent influenza. Vaccinating children with the influenza vaccine each year helps protect them against influenza, especially against severe influenza.
Healthy children over age 2 years who do not wheeze or do not have a history of asthma may have the option of getting the nasal spray vaccine (live attenuated vaccine). Children aged 6 months and older can receive the influenza shot (inactivate/killed vaccine).
Influenza vaccine is neither available nor recommended in infants < 6 months. For them, the source of protection is immunity provided by the mother plus vaccinated family members and the care-providers.
Pregnant women and care-providers of children younger than 6 months or children with certain health conditions essentially need to be vaccinated. Vaccination to the mother is expected to elicit antibody that persists in the infant during the first 6 months when he is particularly prone to influenza. This explains why vaccine is not required by the baby in first 6 months. Neither is any such vaccine available.
Fig. 11.7: Flu vaccine is the “gold standard” and the best preventive modality against flu
170
However, a difficult situation crops-up when mother has not received vaccine because risk to the baby remains. It is, therefore, important that parents and other care-providers ensure taking the vaccine.
The seasonal influenza vaccine protects against three influenza viruses that the research indicates would be most common during the upcoming season. The 2012 to 2013 flu vaccine protects against the three main viruses that are responsible for the most illness of the season. Precisely speaking, it is expected to protect against an influenza A (H1N1) virus, an influenza A (H3N2) virus and an influenza B virus.
The vaccination is especially important for children younger than 5 years of age and children of any age with a long-term health condition like asthma, diabetes and heart disease. These children are at higher risk of serious flu complications if they get the influenza.
The subjects in contact with certain groups of children should get a seasonal vaccine in order to protect the child (or children) in their lives from the influenza. Box 11.4 lists the contacts of children who are recommended for seasonal flu vaccine by CDC.18
Influenza vaccination is the most effective method for preventing influenza virus infection and its potentially severe complications.
There are two types of influenza vaccines (Box 11.5).
Box 11.6 lists some important guidelines/points in relation to flu vaccine in children.171
 
Limitation of the Conventional Flu Vaccines
Trivalent influenza vaccines have helped protect millions of people against flu. There remain two problems: First—Quite a few months taken for producing the seasonal vaccine. Second—Lack of coverage of all strains, leaving possibility of flu attack despite vaccination. The first issue finds solution in FDA approved Novartis’ flu vaccine, Flucelvax which can be produced rapidly.
However, in six of the last 11 flu seasons, the predominant circulating influenza B strain was not the strain that public health authorities selected.
The 2011 to 2012 flu season set a record for the lowest and shortest peak of influenza-like illness, compared with other seasons, according to the Centers for Disease Control and Prevention. As of September 21, only 34 pediatric deaths occurred. But during the 2009 to 2010 flu season, 282 pediatric deaths occurred. This number includes the 2009 H1N1 pandemic.
Center for Disease Control and Prevention (CDC) estimates that about one-third of B-strain flu cases have been caused by the B-strain not included in this year's flu vaccine. Interestingly, this also means the strain protection choices made by the CDC for this year's flu vaccines were spot on; there is just an inherent limitation when you can only incorporate three-strain protection into a vaccine while there are four strains that cause illness that are circulating.
 
New Development in Influenza Vaccine: Fluarix Quadrivalent
Close on the heels of the Novartis'rapid-production flu vaccine Flucelvax, which is grown in mammal cells rather than in eggs, the FDA- approved GlaxoSmithKline (GSK)'s new four-strain seasonal flu vaccine is set to be available for the 2013 to 2014 flu season.19
The currently available typical flu vaccine in the market protects against three strains: 2 A virus strains and one B-strain. The new product adds protection against a second B-strain.
Let's see how the new vaccine scores over the presently employed vaccine. Each year, the viruses included in the vaccine change based on international surveillance and scientists’ estimations as to which types and strains of the flu will circulate. If the strains making the rounds do not match up with the strains found in the trivalent, or three-strain, vaccine, the incident of illness can increase across all age groups. It is here that Fluarix quadrivalent may have an edge by tacking 172on that second B-strain, providing an extraopportunity to match the circulating strain with the antidote.
 
Nonpharmaceutical Measures
In addition to vaccination, nonpharmaceutical measures, need to be enforced at quite a few levels (Boxes 11.7 to 11.9).
 
Flu in the Family: Protecting Children and Others
When a family member is unwell with the flu, the family can limit the spread of the illness to children by certain simple steps.
173
 
Chemoprophylaxis
During an flu outbreak, indications for chemoprophylaxis, include:
  • High-risk cases (both vaccinated and unvaccinated)
  • Healthcare providers of the index case
  • Immunodeficient cases
  • Children in whom vaccine is contraindicated.1174
Approved antiviral agents for chemoprophylaxis are:
  • Oseltamivir
  • Zanamivir
  • Amantadine.
In view of development of increasing resistance to amantadine, its use is no longer encouraged. Hence, we are left with only oseltamivir and zanamivir for a 10-day course for prophylaxis. A view is fast emerging that it is better to give the chemoprophylaxis for the whole period of exposure.
Chemoprophylaxis with zanamivir should be given only in children aged 5 years and beyond, provided that asthma is not coexisting. The dose of zanamivir is 10 mg daily for 10 days by inhalation. Two 5 mg inhalations (making a total of 10 mg) are needed daily.
 
TREATMENT1,6,21
Supportive/symptomatic treatment complements the drug therapy in flu.
 
Supportive Care
Though flu symptoms usually subside, excepting cough and generalized weakness, in around 4 to 5 days, these may last longer than 1 week. Caregivers can relieve and soothe children's aches and pains with basic supportive care. Acetaminophen may be administered for fever and relief of other symptomatology. In children having symptoms of influenza infection or colds, aspirin is not recommended because of an association with Reye's syndrome.175
Table 11.1   Dose of oseltamivir for 10-day chemoprophylaxis of influenza in children
Age group
Dose
Remarks
<1 year
< 3 months
12 mg OD
As a rule, not recommended in view of limited experience; may be employed in compulsive circumstances
3–5 months
20 mg OD
6–11 months
25 mg OD
1 year and beyond
< 15 kg
30 mg OD
15–23 kg
45 mg OD
23–40 kg
60 mg OD
> 40 kg
75 mg OD
Use cough suppressants and expectorants to treat the cough. Steam inhalations may also be useful. If dehydration occurs, administration of oral or intravenous fluids is indicated.
There are useful home remedies and over-the-counter medications to treat flu symptoms in children. Keep in mind that antibiotics are ineffective against the influenza. Antibiotics are useful to treat bacterial infections. However, the flu is a viral infection and antibiotics will not help. Antiviral medicines are sometimes helpful for high-risk patients if they are started in the first two days of getting sick. They generally only shorten the duration of the flu of one to two days. However, the number one line of defense for flu is to get the flu vaccine. Some common home remedies for flu in children include:
  • Getting plenty of rest
  • Drinking plenty of liquids
  • Using paracetamol, mefenamic acid or ibuprofen to lower fever and reduce aches (both are available in children's formulations).
Aspirin must not be employed in children or teenagers. Aspirin may increase risk of Reye's syndrome, a rare disorder that occurs almost exclusively in children and can cause severe liver and brain damage.
Over-the-counter (OTC) cough and cold medicines should not be given to children under 4 to 6 years of age in view of the serious adverse effects from them.
In very young children with congestion, a nasal bulb should be used to remove mucus. Spraying three drops of saline into each nostril provides some relief.
Some children may be at increased risk for serious complications from flu. Especially those with chronic health conditions such as asthma or other lung disease, heart condition, or diabetes.
Indications for hospitalization are:
  • The child has difficulty breathing and does not improve even after nasal suctioning and cleaning.176
  • The skin color appears bluish or gray.
  • The child appears sicker than in any previous episode of illness. The child may not be responding normally. For example, the child does not cry when expected or make good eye contact with the mother, or the child is listless or lethargic.
  • The child is not drinking fluids well or is showing signs of dehydration. Common signs of dehydration include absence of tears with crying, decrease in amount of urine (dry diapers), irritability or decreased energy.
  • A seizure occurs.
 
Antiviral Drugs
Antiviral drugs may be given, if the child is at high risk of serious complications.
In some cases, antiviral drugs can also be used to prevent infection from flu. These drugs block the replication of the flu virus, preventing its spread. In healthy children, antivirals such as oseltamivir (Tamiflu) and zanamivir (Relenza) may shorten the duration of flu and reduce the severity of flu symptoms.
 
Special Considerations for Treatment of Avian Flu
The child with avian influenza needs hospitalization to ensure that ventilator support becomes readily available in the event of respiratory distress. Oseltamivir is the primary drug of choice. Longer therapy may be needed to treat highly pathogenic (HP) avian influenza than seasonal influenza.
The WHO recommendations for HP avian flu A/H5N1 are listed in Box 11.12.
 
COMPLICATIONS2,20,21
Box 11.13 lists the underlying/coexisting/pre-existing conditions that particularly render a child to severe/complicated influenza.
Probability of a complication is significant if fever lasts more than three to four days or if the child complains of breathing difficulty, ear pain, congestion in the face or head, persistent cough, or seems to be getting worse. Young children under age 2 -- even healthy children -- are more likely than older children to be hospitalized from the complications.
Box 11.14 lists various complications of flu. Amongst these, the following are most frequently encountered:
Table 11.2   Antiviral agents for treatment of influenza in children
Drug
Route
Dose
Adverse reactions
Oseltamivir
Oral
12–75 mg BD for 5 days (depending on age/weight)
Nausea, abdominal discomfort, diarrhea, headache, cough, insomnia, skin rash. Must be taken with food to reduce GI upset
Zanamivir (only > 7 years of age)
Powder for inhalation
10 mg BD for 5 days
Bronchospasm, nausea, headache, dizziness, skin rash
177
178
Fig. 11.8: Most frequent complications of flu pertain to ear, upper airway and lower airway
179
Fig. 11.9: Bronchiolitis. Lower respiratory tract involvement in the form of bronchiolitis is frequent in infants and toddlers suffering from flu
  • Ear infection
  • Laryngitis
  • Lower respiratory tract infection (LRTI).
Figure 11.10 Bronchopneumonia. Infants, toddlers and young children < 5 years are particularly vulnerable to develop pneumonia as a complication of influenza.
 
PROGNOSIS AND OUTCOME
Uncomplicated pediatric influenza shows excellent prognosis as for as recovery is concerned.1,2,21 However, full recovery may take a few weeks rather than just days.22
 
SUMMARY AND CONCLUSION
Pediatric flu has certain peculiarities. Though even a neonate is not immune to it, in first 6 months of life, it is infrequent. Moreover, symptoms are atypical and may include lethargy, poor feeding, and poor circulation. The picture mimics other respiratory tract infections such as croup, bronchiolitis, bronchitis, or pneumonia in older children.
On account of their immature immune system, children stand greater chance of getting infected by influenza viruses and have higher frequency and severity of complications. Children already suffering from chronic health conditions like asthma and diabetes are at even higher risk of getting the influenza and experiencing serious influenza-related complications.
That flu vaccine is the best preventive means holds yet more eminently in children. No vaccine is available as yet for < 6 months infants. It is the parents and other care-providers who should get vaccinated themselves and follow prevention 180tips to keep them healthy.
Fig. 11.10: Bronchopneumonia. Note diffuse patches everywhere
Fig. 11.11: Lobart pneumonia. Note the massive right upper lobe consolidation complicating flu in a child who also had coexisting asthma
Beyond 6 months, all children must get the influenza vaccine annually.
If the child is younger than 5 or has any chronic health conditions and experiences influenza-like symptoms, the family must contact a health care provider as soon as possible.
Teaching healthy habits, especially cough etiquettes, to children assists in its prophylaxis.
Treatment comprises supportive measures and specific antiviral drugs (which also have a role in prophylaxis). Zanamivir should not be given to children 181with underlying asthma.
Figs 11.12A to D: Acute otitis media. Middle ear infection is a common complication of flu in children. All children with flu, especially in case of earache, must have the eardrum examined. Note the normal eardrum© and inflamed eardrum
While antipyretic may be given to bring down high temperature, it is important to avoid using aspirin which may cause Reye's syndrome, a fatal hepatic encephalopathy.
 
ACKNOWLEDGMENT
The authors express their indebtedness to Professor EA Whitehead, ICAH, London, known for his outstanding contribution to flu and other infectious diseases, for reviewing the drafts of the script of this chapter and offering worthy suggestions.
REFERENCES
  1. Wright PF. Influenza viruses. In: Kliegman RM, Stanton BF, St Geme III JW, Achor NF, Behrman RE (Eds): Nelson Textbook of Pediatrics, 19th edn. Philadelphia: Saunders/Elsevier  2012:1121-1125.
  1. Gupte S, Gupte N. A-Z Influenza. Gurgaon (NCR), Macmillan  2013.
  1. Gupte S, Pal M, Hamid A. Pediatric flu. Trends and tendencies. Intern Bull Infect Dis 2009;10:212–216.
  1. McIntosh CV, Smith A. Pediatric flu: Trends and tendencies (Follow-up communication-1). Intern Bull Infect Dis 2009;10:302–303.
  1. Elizabeth A. Pediatric flu: Trends and tendencies (Follow-up communication-2). Intern Bull Infect Dis 2009;10:422–423.
  1. Gupte S, Gupte N. Perspectives in Influenza. Gurgaon (NCR): Macmillan  2011.
  1. Centers for Disease Control and Prevention. The danger of flu to children. Available at: http://www.cdc.gov/flu/protect/children.htm. Accessed on: 13 June 2012.
  1. Gupte S, Aggarwal P, Manhas A. Microbiology and pathogenesis. In: Gupte S (Ed): Influenza: Complete Spectrum-1. Gurgaon (NCR): Elsevier  2011:29-53.
  1. Gupte S, Gupte N. Influenza revisited. In: Gupte S, Gupte N (Eds): Pediatric Infectious Diseases. Gurgaon (NCR): Macmillan  2012:125-150.
  1. Shaman J, Pitzer VE, Vibound C, et al. Absolute humidity and the seasonal onset of influenza in the continental United States. PloS Biol 2010;8:e1000316.
  1. Lowen AC, Mubareka S, Stee J, Palese P. Influenza virus transmission is dependent on relative humidity and temperature. PloS Pathog 2007;3:1470–1476.
  1. Eccles R. Understanding the symptoms of common cold and influenza. Lancet Infect Dis 2005;5:8–25.
  1. Das RR, Sami A, Lodha R, et al. Clinical profile and outcome of swine flu in Indian children. Indian Pediatr 2011;48:373–378.
  1. Hu JJ, Kao CL, Lee P, et al. Clinical features of influenza A and B in children and association with myositis. J Microbiol Immunol Infect 2004;37:95–98.
  1. Boyd C. Influenza: Everything You wanted to Know. Philadelphia: Smithsons  2011.
  1. Gupte S, Kumar S. Influenza in children: Issues and controversies. J Eur Soc Virol 2007;19:567–572.
  1. World Health Organization. Influenza update. Available at: www.who.int/csr/disease/influenza/2010_12_17_GIP_surveillance/en/index.html. Accessed on: 2 June 2011.
  1. Centers for Disease Control and Prevention. 2011-2012 Seasonal influenza (flu) vaccine safety. Available at: http://www.cdc.gov/flu/protect/vaccine/general.htm. Accessed on: 4 June 2012.
  1. Fierce Vaccines. FDA approves quadrivalent flu vaccine. Available at: http://www.fiercevaccines.com/story/fda-approves-gsk-quadrivalent-flu-vaccine/2012-12-17?utm_medium=nl&utm_source=internal. Accessed on:21 December 2012.
  1. Gupte S, Gupte N. Immunization and Vaccines. Gurgaon (NCR): Macmillan  2012.
  1. Gupte S. Influenza. Gurgaon (NCR): Macmillan  2010.
  1. Hoffman AB, Henry T. Flu in 21st century. Flu Update 2012;4:62–69.

Pleural Effusion12

Rashna Dass
 
INTRODUCTION
The term, pleural effusion, denotes an abnormal collections of fluid in the pleural space. It can be secondary to a variety of infectious and noninfectious conditions, which cause either excessive filtration or defective absorption of the pleural fluid. Pleural effusion may be a transudate or exudate. Most small effusions do not require any treatment. However, large effusions require some form of treatment.
 
ETIOLOGY
In the pediatric population, the most common cause of pleural effusion is infection. Parapneumonic effusions are the most common cause followed by renal disease, trauma, viral infections, malignancies, congenital heart disease and hepatic failure.1 Parapneumonic or synpneumonic pleural effusions occur in the presence of a pneumonia, lung abscess or bronchiectasis in the adjacent lung parenchyma. Tuberculosis is an important cause of pleural effusions in our country. Trauma can lead to rupture of the thoracic duct and collection of chyle in the pleural cavity.2 Chylous effusion can also be congenital and is a common cause of pleural effusion in the 1st week of life.3 The most common malignancy that causes pleural effusion is lymphoma followed by leukemia, neuroblastoma, Wilms tumor, seminoma and hepatoma.1 Hemothorax can occur secondary to trauma, malignancy, pulmonary infarction, arteriovenous malformation, postpericardiectomy syndrome and rupture of pulmonary sequestration.1 Other causes in our settings include hypoalbuminemia (malnutrition or nephrotic syndrome), liver cirrhosis and a misplaced central line or ventriculoperitoneal shunt. Bilateral pleural effusions are usually seen with generalized anasarca, nephritic syndrome, congestive cardiac failure, connective tissue disorders and malignancies.
 
Transudate Versus Exudates
It is important to distinguish between a transudate and an exudates as it has a direct bearing on the treatment modality. The main differentiating characteristics between the two are summarized in Table 12.1.185
Table 12.1   Differences between transudates and exudates4
Parameter
Transudates
Exudates
Pleural fluid protein
< 3 g/dL
≥ 3 g/dL
Pleural fluid LDH
< 2/3
> 2/3
Pleural fluid pH
> 7.45
< 7.3
Pleural fluid glucose
< 50% of blood glucose or < 40 mg/dL
≥ 40 mg/dL or ≥ 50% of blood glucose
Plasma: Serum protein
< 0.5
≥ 0.5
Plasma: Serum LDH
< 0.6
> 0.6
Pleural fluid cell counts
Lymphocytes, macrophages, monocyte
Neutrophils
The most accurate among the above parameters is the pleural fluid pH. A pH of > 7.45 is consistent with a transudate whereas a pH of < 7.3 occurs in the presence of increased carbon dioxide due to an infection.
 
CLINICAL FEATURES
Most children with an infective etiology will present with symptoms of respiratory involvement such as fever, cough, chills and respiratory distress. Others with a noninfective etiology such as nephrotic syndrome or congestive cardiac failure will be asymptomatic unless the effusion is large enough to cause respiratory compromise and present with dyspnea or orthopnea. Older children may have a pleuritic pain initially due to stretching of the pleural nerves and this disappears later on as the pleural fluid amount increases and both the layers of the pleura get separated. Pleural rub may be heard initially, but disappears later on. Percussion reveals a dull note which may be difficult to elicit in smaller babies. Occasionally, pericardial involvement will reveal decreased heart sounds. A thorough search for other organ involvement, lymphadenopathy, organomegaly, testicular enlargement, abdominal masses and bruits must be looked for.
 
Imaging
The first and easily available tool to detect a pleural effusion is the chest radiograph. Obliteration of the costophrenic angle is the earliest finding suggestive of a pleural effusion. Presence of more than 10 mm of fluid between the inner aspect of the chest wall and the lung parenchyma indicates that the effusion is significant and requires drainage. The other useful modality of imaging is ultrasonography (USG) of the chest. It also is useful to differentiate between a solid mass and fluid. In addition it gives information on presence of fibrin strands and loculations. Computed tomography (CT) is rarely required to be done for pleural effusions except for studying the underlying pleura and parenchyma. It is best avoided as it causes a high-radiation exposure. 186
 
Diagnostic Tapping of the Pleural Fluid
A diagnostic thoracocentesis should be done in all children except in very small effusions. A pale yellow fluid suggests a transudate whereas a milky fluid suggests chyle. Chyle may be clear in neonates or if a patient is fasting. The physical characteristics of chyle, which helps to differentiate it from other types of effusion are the milky color, lymphocytic predominance on cell count, total fat content more than plasma, protein more than 3 g/dL, glucose and electrolytes similar to that found in plasma, fat globules on Sudan stain and change of color of the chyle on injecting lipophilic dyes.1 Blood stained fluid usually indicates malignancy, trauma or sometimes even infection.5 The pleural fluid must be sent for malignant cytology in all cases of hemorrhagic effusion. In addition to the cytological and biochemical analysis, the pleural fluid must always be sent for a gram stain, acid fast bacilli stain and aerobic and anaerobic cultures wherever possible. Tubercular etiology is usually suggestive if the cells are mostly lymphocytic in origin, protein content is > 4 g/dL, sugar < 40 mg/dL and the lactate dehydrogenase (LDH) levels are elevated. The fluid can also be sent for estimation of the adenosine deaminase (ADA) levels. Levels of > 36 IU/L are suggestive of the likelihood of a tubercular etiology and > 100 IU/L are all due to tubercular etiology.6
 
TREATMENT
Treatment consists of immediate measures and treatment of the underlying cause.
 
Immediate Measures
If the effusion is large and causing respiratory compromise, one should go in for a thoracocentesis and the fluid removed slowly so that the respiratory compromise is relieved. One should not attempt a fast removal as it causes re-expansion pulmonary edema, hypotension and circulatory collapse.7 Though studies are lacking in children, adult recommendations state that not more than 10 mL/kg or 1.5 liters per day should be removed or up to 500 mL/hour can be removed.8 If the pleural effusion is due to hypoalbuminemia, then a concomitant slow albumin infusion can also be started at 25 cc of 25% albumin for every 2 liters of fluid drained. If required, repeated thoracocentesis can be done. Fluid can be removed till patient develops chest pain or sever coughing. Small effusions do not require drainage and can be managed conservatively.
 
Treatment of the Underlying Cause
This depends on the etiology of the pleural effusion.
 
Chylous Effusions
Most require complete drainage by single thoracocentesis use of medium chain triglyceride as a major dietary source and replacement of nutrient losses. Many practitioners would do a refeeding of the chylous collections by a nasogastric tube. This helps to maintain the nutrition and electrolyte balance. Conservative 187treatment is usually continued for a period of 4 to 5 weeks to allow the thoracic duct rent to close by itself. In case of persistence of chylous pleural effusion inspite of adequate conservative management, then one can consider other measures such as pleurodesis or ligation of the thoracic duct. Chest tube insertions are hardly required as the fluid is sterile and also has its own bacteriostatic properties.
 
Malignant Pleural Effusions
These usually do not require drainage unless causing respiratory distress. Treatment of the underlying disease with the appropriate chemotherapy is usually sufficient. However, if the effusion continues to recollect then one can do a pleurodesis or a shunting of the pleural fluid to the peritoneal cavity (pleuroperitoneal shunt).
 
Tubercular Pleural Effusions
These do not require treatment most of the times unless there is severe respiratory compromise or there is suspicion of a superadded infection. Most respond well to antitubercular therapy and steroids.
 
Parapneumonic Effusions
These also do not require drainage if small. Most respond well to conservative treatment with antibiotics and symptomatic management. However, tube thoracostomy should be considered in the following situations:1
  1. Pleural fluid pH < 7.2 or > 0.05 units below the arterial pH.
  2. Pleural fluid glucose < 40 mg/dL.
  3. Pleural fluid LDH > 1,000 U/L.
  4. Presence of frank pus.
  5. Positive gram stain.
  6. Sepsis due to Staphylococcus aureus or Haemophilus influenzae.
    The chest tube is usually removed once the drainage reaches 30 to 40 mL/day for at least two consecutive days. Details of treatment of empyema are discussed later in the chapter on empyema.
 
Traumatic Pleural Effusions
This usually require a chest drain insertion to drain all the blood out and also as the patient stands a risk of developing a pneumothorax during the course of recovery due to injury to the underlying lung. A thorough examination of other mediastinal and abdominal organ involvement must be done.
 
SUMMARY AND CONCLUSION
Pleural effusions result from various infective and noninfective causes. In children, bacterial etiology appears to be the most common followed by tuberculosis in the Indian context. Noninfective causes can be due to chyle, malignancy, trauma or hypoalbuminemia. It is important to distinguish between a transudate and an exudates by pleural fluid analysis. Children with pleural effusions usually present 188with features of respiratory distress, which is confirmed by a chest X-ray. The USG chest is helpful to distinguish between an effusion and a solid mass and to provide information on presence of fibrin strands and loculations. Diagnostic thoracocentesis is indicated in all patients. The color of the pleural fluid is useful to distinguish between different etiologies (chyle, malignancy, trauma, transudate). Tubercular etiology is likely if the pleural fluid ADA is > 36 IU/L. Large effusions require thoracocentesis and slow removal followed by treatment of the underlying cause. Intercostal water seal drainage (ICWSD) is only required for those cases, which suggest an infective etiology on pleural fluid analysis. Prognosis depends on the underlying etiology.
REFERENCES
  1. Efrati O, Barak A. Pleural effusions in the pediatric population. Pediatr Rev 2002;23: 417–426.
  1. Soto-Martinez M, Massie J. Chylotorax: diagnosis and management in children. Pediatr Res Rev 2009;10:199–207.
  1. Sassoon CS, Light RW. Chylothorax and pseudochylothorax. Clin Chest Med 1985; 6:163–171.
  1. Light RW. Pleural effusion. NEJM 2002;346:1971–1977.
  1. Dass R, Deka NM, Barman H. Empyema thoracis: Analysis of 150 cases from a tertiary care centre in north East India. Indian J Pediatr 2011;78:1371–1377.
  1. Verma SK, Dubey AL, Singh PA, Tewerson SL, Sharma D. Adenosine deaminase (ADA) level in tubercular pleural effusion. Lung India 2008;25:109–110.
  1. Feller-Kopman D, Berkowitz D, Boiselle P, Ernst A. Large-volume thoracentesis and the risk of reexpansion pulmonary edema. Ann Thorac surg 2007;84:1656–1661.
  1. Balfour-Lynn IM, Abrahamson E, Cohen G, et al. BTS guidelines for the management of pleural infection in children. Thorax 2005;60:9(Suppl):11-121. Doi: 10.1136/thx.2004.030676.

Empyema Thoracis13

Rashna Dass
 
INTRODUCTION
Empyema thoracis is a Latin term, meaning presence of pus in the pleural space. Pleural empyema is a known complication of pneumonia. The earliest descriptions of empyema thoracis and its surgical management was made by Hippocrates.1 By the 19th century, aspiration of pleural contents, under water seal drainage and surgery, i.e. rib resections for open drainage were all practised.2 Though empyema thoracis was considered a rare event in the past in the developed world due to effective antibiotic treatment, recent reports suggest that it appears to be on the rise in the developed world as well.3,4 It still remains a major problem in developing nations including India. About 40% of pneumonias progress to effusions and of these about 60% of the effusions result in formation of empyema.5 Thus, empyema thoracis though low in incidence remains a major cause of morbidity in children with pneumonia throughout the world.6,7 The main difference between adult and pediatric empyemas is the absence of underlying lung disease in the pediatric age group, thus resulting in an excellent outcome. Optimal management, however, remains controversial till date.
 
EPIDEMIOLOGY
The incidence of parapneumonic effusions and empyema in children is about 3.3 per 100,000 children.8 Though a small number of reports exist from India, none have been able to describe the exact incidence of the problem as most are hospital-based clinical studies and not epidemiological surveys. So, the true extent of the problem in our country is not known till date. However, it has been seen that most children affected are below the age of 5 years and males are affected more than females.9,10 Most cases are reported to present in the winter and spring months from the Western literature9 in contrast to reports from India, where the cases are more common during the hot and humid months (April to August).11 190
 
PATHOPHYSIOLOGY AND PATHOLOGY
The pleural space contains about 0.3 mL/kg of body weight of pleural fluid, which continuously circulates.12 Normally the pleural space can handle several hundred milliliters of extrafluid in 24 hours.13 Pleural effusion occur when the balance between formation of the pleural fluid and drainage is altered. An infection of this fluid results in empyema. Normally, the pleural fluid contains a small number of cells consisting of mostly mesothelial cells, macrophages and lymphocytes, low-protein levels (0.1g/L) and lactate dehydrogenase (LDH), higher levels of bicarbonate, lower levels of sodium and same levels of glucose compared to the serum levels of the same substances.14 Disease processes such as an infection of the adjacent lung alter these parameters by activating an immune response and pleural inflammation. The pleural inflammation results in increased pleural vascular permeability, which in turn allows the migration of inflammatory cells like neutrophils, lymphocytes and eosinophils into the pleural space.12 The process of migration of inflammatory cells in to the pleural space is mediated by cytokines such as interleukin (IL), i.e. IL-1, IL-6, IL-8, tumor necrosis factor (TNF)-α and platelet activating factor released by the mesothelial cells lining the pleural space.12 This results in the exudative stage of the pleural effusion. Bacterial invasion occurs when this progresses to the fibropurulent stage. Further neutrophil migration occurs along with activation of the coagulation cascade resulting in increased procoagulant activity and decreased fibrinolysis.15 Fibrin deposition in the pleural space leads to septation or loculation and there is also a rise in the pleural fluid LDH and fall in the pH and glucose levels.16
Host factors also play an important role in the development of parapneumonic effusions. Increasing pleural permeability in non-infectious inflammatory diseases, trauma or malignancy allows the collection of a thin serous fluid in the pleural cavity, which may become secondarily infected. As the body attempts to ward off the infection, the pleural space starts to fill up with fluid, pus and dead cells. The process of development of empyema is slow and occurs in the following three phases:
  1. Exudative phase (Acute phase): This phase is characterized by increase pleural permeability and collection of a serous fluid in the pleural cavity. The fluid mostly contains neutrophils and is sterile.
  2. Fibrinopurulent phase: The second phase is characterized by thickening of the fluid, accumulation of fibrin, formation of the fibrin membrane deposition leading to loculations within the pleural space.
  3. Organizing phase (Chronic phase): Failure to treat or inadequate or ineffective or delayed treatment of the infection results in the progression to the third phase when resorption of the fluid occurs forming a thick fibrous material (pleural peel), which can entrap the lung.
Sometimes, the empyema burrows through the parietal pleura into the chest wall to form a subcutaneous abscess. This subcutaneous abscess may eventually rupture through the skin and discharge spontaneously forming what is traditionally known as empyema necessitans.17191
 
ETIOLOGY
Empyema thoracis never occurs as a primary event. Parapneumonic effusion and its subsequent infection is the most common cause of empyema in childhood.
The causes of empyema in children include the following:
  1. Pneumonia caused mostly by bacteria and seldom by tuberculosis or viruses
  2. Ruptured lung abscess
  3. Bronchiectasis
  4. Trauma
  5. Rupture of amebic liver abscess
  6. Malignancies
  7. Spread of infection from contiguous structures such as the esophagus, mediastinum, retropharyngeal, paravertebral or subphrenic spaces.
 
MICROBIOLOGY
The reported isolation of bacteria from the pleural fluid varies from 8 to 76%.9,18,19 Studies from India have shown culture positivity of 48 to 75% in one11 and 32% in another study.10 The wide variation in the yield of positive cultures may be due to differences in sampling methods and in the current scenario the widespread and prior use of antibiotics which renders the pleural fluid sterile. Newer and sophisticated molecular techniques such as polymerase chain reaction (PCR) help to identify the etiological agent in about 75% of the cases.20
The list of bacteria causing empyema includes Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Mycobacteria, Pseudomonas aeruginosa, anaerobes, Mycoplasma pneumoniae and fungi. In the preantibiotic era, S. pneumoniae was the most common organism isolated followed by S. pyogenes and S. aureus.14 Use of penicillin and sulfonamides reduced the incidence of S. pneumoniae and S. pyogenes to a great extent and in the 1960s there were increasing reports of S. aureus as the common organism causing empyema.14 However with the introduction of penicillinase stable penicillins and other anti-staphylococcal agents the incidence of S. pneumoniae empyema has increased once again. Currently studies from the West as well as India reflect S. pneumoniae to be the most common isolate detected from pleural fluid cultures.10,20,21 The bacteriological profile in developing countries differs with S. aureus being the most common pathogen during the hot and humid season, when staphylococcal skin infections are more common.11 Most of the S. pneumoniae were still penicillin sensitive and the S. aureus strains showed both methicillin sensitivity as well as methicillin resistance.
Tubercular empyema can result from progressive pulmonary tuberculosis. Tubercular empyema accounts for about 6% of empyema cases worldwide.14
 
CLINICAL FEATURES
The clinical features depend up on the stage of the disease, host factors and presence of complications if any. There are two common modes of presentation.192
 
Classical Presentation
Here the child will have fever, malaise and lethargy early on in the disease. This progresses to cough, breathlessness, exercise intolerance due to the underlying pneumonic process. Some patients also have halitosis and others may have associated abdominal pain (referred pain due to the pneumonic process). The symptoms may become more pronounced due to the pleural involvement when the patients are more unwell. Chest pain may develop due to the involvement of the pleura and children are often seen to lie on the affected side in an effort to splint the chest and reduce the pain. Others may present with increasing respiratory distress, air hunger and cyanosis in the extremely sick patients. On examination, the children are found to have tachypnea with or without subcostal retractions. Pleural effusion is suggested by the presence of fullness of the chest wall along with decreased chest expansion on the affected side. There is presence of dullness on percussion and diminished or absent air entry on the affected side. Trachea is usually deviated to the opposite side. In extremely sick cases there is cyanosis off oxygen due to a ventilation-perfusion mismatch.
 
Alternative Presentation
This is usually in those patients who have already been diagnosed as pneumonia, but does not respond to the usual and appropriate antibiotics. Fever continues along with increasing respiratory distress. Such patients who do not respond to antibiotics and supportive treatment after 48 hours of initiation of treatment require re-evaluation for the presence of a pleural collection. These patients require a thorough clinical examination and radiographic studies for the detection of fluid or pus in the pleural cavity.
Table 13.1   Childhood severity assessment22
Age group
Mild
Severe
Infants
Temperature < 38.5°C
Respiratory rate < 50 breaths/min
Mild recession
Taking full feeds
Temperature > 38.5°C
Respiratory rate > 70 breaths/min
Moderate to severe recession
Nasal flaring
Cyanosis
Intermittent apnea
Grunting respiration
Not feeding
Older children
Temperature < 38.5°C
Respiratory rate < 50 breaths/min
Mild breathlessness
No vomiting
Temperature > 38.5°C
Respiratory rate > 50 breaths/min
Severe difficulty breathing
Nasal flaring
Cyanosis
Grunting respiration
Signs of dehydration
193
Table 13.2   List of initial investigations for suspected parapneumonic collections
S. no.
Tests
1.
Chest radiograph
2.
Ultrasonogarphy of the chest
3.
Blood cultures (aerobic and anaerobic)
4.
Full blood count
5.
Serum electrolytes (to rule out syndrome of inappropriate ADH* syndrome)
6.
Serum albumin
*ADH = Antidiuretic hormone
 
ASSESSMENT OF SEVERITY OF THE ILLNESS
Once a pleural collection is suspected on clinical grounds then one has to assess the severity of involvement based on the British Thoracic Society (BTS) guidelines as outlined in Table 13.1.22 These guidelines are the same as that used for the assessment of pneumonia with special emphasis on assessment of oxygen saturation (SaO2) levels with levels below 92% indicating towards a more severe illness.22
 
DIAGNOSIS
Diagnosis of empyema is based on a good history, clinical findings and investigations. The initial investigations are outlined in Table 13.2.
 
Radiology
 
Chest X-ray
Chest X-ray is recommended that a posteroanterior (PA) or anteroposterior (AP) view should be taken. There is no role for a routine lateral chest X-ray.14
The earliest sign of a pleural effusion is the obliteration of the costophrenic angle along with a rim of fluid ascending along the lateral chest wall (meniscus sign) on an AP or PA view (Fig. 13.1A). In case of a supine film in a younger child the appearance is that of a homogeneous increase in opacity over the lower lung fields. In this case there is no blunting of the costophrenic angle. Sometimes large amount of fluid leads to a total whiteout of the lung field and in such a situation it is difficult to understand whether the whiteout is due to a solid underlying lung pathology or a large effusion (Fig. 13.1B). Occasionally one sees a whiteout on affected side with collapsed lung parenchyma due to pyopneumothorax, significant mediastinal shift and scoliosis (Fig. 13.1C). Lateral X-rays do not add any useful additional information.
 
Ultrasonography of the Chest
Ultrasonography (USG) is recommended for the confirmation of the presence of fluid in the pleural space and also as a guide for aspiration of the pleural contents 194as well as placement of the drainage catheters (thoracocentesis).14
Figs 13.1A and B:
The USG helps to confirm the presence of fluid and also helps to estimate the size of the effusion, detect the loculations and also comment on the echogenecity of the fluid, presence of fibrin strands, pleural thickening and organized collections (Fig. 13.1D). The USG is helpful in guiding pleural fluid aspiration or placement of intercostal 195chest drainage tubes especially for loculated effusions where the optimum site for drainage is marked on the skin.
Figs 13.1A to D: Empyema thoracis: (A) Meniscus sign; (B) Right sided whiteout lung in a supine film; (C) Supine film showing whiteout left lung field along with collapsed lung parenchyama (arrows) due to pyopneumothorax, mild scoliosis and mediastinal shift. Note that air-fluid level is not well appreciated since this is a supine film; (D) Fibrin stands and loculations (white arrows) in USG of chest
196It is also a good non-invasive way of assessing response and deciding on withdrawal of drainage catheters as it obviates the radiation exposure present with the use of repeated chest X-rays.
 
Chest Computed Tomography
These are routinely not recommended for empyema.14 Studies have shown that there is no added benefit of doing computed tomography (CT) chest when compared to USG chest.23,24 Moreover the exposure to high degree of radiation limits the use of CT as a routine practice in empyema or pleural effusion. The radiation dose to a child from one CT scan is equivalent to about 400 chest X-rays.14 CT is said to be useful these days only for a few select cases where USG is technically difficult or in complicated cases prior to surgery for a proper delineation of the anatomy and see for the presence of parenchymal lesions such as a lung abscess. This helps in proper planning of the surgery.14 However in resource limited settings one need not delay surgical intervention waiting for a CT chest.10
 
Blood Culture
It is recommended that all patients with parapneumonic effusion should have a blood culture prior to start of antibiotic therapy.14 Performance of blood culture has been found to a worthwhile test.25 Though the rate of positivity is low (10%), a positive blood culture is helpful not only to guide choice of antibiotics but also to know about the current prevalent strains in the community and the resistance patterns. Thus, it helps to establish rational antibiotic policies.
 
Acute Phase Reactants
Acute phase reactants such as white cell count, C-reactive protein, erythrocyte sedimentation rate and procalcitonin were done initially to differentiate between viral and bacterial infections, but are generally not very useful in the clinical setting. These tests are also not useful in predicting the progression of a pneumonia to a parapneumonic effusion.
 
Serum Albumin
The serum albumin is usually low especially in the setting of protein energy malnutrition, which is widely prevalent in developing countries such as India. However, albumin replacements are rarely required.
 
Pleural Fluid Analysis
All effusions must be sent for analysis by performing a diagnostic test. The pleural fluid is routinely collected in sterile containers and sent for the following analyses:
  1. Gram stain and culture: Gram stain examination improves the yield of bacteria and is available quickly and aids the management decisions. Majority of the patients may have received some form of antibiotics which renders the culture sterile in most cases. However, culture and sensitivity must be done for 197whatever yield is possible as this helps for epidemiological purposes as well as knowing the sensitivity and resistance patterns of the prevailing organisms in the community and help to guide decisions on appropriate antibiotic choice and encourage rational prescription practices. The yield or organisms after pleural fluid culture varies from study-to-study. Some studies have shown a positivity of 32 to 82%.10,26-30 Stains for Mycobacterium tuberculosis must also be performed.
  2. Cytology: The aspirated pleural fluid must be sent for a total and differential cell count. Most fluids will show a polymorphonuclear cell predominance. Predominance of lymphocytes should raise the suspicion of a tubercular or malignant process. A Mantoux test must be performed whenever there is a lymphocytic predominance. However, one must remember that 10% of tuberculous pleural effusions show a neutrophilic predominance.31 Malignant pleural effusions are usually hemorrhagic in children and must be sent immediately for examination for malignant cells.
  3. Biochemistry: Biochemical analysis of pleural fluid has not been found to be of any practical management in the treatment of children with pleural effusions or empyema. The BTS guidelines therefore recommend that biochemical analysis of pleural fluid is therefore unnecessary in the management of uncomplicated parapneumonic effusions or empyema.14
Bronchoscopy: The BTS guidelines recommend that there is no role for routine flexible bronchoscopy in children with empyema.14
 
MANAGEMENT
Management consists of initial stabilization and continuing care thereafter.
 
Initial Stabilization
The initial stabilization consists of:
  1. Oxygen therapy: All patients must have a SaO2 measurement done, if possible. If SaO2 is < 92%, then oxygen is given via a nasal catheter or a face mask and titrated to maintain an SaO2 > 92%. If there are no facilities to measure the SaO2 then one can empirically start on oxygen supplementation to improve the respiratory dynamics.
  2. Intravenous fluid, if child unwilling or unable to take orally.
  3. Analgesia and antipyretics.
  4. First dose of antibiotics: All cases should be managed with intravenous antibiotics. The antibiotic must be active against both S. pneumoniae, S. pyogenes and S. aureus. Most of the strains in India are still penicillin sensitive.10,11 Most of the strains of S. aureus from India are still sensitive to cloxacillin and methicillin resistant strains of S. aureus is still very low in India.10,11 Since different studies in India have shown S. pneumoniae and S. aureus as the most common strains in India,10,11 it is wise to start an antibiotic which covers both. Intravenous ampicillin-cloxacillin combination is a good choice as an initial antibiotic.198
  5. Chest drain if indicated: Some patients may come with impending respiratory failure due to a massive pleural collection or the presence of pyopneumothorax and such patients benefit with immediate chest tube insertion and drainage. This helps to expand the lung and improve oxygenation.
 
Continuing Care
Here the decision has to be taken on conservative management and surgical interventions.
 
Conservative Management
The BTS guidelines recommend that all cases with empyema should be managed with intravenous antibiotic and intercostal water seal drainage (ICWSD) for those with significant effusions.14 Small effusions can be treated with antibiotics only, but with close monitoring for clinical response and any evidence of enlargement of the effusion or progression of the parapneumonic collection to a fibropurulent or organized phase when ICWSD becomes a necessity. Long-term results with antibiotics and ICWSD shows a response in about 92% of cases.32 Studies from India show a lower success rate of 62% and 78%.10,11 The reasons for this could be a late referral of cases with more advanced stage of the disease at presentation. The duration of hospital stay with antibiotics and ICWSD range from a mean of 6 days in Western literature32 to 7.4% and 12% in studies from India.10,11 However, long-term results with antibiotics and ICWSD are good and most patients achieve full lung expansion and return of normal lung function. There is no role for management with repeated thoracentesis and therefore in all those with significant pleural collection, ICWSD should be inserted at the beginning of treatment.14 The duration of intravenous antibiotics should be for at least 1 to 3 weeks or till there is control of infection as evidenced by subsidence of fever and respiratory distress, improvement in general condition and cessation of pus discharge.10 This is then followed by oral antibiotics to complete at least 4 to 6 weeks of total antibiotic treatment or longer depending on resolution of symptoms.
 
Intrapleural Fibrinolytics
Fibrinolytic drugs such as streptokinase, urokinase and alteplase help to lyse the fibrinous strands in empyemas and thus clear the lymphatic pores. This helps to establish the process of effective filtration and reabsorption of the pleural fluid and thus normalize the pleural fluid hemodynamics. Fibrinolytics have been seen to increase the pleural fluid drainage and reduce the hospital stay significantly from various studies.33-35
One study from India did not show any significant difference in the hospital stay with use of fibrinolytics and this could be attributed to a more conservative management approach with fibrinolysis being used at a later stage when patients did not show good drainage or USG showed presence of fibrin strands or loculation. The BTS guidelines, therefore, suggest the upfront use of fibrinolytics in all cases of complicated parapneumonic effusions (thick fluid with loculations) or in those with frank empyema at admission.14 There is no evidence to suggest that any of the 199three fibrinolytic agents are more superior to others and all can be used depending on their availability and cost factor. In a study from India, both streptokinase and urokinase were used in 22% vs 16% patients respectively depending on availability and affordability.10 The dose of streptokinase is 12,000 to 15,000 units/kg in 50 mL 0.9% saline once daily with a dwell time of 1 to 2 hours as used in different studies36,37 and that for urokinase is 40,000 units in 40 mL 0.9% saline twice daily for 3 days to children above 1 year of age and 10,000 units in 10 mL 0.9% saline twice daily for 3 days in those children below 1 year of age with a dwell time of 4 hours.14 Alteplase is used in a dose of 0.1 mg/kg once daily with a dwell time of 1 hour.35 There are reports of complications such as fever and hemorrhage with the use of streptokinase. Urokinase does not cause many side effects except for a rare case of hypersensitivity reaction. Children most often describe chest discomfort and pain on intrapleural instillation and this can be reduced by addition of 0.25% bupivacaine at a dose of 0.5 to 1.0 mL/kg along with the intrapleural fibrinolytic agent.14
 
Surgery
Certain proportions of patients with empyema invariably do not respond to conservative management and require surgery. There are three kinds of surgical interventions available to treat complicated unresponsive empyemas:
  1. Video-assisted thoracoscopic surgery (VATS)
  2. Mini-thoracotomy
  3. Decortication.
Video-assisted thoracoscopic surgery is a minimally invasive procedure where the debridement of the fibrinous pyogenic material is done under direct thoracoscopic view. It leaves behind three small scars. Mini-thoracotomy is similar to VATS in that it achieves debridement under a small opening of the thoracic cavity. It is an open procedure. Decortication involves an open thoracotomy in the posterolateral chest wall followed by excision of the thick fibrinous pleural rind and evacuation of pyogenic material. It is a longer procedure leaving behind a long linear scar. All the above three procedures are followed by insertion of an ICWSD to facilitate drainage of residual fluid or pus.
The availability of thoracic surgeons or general surgeons or pediatric surgeons trained in thoracic surgery is a major issue in deciding to send patients for a surgical intervention. The VATS is a recent development which has come into practice, especially in the pediatric age group. Therefore, the use of VATS depends on the availability of trained individuals as well as the equipment required for the same. However, the surgeons must be involved early on in the management wherever possible for a better outcome. There are no clear cut guidelines on the timing of surgery. Studies have shown that early antibiotics and ICWSD are quite effective in treatment of pediatric empyema even in the presence of significant pleural thickening at discharge. These patients on follow up have good lung expansion and function.38 So these authors suggest that radiological presence of thickened pleura may not be enough to decide on the need for a surgical intervention. Adult guidelines suggest that failure of sepsis to resolve within 7 days is an appropriate period to consider a surgical opinion. This appears to be a reasonable approach to pediatric empyema 200also. The BTS guidelines suggest that failure of chest tube drainage, antibiotics and fibrinolytics should prompt early discussion with a thoracic surgeon and patients should be considered for surgical treatment if there is persisting sepsis in association with a persistent pleural collection, despite chest tube drainage and antibiotics.14 There are increasing studies done in recent times, which suggest that in patients with early stage multiloculated empyema, VATS deloculation and debridement is better than tube thoracostomy or fibrinolytic therapy and results in reduced drainage time and hospital stay. It was also seen to have a high success rate without significant morbidity.39 Concerns of substantial increase in cost of VATS have been a concern in the Western countries, but studies have again demonstrated that the charges incurred for primary VATS were not much compared to primary chest tube placement as the additional cost of performing VATS is offset by the reduction in the total number of hospital stay and cost of other procedures.40 Early use of VATS facilitates full expansion of the collapsed lung and drainage of the empyema fluid41,42 by separation of the loculi under direct vision.43 However, this method is not suitable for cases that present late and with advanced organized empyema.41,44 Though there are people in favor of doing a mini-thoracotomy and debridement,45 these have not become very popular due to their invasive nature and good results with conservative management in children. Though till date no consensus exists on the best modality of surgical intervention, there are studies which show that VATS in children is associated with significantly less midterm musculoskeletal sequelae and better cosmetic outcome.46 It is expected that with more randomized controlled trials it will become clear as to which approach to adopt.
Open surgery and decortications has a definite role in those symptomatic children with organized empyema. Those patients who progress to a chronic state develop a thick fibrous peel. The fibrous peel causes restricted lung expansion and chronic sepsis with fever. Such patients require a formal thoracotomy with excision of the pleural rinds (decortication) to achieve full lung expansion14 (Fig. 13.2). CT scan with contrast is a useful imaging modality prior to surgery. Careful and early removal of the peel is required to avoid significant morbidity such as bleeding, air leaks and injury to nerves. There is no role of surgical removal of an associated lung abscess.14 Bronchopleural fistulas (primary or post surgery) are usually managed conservatively with chest tube drainage and low pressure suction or by surgical repair and by talc pleurodesis.47 Studies have shown that the duration of disease has a direct relationship with the thickness of pleura and injury to the underlying lung. Therefore undue delay in referral of empyema cases causes irreversible changes in the lung, which affects the final outcome. The three most common morbidities noted in one large study of open thoracotomy and decortications from India showed that the significant changes which affect morbidity are consolidation of lung, cavitary necrosis and poor compliance or fibrosis with poor lung expansion.48 All these prolong the time to recover and ICWSD removal.
 
Analgesia and Antipyretics
Antipyretics are required for control of fever and analgesics for the control of pleuritic pain or pain secondary to ICWSD or surgery. Adequate analgesia helps 201in breathing and lung expansion and also prevents secondary scoliosis and allows early mobilization.
Fig. 13.2: Empyema thoracis. Postdecortication with chest tubes in situ showing right sided crowding of ribs and scoliosis with expanded right lung field
 
Physical Rehabilitation
Physical rehabilitation in the form of chest physiotherapy is not recommended14 as studies have shown that it is not beneficial at all.22 Early mobilization and physical exercise are more beneficial. Children can be asked to use the incentive spirometer in an effort to improve the lung expansion. The incentive spirometer works on the principle of sustained maximal inspiration (SMI). In SMI, the patient is asked to sustain his inspiratory effort for a minimum of 3 seconds, this increases transpulmonary pressure, inspiratory volumes, improves inspiratory muscle performance and re-establish or simulate the normal pattern of pulmonary expansion.49 This is effective when done for 30 to 60 seconds once every hour with 4 to 5 repetitions.48 Very often alternative measures or modified breathing exercises can be used. The modified breathing exercises consist of balloon blowing, blowing of air into water with a straw, blowing musical instruments such as the trumpet, flute or mouth organ and are found to be quite effective in children and help in lung expansion.50 Children find balloon blowing interesting and acceptable than the incentive spirometer (personal experience-unpublished). Laughing is a good exercise and younger children and infants can be tickled to induce laughter.49 202
 
Secondary Scoliosis
Scoliosis can occur secondary to pleuritic pain and discomfort from ICWSD (Fig. 13.5). It is however transient and is relieved with the resolution of the disease and hence requires no specific treatment.14
 
Follow-up
Follow-up depends on the time when the patient was discharged from the hospital. Most patients would require to be seen within 4 to 6 weeks of discharge and till they fully recover and chest radiographs return to normal. Chest radiographs invariably remain abnormal at discharge and a repeat imaging is to be done at least 4 to 6 weeks after discharge. Most radiographs return to normal by 3 to 6 months.51 In case patients have been discharge following chest tube removal, then they need to come back earlier for stitch removal and assessment of the scar. Follow-up is also important to look for non-resolving symptoms or new findings clinically or radiologically as a small proportion of patients may turn out to have a tubercular etiology on follow-up.10 Follow-up is also required to detect the rare case of cystic fibrosis or immunodeficiency, if symptoms are recurrent or persistent. This is true if the infecting organism is P. aeruginosa or S. aureus, especially in young children and infants.14
 
Intercostal Water Seal Drainage Placement
Intercostal water seal drainage should ideally be placed by persons who are well versed with the technique to avoid complications. For those doing it for the first time, such as postgraduates, it should be done under supervision. All such procedures must be done in the presence of a trained assistant and nurse. Usually no specific investigations such as a platelet count or a coagulation profile is required before the procedure unless there is evidence of a bleeding diathesis when the parameters should be normalized before the procedure. A chest radiograph and an USG of the chest is a must prior to insertion of the chest drain unless the patient has severe respiratory compromise or impending respiratory failure when one cannot wait for these investigations. The USG chest is especially helpful to mark the exact site of insertion, where a loculated empyema is detected. The location should be marked by an ‘ X ’.
An informed consent should be taken from all patients. Usually most of the chest drains can be inserted using a local anesthetic agent such as lignocaine (2%) or bupivacaine (0.25%) subcutaneously, into the intercostals muscles, periosteum of the rib and parietal pleura. Asepsis must be maintained and all equipments used for the procedure should be sterilized. The procedure must be done under suitable lighting and under monitoring especially when there is a need to use sedatives such as midazolam in an uncooperative child. The drain site identified by USG or clinically (safe triangle in the midaxillary line formed by the anterior border of latissimus dorsi, lateral border of pectoralis major and a line superior to a horizontal line above the nipples and the apex of the axilla) is cleaned with spirit and an antiseptic agent. After local anesthetic insertion, a knick is made on the skin and subcutaneous tissue with a number 11 scalpel blade. The muscles 203are separated by blunt dissection and the soft tube is inserted into the pleural cavity (which is identified by a give-away sensation). Usually small bore drains or pig-tail catheters are better than large bore drains. Large bore drains offer no additional benefits but serve to increase the discomfort of the patient. There is no need to use a trocar for the chest tube placement and excessive force should also be avoided. The drain can be secured by two stay sutures and an occlusive transparent adhesive dressing is applied. The chest tube is then connected to a unidirectional water seal drainage system where the end of the tube is kept under water. The port in the drainage system, which lets out air should be kept open at all times. Low pressure suctions (5–10 cm of water) can be used to facilitate drainage or in case of a bronchopleural fistula. In such cases close monitoring is required. The under-water seal drainage system should always be placed below the level of the patient. A note of the daily drain output is strictly maintained. In larger children and adolescents not more than 1.5 liters of fluid should be drained out at one time to avoid the risk of re-expansion pulmonary edema. If there is suspicion of a drain block then it should be rectified by flushing with about 10 mL of saline or by milking the tube. Drains are usually removed once the drainage has stopped or has reached 10 to 20 mL/day for three consecutive days, child is afebrile and no respiratory distress. A chest X-ray and USG chest are mandatory. After clamping the drain, a close watch is kept for increasing respiratory distress and also for radiological expansion of the lung. Staff must be trained in management of the chest tube drainage system.
A suggested algorithm for the management of empyema is given in Flow chart 13.1.51
 
SUMMARY AND CONCLUSION
Empyema thoracis is a common problem in the pediatric patients, frequently occurring following a pneumonia. The most common organisms causing empyema are S. pneumoniae and S. aureus. It can affect any age group. Most patients have a classical presentation of fever, malaise, lethargy, increasing breathlessness and air hunger. Diagnosis is relatively easy and can be done on clinical grounds and confirmed by an X-ray. Conventional radiology is good enough for initial diagnosis. USG of chest is useful for detection of fibrin strands, loculations and pleural thickening. CT scan is rarely required for detection of complications or prior to surgery to delineate the anatomical abnormalities. Blood culture and pleural fluid analysis are must before embarking on therapy. The first modality of therapy for significant empyema is stabilization and initiation of broadspectrum intravenous antibiotics (antipneumococcal and antistaphylococcal) with thoracentesis and ICWSD. Presence of loculations and fibrin strands or pus at initial diagnosis indicate the need for fibrinolytic therapy. Nowadays, early VATS deloculation and debridement are indicated for multiloculated empyema. In more complicated cases, such as organized empyema or those unresponsive to the conservative management, surgical intervention, i.e. thoracotomy and decortications are indicated and children respond well. Respiratory physiotherapy (in the form of balloon blowing or blowing of air into water with a straw) is an important aspect of 204therapy and should be started early.
Flow chart 13.1: Management of pleural space infection in children
205There is no role of brochoscopy. IV antibiotics are usually given for 1 to 3 weeks followed by oral antibiotics to complete a total duration of therapy for 4 to 6 weeks. Follow-up is usually required after about 4 to 6 weeks following discharge to assess lung expansion and need for further assessment and therapy. Most cases do well on completion of therapy.
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  1. Miserocchi G. Physiology and pathophysiology of pleural turnover. Eur Respir J 1997;10:219–225.
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  1. Kroegel C, Anthony VB. Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy. Eur Respir 1997;10:2411–2418.
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  1. Mandal AK, Thadepalli H, Mandal AK, Chettipally U. Outcome of primary empyema thoracis: therapeutic and microbiologic aspects. Ann Thorac Surg 1998;66:1782–1786.
  1. Chonmaitree T, Powell KR. Parapneumonic pleural effusions and empyema in children. Review of a 19-year experience, 1962-1980. Clin Pediatr (Phila) 1983;22: 414–419.
  1. Alkrinawi S, Chernick V. Pleural infection in children. Semin Respir Infect 1996;11: 148–154.
  1. Saglani S, harris KA, Wallis C, Hartley JC. Empyema: the use of broad-range 16S rDNA PCR for pathogen detection. Arch Dis Child 2005;90:70–73.
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  1. British Thoracic Society Standards of Care Committee. British Thoracic Society guidelines for the management of community acquired pneumonia in childhood. Thorax 2002; 57 (Suppl 1): i1–24.
  1. Donnelly LF, Klosterman LA. CT appearance of parapneumonic effusions in children: findings are not specific for empyema. Am J Roentgenol 1997;169:179–182.
  1. Kurian J, Levin TL, Han BK, Taragin BH, Weinstein S. Comparison of ultrasound and CT in the evaluation of pneumonia complicated by parapneumonic effusion in children. AJR 2009;193:1648–1654.
  1. Byington CL, Spencer LY, Johnson TA, et al. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis 2000;34:434–440.
  1. Maziah W, Choo KE, Ray JG, Ariffin WA. Empyema thoracis in hospitalized children in Kelantan, Malayasia. J Trop Pediatr 1995;41:185–188.
  1. Mangete EDO, Kombo BB, Legg-Jack TE. Thoracic empyema: a study of 56 patients. Arch Dis Child 1993,69:587–588.
  1. Mishra OP, Das BK, Jain AK, Lahiti TK, Sen PC, Bhargara V. Clinico-bacteriological study of empyema thoracis in infants and children. J Trop Pediatr 1993;39:380–381.
  1. Asindi AA, Efem SE, Asuquo ME. Clinical and bacteriological study on childhood empyema in south eastern Nigeria. East Afr Med J 1992;69:78–82.
  1. Ghosh S, Chakraborty CK, Chatterjee BD. Clinico-bacteriological study of empyema thoracis in infants and children. J Indian Med Assoc 1990;88:189–190.
  1. Levine H, Metzger W, Lacera D, Kay L. Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 1970;126:269–271.
  1. Gocmen A, Kipper N, Toppare M, Ozcelik U, Cengizlier R, Cetinkaya F. Conservative management of empyema in children. Respiration 1993;60:182–185.
  1. Rosen H, Nandkarni V, Theroux M, Padman R, Klein J. Intrapleural streptokinase as adjunctive treatment for persistent empyema in pediatric patients. Chest 1993;103: 1190–1193.
  1. Barbato A, Panizzolo C, Monciatti C, Marcucci F, Stefanutti G, Gamba PG. Use of urokinase in childhood empyema. Pediatr Pulmonol 2003;90:1025–1028.
  1. Wells RG, Havens PL. Intrapleural fibrinolysis for parapneumonic effusion and empyema in children. Radiology 2003;228:1539–1540.
  1. Singh M, Mathew JL, Chandra S, Katariya S, Kumar L. Randomized controlled trial of intrapleural streptokinase in empyema thoracis in children. Acta Pediatr 2004;93: 1443–1445.
  1. Yao CT, Wu JM, Liu CC, Wu MH, Chuang HY, Wang JN. Treatment of complicated parapneumonic pleural effusion with intrapleural streptokinase in children. Chest 2004;125:566–571.
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  1. Shah SS, Have TRT, Metlay JP. Cost of treating children with complicated pneumonia: A comparison of primary Video-Assisted Thoracoscopic Surgery and chest tube placement. Pediatr Pulmnol 20104571–77. Doi:10.1002/ppul.21143.
  1. Klena JW, Cameron BH, Langer JC, Winthrop AL, Perez CR. Timing of video-assisted thoracoscopic debridement for pediatric empyema. J Am Coll Surg 1998;187: 404–408.
  1. Merry CM, Bufo AJ, Shah RS, Schropp KP, Lobe TE. Early intervention by thoracoscopy in pediatric empyema. J Pediatr Surg 1999;34:178–181.
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  1. Lawlal TA, Goseman JH, Kuebler JF, Glüer S, Ure BM. Thoracoscopy versus thoracotomy improves midterm musculoskeletal status and cosmesis in infants and children. Ann Thorac Surg 200987224–228. Doi: 10.10'6/j.athoracsur.2008.08.067.
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Pulmonary Aspiration Syndromes14

T Arun Babu, C Barathy
 
INTRODUCTION
The term, aspiration syndromes, includes a wide range of clinical syndromes that arise from an ‘aspiration event’. The clinical features of individual aspiration syndromes are variable with the varying etiopathophysiology. The nature of aspiration, the type of contents, the volume, the severity of aspiration and nature of host responses determine the clinical spectrum1 which range from asymptomatic, cough, wheeze, apnea, diffuse bronchiolitis, bronchitis, chemical pneumonitis, aspiration pneumonia, recurrent pneumonia, interstitial lung disease to life threatening events and even death in some cases.
Aspiration is often underdiagnosed or misdiagnosed. However, not all aspiration events are of clinical significance. Knowledge about the risk factors predisposing to aspiration and a high index of suspicion are prerequisite for prompt diagnosis and management of aspiration syndromes.
 
DEFINITION
Aspiration is defined as misdirection of oropharyngeal or gastric contents into the larynx and lower respiratory tract.1 It is also termed “aspiration lung injury” or “aspiration lung disease”. Aspiration syndromes include wide spectrum of pulmonary syndromes resulting from aspiration due to structural and functional disorders of oropharygo-gastroesophageal tract.
 
TYPES OF ASPIRATION
Aspiration may occur acutely or in a chronic and recurrent fashion as in a child with neurological impairment. Aspiration of oropharyngeal contents is termed as direct or antegrade aspiration while aspiration of gastric contents is called indirect or retrograde aspiration. The former occurs due to dysfunctional swallowing and is also called ‘dysphagic aspiration’ while the latter occurs during gastroesophageal reflex and hence also known as ‘reflux aspiration’.
Swallowing is a complex neuromuscular activity involving three phases of coordinated contractions namely oral, pharyngeal and esophageal. The oral 209phase is voluntary while the pharyngeal and esophageal phases are involuntary. The oral phase initiates the act of swallowing with bolus directed into the pharynx while preventing misdirection into respiratory tract. The pharyngeal phase propels the bolus through the pharynx and relaxes the upper esophageal sphincter causing it to enter upper esophagus while providing airway protection. The esophageal phase directs the bolus by peristaltic movements into lower esophagus. Lower esophageal sphincter relaxation then permits passage into the stomach. Dysfunctional swallowing can lead to aspiration and is commonly seen in neurological impairment, cerebral palsy and in intubated children.2 Symptoms of aspiration can be overt with choking and coughing or it could be silent.3
A variety of substances including liquids and solids may be aspirated. The liquid may be acidic as in gastroesophageal reflux, nonacidic as in salt water or fresh water drowning, infective as in a critically ill patient and toxic as in hydrocarbon ingestion.
The solids aspirated may be powders such as talc, particulate matter such as food particles in vomitus and gastroesophageal reflux, smaller size solids such as beads and peanuts or larger as in meat bolus.
 
NORMAL DEFENCE MECHANISMS
The structures that provide aero-digestive protection are upper esophageal sphincter (UES), glottis and lower esophageal sphincter (LES).4 The function of UES is facilitated by a coordination of mulitple reflexes involving pharynx, larynx and upper esophagus.5 The glottis is involved in protection during swallowing and preventing gastro-esophageal reflux through pharyngo-glottal closure reflex.6 The epiglottis is mainly involved in directing swallowed food into esophagus and offers little protection in preventing aspiration.7 LES tone and pressure are important determinants in preventing gastroesophageal reflux.
Cough reflex and mucociliary escalator mechanism helps in clearing foreign substances from the respiratory tract along with cellular and immune mechanisms. The normal defence mechanisms of body against aspiration are summarized in Box 14.1.
 
RISK FACTORS FOR ASPIRATION
Aspiration occurs when one or more of the defense mechanisms are impaired. Common risk factors for aspiration are:
  • Impaired consciousness/anesthesia: There is impaired coordination between breathing and swallowing, thus compromising airway protection.8 Impaired cough and gag reflex alone may not result in an aspiration.9
  • Seizures: Impaired consciousness and spasm of pharyngeal muscles results in aspiration.
  • Decreased LES tone and pressure: Decreased LES tone and pressure cause reflux of gastric contents and aspiration into lungs.
  • Increased intra-abdominal pressure, abdominal strain facilitate gastro-esophageal reflux.210
  • Vomiting and regurgitation
  • Depressed immune system.
Common Medical Conditions associated with aspiration are summarized in Box 14.2.
 
PATHOPHYSIOLOGY
Aspiration can be broadly classified as acid aspiration, nonacid aspiration and solid or particulate aspiration.
 
Solid Aspiration
Solid aspiration can result in upper airway obstruction and cause hypoxemia and acute life threatening events. Smaller solids and particulate matter can enter lower airways and cause partial or complete obstruction. Partial obstruction results in hyperexpansion. Complete obstruction cause distal atelectasis. This leads to ventilation-perfusion mismatch, hypoxemia and hypercapnia. Irritative substance can incite inflammation resulting in pneumonitis. Retained foreign body is risk factor for secondary infection and can lead to pulmonary abscess.
 
Nonacid Aspiration
Nonacid aspiration causes damage to lung surfactant leading on to alveolar damage and late inflammatory reaction which results in alveolar collapse, atelectasis and hypoxia. 211
 
Acid Aspiration
Gastric acid reflux into distal esophagus causes vagal stimulation with reflex bronchospasm in airway. Microaspiration sets off an initial phase of tissue damage to alveolar epithelial cells and endothelial cells with desquamation of ciliated and nonciliated epithelial cells resulting in chemical pneumonitis.10 There is increased alveolar capillary permeability due to the breakdown of alveolar-capillary barrier, causing interstitial edema.1 Damage to type 2 alveolar epithelial cells leads to decreased surfactant and atelectasis.12 There is increase in the airway resistance with decreased compliance with arterial hypoxemia and hypercapnia. Second phase of inflammation recruits neutrophils with alveolar consolidation.10 Neutrophils are the main mediators of injury due to release of reactive oxygen species and elastase.11 Macro-aspiration of gastric contents causes additional particulate injury increasing the arterial hypoxemia. Gastric contents may not be sterile like endogenously secreted gastric acid and thus bacterial pneumonia is possible.13 212
 
CLINICAL SYNDROMES
 
Cough and Wheeze
Acute coughing and choking follows an acute aspiration event, as in foreign body aspiration. Chronic cough, defined as cough more than 3 weeks in duration may underlie recurrent aspiration. Asthmatic patients showing poor response to standard therapy can be due to underlying occult aspiration secondary to gastroesophageal reflux.
 
Acute Life-threatening Events
Laryngospasm may result in obstructive apnea which is characterized by weak and ineffective respiratory efforts. Central apnea can also be associated with aspiration events which is usually characterized by absence of respiratory efforts. A massive aspiration can have a mortality of 25%.14
 
Upper Respiratory Tract Involvement
Aspiration can cause laryngeal inflammation with hoarseness of cry/voice. Stridor, cyanosis and chronic rhinosinusitis may be seen.
 
Aspiration Pneumonitis
Aspiration pneumonitis is defined as acute lung injury following the aspiration of regurgitated gastric contents.1 This usually occurs in patients with impaired consciousness such as in seizures, sedation, cerebrovascular accident and anesthesia. The risk of aspiration increases with the degree of unconsciousness.15 Acid in the gastric contents causes chemical injury. The critical pH required to cause aspiration pneumonitis is less than 2.5. However, presence of particulate food matter in gastric contents may cause severe pulmonary damage, even if the pH is above 2.5.
Aspiration of gastric contents results in chemical burn of the tracheobronchial tree with a parenchymal inflammatory reaction. This inflammatory reaction is called aspiration pneumonitis and usually presents with fever, cough and leukocytosis. The proinflammatory cytokines, including tumor necrosis factor-α and CXC chemokines mediate neutrophil recruitment. The parenchymal damage also predisposes to secondary bacterial infection.16 Risk factors for gastric microbial colonization like the use of antacids, H2 blockers and proton pump inhibitors increases the chances of infection.
Most patients are asymptomatic though some can present with cough or wheeze. Sometimes, the only findings are radiological evidence of aspiration with arterial hypoxemia. In severe aspiration, shortness of breath, wheezing, coughing, cyanosis, pulmonary edema, hypotension, and hypoxemia may be seen which may progress rapidly to severe acute respiratory distress syndrome and death. During monitoring, aspiration pneumonitis is often a recognizable event and can be immediately managed by airway suctioning and endotracheal intubation, if airway is unprotected.
213Bronchodilators–inhaled β2-agonists may be used for symptomatic treatment of wheeze.17 Prophylactic antibiotics are usually not indicated. Antimicrobial therapy is initiated only if aspiration pneumonitis fails to resolve within 48 hours and broad spectrum antibiotics are recommended for this purpose. In animal models, corticosteroids, pentoxifylline, antiplatelet drugs and omega-3 fatty acids have been shown to attenuate the acute lung injury secondary to aspiration.18-21
 
Aspiration Pneumonia
Bacterial infection following oropharyngeal aspiration may result in pneumonia with development of classical radiographic features. Dysphagic aspiration in the presence of impaired host defence predisposes to aspiration pneumonia. Increased volume of aspirate increases the bacterial burden from oropharynx thereby increasing the chances of pneumonia.22 Other risk factors for aspiration pneumonia are oropharyngeal microbial colonization, colonization of dental plaques, poor oral hygiene, impaired cough and mucociliary clearance and impaired immunity.
In patients who aspirate in recumbent position, radiological infiltrates are seen commonly in posterior segments of upper lobe and apical segments of the lower lobe. Aspiration in upright or semi-recumbent position, preferentially involves the basal segments of the lower lobes.
Treatment of aspiration pneumonia requires antibtiotic therapy. Thickened liquids and a ‘chin-down’ posture limit aspiration in these patients.23 Maintaining good oral hygiene will reduce colonization with potentially pathogenic organisms and can decrease the bacterial load.24 Angiotensin-converting enzyme inhibitors prevent the breakdown of substance P, which is believed to play a major role in both the cough and swallow sensory pathways and may be useful in some cases.25 Antihistamines and drugs with anticholinergic activity dry up secretions and make swallowing more difficult and should be avoided.
 
Diffuse Aspiration Bronchiolitis
This is usually seen in infants with gastroesophageal reflux disease (GERD) causing recurrent and frequently silent aspiration. It presents with recurrent episodes of dyspnea, bronchorrhea and bronchospasm. Chest radiograph shows regional or disseminated small nodular shadows and hyperlucency. Chest computed tomography (CT) demonstrate diffuse centrilobular nodules with a tree-in-bud pattern.26
 
Lung Abscess
Lung abscesses usually develop as a result of aspiration of organisms in patients with dental caries, aspiration of foreign bodies or as a consequence of severe necrotising pneumonia due to Staphylococcus aureus and Klebsiella pneumoniae. Patients with altered conscious states and with swallowing difficulties are at high risk. Antibiotics for 2 to 4 weeks and chest physiotherapy are usually required. Drainage of the abscess via a percutaneous catheter under ultrasound or computerised tomography guidance may be required in large lung abscess and in cases refractory to medical therapy. 214
 
SPECIFIC ENTITIES
 
Hydrocarbon Aspiration
Hydrocarbon ingestion affects the lung, liver, heart and central nervous system. Aspiration is possible during ingestion or during vomiting and aspiration pneumonitis may occur. However, significant pneumonitis occurs in less than 2% of all ingestions.27 In severe cases, acute respiratory failure and pulmonary edema can occur. Risk of aspiration is correlated with viscosity, measured in Saybolt Seconds Universal (SSU) Units.28 Ingestion of large volume (>30 mL), hydrocarbons with lower surface tension and those with lower viscosity present greater risk of aspiration pneumonitis.28
In the lungs, hydrocarbons causes dissolution of membrane lipids, incites inflammation and bronchospasm with surfactant damage resulting in pneumonitis, atelectasis and emphysema. Over-distension of alveoli can result in pneumatocoele.29 Pulse oximetry and Blood gas analysis is done to monitor oxygenation. Chest radiograph is taken, even if the patient is asymptomatic. The ECG and cardiac monitoring are required for dysrhythmia. Management consists of monitoring and oxygen therapy to correct hypoxemia. Endotracheal intubation and mechanical ventilation may be required in severe cases. Bronchodilators may be tried but are usually of limited benefit but cortico steroids have no role. Antibiotic are given if there is any evidence of secondary infection. Surfactant therapy has been successfully used in a patient with acute respiratory failure secondary to hydrocarbon aspiration.30
 
Gastroesophageal Reflux Disease
Gastroesophageal reflux (GER) is physiological in infants. The GER is defined as effortless entry of gastric contents in a retrograde fashion into the esophagus or oral cavity due to failure of protective mechanisms at lower esophageal sphincter.
Normal defense mechanisms at lower esophageal junction are resting LES tone and pressure, angle at the cardia, intra-abdominal portion of esophagus and pinch-cock action of diaphragmatic crura at esophageal hiatus.
Most common mechanism is transient LES relaxation.31 Full stomach causes gastric distension which in turn via vagal pathway increases the transient LES relaxation.32 Fatty foods also increase transient LES relaxation.33 LES hypotension, where increased intra-abdominal pressure overcomes the LES pressure is another mechanism that results in reflux.34 Certain foods items like fat, chocolates, peppermint, caffeine decrease LES pressure and results in reflux. Alcohol, smoking, medications such as salbutamol and theophylline also reduce LES pressure. Scleroderma and increased progesterone in pregnancy decreases LES pressure.35, 36 Widening of esophagogastric opening and decrease in the length of intraabdominal portion of esophagus, reduced LES pressure and reduced pinch cock action of diaphragmatic crurae can cause GERD in patients with hiatus hernia.37
Clincial spectrum can range from being asymptomatic to recurrent cough, wheezing, apnea, laryngeal involvement, chronic rhino sinusitis, aspiration pneumonitis and aspiration pneumonia.
215Extrapulmonary manifestations such as failure to thrive and Sandifer syndrome due to neurohumeral mechanism may be seen. Noncardiac chest pain and epigastic pain in older children, crying episodes with recurrent vomiting and feed refusal in infants due to of esophagitis pain are also seen.
 
Lipoid Pneumonia
Exogenous lipoid pneumonia is an aspiration pneumonia that occurs secondary to aspiration of mineral or vegetable oils. Nasal instillation of various vegetable oils to infants and children in the recumbent position is practiced in many parts of India to relieve nasal congestion.
It elicits a chronic foreign body reaction and the pathophysiology occurs in three stages. First stage involves exudation into alveoli. Second stage is characterized by stimulation of pulmonary macrophages and diffuse fibrosis and third stage by granulomas and nodules.38 Dyspnea, cough, fever with nights sweats are common clinical features. Hemoptysis is rare.39 Bacterial pneumonia can result due to superinfection. CT scan shows low attenuation infiltrates with crazy paving pattern.40 The MRI shows high signal intensity in T1 weighted image.38 Chest radiograph shows multilobar involvement with subpleural sparing. Lipid-laden macrophages can be demonstrated in sputum, bronchoalveolar lavage fluid, or fine needle aspiration cytology or lung biopsy. It is treated with antibiotics and may respond to steroids and immunoglobulins. Repeated bronchoalveolar lavage may be required.41
 
DIFFERENTIAL DIAGNOSIS
Aspiration may mimic sudden infant death syndrome (SIDS), respiratory syncytial virus infection which causes bronchiolitis and viral pneumonia in infants and young children, cystic fibrosis, immunodeficiency, lung sequestration, lobar emphysema, which may present as persistent or recurrent pneumonia, status asthmaticus and right middle lobe syndrome.
 
INVESTIGATIVE WORK-UP
  • Complete blood count shows neutrophilic leukocytosis.
  • Pulse oximetry to monitor SpO2: Blood gas analysis to assess oxygenation and pH status. There is acute hypoxemia and normal to low partial pressure of carbon dioxide with respiratory alkalosis in aspiration pneumonia. The lactate levels can be used as an early marker of severe sepsis or septic shock.
  • Chest radiograph (CXR) has poor sensitivity and specificity. There is no single finding that is pathognomonic for aspiration. The CXR can even be normal. Findings usually seen are unilateral or bilateral perihilar or pulmonary infiltrates, hyperinflation and consolidation in dependent lobes. In neonates and young infant, upper lobe consolidation is suggestive of aspiration. Lower lobe is more commonly involved in chemical pneumonitis.216
  • Cultures of blood samples, bronchoalveolar lavage, transthoracic lung fluid aspiration are useful in aspiration pneumonia.
  • Swallow studies: Swallow studies are essential to find out the anatomical and functional disorders of the oropharynx. Several tests are available such as VFSS–videofluoroscopic swallow study, fiberoptic endoscopic evaluation of swallowing (FEES) with or without sensory testing, salivagram, barium swallow and nuclear studies. Gold standard is videofluroscopy with barium swallow.42 CT and MRI can be useful in evaluating central nervous system causes of dysfunctional swallowing.
  • Gastroesophageal reflux43: Esophagogastroduodenoscopy and biopsy allows direct visualization of the mucosal tract, confirms reflux and allows a histological diagnosis and can detect complications and associated anatomical abnormalities. Esophageal pH monitoring using a 24-hour pH probe is most sensitive and is the gold standard. Catheter free pH monitoring is possible using a gelcap. Esophageal intraluminal electrical impedance detects reflux into esophagus. Barium fluoroscopy picks up reflux into esophagus as well as other anatomical disorders. Technetium milk scan has low radiation exposure but has poor sensitivity and specificity in diagnosing reflux. Nuclear scintigraphic studies are available and may be useful in silent aspiration.44 Flexible fiber optic bronchoscopy and bronchoalveolar lavage cytology showing lipid laden macrophages are taken to be suggestive of aspiration. Several other markers are looked for. Recently pepsin in respiratory secretions is considered indicative of aspiration.45 Similarly glucose or lactose detection tests and dye tests on respiratory secretions are being developed.46
 
Biomarkers in Aspiration
Since it is difficult to differentiate the aspiration syndromes on clinical grounds alone, numerous biomarkers have been studied in aspiration but none is able to distinguish between aspiration syndromes with accuracy and reliability.
Recent markers are alveolar soluble triggering receptor expressed on myeloid cells (sTREM-1) levels, CRP, cytokines, exhaled breath condensate leukotrienes, carbamoyl phosphate synthase (CPS)-1, Endothelin (ET)-1 and ET-1 precursor peptides (proET-1), receptor for advanced glycation end products (RAGE), Copeptin, adrenomedullin (ADM) and pro-ADM.47 Cytokines are considered characteristic signature of aspiration pneumonitis in animal model. Microarray data enriched with comparative genomic and proteomic analysis may be future key areas of studies in aspiration.
Recurrent pneumonia: Silent aspiration may underlie recurrent pneumonia which is frequently multilobar. Common causes of recurrent pneumonia are aspiration from oropharyngeal incoordination, asthma, congenital disorders of the cardiorespiratory system, immunodeficiency, cystic fibrosis and pulmonary hemosiderosis. The differential diagnosis for recurrent pneumonia are summarized in Table 14.1. 217
Table 14.1   Differential diagnosis for recurrent pneumonia
Differential diagnosis
Test
Aspiration pneumonia
Tests for swallowing dysfunction
Tests for GERD (as already described)
Asthma
Pulmonary function tests
Low FEV1 (relative to percentage of predicted norms)
FEV1/FVC ratio < 0.8
Improvement in FEV1 ≥12% with bronchodilator
Worsening in FEV1 ≥15% with exercise
Airflow limitation
Spirometry
Peak flow morning-to-afternoon variation ≥20%
Trial of brochodilator therapy
Congenital disorders of cardiorespiratory tract
High resolution CT
Echocardiography
Cystic fibrosis
Two elevated sweat chloride test > 60 mEq/l, obtained on separate days
Identification of two CF mutations
An abnormal nasal potential difference measurement
Immunodeficiency disorders
Immunoglobulin assay- IgG,IgA,IgM
Qualitative testing
Disorders of cilia
Saccharin clearance test
Ciliary beat frequency
Pulmonary hemosiderosis
BAL for hemosiderin laden macrophages
Lung biopsy
 
TREATMENT
Management is dictated by the type of aspiration syndrome.
  • Positioning: Head end elevation to 30 degree and nursing in prone or right lateral position is useful in minimizing aspiration.48,49 Supine position should be avoided.50
  • Feeding techniques: Dietary modification such as small frequent meals and thickened feeds are used with positioning which is useful in dysphagic aspiration.
  • Lifestyle changes: Weight management to prevent obesity and avoiding overfeeding to prevent full stomach are advised. Carbonated beverages, caffeine, and citrus fruits and chocolates which increase reflux should be avoided.
218
 
Management of Acute Aspiration
‘Acute aspiration event’ requires immediate airway clearance, oxygen therapy and endotracheal intubation if airway cannot be protected. Therapeutic rigid bronchoscopy is required if there is suspected foreign body. Inhaled or nebulized bronchodilators may be tried in bronchospasm. Steroids are not of proven benefit. Empirical antibiotics are not required except in infective pneumonia or secondary infection. If antibiotics need to be given, second or third generation cephalosporins are given.
 
Management of Chronic Aspiration
A multidisciplinary approach is often required addresseding the underlying cause.
 
Direct Aspiration, Dysphagic or Antegrade Aspiration
Effective management requires complete assessment of swallowing dysfunction. Positioning, dietary modifications such as thickened feeds, changes in feed viscosity and texture can help. Starch-based thickeners are available commercially.
Antibiotic therapy targeting organisms such as Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae are indicated in aspiration pneumonia. Seven days of therapy is usually adequate, but lung abscess requires 2 to 4 weeks therapy and surgery in refractory cases.
Salivary aspiration can be managed conservatively by positioning and thickened feeds. If conservative approach fails, medical management with anticholinergic agents such as glycopyrrolate is used to reduce salivation.
Table 14.2   Antibiotic therapy in aspiration pneumonia
Initial treatment
of aspiration pneumonia
Benzylpenicillin 30 mg/kg (up to 1.2 g) IV, 6-hourly
+
Metronidazole 12.5 mg/kg IV, 12-hourly (up to 500 mg)
or
Metronidazole 10 mg/kg orally, 12-hourly (up to 400 mg)
In immediate penicillin hypersensitivity
Clindamycin 10 mg/kg up to 450 mg IV or orally, 8-hourly
or
Lincomycin 15 mg/kg up to 600 mg IV, 8-hourly
Staphylococcal pneumonia
Amoxycillin + clavulanate
or
Clindamycin
Vancomycin or linezolid in patients at risk of infection with methicillin-resistant Staphylococcus aureus
Gram-negative pneumonia
Piperacillin + tazobactam
or
Ticarcillin + clavulanate
or
Third generation cephalosporin with metronidazole used
219If refractory to medical therapy, repositioning or ligation of ducts or excision of the glands or laryngotracheal separation are available surgical strategies.
 
Indirect/Retrograde/Reflux Aspiration-GERD
Conservative management: In infants crib elevation and nursing in prone position minimizes reflux aspiration. In children prone position with head elevation to 30 degree and right lateral position is useful.
 
Dietary Modifications
Small volume feeds, frequent feeds and thickened feeds help in managing reflux. There is not much evidence regarding outcome of feed thickening in GERD. Avoid precipitants of reflux such as chocolates and carbonated drinks. In some children, postpyloric feeds may be required.
 
Medical
  • Pro-kinetic drugs: Domperidone increases LES tone and improves gastric emptying. Erythromycin increase gastric motility and is tried in neonates. Metoclopramide and cisapride are usually avoided in children.
  • H2 receptor: Antagonists. Includes ranitidine, cimetidine, famotidine and nizatidine.
  • Proton pump inhibitors: Includes omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole.
 
Surgical
Surgical therapy is indicated in anatomical abnormalities or failure of lifestyle modification and medical management. Procedures such as endoscopic sewing, endoscopic electrocoagulation at LES, laparoscopic Nissen and Thal fundoplication and laryngotracheal division are available.51
 
PROGNOSIS
Prognosis depends on underlying cause, complications and host response. Chronic lung conditions such as chronic bronchitis, bronchiolitis obliterans-like lesions, pulmonary fibrosis, interstitial lung disease and bronchopulmonary dysplasia may develop.
Serial measurements of serum procalcitonin may be helpful in predicting survival from pulmonary aspiration.52 Presence of complications increase the mortality rate.
 
SUMMARY AND CONCLUSION
The term, aspiration, aspiration lung injury or aspiration lung disease, denotes a misdirection of oropharyngeal or gastric contents into the larynx and lower 220respiratory tract. The term, aspiration syndromes, include wide spectrum of pulmonary syndromes resulting from aspiration due to structural and functional disorders of oropharygogastroesophageal tract. Antegrade or dysphagic aspiration is secondary to dysfunctional swallowing. Retrograde or reflux aspiration occurs secondary to gastroesophageal reflux. Aspiration pneumonitis is acute lung injury usually seen in reflux aspiration. Aspiration pneumonia is bacterial pneumonia usually seen in oropharygeal or dysphagic aspiration. Antibiotics are indicated in aspiration pneumonia but not in aspiration pneumonitis. Positioning, feeding techniques and lifestyle modifications can decrease aspiration. Whereas an acute aspiration event requires immediate airway clearance, oxygen therapy and endotracheal intubation if airway cannot be protected, chronic aspiration warrants multidisciplinary approach.
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  1. Kinniry P, Amrani Y, Vachani A. Dietary flaxseed supplementation ameliorates inflammation and oxidative tissue damage in experimental models of acute lung injury in mice. J Nutr 2006;136:1545–1551.
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  1. Russo. Case of exogenous lipoid pneumonia: steroid therapy and lung lavage with an emulsifier. Anesthesiology 2006;104:197–198.
  1. Colombo JL. Chronic recurrent aspiration. In: Kliegman RM, Stanton BF, St Geme JW, Schor NF, Behrman RE (Eds): Nelson Textbook of Pediatrics, 19th edn. Philadelphia: Saunders/Elsevier  2011:1471.
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  1. Ward C, Forrest IA, Brownlee IA. Pepsin like activity in BAL is suggestive of gastric aspiration in lung allografts. Thorax 2005;60:872–874.
  1. Kinsey GC, Murray MJ, Swensen SJ, Miles JM. Glucose content of tracheal aspirates: Implications for the detection of tube feeding aspiration. Crit Care Med 1994;22: 1557–1562.
  1. Jaoudeetal. Biomarkers in the diagnosis of aspiration syndromes. Expert Rev Mol Diagn 2010;10:309–319.
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  1. El-Solh AA, Vora H, Knight PR 3rd, Porhomayon J. Diagnostic use of serum procalcitonin levels in pulmonary aspiration syndromes. Crit Care Med 2011;39:1251–1256.

Pulmonary Edema15

T Arun Babu, BV Balachandar, C Barathy
 
INTRODUCTION
The term, pulmonary edema, refers to the accumulation of fluid into the alveolar spaces throughout the lungs resulting from disruption of the normal fluid flux within the lungs.1 This condition is commonly seen in both outpatient and inpatient settings. It can lead to respiratory failure if not treated immediately. Prompt diagnosis and its intervention necessary to prevent clinical deterioration and mortality.
Pulmonary edema occurring in children can be broadly classified into two types:
  1. Cardiogenic pulmonary edema (hydrostatic, hemodynamic edema)
  2. Noncardiogenic pulmonary edema (acute lung injury, acute respiratory distress syndrome, depending upon severity).
Although the two types have distinct pathophysiology and etiology, often it is difficult to distinguish between the two in clinical settings because of the similarity and considerable overlap in clinical manifestations.
This chapter focuses on recent advances in our understanding about this condition including the causes, clinical presentation, diagnosis and various treatment modalities.
 
DEFINITION
Pulmonary edema is defined as an excessive accumulation of fluid in the interstitium and air spaces of lung. It is a sequelae of different pathologic processes and is a final common pathway.2
 
PHYSIOLOGY
Normally, the fluid exchange occurs between the interstitium and the vascular bed, across the alveolar capillary membrane, as determined by Starling's relationship.
The net flow of fluid across a membrane is determined by Starling's equation
Where, Q = K (Pcap - Pis) - r (pc - pi),
Q is net fluid filtration
K is a constant called the filtration coefficient
225Pcap is capillary hydrostatic pressure, which tends to force fluid out of the capillary
Pis is hydrostatic pressure in the interstitial fluid, which tends to force fluid into the capillary
r is the reflection coefficient, which indicates the effectiveness of the capillary wall in preventing protein filtration
pc is the colloid osmotic pressure of plasma, which tends to pull fluid into the capillary
pi is the colloid osmotic pressure in the interstitial fluid, which pulls fluid out of the capillary.
 
ETIOPATHOPHYSIOLOGY AND CLASSIFICATION
According to Starling's law, fluid leaks across the capillary wall when the oncotic pressure within the capillary decreases or when the hydrostatic pressure increases more than that of interstitium.
 
Hemodynamic Edema
  • Increased hydrostatic pressure in pulmonary veins:
    • Cardiogenic, e.g. pulmonary venous outflow obstruction as in the case of mitral stenosis and LV failure due to systolic or diastolic dysfunction of the left ventricle, myocarditis, etc.
    • Noncardiogenic, e.g. volume overload, pulmonary veno-occulsive disease, pulmonary venous fibrosis, mediastinal tumors, etc.
  • Decreased oncotic pressure:
    • Hypoalbuminemia, such as nephrotic syndrome, liver disease, protein losing enteropathy, malnutrition.
  • Lymphatic obstruction, such as congenital and acquired.
 
Increased Negative Interstitial Pressure
  • Upper airway obstructive lesions—croup, epiglottitis, laryngospasm
  • Re-expansion pulmonary edema.3
 
Microvascular Injury
It results in leaky capillaries leading to acute lung injury and acute respiratory distress syndrome (ARDS). It occurs due to pulmonary or systemic insults and are classified accordingly.
  • Pulmonary or direct insults:
    • Diffuse widespread pneumonia due to variety of causes, such as viral, Mycoplasma, Pneumocystis carinii and miliary tuberculosis
    • Aspiration, e.g. gastric contents, water (near drowning)
    • Inhalation, e.g. toxic gases-smoke, oxygen toxicity, ammonia, chlorine, nitrogen dioxide, sulfur
    • Embolism, e.g. thrombus, fat, air, amniotic fluid
    • Lung contusion
    • Radiation exposure.
  • 226Systemic or indirect insults:
    • Sepsis
    • Severe trauma, e.g. multiple bone fractures, head trauma
    • Multiple transfusions
    • Disseminated intravascular coagulation (DIC)
    • Burns
    • Pancreatitis
    • Cardiopulmonary bypass.
 
Mixed or Unknown Causes
  • Neurogenic pulmonary edema
  • High altitude pulmonary edema (HAPE)
  • Postoperative—negative pressure pulmonary edema
  • Narcotic overdose
  • After cardioversion
  • Eclampsia.
Most common causes are limited to very few insults, such as sepsis, diffuse pulmonary infections, gastric aspiration and trauma.
 
PATHOPHYSIOLOGIC MECHANISMS4
 
Hemodynamic Edema
  • Increased hydrostatic and decreased oncotic pressures lead to transudation of fluid from capillaries to interstititum and then to alveolar spaces.
  • Fluid homeostasis in the normal lung requires drainage via lymphatics. Obstruction of lymphatics occurs rarely leads to accumulation of fluid in the interstitium which spills over to alveolar spaces.
  • The increase in negative pressure in interstitium, as seen in obstruction of large upper airways leads to shift of fluid from capillaries to interstitium. Increased CO2 tension, decreased O2 tension and extreme increase in cardiac afterload also contributes.
 
Neurogenic Pulmonary Edema5
Neurogenic pulmonary edema (NPE) occurs secondary to cerebral injury or neurological insult. Increased intracranial tension is a key factor, which plays a vital role in the pathogenesis. There is massive sympathetic discharge, in turn, leads to systemic vasoconstriction. This shifts blood from systemic to pulmonary circulation. There is increased left atrial pressure and pulmonary venoconstriction. This increases hydrostatic pressure in capillaries resulting in fluid shift from capillary to interstitium and then to alveolar spaces. Microvascular injury is an additional contributory factor increasing capillary permeability. The rapid increase in pulmonary vascular pressure because of pulmonary vasoconstriction and increased pulmonary blood flow causes microvascular injury. Secondary mediators also contribute to microvascular injury. Thus both hemodynamic and nonhemodynamic factors contribute to the development of NPE.227
 
High Altitude Pulmonary Edema
Ascent to high altitudes may result in acute mountain sickness, high altitude cerebral edema or high altitude pulmonary edema which is noncardiogenic edema. The hypobaric hypoxia at high altitude results in permeability edema. This occurs due to various factors such as increased sympathetic tone, pulmonary vasoconstriction and pulmonary hypertension. This results in patchy breakdown of small blood vessels and alveolar capillary barrier leading to increase in capillary permeability and thus shift fluid across the membranes into the air sacs. Some cases could be immunologically mediated by HLA susceptibility to pulmonary hypertension.6
 
Scorpion Envenomation
The manifestations of scorpion envenomation are due to release of mediators, such as catecholamines, cytokines and platelet activating factor in addition to the venom itself. Increased symphathetic activity and myocarditis leads to left ventricular failure. This leads to increase in hydrostatic pressure, which causes net efflux of fluid into interstitium and alveoli.7
 
Acute Lung Injury and Acute Respiratory Distress Syndrome8
The natural history of acute lung injury (ALI)/ARDS is marked by three phases:
  1. Exudative
  2. Proliferative
  3. Fibrotic phases.
 
Exudative Phase
This phase is characterized by rapid onset of severe dyspnea that occurs about 12 to 48 hours after the insult. Sometimes, the onset may occur 5 to 6 days after the initial insult. It lasts for about 7 days.
228Their levels are being assessed in serum or alveolar space as predictors of ARDS in those with ALI.
Condensed plasma proteins, cellular debris and dysfunctional surfactant contribute to hyaline membrane formation which impairs gas diffusion and result in hypoxia. Surfactant dysfunction also results in alveolar collapse.
Endothelial cell injury leads to release of tissue factor, von Willebrand factor and endothelin which further contributes to cell injury. Tissue factor release activates coagulation pathway and causes microthrombi formation in pulmonary vasculature, contributing to hypoxia and hypercapnia.9
Edema is seen predominantly in dependant portion of the lung where there is minimal vascular redistribution. This is in contrast to hemodynamic edema where vascular redistribution is seen and upper lobes are more commonly involved. Further, pleural effusion rarely occurs in ARDS in contrast to hemodynamic edema. Edema is more central in hemodynamic edema whereas it is more peripheral in ARDS (in earlier phases).These changes are reflected in chest radiograph.
 
Proliferative Phase
This phase lasts from 7 to 21 days. Type 1 pneumocytes are replaced by proliferation and differentiation of Type 2 pneumocytes. This also replenishes surfactant. Endothelial cells are replaced by proliferation of marrow derived endothelial progenitor cells. Macrophages clear exudates and tissue debris. Most patients recover rapidly during this phase.
 
Fibrotic Phase
Early changes of pulmonary fibrosis start during proliferative phase. Extensive alveolar duct and interstitital fibrosis are seen. Acinar architecture is disrupted leading onto emphysema like changes with large bullae. Intimal proliferation in alveolar capillaries leads to pulmonary hypertension. This results in risk of pneumothorax and reduction of lung compliance. Some patients may develop progressive lung injury.
 
CLINICAL FEATURES
Pulmonary edema is broadly classified as cardiogenic and noncardiogenic pulmonary edema (NCPE).
Cardiogenic pulmonary edema (CPE) is due to alteration in Starling's forces. Noncardiogenic edema occurs predominantly due to damage to the alveolar capillary barrier.
 
Cardiogenic Pulmonary Edema
The fluid accumulation occurs in three stages:
  • Stage 1 consists of increased dilatation of the pulmonary vessels.
  • Stage 2 consists of fluid accumulation in the interstitium.
  • Stage 3 consists of interstitial and alveolar flooding.
229
 
Clinical Features
Bronchial wall edema and accumulation of secretions cause narrowing of lumen and results in wheeze and crepitations. Hypoxia leads to increased work of breathing which manifests as dyspnea, tachypnea, subcostal and intercostal retractions. Reduced carbon dioxide excretion and increase in reduced hemoglobin result in cyanosis. The transudate in alveoli gives rise to fine crepitations. In cardiogenic pulmonary edema, additional signs of cardiac failure are seen including elevated JVP, peripheral edema, gallop and tender hepatomegaly. There is also cough with pink frothy sputum, hemoptysis and pain abdomen.
 
Laboratory Investigations
  • Complete blood count: Anemia, leukocytosis in sepsis
  • Serum electrolyte: Hypokalemia in chronic congestive heart failure (CHF)
  • Blood urea nitrogen and creatinine
  • Pulse oximetry to assess hypoxia and response to oxygen therapy
  • Arterial blood gas analysis
  • Electrocardiography: Left atrial enlargement and left ventricular hypertrophy, acute tachy or bradyarrhythmias.
  • Plasma brain natriuretic peptide (BNP) and NT: proBNP testing.
The BNP testing is useful in differentiating heart failure from pulmonary causes of dyspnea. A cut off value of 100 pg/mL is generally accepted. The level of BNP increases with age. Renal dysfunction may be associated with a significantly increased level of BNP. Ventricular myocytes secrete proBNP in response to muscle-wall tension which can be measured.230
 
Chest Radiography
  • Cardiomegaly
  • Kerley-B lines –Thickening of interlobar septa
  • Basilar edema
  • Absence of air bronchograms
  • Presence of pleural effusion (particularly bilateral).
 
Echocardiogram
Echocardiography is useful to evaluate left ventricular function, valvular function and pericardial disease.
 
Pulmonary Capillary Wedge Pressure
Pulmonary capillary wedge pressure (PCWP) can be measured with a pulmonary arterial catheter. This method helps in differentiating CPE from NCPE. In CPE, PCWP is elevated and large V waves and rapid Y descent may be seen.
 
Acute Respiratory Distress Syndrome and Acute Lung Injury10-12
The ARDS is a clinical syndrome of severe dyspnea of rapid onset, hypoxemia and diffuse pulmonary infiltrates leading onto respiratory failure. Acute lung injury is a less severe disorder but with a potential to evolve into ARDS.13 American- European Conference Consensus (AECC) diagnostic criteria used to diagnose ARDS and ALI in children.2
In both ALI and ARDS, essential feature is that left atrial hypertension should be absent, i.e. PCWP should be ≤ 18 mm Hg or no clinical evidence of raised left atrial pressure. Routine use of Swan Ganz catheter to measure PCWP is not recommended. Its use is restricted to only selected cases where diagnosis is uncertain.
The AECC criterion may not be accurate in ventilated patients as the level of positive end expiratory pressure (PEEP) at which, measurement of PaO2/FiO2 ratio is done is not taken into account.14,15
There are few modifications to AECC criteria. One such criteria, the Murray Lung Injury Score for ARDS utilizes lung compliance, PaO2/FiO2 ratio, degree of alveolar consolidation and level of positive end-expiratory pressure for defining ARDS.16
231
 
Chest Radiography17
  • Hemodynamic: Peribronchial and perivascular cuffing, diffuse streakiness— indicated interlobular fluid and distended lymphatics,
  • Septal lines: Kerley A and B,
  • Butterfly sign: Perihilar opacity (vascular pedicle > 70 mm),
  • Upper zone involvement is an early finding (vascular redistribution),
  • Diffuse patchy opacity: Late finding, cardiomegaly.
 
ARDS
Diffuse alveolar and interstitial opacity involving at least three quarters of the lung field, costophrenic angles are usually spared, upper zones are less involved (No pulmonary vascular redistribution), air bronchogram is seen in more than 80% of cases, pleural effusions and cardiomegaly are not usually seen.
Now attempts at finding the exact etiology by bronchoalveolar lavage (BAL), open lung biopsy, serum or alveolar biomarkers are being made to modify the course and prognosticate.18-20
 
Differential Diagnosis of ARDS
Common:
  • Cardiogenic pulmonary edema
  • Diffuse pneumonia
  • Alveolar hemorrhage.
Less common:
  • Acute interstitial lung disease
  • Acute immunological injury (Hypersensitivity pneumonitis).
Differentiation of cardiogenic from noncardiogenic pulmonary edema can be made by estimating BNP. It is often elevated in heart disease. A BNP level > 500 pg/mL suggests heart disease, a level < 100 pg/mL suggests lung disease.21,22232
 
Neurogenic Pulmonary Edema
The exact mechanism causing neurogenic pulmonary edema is not clear. Any neurological insult produces massive sympathetic discharge leading onto increased pulmonary and systemic vasoconstriction, causing flooding of fluid into pulmonary vasculature, thereby increasing capillary pressure and edema formation. Symptoms of NPE start within minutes to hours of the neurological insult. There is sudden onset of dyspnea, tachynea and tachycardia. The jugular venous pulse is normal. On auscultation, bibasilar crepitations can be heard with absence of gallop sound.
 
High Altitude Pulmonary Edema
The exact mechanism underlying HAPE is still unclear. It is thought to be due to high altitude induced increased sympathetic outflow, increased pulmonary vascular resistance and hypoxia induced increase in capillary permeability resulting in edema.
Symptoms start gradually within the first 2 to 4 days at high altitude. The earliest symptoms are dyspnea with exercise and decreased exercise performance and delayed recovery from exercise. The symptoms then progress to severe dyspnea at rest, a persistent dry cough, sometimes frothy with blood, chest tightness and severe weakness. They may progress to unconsciousness, coma, and death.
 
Risk Factors for HAPE
  • Young age
  • Genetic constitution
  • Cold weather
  • Physical exertion
  • A previous history of HAPE
  • Intrapulmonary or intracardiac shunts
  • Pre-existing high pulmonary artery pressure
  • High altitude ascent with a respiratory infection.
 
Investigations
  • Complete blood count: Leukocytosis
  • Increase in IL-6, IL-1 and CRP
  • Arterial oxygen tension of 30 to 40 mm Hg and respiratory alkalosis.
  • Chest X-ray: Normal cardiac shadow with bilateral patchy infiltrates in the lungs and full pulmonary arteries confirms the diagnosis.
  • ECG shows right-sided heart strain pattern due to pulmonary hypertension
  • Stress echocardiography showing abnormal vascular response to hypoxia and exercise.
 
MANAGEMENT
Initial management of patients should focus on the “ABCs” of resuscitation, i.e. managing airway, breathing and circulation. Large bore intravenous (IV) lines, 233preferably two in number should be in place to administer needed medications. Patients should be placed in an upright sitting position attached to a cardiac monitor and pulse oximetry.
 
Diagnostic Criteria
 
Cardiogenic Pulmonary Edema
 
Supplemental Oxygen23,24
Oxygen increases alveolar oxygen tension and dilates pulmonary vasculature. This decrease pulmonary vascular resistance leading to reduction in work of breathing, decrease in afterload and increase in PaO2. Initially noninvasive positive pressure ventilation (NIPPV) is preferred to deliver oxygen. The NIPPV delivers CPAP through mask or nasal prongs. It acts by preventing closure of alveoli at end of expiration, increasing functional reserve capacity, compliance and surfactant functioning. This is not due to decrease in lung fluid. BiPAP may also be used.25-27 Mechanical ventilation is indicated when hypoxia does not respond to noninvasive supplemental oxygenation or in event of impending respiratory failure.
 
Respiratory Support
Noninvasive positive pressure ventilation: The NPPV has been used successfully in patients who present with CPE and has been proven to limit the need for mechanical ventilation.2527 There are two types of NPPV, continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). In CPAP, the patient breaths against a continuous flow of positive airway pressure. In BiPAP, the patient receives additional positive pressure during inspiration. Therefore, higher pressures can be applied during inspiration and lower pressures during expiration, allowing for greater patient comfort.
Mechanical ventilation: Endotracheal intubation and mechanical ventilation provide definitive airway support and allow for maximal oxygenation and ventilation. The decision to ventilate should be made on clinical grounds and should not wait for arterial blood gas testing. General indications in a patient with CPE includes hypoxia despite maximal supplemental oxygenation, failed attempts at NPPV, decreased level of consciousness, worsening clinical scenario and cardiogenic shock.
234The addition of PEEP to ventilator settings produce the same hemodynamic benefits as NPPV, including improvements in preload, afterload, and cardiac output, and decreases the duration of mechanical ventilation.
 
Afterload Reduction
Most patients who present with CPE have elevated catecholamine levels which causes increase in systemic vascular resistance (afterload). The already compromised heart has difficulty in producing an effective cardiac output negotiating this increased resistance. Afterload reduction with vasodilator medications produces an increase in cardiac output and reduction in pulmonary interstitial edema. Another benefit is improved renal perfusion, which can lead to substantial improvements in diuresis even before administration of diuretics.28
ACE inhibitors: The ACE inhibitors reduce afterload and improved stroke volume and cardiac output. When renal perfusion improves, they cause a slight reduction in the preload. ACE inhibitors show excellent treatment results with reduced need for intubation and ICU admission.
Angiotensin II receptor blockers: They reduce incidence of arrhythmias.29
ACE inhibitors and ARBs prevent structural and electrical remodeling of the heart.
Nitroprusside: Useful in critically ill patients. They reduce preload and afterload by smooth muscle relaxation. Side effects are coronary steal phenomenon, thiocyanate toxicity and tolerance.
 
Inotropes
Although inotropic agents should improve outcomes in patients who present with CPE and depressed MI, routine use of inotropes is not recommended. Inotropic agents can cause tachycardia, dysrhythmias, increased myocardial oxygen demand, myocardial ischemia, and sometimes increased mortality. Therefore, these medications should be reserved for patients who have hypotension where the use of preload- and afterload-reducing medications cannot be tolerated. Two main classes of inotropic agents are available: catecholamine agents and phosphodiesterase inhibitors (PDIs).
Dobutamine is mainly beta-1-receptor agonist with some beta-2-receptor and minimal alpha-receptor activity. It has significant inotropy and mild chronotrophy on the heart. It decreases afterload due to mild peripheral vasodilation. It is better avoided in moderate-to-severe hypotension.
Dopamine 5 to 10 mcg/kg/min stimulates beta-receptors in the myocardium and increases cardiac contractility and heart rate. Higher doses stimulate alpha receptors and increase peripheral vasoconstriction and blood pressure.
Norepinephrine primarily stimulates alpha receptors and significantly increases afterload. It is useful in patients with profound hypotension.
235Phosphodiesterase inhibitors increase the level of intracellular cyclic adenosine monophosphate (cAMP) by preventing the breakdown of cAMP to 5' AMP. This results in a positive inotropic effect on the myocardium, in peripheral vasodilation (decreased afterload), and in a reduction in pulmonary vascular resistance (decreased preload).
 
Preload Reduction
The first goal in pharmacologic treatment of CPE is preload reduction. Preload reduction reduces right heart and pulmonary venous return leading to decreased pulmonary capillary hydrostatic and right-heart filling pressures. This decreases the cardiac workload and causes symptomatic improvement in dyspnea.
The usual medications used for preload reduction are loop diuretics, morphine
sulfate, and nitroglycerine. Recently, a recombinant form of BNP known as nesiritide has been used for preload reduction.
Loop diuretics : Intravenous loop diuretics, especially furosemide, have been used for many years as the first-line treatment in children with CPE. These medications produce a decrease in preload by inhibiting sodium chloride reabsorption in the ascending loop of Henle, which promotes increases in urine volume and excretion.28
Since renal perfusion in markedly diminished in CPE due to elevated systemic vascular resistance (afterload), diuretics have a significantly delayed effect, often taking 45 to 120 minutes to produce effective diuresis.28,30 Also, significant proportion of patients with CPE have intravascular euvolemia or hypovolemia and therefore diuretics can cause hypotension and electrolyte abnormalities due to overdiuresis.28,30
Morphine sulfate: Morphine sulfate (MS) has been used as a standard preload-reducing medication for many years, but its role in improving clinical outcomes has not been documented by any RCTs. It exerts mild indirect hemodynamic benefits through anxiolysis, which results in a decrease in catecholamine production, indirectly resulting in vasodilation. It acts by causing mild sedation, reduces anxiety level and reducing symphathetic outflow which in turn reduces afterload and oxygen consumption. It also causes venodilatation which helps in preload reduction.
Nitroglycerine: The most effective and rapidly-acting preload-reducing medication is nitroglycerine (NTG).31 Multiple adult studies have demonstrated the superiority of NTG over furosemide and morphine sulfate for preload reduction, symptomatic improvement, and safety.28,32 NTG has short half-life and therefore titration becomes relatively easier. Even if the patient develops a precipitous fall in blood pressure, discontinuation causes prompt raise in blood pressure within 5 to 10 minutes. Loop diuretics act on the ascending limb of the loop of Henle and decrease preload by two mechanisms—diuresis and venodilation. 236
 
Others
Nesiritide: It is a recombinant human BNP. It decreases the pulmonary artery pressure and systemic vascular resistance and increases the cardiac index. It also decreases plasma renin-aldosterone, norepinephrine, and endothelin-1 levels. It reduces heart rate variability and ventricular tachycardia. It is associated with hypotension, renal failure and increased mortality.33
Levosimendan is a calcium sensitizer that has inotropic, metabolic, and vasodilatory effects. It increases contractility by binding to troponin C. It does not increase myocardial oxygen demand, and is not proarrhythmogenic. It opens potassium channels sensitive to adenosine triphosphate (ATP) and causes peripheral arterial and venous dilatation. It also increases coronary flow reserve and has anti-inflammatory effect. Common adverse effects are hypotension and headache.34
Tolvaptan: Tolvaptan is an oral vasopressin V2-receptor antagonist tried with limited success in cardiogenic shock.35
Intra-aortic balloon pumping: The intra-aortic balloon pump (IABP) can be tried in addition to medical therapy in the treatment of refractory cardiogenic shock in children. Placement of IABP can be a life-saving intervention and serves as a temporizing measure while preparations for more definitive therapies are made. The IABP counterpulsation provides blood pressure support while also providing improvements in coronary diastolic perfusion, afterload, and cardiac output.28
 
Neurogenic Pulmonary Edema
Treatment includes addressing the underlying neurological insult and controlling the neurogenic pulmonary edema by supportive measures till it resolves.
The neurogenic pulmonary edema (NPE) is a self-limiting condition and usually resolves by 48 to 72 hours. Supportive measures are supplemental oxygen, mechanical ventilation and diuretic therapy.
Supplemental oxygen is given for hypoxemia. Noninvasive mechanical ventilation via face mask can be given. Endotracheal intubation and mechanical ventilation may be required in few cases. Low tidal volume and prone position are useful.36
Diuretic therapy minimizes fluid overload and thus total lung water. However, cardiac output and cerebral perfusion pressure must be maintained. This can be effectively done using Swan-Ganz catheterization. Pharmacological agents are not used routinely. Alpha-adrenergic antagonists,37 beta-adrenergic blockers, low dose dopamine, dobutamine,38 and chlorpromazine are some mentioned in literature.
 
High Altitude Pulmonary Edema
The high altitude pulmonary edema (HAPE) is treated by altitude descent, supplemental oxygen, portable CPAP, portable hyperbaric chamber and medication such as nifedipine.
Supplemental oxygen and bedrest are the mainstays of treatment and may completely reverse the symptoms. Supplemental oxygen improves the oxygenation in the blood and lowers the pressure in the pulmonary vessels. Altitude descent 237normalizes the pressure in the vessels and stops the fluid leakage. Altitude descent is mandatory if supplemental oxygen is not available or if the patient does not improve with oxygen therapy. Exertion should be avoided during the descent. Warmth and avoidance of exposure to cold temperature is important.
Hyperbaric chambers including portable ones such as the Gamow bag may be used to lower the altitude if a person is unable to descend immediately. A simulated descent of approximately 2000 m can be achieved using hyperbaric chambers. Medications such as nifedepine and sildenafil may be used if oxygen therapy and descent is not possible. Recurrence is prevented by nifedipine or beta adrenergic agonist inhalation.
 
Prevention
Prevention is by slower and gradual ascent. A diet rich in carbohydrates helps in preventing HAPE. Prophylaxis with nifedepine, acetazolamide or dexamethasone is useful. Nifedepine, a calcium channel blocker causes pulmonary vasodilation and improves SaO2. Acetazolamide, carbonic anhydrase inhibitor promotes renal excretion of bicarbonate, which stimulates respiration. Dexamethasone reduces vasogenic cerebral edema and improves endothelial integrity. Prophylaxis must be started 24-hour before ascent and continued for 48 to 72 hours at high altitude. Acetazolamide is the drug of choice due to low incidence of side effects.
 
Noncardiogenic Pulmonary Edema (ARDS and ALI)
 
General Principles
  • Recognition and treatment of underlying medical and surgical disorder
  • Minimizing procedures and complications
  • Prophylaxis against venous thromboembolism, gastrointestinal bleeding, central venous catheter insertion
  • Prompt recognition of nosocomial infection
  • Provision of adequate nutrition.
 
Control of Causative Factor
  • Identifying the cause of ARDS and factors precipating ARDS and initiating specific therapy targeting those is an vital step in the management of ARDS.
  • In children, sepsis is a common cause for ALI/ARDS. Therefore, early antibiotic therapy is recommended in suspected cases of sepsis.
  • Shock, which is often coexisting and contributory, should be managed with intravascular volume expansion with crystalloids and vasopressors.
 
Endotracheal Intubation
Though there are no definite guidelines for intubation and ventilation in children with ALI and ARDS, poor sensorium and inability to protect airway are practically used indications for intubation. Using cuffed endotracheal tubes are recommended 238in order to achieve adequate positive end-expiratory pressure delivery and can be used safely in all age groups.39
 
Mechanical Ventilation
The primary aim of ventilating patients with ALI/ARDS is to maintain adequate gas exchange with minimal ventilator-induced lung injury (VILI). Mechanical ventilation is often complicated by ventilator-induced lung injury resulting from volutrauma due to low lung compliance and high ventilatory pressures and also due to repeated alveolar collapse, re-expansion and oxygen toxicity.
Supporting respiratory functions until the disease runs its own course is extremely crucial in the management of ALI/ARDS. Endotracheal intubation and mechanical ventilation early in the course of disease progression can be associated with better outcome. In ALI/ARDS the only proven therapy to reduce mortality is protective ventilation strategy. It decreases the incidence of ventilator-induced lung disease.
 
Pharmacologic Paralysis
Neuromuscular blocking agents (NMBA) are frequently used in the management of ARDS to facilitate patient-ventilator synchrony and improve poor oxygenation when traditional sedation is not adequate. Under these conditions, NMBA are frequently effective.
Short-term paralysis may facilitate patient-ventilator synchrony in the setting of lung protective ventilation. Short-term paralysis would eliminate patient triggering, active expiratory muscle activity, and over ventilation. In combination, these effects may serve to limit regional overdistention (volutrauma) and cyclic alveolar collapse (atelectrauma). Paralysis may also act to lower metabolism and overall demand due to respiration.
 
Ventilation Strategies
Oxygen therapy and permissive hypercapnia: There are no evidence based recommendations for target PaO2 to be maintained in children. In adults, the National Institutes of Health ARDS Clinical Trials Network (ARDSNet) recommends PaO2 target is 55 to 80 mm Hg and SpO2 target of 88 to 95%.40 For children, these values are extrapolated from the evidence-based ventilator management protocol for adults. In children, a PaO2 of 60 to 80 mm Hg is usually considered safe. In general, FiO2 should be kept as low as possible to decrease the risk of direct cellular toxicity and to avoid reabsorption atelectasis.
The term permissive hypercapnia defines a ventilatory strategy for acute respiratory failure in which the lungs are ventilated with a low inspiratory volume and pressure. The aim of permissive hypercapnia is to minimize lung damage during mechanical ventilation, but its limitation is the resulting hypoventilation and carbon dioxide (CO2) retention.41
Permissive hypercapnia during mechanical ventilation has led to significant decrease in ARDS mortality. Target arterial pH levels in children with ALI/ARDS are pH of 7.30 to 7.45 which is same as that of adults.40
239Lower tidal volume : In our unit, we ventilate children with VT <6 mL/kg and plateau pressure <30 cm H2O. If a child is ventilated on a pressure controlled mode, the tidal volumes should be accurately monitored.
Although numerous ventilatory strategies have been investigated, low tidal volume of 6 mL/kg ideal body weight (IBW) tidal volume was found to be associated with better outcome when compared with higher tidal volumes.42 Published reports in pediatric ALI/ARDS with historical controls suggest that combining lower tidal volumes with higher PEEP improves outcome.43-45
The low tidal volume strategy is also associated with a reduction in measured plasma biomarkers [tumor necrosis factor receptor (TNF-α, interleukin-6, and interleukin-8)], inflammatory mediators typically reflective of more severe lung injury. The enhanced inflammation associated with VILI, leading to the release of inflammatory mediators from the lung into the bloodstream, has been called biotrauma.
Positive end-expiratory pressure (PEEP)42-47: The PEEP improves oxygenation in ARDS/ALI by forcing movement of fluid from the alveolar to interstitial space, recruiting small airways and collapsed alveoli and by increasing functional residual capacity.
The heterogeneous nature of ARDS, however, complicates the interaction of PEEP with the injured lung. In diseased regions, PEEP acts to stabilize lung volume and reduce the amount of lung volume undergoing tidal cycling opening and closing. In normal regions, PEEP leads to overdistention and exacerbates tidal hyperinflation.
In absence of static pressure-volume curve measurement, PEEP should be maintained between 8 to 20 cm H2O. The PEEP should be progressively increased by 2 to 3 cm H2O increments to maintain saturation between 90 and 95% with FiO2 <0.6. Meticulous monitoring for any evidence of cardiovascular compromise and hyperinflation is vital. If pressure-volume loops can be monitored, then it is desirable to keep the PEEP above the lower inflection point.48
Recruitment maneuvers49: Recruitment is a physiological process of re-aeration of a previously gasless lung region by positive pressure ventilation. Alveolar recruitment maneuvers are done to open up collapsed alveoli by using continuous or repetitive application of increased levels of distending pressure usually much higher than recommended for ventilation in children. By increasing the lung volume, recruitment maneuvers (RMs) may render ventilation more homogeneous, improving gas exchange and limiting distention of healthy lung units. Numerous methods have been employed to carry out RM.
Despite recent advances, optimal recruitment strategies in ARDS have not been well-established and considerable uncertainty remains regarding the appropriateness of RMs and its long-term outcome.
There are no randomized studies to indicate whether recruitment maneuvers influence outcome in children. Also, RM can cause numerous adverse effects like alveolar epithelial injury, worsened pulmonary function, hemodynamic compromise, desaturation, new air leaks, dissemination of intratracheal organisms and bacteremia.50
240With the current available evidence, RMs should be reserved for cases with refractory hypoxemia despite high pressures and FiO2 and its routine use in all ventilated children with ALI or ARDS should be discouraged.
Weaning and extubation: There are no clinical trials evaluating methods of weaning from mechanical ventilation in children with ALI/ARDS. Therefore, there is no evidence to support a specific weaning method for using in ventilated children.51
The weaning is started by reducing the frequency of controlled breaths allowing spontaneous breathing. In volume-controlled ventilation, the tidal volume is usually reduced to about 4 to 6 mL/kg. In pressure-controlled ventilation, the peak inspiratory pressure is gradually reduced in steps of 1 to 2 cm H2O. PEEP and FiO2 are reduced while monitoring the PaO2. As the amount of mandatory support is reduced, PSV can be introduced into SIMV mode with PSV of about 5 to 10 cm above PEEP.48
Extubation is planned once the child's respiratory condition improves allowing decrease in ventilator settings to minimal-FiO2 of less than 40%, PEEP of 4 to 5 cm H2O, rate of 15/min or less, PIP of less than 15 cm H2O. The child should be hemodynamically stable and with normal sensorium and with the presence of protective reflexes.
Dexamethasone may be used prior to extubation in case ventilation is prolonged for more than 10 to 14 days to reduce airway edema. A recent evidence-based review has concluded that expert clinical judgment is more accurate than any extubation criteria present for children with ALI/ARDS.51
High-frequency oscillatory ventilation: An alternative approach to the tidal cycling of conventional ventilation is the use of high-frequency oscillatory ventilation (HFOV). The HFOV is considered in children who fail to improve or deteriorate with conventional ventilation. The HFOV employs a relatively constant airway pressure, with CO2 exchange accomplished through nonconvective mechanisms produced by rapid pressure oscillations (300-900 breaths per minute) in the airway. This lung protective strategy of HFOV is theoretically achieved by alveolar recruitment with a relatively constant mean airway pressure and avoiding the low and high tidal swings in alveolar pressure associated with conventional ventilation. The risks of HFOV relate to barotrauma and hemodynamic compromise in association with the sustained elevation in mean airway pressure. HFOV is best considered in a rescue regimen for patients with intractable hypoxemia.52,53
In a trial conducted on children with ALI/ARDS, it was found that high-frequency oscillatory ventilation is associated with higher mean airway pressures, improved oxygenation, and a reduced need for supplemental oxygen at 30 days.54
Extracorporeal membrane oxygenation: Use of ECMO is limited to those patients in whom conventional therapies have failed. It is the most optimal methodology to achieve lung rest. The potential benefit of ECMO is negated by an increased bleeding risk related to the need for anticoagulation, and an additional risk of infection related to the use of intravascular catheters. Because of the extreme cost of the intervention, additional studies will be needed to define the role of extracorporeal support in the management of severe ARDS patients. The ECMO 241has been used as a rescue therapy for over two decades in children with ALI/ARDS, with reported survival rates of 50%.55
Prone positioning56,57: This helps in increase in end-expiratory lung volume, improved ventilation-perfusion matching, more uniform distribution of lung stress and strain with tidal cycling, and regional improvement in lung and chest wall mechanics. Regardless of mechanism, an improvement in oxygenation occurs in a majority of patients when this intervention is applied. The potential risks of this intervention are primarily pressure related injury and endotracheal tube dislodgement with turning maneuvers. Collectively, the existing data suggest prone positioning is best considered a “rescue” regimen employed for patients with intractable hypoxemia. However, a recent RCT performed in children with ALI showed no significant benefit of prone positioning despite improved oxygenation.58
Fluid management : Aim is to maintain normal or low left atrial filling pressure to minimize pulmonary edema. Fluid restriction and diuresis should be important part of management. Early and aggressive fluid resuscitation of patients with sepsis, the most common etiology of ARDS, has been shown to improve patient outcome and limit progression to organ failure. However, elevations in pulmonary capillary occlusion pressure, to achieve greater preload response, are classically associated with increasing lung water in the setting of injury to the alveolar: capillary membrane. The fluid conservative strategy improves oxygenation and reduces the duration of time on mechanical ventilation. The fluid intake should be restricted to about two-thirds of maintenance once the child is hemodynamically stable inorder to minimize the capillary leak and control pulmonary edema. Fluid restriction should only be implemented after children have been resuscitated adequately from septic shock. The routine use of echocardiography allows informed clinical decisions in critically ill patients. The advance of portable imaging techniques should bring this information more readily to the patient's bedside.59,60 No association has been shown between cumulative fluid balance and duration of mechanical ventilatory weaning or extubation outcomes in children.61
 
Supportive Therapies
Hemoglobin should be maintained above 10 g/dL in children with shock or profound hypoxia and >7 g/dL in children who are clinically stable.62
Enteral nutrition should be initiated as early as possible. The volume should be slowly increased as tolerated. In children who are unlikely to tolerate enteral feeds, parenteral nutrition should be promptly initiated. Though there is some supportive evidence that Omega 3 fatty acid supplementation improves clinical outcomes in adult patients with ARDS, no such benefit has been documented in children.63
Analgesics and sedation should be used to minimize physical and mental discomfort in children. Midazolam infusion for sedation can be used as it shortacting and the dose can be titrated. Fentanyl or morphine can be used for analgesia and muscle relaxants are not routinely indicated.
242Blood glucose values should be monitored regularly and insulin maybe required if the values are persistently above 180 mg/dL. Strict glucose control in children with ALI/ARDS is not warranted as its safety and efficacy is not proven by any trials.
Coagulopathy and mechanical ventilation are risk factors for clinically important gastrointestinal bleeding in children. Stress ulcer prophylaxis with intravenous H2 antagonist or proton pump inhibitor is required. Care should be taken to prevent nosocomial infections. Early diagnosis and prompt treatment of these infections are crucial to their recovery. Bronchodilators are indicated when there is clinical evidence of bronchospasm.
The families of children should be counseled and psychological support must be extended to them.
Pulmonary artery catheters and other invasive procedures need to be used judiciously as it has been showed that there is no differences in clinical outcomes with respect to 60-day survival, ventilator-free days, renal function, need for hemodialysis, or vasopressor therapy.
 
Novel Therapies
Surfactant: Surfactant has been tried in treatment of ALI/ARDS in children. A meta-analysis of six trials in children with ALI showed decreased mortality, increased VFDs, and decreased duration of mechanical ventilation with surfactant therapy.64 Potential complications of surfactant therapy in children with ALI/ARDS may be hypotension, hypoxia, and barotrauma.
Corticosteroids: Corticosteriods do not prevent the development of ARDS and it is not beneficial when given during the initial phase. Corticosteroids decreases the production of inflammatory and profibrotic mediators by multiple mechanisms thereby decreasing lung parenchymal tissue injury.
There are no studies of corticosteroids for treatment of ALI/ARDS in children. Studies done in adults regarding steroid use in ALI/ARDS show inconclusive results.65,66 At present, there is no evidence to support routine use of steroids in children with ARDS.
Inhaled vasodilators: Pulmonary hypertension, right heart dysfunction, and severe hypoxemia characterize ARDS. So inhaled vasodilators have been considered as promising agents for treatment of hypoxemia and pulmonary hypertension. Systemic administration of vasodilators including nitric oxide, prostaglandin- based vasodilators and sildenafil have been unable to show a therapeutic effect in ARDS and are often associated with worsening of oxygenation indices. These medications should be used only with extreme caution in patients with advanced hypoxemia.
The use of inhaled vasodilators must be considered a rescue therapy for patients with intractable hypoxemia and/or pulmonary hypertension where other interventions such as high PEEP titration, prone positioning, and HFOV have been unsuccessful. A meta-analysis of multiple studies showed that inhaled nitric oxide improved oxygenation without improving overall clinical outcomes in children and adults with ALI/ARDS.67243
Flow chart 15.1: Algorithmic approach in noncardiogenic edema
244
 
Evidence-based Recommendations for ARDS Therapies
Table 15.1   Recommendations for various therapies targeting ARDS
Mechanical ventilation
Recommendation
Low tidal volume
A
High PEEP
C
Prone position
C
Recruitment maneuver
C
High frequency ventilation
C
ECMO, Partial liquid ventilation (PLV) with perfluorocarbon68
D
Minimize left atrial filling pressure
B
Glucocorticoids69
C
Surfactant replacement70, Inhaled NO71 and other anti-inflammatory therapy (Ketoconozole, NSAIDs)
D
A-Recommended based on strong clinical evidence from RCT
B-Supportive but limited clinical data
C-Indeterminate evidence, recommended only as an alternative therapy
D-Not recommended
Approach to a child with noncardiogenic pulmonary edema.
 
PROGNOSIS
Pulmonary edema carries a high mortality ranging from 40 to 65%. Sepsis and nonpulmonary organ failure accounts for more than 80% of deaths.72 Most survivors of ARDS are left with residual pulmonary symptoms like cough, dyspnea and sputum production which improve over a period of time. Mild abnormalities of oxygenation, diffusion capacity and lung mechanics persists in some patients.73 In children with ALI/ARDS the severity of hypoxia at presentation and multiple organ failure are strong predictor of mortality.74,75 The presence of alveolar type 3 procollagen peptide, a marker of pulmonary fibrosis, is associated with protracted clinical course and increased mortality. Classification of ARDS by CT scan into diffuse and lobar infiltrative pattern appears to predict outcome. Prognosis of trauma related ARDS is better than sepsis related ARDS.76 Most of patients with ARDS succumb to multiorgan failure with less than 5% of deaths being actually due to respiratory failure.48 In recent clinical trials of children with ALI/ARDS, the overall mortality was found to be between 8 and 27.5%.77,78245
 
SUMMARY AND CONCLUSION
Pulmonary edema, an excessive accumulation of fluid in the interstitium and air spaces of lung, can lead to respiratory failure if diagnosis and intervention is delayed. Hemodynamic edema, increased negative interstitial pressure and microvascular injury are three important pathophysiologic mechanism responsible for pulmonary edema. Neurogenic pulmonary edema occurs secondary to cerebral injury or neurological insult. High altitude pumonary edema is mainly due to hypobaric hypoxia present in high altitude which results in permeability edema. Cardiogenic pulmonary edema is due to alteration in Starling's forces. Signs and symptoms of cardiac disease and elevated pulmonary capillary wedge pressure (PCWP) and left atrial pressures. Oxygenation, preload, afterload reducing agents and inotropic agents are common line of management. Noncardiogenic pulmonary edema occurs predominantly due to damage to the alveolar capillary barrier. Principles of ARDS management include oxygenation, Ventilation strategies and supportive measures like hydration, glucose control, nutrition and fluid management.
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  1. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. J Parenter Enteral Nutr 2003;27:355–373.
  1. Duffett M, Choong K, Ng V, Randolph A, Cook DJ. Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Crit Care 2007; 11:R66.
  1. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ 2008;336:1006–1009.
  1. Steinberg KP, Hudson LD, Goodman RB. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671–1678.
  1. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007;334:779.
  1. Hirschl RB, Croce M, Gore D, Wiedemann H, Davis K, Zwischenberger J, et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:781–787.
  1. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007;131:954–963.
  1. Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventós AA, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996;334:1417–1421.
  1. Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004;291:1603–1609.
  1. Suntharalingam G, Regan K, Keogh BF, Morgan CJ, Evans TW. Influence of direct and indirect etiology on acute outcome and 6-month functional recovery in acute respiratory distress syndrome. Crit Care Med 2001;29:562–566.
  1. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293–1304.
  1. Dahlem P, van Aalderen WM, Bos AP. Pediatric acute lung injury. Paediatr Respir Rev 2007;8:348–362.
  1. Erickson S, Schibler A, Numa A. Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8:317–323.
  1. Sheu CC, Gong MN, Zhai R, Chen F, Bajwa EK, Clardy PF, et al. Clinical characteristics and outcomes of sepsis-related vs. nonsepsis-related ARDS. Chest 2010;138:559–567.
  1. Curley MA, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA 2005;294:229–237.
  1. Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: A randomized controlled trial. JAMA 2005;293:470–476.

Acute Respiratory Distress Syndrome16

Ashish Jain, Neetu Jain, Satish Tiwari
 
INTRODUCTION
In 1967, Ashbaug et al,1 described a clinical entity of dyspnea, cyanosis resistant to supplemental oxygen and bilateral chest infiltrates on chest radiography in a group of adult patients. Similarity was noted between their patients and neonatal respiratory distress syndrome (RDS), also known as hyaline membrane disease (HMD). Hence, the term adult RDS was coined to describe the patients with diffuse alveolar–capillary damage occurring in a diverse group of disorders. Since such an illness also occurs in children of all ages, it is now known as “acute respiratory distress syndrome” (ARDS). In 1994, European North American Consensus Conference agreed on standard definition of ARDS and of a less severe injury, the so-called “acute lung injury” (ALI).2
The definition is based on:
  1. Appearance on chest radiograph.
  2. The ratio of partial pressure of O2 in arterial blood to the fraction of inspired oxygen (PaO2/FiO2 ratio).
  3. Assessment of left atrial filling pressure.
 
DEFINITION
According to 1994 European American Consensus Conference, ARDS is defined as:2
  1. Acute onset of respiratory symptoms.
  2. PaO2/FiO2 < 200; regardless of positive end-expiratory pressure (PEEP) level.
  3. Acute onset bilateral infiltrates on chest radiograph.
  4. Non-cardiogenic pulmonary edema or pulmonary capillary wedge pressure <18 mm Hg.
Acute lung injury (ALI) is defined by all the above except that partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) is below 300.252
 
PATHOPHYSIOLOGY
Pathophysiology of ARDS is complex and multifaceted. It is dependent upon three distinct phenomena:
  1. The nature of stimulus that initiates or causes ARDS.
  2. The host response to the stimulus.
  3. The role that the damage plays in the progression and outcome of this condition.
There is an increase in alveolar and pulmonary capillary permeability leading to massive cell damage, alveolar denudation and sloughing of the cell debris into the lumen of the alveoli. The neutrophilic and macrophage influx initiates an inflammatory cascade, which involves the release of interleukins (IL-1, IL-6, IL-8), tumor necrosis factor-α (TNF-α) and other inflammatory mediators.3 Furthermore, surfactant is markedly inactivated and all these events lead to increase work of breathing. Surfactant loss leads to alveolar collapse because of increased surface tension, which is analogs to the situation seen in premature infants with RDS. Alveolar collapse causes lung volume to decrease below the patient's functional residual capacity (FRC) and further increases the work of breathing and reduced compliance. Although the total lung compliance is decreased, as little as 25% of the lung may be participating in the gas exchange. The areas involved in the gas exchange are normally compliant and are only subject to overdistension, when excessive inflating pressures are given.
Collapsed alveoli result in either low ventilation/perfusion (V/Q) ratio or a right to left pulmonary shunt resulting in marked venous admixture further increasing the effort of the respiratory muscles leading to fatigue and finally the respiratory failure ensues (Table 16.1).
Additionally, hypoxia, hypercarbia and small vessel thrombosis also lead to increased pulmonary artery pressures leading to increased right ventricular work and filling, ultimately causing septal shift towards the left side. This may decrease cardiac output, further decreasing oxygen delivery to the tissues. In addition, iatrogenic problems further add to the complications.
A high FiO2 (>95%) may cause absorption atelectasis reducing the number of patent alveoli, lung toxicity and possibly systemic toxicity. Oxygen toxicity can be seen with FiO2 more than 60% over a period of time. Higher mean airway pressures and peak airway pressure may cause air leaks and decrease cardiac output, further compromising the cardiorespiratory function.4-8 Fluid retention may also lead to further alveolar and pulmonary interstitial flooding with worsening compliance and oxygenation.
Table 16.1   Pathophysiology of ARDS
Capillary damage
Alveolar damage
  • Platelet aggregation
  • Neutrophil chemotaxis
  • Activated neutrophils
    • Alveolocapillary damage-Increased permeability
  • Vasoconstriction
    • V/Q mismatch
  • Type 2 cell damage
  • Surfactant inactivated/decreased production
  • Decreased compliance
  • Atelectasis
253Course of ARDS can be divided into the following three histopathological stages:9
Exudative stage: It is characterized by the injury to lung endothelial cells and alveolar epithelial cells resulting in the filling of air spaces with exudates and fluid and development of microvascular thrombi. Patients presenting in the emergency department (ED) are typically confined to this stage.
Proliferative stage: Type II pneumocytes, fibroblasts and myofibroblasts proliferate resulting in the widening of alveolar septa and conversion of intra-alveolar hemorrhagic exudates into cellular granulation tissue. This stage occurs between the 1st and 3rd week of initial insult.
Fibrotic stage: If the patient survives for 3 weeks, the lungs exhibit remodeling and fibrosis.
 
EPIDEMIOLOGY
Worldwide, the incidence of ARDS varies between 8.5 and 27 cases per 1,000 pediatric intensive care unit (PICU) admissions.4-8 In 2005, the first population-based study was done in Germany and it showed an incidence of 3.1 × 10-5 cases per 100,000 population per year in pediatric patients aged 1 month to 18 years.10 The incidence of ARDS in a case series at All India Institute of Medical Sciences (AIIMS) in India, by Lodha et al was found to be 20/1,000 PICU admissions, whereas Khilnani et al found 30.7/1,000 PICU admissions with ARDS.11-12
The overall, mortality in ARDS is approximately between 35 to 50% and death is likely due to multiorgan system failure rather than pulmonary failure per se.13 Nevertheless, published estimated mortality rates for ARDS vary in both adults and pediatric populations. Since the 1980s, when the studies revealed mortality rates of 29 to 94% for children; mortality rates have declined, as shown in the studies from 1990s that yielded rates of 30 to 50%.14 However, the definition of ARDS was not standardized in early 1980s. Pediatric studies over the past decade have demonstrated mortality rate of 8 to 26%.10,15-17 This change is mostly because of the emergence of highly specialized PICUs, skilled staff and improvement in transportation of critically ill children, change in the definition of the illness itself and most importantly; changes in the management of this illness, specifically ventilatory management.
 
ETIOLOGY
Acute respiratory distress syndrome (ARDS) can be the result of either:18
  1. Direct lung injury of alveolar epithelium—pulmonary ARDS.
  2. Indirect lung injury of vascular endothelium by inflammatory mediators—extrapulmonary ARDS (Table 16.2).
254
Table 16.2   Etiology of ARDS
Pulmonary ARDS
Extrapulmonary ARDS
  1. Pneumonia—bacterial, viral, fungal
  2. Aspiration pneumonia
  3. Aspiration of gastric contents and other noxious substances (example: hydrocarbons)
  4. Inhalational injury (thermal, noxious gases)
  5. Pneumocystis
  6. Fat emboli
  7. Near drowning
  8. Barotraumas, volutrauma secondary to mechanical ventilation
  9. Lung contusion
  1. Sepsis
  2. Septic shock
  3. Abdominal peritonitis, occlusion, mesenteric ischemia
  4. Acute pancreatitis
  5. Trauma (non-thoracic)
  6. Hyper transfusion for emergency resuscitation
  7. Cardiopulmonary bypass (rare)
 
CLINICAL PRESENTATION
Acute respiratory distress syndrome (ARDS) should be considered in any critically ill child with significant risk factors associated with some direct or indirect lung injury. It develops acutely after temporally related risk factors (such as severe trauma, sepsis, aspiration, etc.) and persists for days to weeks.
The provocative event is obvious in many cases, but in others it may be harder to identify. Typically, the illness develops within 12 to 48 hours after an inciting event, although in rare instances, it may take up to a few days. Pediatric ARDS is characterized by acute lung injury followed by a latent period of 12 to 48 hours in most cases. During this period, patient may notice dyspnea on exertion which later progresses to tachypnea, dyspnea and respiratory failure requiring higher concentration of oxygenation. Lastly, severe hypoxemia refractory to oxygen therapy and multiorgan failure develops.
Physical findings are often non-specific and include tachypnea, tachycardia and the need for high FiO2 to maintain oxygen saturation. The patient may be febrile or hypothermic. Associated hypotension and peripheral vasoconstriction with cold extremities may be present, because ARDS often occurs in the setting of sepsis. Cyanosis of the lips and nail bed might occur. Examination of lungs may reveal bilateral rales, but rales might not be present despite wide spread involvement. Manifestations of the underlying disease process may be present.
 
DIAGNOSIS
Acute respiratory distress syndrome (ARDS) is a clinical diagnosis, and no specific laboratory abnormalities are noted beyond the expected disturbances in gas exchange and radiographic findings. Diagnostic work-up includes selected laboratory tests, diagnostic imaging, hemodynamic monitoring and bronchoscopy (Table 16.3). In addition, patients need to be investigated to find the underlying cause of ARDS. 255
Table 16.3   Diagnostic work-up
Medical history
Physical examination
Chest radiograph
Arterial blood gases and lactates
Complete blood count
Echocardiography
Urine analysis
Blood culture
Urine culture
Sputum gram stain and culture
Liver function tests
Renal function tests
Computed tomography
Bronchoscopy
 
Arterial Blood Gas Analysis
Arterial blood gas (ABG) will assess the severity of hypoxemia and identify the development of respiratory or metabolic acidosis. At the onset of ARDS, there would be marked increase in pulmonary arterio-alveolar (A/a) O2 gradient. PaO2/FiO2 ratio would be decreased, ≤ 200 in ARDS and < 300 in ALI. Oxygenation is assessed by pulse oximetry.
 
Chest Radiography5
It will show bilateral pulmonary infiltrates with maximal severity within the first 3 days and can be interstitial, characterized by alveolar filling or both. Initially, the infiltrates are patchy with peripheral distribution, but soon they progress to diffuse bilateral involvement with ground glass changes or frank alveolar infiltrates.
 
Computed Tomography
The heterogeneity of alveolar involvement is apparent on CT scan. It shows opacities that are distributed throughout the lung with a predisposition for the dependant areas.18,19 Therefore, the disease is not as diffuse as the chest radiograph findings alone suggest.18,20-23 The findings may also include pleural effusion, compression atelectasis, consolidation with air-bronchogram, etc.
Computed tomography (CT) can also differentiate between pulmonary and extrapulmonary ARDS. Pulmonary ARDS tends to be asymmetrical, with a mix of consolidation and ground-glass opacification, predominantly in non-dependant areas. Extrapulmonary ARDS has predominantly symmetric ground-glass opacification in the dependant locations.24
 
Echocardiography
It is a non-invasive method to detect left atrial hypertension and to evaluate left ventricular preload and cardiac output. Transesophageal echocardiography (TEE) is done in patients with severe ARDS in prone position.256
 
Invasive Hemodynamic Monitoring
Hemodynamic monitoring with pulmonary artery (Swan-Ganz) catheterization can be done:
  • To distinguish between cardiogenic and non-cardiogenic pulmonary edema (pulmonary artery occlusion pressure, (PAOP) < 18 mm Hg is usually seen with non-cardiogenic pulmonary edema).
  • To calculate systemic vascular resistance (SVR), for clinical suspicion of sepsis.
  • To facilitate appropriate fluid control management.
  • To adjust ventilator parameters and vasodilator support by assessing mixed venous oxygen saturation and in goal-directed therapy for sepsis.
 
Additional Investigations
Complete blood count (CBC): It may indicate an infectious etiology. Leukopenia or leukocytosis may be present in sepsis. Thrombocytopenia may be present.
Liver function and renal function tests: A are usually deranged and are associated with multiple organ dysfunction syndrome (MODS).
Electrolyte panel: Reveals intravascular volume status, anion gap acidosis and other potential comorbidities.
Blood lactate level: It is an ominous finding and is associated with mortality in patients presenting with shock.
Bronchoscopy for bronchonchoalveolar lavage (BAL) is not required for diagnosis of ARDS. It may be considered to evaluate the possibility of infection. The BAL fluid culture and staining may reveal the offending organism and may guide the antibiotic therapy.
 
MANAGEMENT
There is no definite treatment for ARDS and the cornerstone of management is impeccable intensive care. Ventilatory management and pharmacological manipulation form the two main strategies of treatment. Treatment of the primary cause (e.g. sepsis, pneumonia) as well as, minimizing the risk of multiorgan failure and ventilator-induced lung injury (VILI) is essential.
 
Mechanical Ventilation
Mechanical ventilation is the cornerstone of treatment in patients with ARDS. Maintaining optimal oxygenation while minimizing VILI, is an important aspect in treatment of ARDS.
 
Non-invasive Ventilation25,26
Non-invasive ventilation (NIV) has been used early in ALI and ARDS to avoid endotracheal intubation. The NIV has a limited role in pediatric ARDS, but it can be tried in hemodynamically stable and alert children. During trial of NIV, patients should be adequately monitored for improvement in gas exchange and respiratory mechanics, to avoid unnecessary delay in endotracheal intubation.257
 
Invasive Ventilation
Conventional ventilatory strategies maintain normal blood gas values, often at the expense of high tidal volumes and pressures, with high morbidity and mortality rates. Ventilation with larger tidal volumes over-distends even the normal uninvolved lung. It disrupts the alveolar epithelium and capillary endothelium and also promotes the release of proinflammatory cytokines like IL-6 and TNF-α, causing further inflammation and lung injury. The use of lung protective strategies with low tidal volumes along with optimal PEEP for alveolar recruitment, remain the mainstay of management of ARDS.
 
Lung Protective Strategies27-29
Low tidal volume ventilation (≤ 6 mL/kg body weight): It has been the most revolutionary change in the management of ARDS and has become standard of care for pediatric ARDS. It not only optimizes oxygen delivery, but also reduces VILI. Children with ARDS should be ventilated with the following ventilator settings:
  1. Avoiding tidal volume (TV) ≥ 10 mL/kg.
  2. Limiting plateau pressure to ≤ 30 cm H2O.
  3. Maintaining arterial pH 7.3 to 7.45.
  4. PaO2 60 to 80 mm Hg (SpO2 ≥ 90%).
 
Positive End-Expiratory Pressure
Positive end-expiratory pressure (PEEP) is an essential component of mechanical ventilation for patients with ARDS. It lowers the peripheral vascular resistance (PVR) and expands the alveoli, hence decreasing the ventilation/perfusion (V/Q) mismatch. The PEEP acts as a counterforce and prevents the compression atelectasis occurring as a result of severe pulmonary edema, so it is effective in early ARDS.30 Titrating PEEP to best static lung compliance compatible with plateau pressure of ≤ 30 cm H2O is reasonable in children. Traditionally, PEEP values of 5 to 12 cm H2O have been used in the ventilation of patients with ARDS, but a stepwise approach to increase PEEP to a level which maintains arterial oxygen saturation (SaO2) to 90% at FiO2 of 50 to 60% is recommended31 (Tables 16.4 and 16.5). PEEP above 15 to 20 cm H2O may reduce venous return, in turn compromising the cardiac output. If cardiac output remains depressed despite volume resuscitation and inotropic support, PEEP needs to be decreased till hemodynamic stability is restored.
Positive end-expiratory pressure (PEEP) is more effective in alveolar recruitment in patients with extrapulmonary ARDS, whereas it may result in alveolar hyperinflation and worsening lung injury in pulmonary ARDS.
Permissive hypercapnea:32-35 An acutely elevated arterial partial pressure of carbondioxide (PaCO2) may result in vasodilatation, tachycardia and hypotension. Multiple studies have demonstrated that modest, permissive hypercapnea occurring as a result of lowering tidal volumes and minute ventilation is safe. However, patients with pre-existing metabolic acidosis may require treatment to 258prevent worsening acidosis, so that the pH is not lowered below 7.1. Permissive hypercapnea is contraindicated in patients with increased intracranial tension, pulmonary hypertension and severe cardiac dysfunction.
Table 16.4   Lower PEEP/higher FiO2
FiO2
PEEP
0.3
5
0.4
5
0.4
8
0.5
8
0.5
10
0.6
10
0.7
10
0.7
12
0.7
14
0.8
14
0.9
14
0.9
16
0.9
18
1.0
18–24
Table 16.5   Higher PEEP/lower FiO2
FiO2
PEEP
0.3
5
0.3
8
0.3
10
0.3
12
0.3
14
0.4
14
0.4
16
0.5
16
0.5
18
0.5–0.8
20
0.8
22
0.9
22
1.0
22
1.0
24
 
High Frequency Oscillatory Ventilation36,37
High frequency oscillatory ventilation (HFOV) rapidly delivers small tidal volumes that are typically 1 to 5 mL/kg. Early use of HFOV meets the need of high PEEP, low tidal volume strategy and also minimizes the repetitive opening and closing and possibly reduced VILI, if the lung is sufficiently recruited. Further, carbon dioxide can be maintained at satisfactory levels, because of extremely high respiratory rates. Optimal lung volume is gauged with clinical assessment, monitoring of arterial oxygen saturation, ABG's and lung inflation on chest radiography.
 
Airway Pressure Release Ventilation
Airway pressure release ventilation (APRV) has been described as ventilation with continuous positive airway pressure (CPAP) with regular, brief, intermittent releases in airway pressure.38 It is a relatively new mode of ventilation that allows for spontaneous ventilation with mean airway pressures similar to that achieved with HFOV. It facilitates both oxygenation and CO2 clearance and also allows for better ventilation of dependant lung region.39 259
 
Inverse Ratio Ventilation40,41
Inverse ratio ventilation (IRV), the ratio of inspiratory time to expiratory time exceeds 1(one) and it can be achieved using either volume or pressure modes of ventilation. This prolongation results in increased mean airway pressures, improving oxygenation.
 
Weaning From Mechanical Ventilation
Majority of mechanically ventilated patients for acute respiratory failure spend approximately two-thirds of their time on the ventilator in the “weaning” period.31 So, a systematic approach to liberate ARDS patients from mechanical ventilation is an essential component of their care. Patients managed with appropriate and timely weaning are extubated more quickly.
A once daily spontaneous breathing trial (SBT) for a period of 30 to 120 minutes of unassisted breathing has been found to significantly reduce the duration of mechanical ventilation.42-44 A T-piece, CPAP or pressure support ventilation of ≤ 7 cm H2O may be utilized for it.45 SBT should be resorted to in the patients, who fulfill the following criteria:46
  1. Some reversal of underlying cause for respiratory failure.
  2. FiO2 of ≤ 50% and PEEP of ≤ 8 cm H2O.
  3. Hemodynamic stability.
  4. Ability to initiate inspiratory efforts.
If SBT is tolerated for 30 minutes, extubation should be considered. If it is not tolerated, pre-weaning settings should be resumed.
 
Adjunctive Therapy
Adjunctive therapy is used as an adjunct to ventilator management. These maneuvers mainly remain as rescue therapies.
 
Prone Position
Prone positioning is known to rapidly improve oxygenation in 70% of patients with ARDS, by the following probable mechanisms:
  • It reduces atelectasis in the dependant areas of the lung, optimizing V/Q matching.
  • Improved mobilization and drainage of secretions.
  • Altered diaphragmatic mechanics by decreasing the abdominal compression of the thorax.47
 
Continuous Rotational Therapy
Continuous rotational therapy could serve as an alternative, when prone positioning is inadvisable.48
 
Recruitment Maneuvers
Recruitment is a strategy aimed at re-expanding the collapsed lung tissue and then maintaining high PEEP to prevent subsequent derecruitment.49260
Various types of recruitment maneuvers described are:
  • Application of sigh during lung protective strategy.
  • Three consecutive sighs per minute at 45 cm H2O of plateau pressure for 1 hour in patients with protective strategy.
  • Sustained lung inflation with CPAP of 35 to 45 cm H2O for 20 seconds, etc.50
 
Steroid Therapy51,52
Steroids may be beneficial when used in fibroproliferative phase. Due to their anti-inflammatory and antifibrotic properties, corticosteroids might have a role in modulating the course of ARDS. There have been numerous trials in adults, but limited data is available in pediatric population. Methylprednisolone at a dose of 2 mg/kg daily has been used in adults at an early stage. Available evidence argues against the routine use of steroids in ARDS given their doubtful efficacy and potential for causing serious adverse effects like prolonged weakness after ARDS.
 
Surfactant
One of the key events in the progression of ARDS is a reduction in volume and function of surfactant. So, surfactant therapy has a possible role in ARDS. Synthetic, semisynthetic and recombinant surfactant preparations have been used. Children with respiratory failure due to direct lung injury are more likely to benefit from surfactant than those with indirect lung injury. Animal-derived surfactant has been found to be superior to synthetic surfactant. In a multicenter trial, administration of 100 mg/kg of modified bovine surfactant (calfactant) intratracheally under continuous ventilation and PEEP led to a higher PaO2/FiO2.53,54 There are no definite recommendations regarding the use of surfactant in ARDS, however, significant improvement is demonstrated in the oxygenation index, ventilator-free days and in rate of failure of conventional mechanical ventilation.
 
Inhaled Nitric Oxide
Nitric oxide is a selective pulmonary capillary vasodilator and it may attenuate increase in capillary permeability and also decrease overproduction of cytokines in patients with severe ARDS. iNO causes relaxation of the smooth muscle cells via the second messenger 3′, 5′-cyclic monophosphate (cGMP), which is metabolized by phosphodiesterase (PDE) type 5 and increases perfusion of ventilator lung unit, reducing V/Q mismatch. Although in various trials, dose range of inhated nitricoxide (iNO) is 0 to 80 parts per million (ppm), increasing the dose beyond 20 ppm has not been shown to be beneficial.55 iNO improves oxygenation in ARDS without mortality benefit.15 Its routine use is not yet recommended in children with ARDS, however it may be used as rescue therapy in severe cases. Potential side effects are methemoglobinemia, decreased platelet aggregation, elevation of pulmonary arterial pressure and rebound hypoxemia. It also causes inactivation of already decreased defective surfactant by formation of peroxynitrite, hydroxyl radicals and nitrogen dioxide.261
 
Sildenafil
There is no evidence to support the use of Sildenafil in patients with ARDS. Sildenafil inhibits PDE type 5 and stabilizes cGMP and it could be useful in improving responsiveness to inhaled nitric oxide in sepsis induced ARDS.56
 
Partial Liquid Ventilation
In partial liquid ventilation (PLV), the lung is filled with a volume of perfluorocarbon equal to its functional residual capacity and gaseous mechanical ventilation is performed simultaneously.57
The PLV has following advantages:
  • An ability to maintain an open lung.
  • Repetitive opening and closing of the alveoli are minimized (also referred to as liquid PEEP), thus preventing VILI.
  • Intrinsic anti-inflammatory actions.
  • Lavage effect may clear the alveoli and small airways of debris and inflammatory mediators.
Disadvantages of PLV are; increased incidence of pneumothorax, mucus plugging and disruption of normal surfactant system.
 
Surgical Care
Surgical intervention including chest tube placement in cases of pneumothorax, pleural effusion, etc. can be performed depending upon the condition of the patient. The surgically treatable conditions can be managed accordingly.
 
Diet
Importance of providing adequate nutrition to critically ill children is well- established. Enteral nutrition is preferable over parenteral nutrition, whenever possible. Administration of a formula supplemented with eicosapentaenoic acid, gamma-linolenic acid and antioxidants is associated with a reduction in pulmonary neutrophil recruitment, improved gas exchange, decreased requirement for mechanical ventilation, reduced length of intensive care unit (ICU) stay and the reduction of new organ failures.58 However, there is little evidence to support specific dietary modification in ARDS.
 
Activity
The severity of the precipitating illness (e.g. trauma, sepsis) and ARDS limits the patient's activity. Once the patient recovers, no limitation on activity is usually necessary, except in few patients with evidence of extensive pulmonary scarring or fibrosis.
 
Extracorporeal Life Support
Extracorporeal membrane oxygenation (ECMO) may be beneficial in children with severe ARDS unresponsive to maximal conventional therapy. Patient lungs are allowed to rest on low ventilator settings. Survival increases with “early” (7 days or less of mechanical ventilation) institution of ECMO therapy, presumably 262when the disease remains reversible and before VILI occurs. The survival rate with pediatric ECMO is approximately 50%.16,59,60 Invasive nature and high risk of bleeding associated with it requires that it should be considered only in children in whom all other therapies have failed. Ventilator duration for more than 10 days prior to commencing ECMO is a relative contraindication.
 
PROGNOSIS
Prognosis of ARDS is based on a lot of associated factors and etiology. Associated diabetes with ARDS has a positive prognostic significance, possibly because of diminished neutrophil function. Negative prognostic factors are:
  • Age less than 8 years (incomplete lung growth)
  • Elevated cytokine levels in plasma and (BAL) fluid
  • Concomitant sepsis
  • Multiple organ dysfunction syndrome (MODS)
  • Presence of central nervous system (CNS) dysfunction
  • Initial severity of hypoxemia
  • Near-drowning
  • Heart disease
  • Poor ventilator technique.
 
SUMMARY AND CONCLUSION
The term RDS was coined to describe patients with diffuse alveolar–capillary damage occurring in a diverse group of disorders. Pathophysiology of ARDS is complex and multifaceted. Acute respiratory distress syndrome (ARDS) should be considered in any critically ill child with significant risk factors associated with some direct or indirect lung injury. The ARDS is a clinical diagnosis and no specific laboratory abnormalities are noted beyond the expected disturbances in gas exchange and radiographic findings. The cornerstone of management is impeccable intensive care. Ventilatory management and pharmacological manipulation form the two main strategies of treatment. Children with respiratory failure due to direct lung injury are more likely to benefit from surfactant than those with indirect lung injury. Inhaled nitric oxide improves oxygenation in ARDS without mortality benefit. Extracorporeal membrane oxygenation (ECMO) may be beneficial in children with severe ARDS unresponsive to maximal conventional therapy.
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  1. Hickling KG, Joyce C. Permissive hypercapnea in ARDS and its effect on tissue oxygenation. Acta Anaesthesiol Scand Suppl 1995;107:201–208.
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  1. Ferguson ND, Stewart TE. New therapies for adults with acute lung injury. High-frequency oscillatory ventilation. Crit Care Clin 2002;18:91–106.
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Respiratory Distress Syndrome17

Ajay Gaur
 
INTRODUCTION
Respiratory distress syndrome (RDS) is characterized clinically by respiratory rate > 60/min, dyspnea (intercostals, subcostal indrawing, sternal retraction) with a predominantly diaphragmatic breathing pattern and a characteristic expiratory grunt, all presenting within 4 to 6 hours of birth. Oxygen administration is required to prevent cyanosis and there is a reticulogranular chest X-ray (CXR) appearance as a result of widespread atelectasis. Pathophysiologically, the condition is characterized by non-compliant (stiff) lungs, which contain less surfactant than normal and become atelectatic at end-expiration.
Histologically, hyaline membranes give the condition its alternative name, hyaline membrane disease (HMD), which, should be used only in the presence of histological confirmation. Thus, the term RDS is preferred.
It is extremely difficult to clinically diagnose RDS in extremely low birth weight babies. The term respiratory insufficiency of prematurity has also been widely used. Significant advances made in the management of RDS include the development of prenatal diagnosis to identify infants at risk, prevention of the disease by antenatal administration of glucocorticoids, improvements in perinatal and neonatal care, advances in respiratory support, and surfactant replacement therapy. As a result the mortality from RDS has decreased. However, the survival of increasing numbers of extremely immature infants has provided new challenges, and RDS remains an important contributing cause of neonatal mortality and morbidity.
 
ETIOLOGY
The RDS results from immaturity of the lungs, particularly the surfactant-synthesising systems. The risk of RDS is inversely proportional to gestational age and is almost invariable in infants > 28 weeks gestation, it does remain a significant problem up to 34 weeks gestation. The maturation of surfactant synthesis is a mirror image of the incidence of RDS at different gestations.1 Dyspnea and hypoxemia in preterm babies is due to their immature lung structure, with increased connective tissue and poorly developed alveoli as their lung epithelia are leakier than those of 268a baby born at term. It increases the likelihood of protein passing onto the alveolar surface, where it will inhibit surfactant function. They are more prone to asphyxia, hypoxia, hypotension and hypothermia, all of which are likely to impair surfactant synthesis or increase alveolar capillary leakiness. Boys are much more likely to develop RDS than girls, with a male to female ratio of 1.7:1 and are more likely to die from the disease.2,3 In male fetuses, the delayed maturation of the lecithin to sphingomyelin (L:S) ratio and late appearance of phosphatidylglycerol (PG) are androgen induced. Cesarean section carried out before the mother went into labor was reported to increase the risk of her baby developing RDS although this was not a consistent finding.4-7 Babies who are depressed at birth have been reported to be at increased risk of RDS. The incidence of RDS is high in babies when APGAR is low. During fetal asphyxia, lung perfusion falls, resulting in ischemic damage to pulmonary capillaries. When the fetus recovers from the acute asphyxia, pulmonary hyper-perfusion occurs, and if delivery occurs shortly afterwards, a protein rich fluid leaks out of the damaged pulmonary capillaries. The association between asphyxia and RDS is also influenced by the fact that hypoxia and acidemia predispose to pulmonary hypertension and hypoperfusion with a right-to-left shunt and reduce surfactant synthesis by inhibiting synthetic enzymes. RDS following birth depression blends into a spectrum with acute respiratory distress syndrome (ARDS).8-12 Fetuses of diabetic mothers have abnormal surfactant synthesis; in particular delay in the appearance of PG, insulin delays the maturation of alveolar type II cells and decreases the proportion of saturated phosphatidylcholine in the surfactant.13,14 There are decreased levels of surfactant protein A in amniotic fluid from diabetic pregnancies as compared with fluid from non-diabetic women. In cultured human lung tissue, insulin inhibits accumulation of SP-A and its mRNA during culture. The incidences of RDS in infants of diabetic mothers (IDM) were also increased by elective cesarean section before labor at 36 to 37 weeks. Thyroid activity is important in the prenatal development of the surfactant system.15,16 Preterm babies who develop RDS have lower levels of thyroid hormones in their cord blood. Among twins, second twin is more likely to develop RDS, although this is not a consistent finding and others have reported no difference between twins and singletons.17,18 There is similarity of L:S ration in twins, which is greater in monozygotic than dizygotic pairs. Hypothermia, hypoxia and acidemia impair surfactant synthesis. In addition below 34°C even in the presence of adequate amounts of PG, dipalmitoyl phosphatidycholine (DPPC) cannot spread to form an adequately functioning monolayer. Maternal malnutrition compromises fetal surfactant synthesis as well as lung growth.19-21
 
PATHOLOGY
The initial histological finding is alveolar epithelial cell necrosis, which develops within half an hour of birth. The epithelial cells become detached from the basement membrane and small patches of hyaline membranes form on the denuded areas causing diffuse interstitial edema. The lymphatics are dilated by the delayed clearance of fetal lung fluid and the capillaries next to the membranes have a sludged appearance. There are very few osmiophilic granules in the type 269II cells, which in place contain vacuoles, suggesting that all the lamellar bodies have been discharged. In the early stages, all these changes are rather patchy, but by 24 hours, more extensive generalized membrane formation in the transitional ducts and respiratory bronchioles occurs. Figure 17.1 hyaline membranes line the overdistended terminal and respiratory bronchioles, particularly where the airways branch and may extend into the putative alveolar ducts. The most distal component of the respiratory unit, the terminal sacs although collapsed are not lined by membranes. The hyaline membranes are eosinophilic and contain nuclear debris from necrotic pneumocytes. The hyaline membranes are formed by coagulation of plasma proteins, which have leaked onto the lung surface through damaged capillaries and epithelial cells; the fibrillary component of the membrane is derived from exuded fibrin. After, 24 hours, a few inflammatory cells appear within the airway lumen; macrophages are usually the most prominent cell, although some polymorphs may also be present. Ingestion of the membrane by macrophages takes place over the next 2 or 3 days as the membrane separates. Macrophages are also present beneath the membrane within the interstitium, which is usually edematous and where there may be mild fibroblastic response. Epithelial regeneration is detectable after 48 hours, usually edematous and eration is detectable after 48 hours, usually beneath the separating membranes. Cuboidal cells from the unaffected transitional ducts become large and mitotic; they flatten out and spread beneath the hyaline membranes. Other cells produce lamellar bodies. Many of these reparative cells form abnormally thick epithelial squames and with damaged capillaries can present a considerable barrier to efficient gas exchange.
Fig. 17.1: Histological appearance of lungs in respiratory distress syndrome. Hyaline membranes lining the dilated alveolar ducts
270During this stage of repair, surfactant can be detected in increasing quantities on the alveolar surface. By 7 days of age, the hyaline membranes will have disappeared in an infant with uncomplicated RDS.22,23
 
PATHOPHYSIOLOGY
Lung functions are compromised as lungs are noncomplaint, when the disease is at its worst but as surfactant begins to appear, the compliance improves. In severe diseases, the functional residual capacity (FRC) may be as low as 3 mL/kg, whereas the FRC is at a normal level of 25 to 30 mL/kg in recovering babies. Babies with RDS have a low tidal volume large physiological dead space. Minute ventilation, however, may be increased by an elevated respiratory rate in an attempt to sustain alveolar ventilation but this is usually unsuccessfully resulting in alveolar underventilation and carbon dioxide retention. Inspiratory resistance is usually normal in RDS, but expiratory resistance is increased, probably as a result of the closure of the airway prior to the expiratory grunt. It is also increase by the presence of an endotracheal tube. An inevitable sequel of the abnormal lung mechanics is the work of breathing is increased in neonates with a RDS to twice that seen in those without RDS. Clinical studies have shown the respiratory rate of infants with a RDS to about 80 to 90 minutes, with an average inspiratory time of 0.25 to 0.35 seconds. This pattern of respiration may be adopted so that the neonate retains gas within lungs and some level of FRC is maintained.24-26 A characteristic features of RDS is the expiratory grunt. This is the result of the baby attempting to sustain an FRC by delaying the escape of air from his lungs during expiration. They try to do this in two ways; firstly, during expiration, the diaphragm continues to contract trying to delay or brake the reduction in thoracic volume and thus retain gas within the alveoli, secondly, by contracting the constrictor muscles of the larynx and attempt is made to close the upper airway as in the Valsalva maneuver. Since the abdominal muscles contract at the same time as the laryngeal muscles relax, there is an explosive exhalation of air, which is the characteristic ‘grunt’. By passing this laryngeal component of expiratory braking by putting an endotracheal tube (ETT) through the cords results in a fall in the PaO2 in babies with RDS.
Preterm baby is born with poor reserves of surfactant. Surfactant synthesis is a dynamic process that depends on factors such as pH, temperature and perfusion, and may be compromised by cold stress, hypovolemia, hypoxemia and acidosis. Other unfavorable factors, such as exposure to high inspired oxygen concentration and the effects of barotraumas and volutrauma from assisted ventilation, can trigger the release of proinflammatory cytokines and chemokines and further damage the alveolar epithelial lining, resulting in reduced surfactant synthesis and function. The leakage of proteins, such as fibrin in the intra-alveolar space further aggravates surfactant deficiency by promoting surfactant inactivation. Deficiency of surfactant and the accompanying decrease in lung compliance lead to alveolar hypoventilation and ventilation–perfusion (V/Q) imbalance.
Severe hypoxemia and systemic hypoperfusion result in decreased oxygen delivery with subsequent lactic acidosis secondary to anaerobic metabolism. Hypoxemia and acidosis also result in pulmonary hypoperfusion secondary to pulmonary vasoconstriction, and the result is a further aggravation of hypoxemia 271due to right-to-left shunting at the level of the ductus arteriosus and foramen ovale and within the lung itself.27
The deterioration seen with non-surfactant-treated RDS is due in part to the disappearance of these small quantities of surfactant compounded by fatigue as the neonate struggles to sustain ventilation in stiff surfactant-deficient lungs. The disappearance of surfactant is primarily due to the inhibitory effect of proteins of surfactant which leak onto the alveolar surface in the early edematous stage of lung damage. The deleterious effects of hypoxia and acidemia on surfactant synthesis are also contributory factors. The levels of surfactant proteins are also low in the first few hours in babies with a RDS and rise as the babies recover. The lungs remain noncomplaint and atelectatic until surfactant begins to reappear from 36 to 48 hours of age as demonstrated by measurement of L:S ratios of pharyngeal aspirates. Flow chart 17.1 represents series of acute and chronic events that lead to neonatal respiratory distress syndrome.
 
CLINICAL FEATURES
The diagnostic criteria for RDS comprised of respiratory rate above 60/min; grunting expiration; in drawing of the sternum, intercostals spaces and lower ribs during inspiration and cyanosis without added oxygen.28 Although these signs are characteristic for neonatal RDS, they can result from a wide variety of no pulmonary causes, such as hypothermia, hypoglycemia, anemia or polycythemia and furthermore such nonpulmonary conditions can complicate the clinical course of RDS.27 The disease is present within the first 4 hours after birth, over the next 24 to 36 hours the baby tires, his dyspnea worsens and he becomes edematous. In addition to tachypnea, there are marked intercostals and sternal recession, and flaring of the alae nasi. On auscultation, there is a reduction in air entry. An expiratory grunt is a feature of most forms of neonatal respiratory disease, and is an attempt by the baby to sustain his FRC. In uncomplicated RDS, these clinical features gradually return to normal by 7 days at the latest. The presence of apneic episodes at this early stage is an ominous sign that could reflect thermal instability or sepsis but more often is a sign of hypoxemia and respiratory failure.
The heart rate in mild to moderate cases of RDS is 140 to 160/min and shows normal variability. In infants with severe RDS, the heart rate tends to be slower with little beat to beat variation. The heart sounds are normal. Murmurs are not normally present; if heard in the first 24 to 48 hours they suggest congenital heart disease or ischemic myocardial injury and require further investigation. A murmur appearing after 3 to 4 days is usually due to a PDA. This is audible during the recovery phase of RDS, when pulmonary vascular resistance has fallen below systemic levels and there is left-to-right shunting. Heart failure is not a feature of RDS; if present it suggests a cardiac disease.27
Neonates with RDS are often hypotensive and this is associated with a worse prognosis. Hypertension is less common in babies who receive antenatal steroids. There are many causes for the hypotension, including hypoxia and acidemia depressing the myocardium and reducing cardiac output, a low blood volume and high pressure ventilation compromising venous return and reducing cardiac 272output.
Flow chart 17.1: Schematic representation of series of events that lead to neonatal respiratory distress syndrome
Hypotension predisposes to acidemia, which increases pulmonary vascular resistance, renal failure and NEC. It is essential therefore to measure the BP and to correct hypotension as soon as possible.29,30 The RDS babies are hypotonic, inactive and lie in the frog position spending most of his day asleep, if they are preterm. Abnormal neurological signs are often subtle, but if present they are ominous, suggesting development of IVH. Presence of hepatosplenomegaly suggests heart failure or sepsis and should be dealt with accordingly, and an easily felt liver in a baby with severe respiratory failure suggests a right tension pneumothorax.
The urine output is low for the first 24 to 48 hours but soon diuresis ensues. If RDS is uncomplicated recovery starts after 48 hours. The decline in oxygen requirement is relatively rapid after 72 hours, and usually oxygen can be discontinued after 1 week.273
Table 17.1   Differential diagnosis of dyspnea in neonate
Transient tachypnea
Pulmonary hypoplasia
Meconium aspiration
Persistent pulmonary hypertension
Pneumothorax or pneumediastinum
Inhalation of feed
Massive pulmonary hemorrhage
Inborn errors of metabolism
After severe asphyxia infection (pneumonia)
Primary neurological or muscle disease
Congenital malformations
Upper airway obstruction
Congenital heart disease
The VLBW infant (less than 1,500 g) usually will require mechanical ventilation and have a more prolonged course.
 
DIFFERENTIAL DIAGNOSIS
The differential diagnosis in the first 6 hours can usually be made on the basis of the history, gestational age, clinical examination, blood gases and the chest X-ray; however it is difficult to exclude infection at this time. Primary PPHN can be differentiated by the absence of significant parenchymal lung disease and the relevant echocardiographic finding. Infants with RDS, however, may also have marked pulmonary hypertension.31 Respiratory distress presenting after 4 to 6 hours of age in an infant who has been adequately observed is usually due to pneumonia or heart failure secondary to heart disease. Other conditions, such as aspiration and inhalation of the feed, malformations and occasionally a small pneumothorax can present after 6 hours of age but these are less common. The other conditions in which dyspnea may occur in neonate is listed in Table 17.1.23
 
INVESTIGATIONS
Hemoglobin level varies. Anemia may develop later due to IVH or iatrogenic losses. The white blood count is normal for the baby's birth weight and gestation. Thrombocytopenia is not a feature of RDS unless there is disseminated intravascular coagulation (DIC) or the baby is ventilated. Coagulation system is often prolonged due to prematurity in infants with RDS, although disseminated intravascular coagulation DIC is rare. The presence of coagulopathy can be due to complications such a birth asphyxia septicemia or IVH. Infants who have suffered intrauterine growth retardation are also at increased risk of coagulation abnormalities.32-36
The plasma electrolyte pattern is usually normal although marked early hyponatremia can be seen if the mother has been overload with fluid during labor.37 The plasma calcium if frequently low in the first 48 to 72 hours in ill low birth weight (LBW) babies. Although infants of very low birth weight are prone 274to hypoglycemia, when sick they are also susceptible to hyperglycemia. Infection should be considered in a baby with hyperglycemia. Babies with RDS may have impaired renal function, with a reduced glomerular filtration rate and renal plasma flow and a correspondingly raised urea and creatinine,38 they are also poor at excreting hydrogen ions.39
Serum albumin levels are often below 25 to 30 g/L in preterm infants40 and are lower in the cord blood of babies who develop RDS.41 Total complement levels are normal, but anaphylotoxins are released if complications or RDS occur such as pneumothorax or GMH/IVH.42,43
 
Blood Gas Measurement
A mixed metabolic and respiratory acidemia is found in most cases of RDS, with the PaCO2 being raised in all but the mildest cases; indeed the absence of hypercapnia or the presence of a low PaCO2 should suggest a diagnosis other than RDS in a dyspneic neonate.
Cortisol levels of an ill 26-week babies are lower than those of healthy preterm babies they remain low for several days after birth and are further depressed by prenatal therapy with dexamethasone.44 Levels of TSH, T4 and T3 although initially normal in cord blood, drop below normal during the first week.45,46
 
Assessment of Fetal Lung Maturity
  1. The lecithin sphingomyelin ratio is performed by thin layer chromatography. Risk of RDS is very low if the L/S ratio is > 2. Exceptions to the prediction of pulmonary maturity with an L/S ratio > 2 are infants of diabetic's mothers, intrapartum asphyxia and erythroblastosis fetalis. Possible exceptions are intrauterine growth restriction, abruptio placentae, pre-eclampsia and hydrops fetalis. Contaminants such as blood and meconium, affect the interpretation of results. Blood and meconium tend to elevate an immature L/S ratio and depress a mature L/S ratio. As a result and L/S ratio over 2 in a contaminated specimen is probably mature and a ratio under 2 is probably immature.47 The lecithin sphingomyelin ratio and phosphatidylglycerol level remain low in serial tracheal aspirate samples for 48 hours and then increase with recovery; the saturated phosphatidylcholine (SPC) levels remain low in RDS and reach normal levels after 4 to 7 days; the surfactant protein A (SP-A) to SP-C ratio is low in RDS.48
  2. The TDx–fetal lung maturity (FLM) II measure the surfactant albumin ratio using fluoroscent polarization technology. It appears to predict clinically significant RDS when a cutoff of > 45 mg/g is used for mature results. Contamination with blood or meconium may interfere with interpretation of this test.
  3. Lamellar body counts in the amniotic fluid have also been used as a rapid and inexpensive test to determine FLM. Lamellar bodies are “packages” of phospholipids produced by type II alveolar cells and are present in amniotic fluid in increasing numbers with advancing gestational age.49
275
Figs 17.2A and B: Chest X- ray with reticulogranular infiltrates in RDS. Note that the second film depicts a fairly advance stage
Fig. 17.3: Alveolar atelectasis in RDS
 
Chest X-ray
In RDS, the CXR shows diffuse, fine granular opacification in both lung fields with an air bronchogram where the air filled bronchi stand out against the atelectatic lungs (Figs 17.2 and 17.3). The appearance can be very variable, from a slight granularity to lungs that are so opaque that it is impossible to distinguish between 276the lung field and the cardiac silhouette. Occurrence of these densities is influenced by size of the infant, severity of disease, treatment with surfactant and degree of ventilatory support. The densities may be more pronounced at the lung bases than at the apices. The lung volume may appear normal early, especially but ultimately the lung volume is decreased. A whiteout on a 1 hour X-ray however, may be due to retained fetal lung fluid; by 4 hours of age, presumably as a result of clearance of the liquid the CXR appearance may show marked improvement. The CXR appearance also depends on the phase of the respiratory cycle, the appearance being much worse on an expiratory rather than an inspiratory one. Positive pressure support with both CPAP and IPPV can improve the CXR appearance in a baby who had marked X-ray changes while breathing spontaneously or may obliterates diagnostic findings, surfactant treatment has the same effect.50 As a consequence, the appearance of a CXR taken in the first few hours is a poor guide to both prognosis and the response to exogenous surfactant therapy. Heart size is typically normal or cardiomegaly may be prominent as a consequence of birth asphyxia in infants of diabetic mothers, or because of the development of congestive cardiac failure from a patent ductus arteriosus (PDA). Infant with RDS reportedly have a larger thymic silhouette than infants of comparable size without RDS. This supports the theory that patients with RDS have had reduced exposure to endogenous corticosteroids during fetal life. Other conditions such as pneumonia or pulmonary edema may have very similar radiographic features.51,52,27
Echocardiographic studies in neonates with RDS confirm the presence of a PDA in most cases, but are otherwise normal in the absence of PPHN or severe depression of myocardial function. Doppler echocardiography is used to investigate the degree of pulmonary hypertension.
 
TREATMENT
Initial care is during transportation from the labor ward to the neonatal intensive care unit (NICU) ensure that there is no deterioration in a baby lung disease during transfer. Therapy for RDS includes careful application of general supportive measure supplemented by surfactant therapy and specific means of controlling and assisting ventilation. Close and detailed supervision of small infants requires a dedicated, trained staff experienced and interested in problem specific to the newborn and skillful in the unique technical procedures involved such as assessment of neonatal blood gases, putting newborn on ventilator and administration of surfactants.
 
Initial Management in the NICU
As soon as the baby arrives in the NICU he must be put under a radiant heater. Following procedures should be carried out in all neonates with an RDS:
  • Weigh the newborn
  • Examine carefully and thoroughly
  • Measure the head circumference
  • Connect to ECG, SpO2 and respiration monitors277
  • Measure the baby's temperature
  • Insert a UAC and measure PaO2, PaCO2 and pH
  • Measure the BP using a continuously recording device
  • Treat abnormalities of blood gases and BP
  • Draw blood for hemoglobin and white cell count. Cross match all ill neonates
  • Take a set culture, including a blood culture
  • Send blood for electrolyte measurements
  • Measure coagulation in ill and bruised babies and those less than 30 weeks gestation
  • Insert a peripheral cannula for the administration of antibiotics
  • In critically ill infants or that with extremely LBW insert an umbilical or central venous catheter
  • Obtained a CXR preferably after inserting the UAC
  • Give surfactant if it has not been given prophylactically in the labor ward
  • Update the parents.
 
Minimal Stimulation
Manipulations such as hell sticks tracheal suctioning, diaper changes and even weighing should be kept to a minimum as these procedures have been shown to reduce arterial oxygen tension they probably also increase oxygen consumption and may contribute to the genesis of cerebral hemorrhage by rapidly raising arterial blood pressure to excessive levels. Routine suctioning of the ETT are contraindicated.
 
Blood Gas Management
The ability to accurately monitor and interpret the blood gas status of infants is essential in all cases of neonatal respiratory disease. Infants with acute respiratory distress requiring a significantly increased inspired oxygen concentration or assisted ventilation should have blood gases sampled every 4 hours or more often as their clinical condition dictates. In infants with RDS, partial pressure of arterial oxygen PaO2 is customarily maintained between 50 and 80 mm Hg. PaCO2 in the 40 to 55 mm Hg range and pH at least 7.25. Cerebral blood flow increased about 30% with each 1 kPa increased in PaCO2, but a degree of permissive hypercarbia has been associated with a reduced incidence of CLD.53 Higher PaCO2 levels in more mature neonates with RDS and in < 1.50 kg infants more than a week old who are being weaned off IPPV are acceptable, providing the baby is clinically stable with satisfactory pH and base excess levels. Hypocapnia should be avoided because of its role in the genesis of periventricular leukomalacia (PVL) and chronic lung disease (CLD). A rapidly rising PaCO2 is a sign of impending respiratory failure, usually associated with a fall in pH, and therefore indicates that the baby should be intubated and ventilated irrespective of his postnatal age. More gradual changes, a stable high PaCO2 with an acceptable pH, can be managed conservatively, particularly when the baby is not in the acute phase of illness. Metabolic alkalemia is rare, is almost always iatrogenic as a result of excessive intravenous bicarbonate use, and requires no therapy. Respiratory alkalemia is usually due to excessive use of ventilator pressures or a deliberate attempt to dilate the pulmonary vasculature 278in PPHN. Acidemia is common in neonates with RDS. It is always essential to establish whether the acidemia is respiratory, with a raised PaCO2 or metabolic with a normal PaCO2 and a negative base excess or combination of a metabolic and respiratory acidosis which is more usual. The most common cause of metabolic acidemia in a baby with a RDS is a raised lactate form anaerobic metabolism. This in turn can be secondary to hypoxemia, hypertension, anemia, infection, sepsis or strenuous respiratory muscle activity. When a metabolic acidemia does develop, it is essential to identify the causes so direct treatment can be instituted–for example oxygen for hypoxia, antibiotics for infection transfusion for anemia and hypotension or IPPV for exhaustion. Acidemia inhibits surfactant synthesis and increase pulmonary vascular resistance.54 Once the pH falls below 7.15, other physiological functions such as myocardial contractility and diaphragmatic activity begin to deteriorate,55,56 sick neonates having difficulty in excreting acid load.57 Ill VLBW neonates should have their pH kept > 7.25 at all times. If the pH is < 7.25 with a base deficit > 10 mmol/L, intravenous alkali therapy is appropriate if other therapies are not immediately successful. Inappropriately large or fast infusion of base to correct metabolic acidemia however, may cause hypernatremia or cerebral hemorrhage.58 Two alkalis have been used in neonatal therapy sodium bicarbonate and trishydroxymethylaminomethane (THAM). Both are effective. The theoretical risk that following infusion of bicarbonate the cerebrospinal fluid might become even more acidotic does not seem to apply to the neonate.59,60 THAM administrations does not give a sodium load or increase the PaCO2 and is preferable to bicarbonate if the neonate has a high PaCO2 but apnea may result and thus THAM should only be given to ventilated neonates. The dose of base to be given is calculated as:61
Dose (mmol) = based deficit (mmol/L) × body weight (kg) × 0.4
The rate of infusion should never exceed 0.5 mmol/min seven percent THAM solution contains approximately 0.5 mmol/mL of base.
One should bear in mind that normal arterial oxygen tension or saturation does not ensure adequate tissue oxygen delivery, because oxygen delivery is dependent on cardiac output and oxygen content of the blood. Hence, blood gas interpretation should always be correlated with a thorough clinical assessment.
 
Blood Pressure
It is important to monitor blood pressure in RDS. If the hypotension is severe in the first hours after birth, transfusion of blood or albumin are better given. Transfusion should also, be given to babies who are not hypotensive but have features suggesting hypovolemia such as poor capillary filling, peripheral vasoconstriction and a falling pH. If the hypotensive neonate is severely hypoxic or acidemic, his cardiac function may be impaired, then dopamine is the preferred treatment. Dopamine should also be used where volume expansion has failed to increase BP. If plasma volume expansion plus dopamine does not reverse hypotension, other agents like dobutamine, isoprenaline, adrenaline dopexamine hydrochloride and hydrocortisone can be tried.62,63279
 
Oxygen
Delivery of oxygen should be sufficient to maintain oxygen saturations in the 88 to 95% range, a range generally sufficient to meet metabolic demands. In the smallest infants > 1250 g birth weight, lower oxygen saturation targets may be preferable. Higher than necessary fraction of inspired oxygen (FiO2) levels should be avoided because of the danger of potentiating the development of lung injury and retinopathy of prematurity. The oxygen is warmed, humidified and delivered through an air oxygen blender that allows precise control over the oxygen concentration. For infants with acute RDS, oxygen is ordered by concentration not by flow. It should be titrated to the targeted oxygen saturation. When ventilation with an anesthesia bag is required, the oxygen concentration should be similar to that before bagging to avoid hyperoxia and should be adjusted in response to continuous monitoring.
 
Noninvasive Monitoring: Pulse Oximetry
Pulse oximetry is a well-established technique for indirectly determining oxygenation in a noninvasive and continuous manner. The major disadvantage of pulse oximetry is that changes in saturation are small on the flat portion of the hemoglobin dissociation curve at PaCO2 values greater than about 60 mm Hg (depending on the fetal hemoglobin content and other factors affecting position of the hemoglobin dissociation curve). Pulse oximeters are quite sensitive to sudden changes in background signal such as those due to body movements. It is therefore important to ensure that the pulsatile waveforms, from which oxygen saturation is derived, are not distorted. This is typically done by comparing pulse rate from the oximeter with heart rate obtained from a cardiorespiratory monitor; these values should be identical. A new electronic signal processing technique and sensor design, called signal extraction technology, has significantly improved the accuracy and reliability of pulse oximetry measurements. A major effect of pulse oximetry has been the ability to rapidly optimize respiratory care and drastically reduce the time required to determine optimum inspired oxygen concentrations, levels of CPAP, and respirator settings. Other benefits include the ability to assess responses to all procedures, including surfactant instillation, as well as excessive handling. Complications such as pneumothorax, endotracheal tube dislodgement, disconnection from oxygen supply or respirator malfunction will be rapidly recognized so that immediate corrective treatment can be initiated.27
 
Transfusion of Blood and Blood Products
Transfuse all ill neonates when their hemoglobin has fallen below 13 g/dL.64 Routine administration of fresh frozen plasma soon after birth is of no benefit.65 If an over coagulation disturbance occurs, such as DIC or thrombocytopenia, this should be treated by appropriate factor replacement but it is also essential to control and reverse the underlying problem such as hypoxemia or sepsis. Exchange transfusion has no place in the routine management of RDS but may be indicated in the presence of DIC or sepsis. 280
 
Fluid and Electrolyte Balance
Renal functions are impaired in RDS. Increased capillary permeability in RDS results in fluid loss into all tissues, including the lungs and this worsen when pancuronium is given. If fluid and sodium balance are inadequately controlled then risk of PDA, NEC, CLD and probably GMH-IVH are increased. Infants with RDS should start on 40 to 60 mL/kg/24 h of a 10% dextrose solution. The fluid intake subsequently should be guided by the electrolyte levels and the change in the baby's weight. The ill neonate loses about 1.1 to 3.1% of bodyweight per day, a greater loss may indicate dehydration, whereas a static or increase in weight suggests too much fluid has been given.22,66 Serum electrolyte analysis governs supplementation; sodium and potassium do not usually need to be added to the fluid intake for the first 36 to 48 hours though the frequent presence of hypocalcemia in such babies means that calcium should usually be given. Glucose infusion rates in excess of 6 mg/kg/min are likely to cause hyperglycemia, glycosuria and an osmotic diuresis. It is essential to monitor the blood glucose if GIR exceeds 7 to 8 mmol/L and there is glycosuria. Hypoalbuminemia is common in RDS. Infusions of albumin, however do not improve respiratory function, indeed they may impair it and increased the risk of CLD.67,68
 
Nutrition
Neonates with severe respiratory illness may have an ileus and delayed gastric emptying bowel sounds are absent and meconium is not passed. Protein and caloric reserves of the VLBW neonate are low, it is essential protein is to be supplemented after birth as possible. Enteral feeding initially may not be feasible in some ventilated babies < 1.5 kg or some larger sick neonates. Parenteral nutrition initially amino acids and glucose should be given progressing to full TPN including intravenous fat until an adequate enteral intake of protein and calories has been achieved. There are limitations to use intralipid in severe lung disease in which it may cause a fall in PaO2 by increasing pulmonary vascular resistance. Intralipid also predisposes the VLBW baby to Staphylococcus epidermidis sepsis. Pulmonary lipid emboli are more common in but not exclusively limited to neonates receiving intravenous fat. Therefore, if lipid is to be used during the first week in ventilated neonates, the does should not exceed 3 g/kg/24 h, or 2 g/kg/24 h if there is evidence of sepsis.69,70 If stomach is full of milk, it may compromise with ventilation by increasing the work of breathing, lower the PaO2 and even cause apnea. Respiratory problems may be aggravated by the presence of a nasogastric tube obliterating one half of the upper airway. There are several reasons to introduce early enteral feeds. The prolonged absence of enteral feeding compromises gut growth the development of enzymes and normal peristaltic activity and limits early weight gain, with the implication that may have for long term neurological development.71-73
 
Drugs
It is impossible to differentiate severe early onset septicemia from RDS and both conditions may coexist. Without antibiotic treatment, early onset septicemia can be fatal within hours. For this reason all dyspneic newborn babies irrespective of their gestation or chest X-ray appearance, should have appropriate bacterial 281cultures taken and be treated with antibiotics from the earliest signs of respiratory illness as per their institute protocols. Vitamin K should be given to all neonates. Pulmonary hypertension should be suspected in infants whose hypoxia is more severe than would be anticipated from their chest X-ray appearance. Affected infants can benefit from pulmonary vasodilators, with an improvement in oxygenation but all have side effects.
 
Surfactants
Surfactant improves outcome in babies with RDS resulting in reduction in mortality, also associated with a reduction in oxygen requirement, intensity of ventilation and an improvement in blood gases. Exogenous surfactant work in two ways, by coating the alveolar surface and improving lung volume and thus pulmonary perfusion and oxygenation.74 The second effect is, it is incorporated into type II cells and provides substrate for surfactant production.75,76 Natural surfactant, as they more close to the physiological mixture of lipids and proteins (SP-B and SP-C) have a more rapid effect on oxygenation than to synthetic surfactant. Side effect during the administration of the surfactant, are transient hypoxemia and bradycardia. Systemic hypotension and a transient flattening of the EEG were also reported.77-79
 
Closure of the Patent Ductus Arteriosus
Especially in infants weighing less than 1000 g at birth, a PDA may contribute significantly to the overall problem during recovery from RDS and may predispose the infant to the development of BPD. If the ductus is demonstrated to be patent at the age of 3 to 4 days by two dimensional echocardiography and pulsed Doppler ultrasonography the evidence suggests that it is unlikely to close spontaneously within a reasonable time therefore it should be closed either with indomethacin therapy or with surgery.48,80
 
PREVENTION
 
Antenatal Steroids
Not all steroids cross the placenta; cortisol is largely in activated, but degradation is resisted by synthetic steroids such as betamethasone and dexamethasone. Antenatal administration of dexamethasone or betamethasone to pregnant women in preterm labor significantly reduces the incidence of RDS and neonatal death. Several other serious complications of prematurity, including germinal matrix/intraventricular hemorrhage and necrotizing enterocolitis and necrotizing enterocolitis are also reduced. No long term adverse effects have been demonstrated from a single course of antenatal corticosteroids.22,81-83 The effects of antenatal steroids include inducing the enzymes for surfactant synthesis and the genes for the production of the surfactant proteins A, B, C and D and improving the quality of the surfactant produced. Glucocorticoids such as dexamethasone, can cause substantial stimulation of SP-B gene expression to two to three times adult levels in fetal lung explants. They mature the nonsurfactant producing tissues of the lung; the septa become longer, thinner and less cellular, with larger air spaces and 282increased numbers of alveolar divisions.84-88 Maximum benefit occurs if women delivered between 24 and 168 hours of starting the maternal therapy. A smaller but useful benefit is also seen are women receiving less than 24 hours of therapy.89 Antenatal treatment with corticosteroids should be considered for all women at risk of preterm labor between 24 and 36 weeks. A full course consists of two doses of betamethasone (12 mg IM) separated by a 24 hours interval or four doses of dexamethasone (6 mg IM) at 12 hours intervals although incomplete courses may improve outcome. Treatment for less than 24 hours is associated with significant improvement in outcome; thus corticosteroids should be given unless immediate delivery is anticipated.
Other preventive measures includes prevention of prematurity, maternal hypertension intrapratum, postnatal asphyxia, use of depressant to mother, avoidance of maternal fluid overload and maternal diabetes.
 
Prophylactic Surfactant
A large number of studies have been carried out assessing the impact of prophylactic surfactant, i.e. administering surfactant within the first few minutes after birth. Meta-analysis showed positive effects of both synthetic and natural surfactants. Prophylactic use of natural surfactant results in a significant reduction in pnuemothorax mortality and the combined outcome of mortality and CLD but not CLD alone.90-93 Surfactant therapy has shown a reduction in oxygen requirements and the ventilator pressures required. Surfactant also results in elevation of lung volume, in association with increased oxygenation.
 
PROGNOSIS
The chances of survival in RDS are directly related to birth weight and gestational age and are affected by prenatal treatment with antenatal steroids, by surfactant replacement therapy and by the severity and complication of the disease and the facilities available at the treating center.
 
SUMMARY AND CONCLUSION
Respiratory distress syndrome, also termed “hyaline membrane disease”, is a leading cause of respiratory distress in preterm neonates worldwide, the incidence having an inverse relation to gestational age and birth weight. Over and above prematurity, cesarean section and maternal diabetes mellitus are the predisposing factors. The cause is surfactant deficiency. An overwhelming majority of the patients present with respiratory distress with tachypnea, chest retractions, expiratory grunt, cyanosis and systemic hypotension within 6 hours of birth. X-ray of chest shows diffuse, fine granular opacification in both lungs fields with an air-bronchogram where the air-filled bronchi stand out against atelectic lungs. Though early surfactant therapy, the mainstay of management, has considerably improved the prognosis, the best prevention lies in cutting down the incidence of prematurity, and use of prenatal steroids (glucocorticoids) for > 24 hours.283
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Acute Respiratory Failure18

Avash Pani, VSV Prasad, Anjul Dayal
 
INTRODUCTION
Acute respiratory failure (ARF) is a term used to describe any disruption of the respiratory system that impairs its primary functions of delivering oxygen to and removing carbon dioxide from the pulmonary capillary bed.1 Furthermore, respiratory failure may be acute or chronic. Acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status. The manifestations of chronic respiratory failure are less dramatic and may not be as readily apparent.
 
CLASSIFICATION OF RESPIRATORY FAILURE
Respiratory failure is classified as hypoxemic or hypercapnic and may be either acute or chronic.
Hypoxemic respiratory failure (type I) is characterized by a Partial Pressure of Oxygen (PaO2) of less than 50 mm Hg with a normal or low PaCO2. This is the most common form of respiratory failure and it can be associated with acute diseases of the lung, which generally involve fluid filling or collapse of alveolar units. Examples are acute respiratory distress syndrome (ARDS), cardiogenic or noncardiogenic pulmonary edema, pneumonia and pulmonary hemorrhage.
Hypercapnic respiratory failure (type II) is characterized by a PaCO2 of more than 50 mm Hg. Hypoxemia is common in patients with hypercapnic respiratory failure, who are breathing room air. The pH depends on the level of bicarbonate, which, in turn, is dependent on the duration of hypercapnia. Etiologies include drug overdose, neuromuscular disease, chest wall abnormalities and severe airway disorders.
 
PATHOPHYSIOLOGY
Hypoxemia is caused by one of the following abnormalities:
  • Alveolar ventilation (V) and pulmonary perfusion (Q) mismatch
  • Intrapulmonary shunt
  • Hypoventilation
  • Abnormal diffusion of gases at the alveolar-capillary interface.289
 
V/Q Mismatch, Intrapulmonary Shunt and Hypoventilation
The three most important abnormalities in gas exchange that lead to respiratory failure are V/Q mismatch, intrapulmonary shunt and hypoventilation.
The V/Q ratio determines the adequacy of gas exchange in the lung. When alveolar ventilation matches pulmonary blood flow, CO2 is eliminated and the blood becomes fully saturated with oxygen. In the overall healthy lung, the V/Q ratio is assumed to be ideal and equals.1
When V/Q ratio equals 0, pulmonary blood flow does not participate in gas exchange, because the perfused lung unit receives no ventilation (intrapulmonary shunting). Normally shunt is less than 10%. When the intrapulmonary shunt is greater than 30%, resultant hypoxemia does not improve with supplemental oxygenation. PaO2 continues to fall proportionately as the shunt increases.
The shunt fraction can be calculated using the following equation:
where Cc'O2 is the oxygen content of pulmonary capillary blood, CaO2 is the oxygen content of arterial blood and CvO2 is the oxygen content of mixed venous blood.
Treatment consists of recruiting and maximizing lung volume with positive pressure.
In contrast, PaCO2 remains constant because of a compensatory increase in minute ventilation until the shunt fraction exceeds 50%. The protective reflex that reduces the degree of intrapulmonary shunting is hypoxic pulmonary vasoconstriction (HPV); alveolar hypoxia leads to vasoconstriction of the perfusing vessel. This partially corrects the regional V/Q mismatch by improving PaO2 at the expense of increasing pulmonary vascular resistance.
When ventilation is in excess of capillary blood flow, the V/Q ratio is greater than 1. At the extreme, areas of ventilated lung receive no perfusion and the V/Q ratio approaches infinity (alveolar dead-space ventilation). In addition to alveolar dead space, anatomic dead space represents the volume of air in conducting airways that cannot participate in gas exchange.
Combined, the alveolar and anatomic dead-space volumes are referred to as physiologic dead-space, which normally accounts for 30% of total ventilation. Increased dead-space ventilation results in hypoxemia and hypercapnia. This increase can be caused by decreased pulmonary perfusion due to hypotension, pulmonary embolus or alveolar overdistention during mechanical ventilation (Fig. 18.1).
 
Diffusion
Gas must travel through a number of barriers between the alveolus and blood. These barriers include the alveolar epithelial lining, basement membrane, capillary endothelial lining, plasma and red blood cell. In the presence of parenchymal disease, diffusion impairment occurs because of thickening of the alveolar-capillary membrane. Diffusion disequilibrium is also associated with destruction of the pulmonary capillary bed. This results in greatly increased blood flow velocity 290in the remaining capillaries that may allow insufficient time for equilibration.2 Hypoxemia due to diffusion defects responds to supplemental oxygen.
Fig. 18.1: Ventilation-perfusion (V/Q) relationships and associated blood gas abnormalities
 
ETIOLOGY
Box 18.1 lists the etiogic spectrum of ARDS.
 
APPROACH TO A CHILD WITH ACUTE RESPIRATORY FAILURE
When presented with a child who has a decreased level of consciousness, slow/shallow breathing or increased respiratory drive, the possibility of ARF should be considered and the adequacy of breathing systematically evaluated by history, physical examination and measurements of gas exchange.
 
History
The following factors if present increase the risk of respiratory failure:
  • Young age; history of prematurity; immunodeficiency; and chronic pulmonary, cardiac or neuromuscular disease (e.g. cystic fibrosis, bronchopulmonary dysplasia, unrepaired congenital heart disease or spinal muscular atrophy [SMA]).
  • Fever or signs of sepsis. Several infections can lead to respiratory failure because of a systemic inflammatory response, pulmonary edema or acute respiratory distress syndrome or because it can produce a power-load imbalance secondary to increased oxygen consumption.291
  • Pain—pleuritis or foreign-body aspiration.
  • Neuromuscular weakness or paralysis.
    • Bulbar dysfunction suggests myasthenia gravis.
    • Distal weakness that progresses upward suggests Guillain-Barré syndrome.
    • Apnea associated with a traumatic injury suggests a cervical spinal cord injury.
  • History suggestive of a stroke or seizure?
292
 
Signs and Symptoms of Acute Respiratory Failure are Listed in Box 18.2
 
Laboratory Studies
Arterial blood gas (ABG) can be used to define acute respiratory failure. Arbitrary definitions include a PaCO2 greater than 50 mm Hg a PaO2 less than 60 mm Hg, or arterial oxygen saturation less than 90%.
An elevated serum bicarbonate level suggests metabolic compensation for chronic hypercapnia.
Electrolyte abnormalities can contribute to weakness; hypokalemia, hypocalcemia and hypophosphatemia can impair muscle contraction.
Calculate the alveolar-arterial oxygen difference ([A-a]DO2), which is the difference between the alveolar partial pressure of oxygen (PAO2) and PaO2.
  • This value is an index of the efficiency of gas exchange by the lungs.
  • In children, (A-a) oxygen delivery (DO2) is normally 5 to 10 and reflects venous admixture from anatomic right-to-left shunts.
The PaO2/FiO2 ratio is a commonly used indicator of gas exchange.
293
  • A PaO2/FiO2 less than 200 is correlated with a shunt fraction greater than 20%. P/F ratio < 300 is suggestive of acute lung injury (ALI) and < 200 is suggestive of ARDS.3
 
Imaging Studies
Lateral and anteroposterior (AP) radiographs of the neck can depict a radiopaque foreign body or soft-tissue structures encroaching on the lumen of the airway.
Chest radiographs may yield helpful findings.
Evaluate for abnormalities that require immediate intervention (e.g. pneumothorax).
If hypoxemia is present, but the chest radiograph is clear, this finding could suggest cyanotic congenital heart disease, pulmonary hypertension or pulmonary emboli.
Chest CT scanning can be performed is refractory cases (bone lesions, lymph nodes, interstitial lung disease and vascular abnormalities).
Fluoroscopy is valuable to evaluate the movement of the diaphragms and dynamic obstructive lesions of both the extrathoracic and intrathoracic airway.
V/Q scanning can predict a probability of V/Q mismatch secondary to a pulmonary embolism.
 
Procedures
  • Bronchoalveolar lavage (BAL) and lung biopsy for nonresolving pneumonia
  • Fiberoptic and rigid bronchoscopy, thoracentesis, spirometry
  • Electromyography (EMG) or nerve conduction test.
 
Medical Care
Management of acute respiratory failure begins with a determination of the underlying etiology. While supporting the respiratory system and ensuring adequate oxygen delivery to the tissues, initiate an intervention specifically defined to correct the underlying condition. The use of medications in the treatment of respiratory failure depends on the underlying disorder. Corticosteroids and beta-agonist medications treat an asthma exacerbation, whereas antibiotics treat bacterial pneumonia. Patients with pulmonary edema from myocardial dysfunction improve with diuretics and inotropic support.
 
Oxygen Therapy
  • The initial treatment for hypoxemia is to provide supplemental oxygen.
  • High-flow (>15 L/min) oxygen delivery systems include a venturi-type device, NRM mask, oxygen hoods and tents.
  • These agents act to decrease muscle tone in both small and large airways in the lungs. This category includes beta-adrenergics, methylxanthines and anticholinergics.
  • Bronchodilators: These agents are an important component of treatment in respiratory failure caused by obstructive lung disease.
    • 294Salbutamol, Terbutaline act directly on β2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
    • Theophylline has a number of physiological effects, including increases in collateral ventilation, respiratory muscle function, mucociliary clearance and central respiratory drive. Partially acts by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle.
    • Ipratropium bromide is an anticholinergic medication that appears to inhibit vagally mediated reflexes by antagonizing action of acetylcholine, specifically with the muscarinic receptor on bronchial smooth muscle.
    • Corticosteroids have been shown to be effective in accelerating recovery from acute COPD exacerbations and are an important anti-inflammatory therapy in asthma. Although they may not make a clinical difference in the ED, they have some effect 6 to 8 hours into therapy; therefore, early dosing is critical. Methylprednisolone usually given IV in ED for initiation of corticosteroid therapy, although PO should theoretically be equally efficacious.4 They have also been used in the treatment of ARDS although their role is still under study.5
    • Extrathoracic airway support
      For partial upper-airway obstruction, place a nasopharyngeal airway to provide a passageway for air; for example, obstruction caused by anesthesia or acute tonsillitis.
      An oropharyngeal airway can be used temporarily in the unconscious patient.
      Once airway patency has been achieved, assisted ventilation may be necessary if adequate air entry and breath sounds are not observed. Assisted ventilation should not be delayed until placement of an ETT is accomplished, because the vast majority of infants and children with respiratory failure can be successfully ventilated and oxygenated with a bag-valve-mask (BVM) device.
      A laryngeal mask airway (LMA) may be used, when a facemask is difficult to fit or tracheal intubation is difficult.
  • Noninvasive positive pressure ventilation (NPPV)
    • Noninvasive mechanical ventilation refers to assisted ventilation provided with nasal prongs or a face mask instead of an endotracheal or tracheostomy tube.
    • This therapy can be administered to decrease the work of breathing and to provide adequate gas exchange.
    • NPPV can be given by using a volume ventilator, a pressure-controlled ventilator or a device for bilevel positive airway pressure (BIPAP or bilevel ventilator).6
    • Pressures from 3 to 10 cm H2O is applied to increase lung volume and may redistribute pulmonary edema fluid from the alveoli to the interstitium.
  • Tracheal intubation in case of refractory hypoxemia, bradypnea, respiratory acidosis
    • Nowadays, cuffed tubes are preferred in children.7
295
 
Indications for Tracheal Intubation
  • Cardiopulmonary failure/cardiopulmonary arrest
  • Severe respiratory distress/respiratory muscle fatigue
  • Loss of cough or gag
  • Need for prolonged support due to apnea or hypoventilation
  • Interhospital transport of a patient who has the potential for respiratory failure
  • Conventional mechanical ventilation
    • A primary strategy for mechanical ventilation should be the avoidance of high peak inspiratory pressures and the optimization of lung recruitment.
    • Diseased based ventilation strategy
      • In ARDS low tidal volume (6 mL/kg) with optimized PEEP has been showed to provide substantial survival benefit compared with a strategy for high tidal volume.8
      • In reactive airway disease low tidal volume, long expiratory time, with low rates and low PEEP is considered appropriate.9
  • Nonconventional modes of ventilation
  • High-frequency oscillatory ventilation (HFOV)
    • HFOV combines small tidal volumes (smaller than the calculated airway dead-space) with high frequencies to minimize the effects of elevated peak and mean airway pressures.10
  • HFOV has proven benefit in improving the occurrence and treatment of air-leak syndromes, ARDS
  • Inverse ratio ventilation.11
  • Airway pressure release ventilation (APRV)
  • Adjunctive therapies for severe hypoxemia
  • Prone positioning.12,13
    • Prone positioning reduces compliance of the thoracoabdominal cage. There is improved homogeneity of ventilation, which improves oxygenation.
    • This measure may cause a redistribution of blood flow, improving the V/Q match
  • Inhaled nitric oxide (iNO)
    • NO is an endogenous free radical that mediates smooth muscle relaxation throughout the body.
    • When delivered by means of inhalation, the potential benefit of NO is to improve ventilation to perfusion matching by enhancing pulmonary blood flow to well-ventilated parts of the lung.14
  • Administration of exogenous surfactant.
    • Surfactant is an endogenous complex of lipids and proteins that lines the walls of alveoli and promotes alveolar stability by reducing surface tension.
    • Relative surfactant deficiency is variably present as a consequence of many lung diseases.
    • The goal of surfactant administration in ARDS is to reverse functional impairment of the surfactant system by instilling an excess of surface-active material15
  • 296Extracorporeal life support (ECLS)
    • ECLS: Blood is removed from the patient, passed through an artificial membrane, where gas exchange occurs and is returned to the body by either the arterial (venoarterial [VA]) or venous (venovenous [VV]) system.
    • VV ECLS has become the preferred method for patients of all age groups, who do not require cardiac support.16
 
Complications
Noninvasive ventilation poses several risks.
  • It may delay the start of mechanical ventilation by means of an endotracheal tube.
  • Prolonged wearing of the facial interface can lead to nasal congestion, facial reddening, eye irritation or ulceration of the nasal bridge.
  • Gastric distention can occur, with possible pulmonary aspiration.
In a spontaneously breathing person with high minute ventilation, care must be taken to maintain that level if tracheal intubation is required. The purpose is to avoid a sudden increase in PaCO2 that could contribute to hemodynamic instability or cardiopulmonary arrest.
Tracheal intubation may lead to upper-airway edema and difficult extubation, especially in patients with chronic illness and a limited baseline pulmonary reserve.
Ventilator-induced lung injury (VILI) may occur secondary to alveoli overdistention (volutrauma).
Air-leak syndromes, pneumothorax or pulmonary interstitial emphysema may occur secondary to elevated inspiratory pressures.
 
PROGNOSIS
The prognosis depends on the underlying etiology leading to acute respiratory failure.
  • The prognosis can be good, when the respiratory failure is an acute event not associated with prolonged hypoxemia (e.g. in the case of a seizure or intoxication).
  • The prognosis may be fair, when a new process is associated with chronic respiratory failure secondary to a neuromuscular disease or thoracic deformity. This may herald the need for long-term mechanical ventilation.
  • The prognosis can vary, when respiratory failure is associated with a chronic disease with acute exacerbations.
  • Respiratory failure may be the sign of an irreversible progressive disease that leads to death (e.g. idiopathic pulmonary hypertension).
 
SUMMARY AND CONCLUSION
Managing a child who is in respiratory failure is challenging. Failure to recognize and manage respiratory failure appropriately can result in patient death or 297long-term disability. The management of respiratory failure depends on whether respiratory insufficiency develops acutely or gradually. Acute respiratory failure carries the imminent risk of cardiac arrest. Once respiratory failure is recognized, treatment involves initially addressing the adequacy of gas exchange, followed by pursuing the underlying causes and complications of respiratory failure.
REFERENCES
  1. Dobyns EL, Carpenter TC, Drumowicz AG, et al. Acute respiratory failure. In: Cernick V (Ed): Kendigs Disorders of the Respiratory Tract in Children, 7th edn, Philadelphia: Saunders/Elseiver  2006:224-242.
  1. Andrews P, Azoulay E, Antonelli M, et al. Year in review in intensive care medicine. 2005. I. Acute respiratory failure and acute lung injury, ventilation, hemodynamics, education, renal failure. Intensive Care Med 2006;32:207–216.
  1. Bernard GR. The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med 1994;149:818–824.
  1. Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980;92:753–758.
  1. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. The ARDS Network. N Engl J Med 2006;354:1671–1684.
  1. Karen EA, Tasnim S, Neill K.J, Adhikari, et al. Bilevel noninvasive positive pressure ventilation for acute respiratory failure: survey of Ontario practice. Crit Care Med 2005;33:1477–1483.
  1. Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.
  1. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. ARDS Network. N Engl J Med 2000;342:1301–1308.
  1. Heulitt MJ, Wolf GK. Mechanical Ventilation. In: Nichols DG (Ed): Rogers Textbook of Pediatric Intensive Care, 4th edn. Philadelphia: Lippincot, Williams and Wilkins  2008:508-531.
  1. Arnold JH. High-frequency ventilation in the pediatric intensive care unit. Pediatr Crit Care Med 2000;1:93–99.
  1. Goldstein B, Papadakos PJ. Pressure-controlled inverse-ratio ventilation in children with acute respiratory failure. Am J Crit Care 1994;3:11–15.
  1. Gattinoni L, Tognoni G, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001;345:568–573.
  1. Mancebo J, Fernandez R. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;173:1233–1239.
  1. Abman SH, Kinsella JP. Inhaled nitric oxide therapy for pulmonary disease in pediatrics. Curr Opin Pediatr 1998;10:236–242.
  1. Lewis JF, Brackenbury A. Role of exogenous surfactant in acute lung injury. Crit Care Med 2003;31(4 Suppl):S324–S328.
  1. Morton A, Dalton H, et al. Extracorporeal membrane oxygenation for pediatric respiratory failure. Five-year experience at the University of Pittsburgh. Crit Care Med 1994;22:1659–1667.

Tuberculosis in Children19

Ira Shah
 
INTRODUCTION
It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis and each year, about 9 million people develop tuberculosis (TB), of whom about 2 million die. Of the 9 million annual TB cases, about 1 million (11%) occur in children under 15 years of age.1 Every year, 1.8 million persons in India develop TB, of which about 800,000 are infectious; and until recently, 370,000 died of it annually—1,000 every day.2
 
PATHOGENESIS
Infection with M. tuberculosis usually results from inhalation into the lungs of infected droplets from a contact of open TB usually an infectious adult in close proximity. This exposure leads to the development of a primary parenchymal lesion (Ghon focus) in the lung with spread to the regional lymph nodes. The immune response develops about 4 to 6 weeks after the primary infection and stops the multiplication of M. tuberculosis bacilli. In some cases, the immune response is not strong enough to contain the infection and disease occurs within a few months. Risk of progression to disease is increased when primary infection occurs in children less than 10 years of age, particularly in the very young (0–4 years) and in the immunocompromised children. Progression of disease occurs by parenchymal extension of the primary focus or through enlargement of glands, lymphatics and/or hematogenous spread. Children who develop disease usually do so within 2 years following exposure and infection.1 They may also be infected with M. bovis by drinking untreated milk from infected cows. In older children, postprimary TB can occur due to either reactivation or by reinfection.
 
TYPES OF TUBERCULOSIS IN CHILDREN
World Health Organization (WHO) has classified TB into pulmonary and extrapulmonary TB3 to categorize them and determine future course of treatment protocol. Pulmonary tuberculosis (PTB) refers to disease involving the lung parenchyma. Therefore, tuberculous intrathoracic lymphadenopathy (mediastinal 300and/or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, constitutes a case of extrapulmonary TB. A patient with both pulmonary and extrapulmonary TB should be classified as a case of pulmonary TB.4 Extrapulmonary tuberculosis (EPTB) refers to tuberculosis of organs other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, and meninges. The following forms of EPTB are classified as severe: meningeal, pericardial, peritoneal, bilateral or extensive pleural effusive, spinal, intestinal, genitourinary. Lymph node, pleural effusion (unilateral), bone (excluding spine), peripheral joint and skin tuberculosis are classified as less severe.3
 
GUIDELINES FOR SUSPECTING TUBERCULOSIS IN CHILDREN
When to suspect TB: WHO has recommended following guidelines for suspecting TB in children.5 Suspect TB in a child:
  • Who is ill, with a history of contact with a suspect or confirmed case of pulmonary TB;
  • Who does not return to normal health after measles or whooping cough;
  • With loss of weight, cough, fever who does not respond to antibiotic therapy for acute respiratory disease;
  • With abdominal swelling, hard painless mass and free fluid;
  • With painless firm or soft swelling in a group of superficial lymph nodes;
  • With signs suggesting meningitis or disease in the central nervous system.
 
DIAGNOSIS
In children, TB is usually a diagnosis based on clinical suspicion along with relevant investigations such as Mantoux test (MT), chest X-ray (CXR) and history of contact with TB patient. In most children, bacteriological confirmation is usually not possible as either children may not be able to produce sputum (in case of pulmonary TB) or TB may be located in a body organ where bacteriological confirmation is not possible such as abdominal TB.4
 
Contact
Contact is defined as frequent contact with a case of open TB (sputum smear or culture positive TB) within past 2 years.
 
Mantoux Test/Tuberculin Skin Test
Mantoux test (MT) consists of intradermal injection of mycobacterial antigens that lead to a delayed type of induration in patients infected with TB. The MT is the standard method of identifying people infected with M. tuberculosis. A positive test is considered as:
  1. Induration of ≥ 5 mm in human immunodeficiency virus (HIV) infected or malnourished children
  2. Induration of ≥ 10 mm in non-Bacille Calmette-Guérin (BCG) vaccinated children
  3. Induration of ≥ 15 mm in BCG vaccinated children.
301The main drawback of the tuberculin skin test (TST) is its poor specificity in individuals sensitized by prior exposure to nontuberculous mycobacteria (NTM) or by having been vaccinated with M. bovis BCG. Additionally, the TST sensitivity may be low in young children and in individuals with depressed immunity, malnutrition or advanced TB.6 It also does not help in determining the period when the child got infected.
 
Bacteriological Isolation of M. Tuberculosis
Identification of M. tuberculosis on smear or culture gives a definitive diagnosis of TB. In cases of pulmonary TB, appropriate clinical samples include sputum, gastric aspirate or bronchoalveolar lavage (BAL). For extrapulmonary TB, specimens from organs affected are appropriate such as ascitic fluid in TB peritonitis, fine needle aspiration or lymph node biopsy of enlarged lymph node, pericardial fluid in pericardial effusion, cerebrospinal fluid in tuberculous meningitis (TBM) and pus in musculoskeletal TB. All specimens should be sent for both smear and culture.
 
Sputum Collection
Three sputum specimens should be obtained ideally as early morning samples on 3 consecutive days or on the spot specimens for 3 consecutive days can also be collected. Make sure child rinses the month well before collecting the sputum to prevent contamination. Also saliva should not be collected as the sputum. Occasionally, the sputum production can be induced by nebulization with hypertonic saline (3% NaCl). The sputum should be directly collected in the container provided by the laboratory.
 
Gastric Lavage
The young children with a wet cough may swallow sputum and may be unable to expectorate the sputum. Gastric aspiration on an empty stomach early in the morning may help to collect this swallowed sputum. However, gastric lavage (GL) is an invasive procedure, involves insertion of Ryle's tube and general yield of smear and culture positivity is low. Thus this procedure should only be done in sick, young, hospitalized children. The procedure involves insertion of Ryle's tube (RT) into the stomach (preferably the RT should be inserted the previous night) and aspiration of gastric contents (2–5 mL) early in the morning before consumption of food. If no aspirate is obtained, insert 5 to 10 mL sterile water or normal saline and attempt to aspirate again. Again, the GL should be collected on 3 consecutive days to increase the yield of the sample.
 
Bronchoalveolar Lavage
Bronchoalveolor lavage (BAL) is not routinely done in children. It is a procedure that needs general anesthesia, expertise to do bronchoscopy though the yield of sample positivity is highest. It is generally reserved for patients who are suspected to have drug resistant TB (so that specimen can be sent for culture and tested for 302drug sensitivity) and in the immunocompromised patients, e.g. HIV to identify various lung pathogens, such as Pneumocystis carinii, M. tuberculosis and other bacterial infections. With a bronchoscope, alveolar fluid is aspirated or lavaged and sent for culture and smear.
 
Smear for Acid-fast Bacillus
Examination of sputum by Ziehl-Neelsen (ZN) stain is easy to perform. However, it requires ≥ 10,000 bacilli/mL of sputum to give positive results. A patient is diagnosed as sputum smear positive pulmonary TB if even one sputum smear examination is positive for TB along with CXR abnormalities for active TB or sputum culture grows M. tuberculosis. A patient is diagnosed as sputum smear negative pulmonary TB if clinical and radiological findings are suggestive of TB, but all 3 sputum specimens are negative for AFB. Open TB, is considered, if a child with pulmonary TB is sputum smear positive or culture grows M. tuberculosis.
 
Newer Culture Techniques
Older techniques of TB culture, such as inoculation on Loenstein-Jensen (LJ) medium for 6 weeks have now been replaced by better and faster molecular techniques. Culture can detect 100 bacilli/mL of sputum in comparison to more than 10,000 bacilli/mL needed for microscopy. Also culture provides material to identify atypical mycobacteria from M. tuberculosis and also is useful for drug sensitivity testing. The newer culture techniques are described below.
 
Bactec Radiometric System
Bactec system was a breakthrough for diagnosis of M. tuberculosis as it allowed isolation in a few days (within 14 days) as compared to culture media. However, it is expensive, requires special equipment and radioisotopes. However, Bactec system for TB has now been improvised and now turned into Bactec mycobacteria growth indicator tube (MGIT) system, which is non-radiometric, fully automated system with tubes incubated in a compact system that reads them automatically. The MGIT system is based on a glass tube containing a special broth (Middlebrook IH9 broth) together with fluorescence quenching-based oxygen sensor embedded at the bottom of the tube. When inoculated with M. tuberculosis, consumption of the dissolved oxygen produces fluorescence when illuminated by a ultraviolet (UV) light.
 
Molecular Methods for Identification of M. Tuberculosis
Polymerase chain reactions (PCR) are now increasingly used for diagnosis of TB. Species specific deoxyribonucleic acid (DNA) probes that hybridize to r-ribonucleic acid (rRNA) for the identification of several important mycobacterias including M. tuberculosis, M. avium, M. intracellulare, M. avium complex, M. Kansasii and M. gordonae are available and have good sensitivity and specificity. When done on culture positive specimens can help to identify type of Mycobacterium within 2 hours. When PCR is done on tissue specimen 303directly, it cannot differentiate between dead and live bacillus and thus may give false positive results. The false negative results may be seen if amplification reaction inhibitors are present in the specimen. Thus, a negative PCR never eliminates possibility of TB and a positive result is not always confirmatory. However, PCR give rapid diagnosis, help in identification of M. tuberculosis from atypical mycobacteria and can also be used to identification of genetic modifications that are associated with drug resistance.
 
Interferon-Gamma Release Assays
Interferon-gamma (IFN-γ) release assays are based on the fact that T cells sensitized with tuberculous antigens produce IFN-γ when they are re-exposed to mycobacterial antigens. Two commercial assays are currently available are as follows:
  1. QuantiFERON–TB assay
  2. T SPOT–TB test.
These tests measure the production of IFN-γ by T cells in response to TB antigens by enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot, respectively. QuantiFERON-TB initially used purified protein derivative (PPD) as antigen, but the enhanced version QuantiFERON-TB Gold uses the early secreted antigenic target 6 HDa protein (ESAT6) and culture filtrate protein (CFP-10) as antigen, which is tested on whole blood. T SPOT-TB test uses ESAT6 and CFP-10 as antigens and is tested on peripheral blood mononuclear cells. These IFN-γ assays have a high sensitivity to identify infection with TB, are not affected by previous BCG vaccination and do not have boosting phenomenon (as unlike seen with Mantoux test).
Dual testing with IFN-γ release assays and TST can be used in high risk young and/or immunocompromised children to increase sensitivity of diagnosed latent TB infection. Since TST does not tell timing of TB infection, a positive TST along with positive IFN-γ release assays suggests recent TB infection.
 
ELISA Tests for Detection of Anti-TB Antibodies (TB IgM, TB IgA and TB IgG)
Several antibodies to various purified or complex antigens of M. tuberculosis can be detected. However, sensitivity and specificity are not very good and thus is not recommended for routine diagnosis of TB in children and even adults.
 
TREATMENT
Treatment of TB has evolved over decades in form of monotherapy to dual therapy to now polytherapy due to appearance of drug resistance. However, duration of therapy has been shortened from 9 to 12 months to short course chemotherapy (6 months) as it has been documented to be effective for treatment of TB. Anti- TB treatment (ATT) is divided into two phases: An intensive phase (for initial 2 months) and a continuation phase (for 4–6 months). Purpose of intensive phase is to rapidly decimate actively infective organisms and to prevent emergence of drug resistance. Thus, at least 3 to 4 drugs are recommended in this phase. 304Continuation phase is to eradicate the dormant organisms and thus two drugs are generally used.
 
Aims of Treatment3
  1. To cure the patient of TB
  2. To prevent death from active TB or its late effects
  3. To prevent relapse of TB
  4. To prevent transmission of TB to others
  5. To prevent development of acquired drug resistance.
 
Standard Antituberculous Drugs
 
Isoniazid
Isoniazid (INH) is a potent bactericidal drug active against all populations of TB bacilli. Its half-life depends on acetylation in the liver. It has good CNS penetration. The INH can be used alone for treatment of latent TB and asymptomatic contacts at high risk of disease.
 
Rifampicin
Rifampicin is also a potent bactericidal drug active against all populations of TB bacilli. It is also the most potent sterilizing drug available and acts in both cellular and extracellular locations. It has good central nervous system (CNS) penetration. It is extensively recycled in enterohepatic circulation. Rifampicin resistance develops rapidly and thus rifampicin must always be administered in combination with other effective anti TB drugs.
 
Pyrazinamide
Pyrazinamide is weakly bactericidal, but has potent sterilizing activity particularly in an acidic intracellular environment of macrophages and in areas of acute inflammation. Thus, it is highly effective in intensive phase of treatment as it enables short course chemotherapy and reduces risk of relapse. It is metabolized in the liver. It penetrates inflamed meninges.
 
Streptomycin
Streptomycin is bactericidal against rapidly multiplying bacilli. It readily diffuses into extracellular compartment and can penetrate inflamed meninges. It is excreted unchanged in urine. It is usually avoided in children as injections are painful and irreversible auditory nerve damage may occur. It is mainly used in intensive phase of TBM.
 
Ethambutol
Ethambutol is used in combination with other more powerful anti-TB drugs to prevent emergence of drug-resistance strains. It is metabolized in the liver.305
Table 19.1   Dosage schedule of first-line antitubercular drugs
Drug
Dosage
Common adverse effect
Daily
3 times weekly
Isoniazid (H)
5 mg/kg/day
(max 300 mg)
10 mg/kg
Peripheral neuropathy (Pyridoxine supplement prevents it), hepatitis
Rifampicin (R)
10 mg/kg/day
(max 600 mg)
10 mg/kg
Hepatitis, fever, influenza like syndrome. Not to be given with protease inhibitors and non-nucleoside reverse transcriptase inhibitors
Pyrazinamide (Z)
25 mg/kg/day
35 mg/kg
Gastrointestinal intolerance, hepatitis, hypersensitivity, hyperuricemia
Streptomycin (S)
15 mg/kg/day
15 mg/kg
Auditory nerve impairment,
nephrotoxic
Ethambutol (E)
15 mg/kg/day
(adults)
30 mg/kg
Optic neuritis, color blindness
20 mg/kg/day
(children)
 
Dosage Schedule of First-line Antitubercular Drugs
It is depicted in Table 19.1.
 
Treatment Protocols
Treatment with intermittent therapy (thrice weekly) is comparable to daily therapy. Thrice weekly drug therapy facilitates observation, reduces costs and is given in form of directly observed treatment short (DOTS) course where treatment is given by health care personnel under direct observation. The DOTS is implemented by the government under Revised National TB Control Programme (RNTCP).2 The WHO-recommended DOTS strategy was launched formally as Revised National TB Control Programme in India (1997). The key components of DOTS are case detection by sputum smear microscopy examination among symptomatic patients and anti-TB drugs are given to patients under the direct observation of the health care provider/community.
The WHO has classified treatment strategy into 3 regimens based on clinical presentation. Category 3 is for mild pulmonary disease and less severe extrapulmonary TB. Category 1 is for severe pulmonary disease (miliary TB, primary progressive TB, cavitatory TB) and extrapulmonary TB (disseminated TB, abdominal TB, TBM, Spinal TB, Bone TB, pericardial TB). Category 2 stands for relapsed or recurrent TB in previously treated sputum positive TB patient (Table 19.2).306
Table 19.2   Recommended treatment regimen3
Category of TB patients
Treatment Intensive phase
Continuation phase
Category 3: (Less severe TB)
  • Primary complex
  • Mediastinal adenopathy
  • TB lymphadenopathy
  • Unilateral pleural effusion
2 HRZ
4 HR
Category 1: (Severe TB)
  • Primary progressive TB
  • Miliary TB
  • Cavitatory TB (Sputum positive TB)
  • Disseminated TB
  • Abdominal TB
  • TBM
  • Spinal TB, bone TB
  • Pericardial TB, extensive or bilateral, pleural TB
  • Renal TB
2 HRZE/
2 HRZS (in TBM)
4 HR
Category 2: Previously treated sputum positive TB
  • Relapse
  • Recurrent TB
2 HRZES
+ 1 HRZE
5 HRE
Note: Treatment of TB meningitis is controversial and though WHO recommends 2 HRZS + 4 HR, according to Red Book (2003) of American Academy of Pediatrics (AAP) a regimen of 2 HRZ ( S or Ethionamide) + 7–10 HR is as effective (Ethionamide crosses both healthy and inflamed meninges)
 
Treatment of Tuberculosis in Special Situations
  1. Treatment of children who are in contact with an adult suffering from sputum positive TB: Young children (especially those less than 5 years of age) are at high risk of getting TB, if they live in close contact with a patient suffering from sputum-positive pulmonary TB. Such children and older symptomatic children should be screened for TB and if they are detected to have TB infection (Latent TB) or disease, they should be treated according as per the appropriate regimen. However, even if the screening is negative, asymptomatic children less than 5 years of age should be given preventive therapy in form of INH (5 mg/kg/day) for 6 months to prevent infection. If the adult source is sputum negative, then there is no need to give preventive therapy in contacts. However in an HIV positive child, even if the child is more than 5 years of age, then also preventive therapy may be given.
  2. Treatment of latent TB: Patients with asymptomatic positive Mantoux test (have TB infection, but not disease) should be treated with ATT to prevent progression to disease. INH (5 mg/kg/day) for 6 to 9 months is effective for the same.307
  3. Treatment of a child born to mother suffering from TB: If the mother has been on ATT for 2 to 3 weeks prior to the baby being born, then there is no need to give any prophylaxis in the child. In case mother was diagnosed to have TB just before or after delivery, then the baby should receive 6 months of INH followed by BCG vaccination. In case, the baby is symptomatic for TB, then appropriate regimen for treatment of TB should be given, breastfeeding is not a contraindication.
  4. Role of pyridoxine, while on antitubercular therapy: Isoniazid can cause pyridoxine deficiency especially in children above 6 years of age, malnourished children, HIV infected children and breastfeeding infants. Thus, pyridoxine supplementation is recommended for above mentioned patients, while on isoniazid in dose of 5 to 10 mg/day.4
Response to therapy: Clinical, radiological and bacteriological responses are considered, while judging response to therapy. Several definitions have been described to determine response to therapy. They are:
  • Cured: Patient who is sputum smear negative in the last month of treatment and on at least one previous occasion
  • Completed treatment: Patient who has completed treatment, but who does not meet the criteria to be classified as cured or treatment failure
  • Defaulted: Patient whose treatment was interrupted for 2 consecutive months or more
  • Died: Patient who dies for any reason during the course of treatment
  • Treatment failure: Patient who is sputum smear positive at 5 months or later after starting treatment. In children, it is difficult to determine treatment failure based on this definition. Thus treatment failure in a child would be suspected if the child, while on treatment continues to have clinical symptoms, worsens on therapy, loses weight, has radiological deterioration or becomes smear or culture positive ensuring that ATT regime, dose administered were adequate and child was adherent to the regime. In such a situation, patient should be shifted to category 2 regimen of and subsequent testing for drug resistant TB should be done.
In children, since it is difficult to determine treatment cure, we consider completed treatment as criteria for stopping treatment in them.
 
SUMMARY AND CONCLUSION
Tuberculosis is a disease that has been accompanying humans since thousands of years of evolution. One-third of the world's population is infected with Mycobacterium tuberculosis. Each year, about 9 million people develop TB, of whom about 2 million die. Of the 9 million annual TB cases, about 1 million (11%) occur in children under 15 years of age. Every year, 1.8 million persons in India develop tuberculosis (TB), of which about 800,000 are infectious; and until recently, 370,000 died of it annually.
The TB has become complex and drug resistant and is an increased cause of morbidity and mortality in children. With first cases of drug-resistance being 308reported in 1940s, the disease now has progressed to become multidrug resistance (MDR) and even extended drug resistant (XDR) TB, while therapy has evolved from mono drug therapy to dual drug therapy to poly drug therapy to tackle issues of drug resistance. Thus, proper management of TB will help to prevent emergence of drug resistance in these patients.
REFERENCES
  1. World Health Organization. Guidance for National Tuberculosis Programs on the Management of Tuberculosis in Children. Geneva: WHO  2006.
  1. Revised National TB Control Program (RNTCP). Available at URL: http://www.tbcindia.org/RNTCP.asp. Accessed on: 2011.
  1. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programs. Geneva: WHO  2003.
  1. Shah I. Tuberculosis. Pediatric Oncall. Mumbai 2010.
  1. World Health Organization. Tuberculosis and Fact sheets. TB and Children. Available at URL: http://www.searo.who.int/en/Section10/Section2097/Section2106_10681.htm. Accessed on: 18 June 2011.
  1. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993;17:968–975.

Bronchiectasis20

Sonal Bhatia, Milind S Tullu
 
INTRODUCTION
Bronchiectasis, a clinical condition associated with chronic productive cough and dilated inflamed bronchi, was first described by Laënnec in 1819. The first case he used to illustrate his description of this disease was a boy aged 3.5 years with copious expectoration of fetid sputum secondary to an attack of whooping cough (3 months earlier) and the second case was that of a 72-year-old woman who suffered from chronic productive cough, frequent attacks of hemoptysis and breathing difficulties for more than 50 years of her life.1 Laënnec defined this condition under the heading of “dilatation of the bronchi” and used various objects such as seeds and quills to define the caliber of the abnormally dilated bronchi, while others have described it as “production of fetid sputum along with bronchial dilatation”.1,2 Childhood bronchiectasis has varying etiologies—from CF to postinfectious and is a significant cause of morbidity and mortality, especially in developing countries. Bronchiectasis can be defined as chronic inflammatory disease characterized by destruction of the bronchial and peribronchial tissues, with dilatation of the bronchi and accumulation of infected material in the dependent bronchi. It has also been described as permanent dilatation of sub-segmental airways (caused by prior illness with accumulation of exudative material) associated with chronic cough and foul-smelling sputum production.
 
INCIDENCE
The overall incidence of bronchiectasis has reduced in the developed world, but the problem still persists in the developing countries owing to poor sanitation, overcrowding and a large proportion of untreated respiratory tract infections with an additional burden of TB. Hence, determining the precise prevalence of this condition is difficult; also, quantitative studies analyzing the prevalence in children are lacking. Twiss et al have described the results of a national survey of pediatricians from New Zealand which suggests that the incidence of non-cystic fibrosis related bronchiectasis is in the region of 3.7 per 100,000 with a prevalence of 1 in 3,000.3 Data from the North East of England demonstrates a prevalence of 1 in 5,800 children.4 The autopsy incidence of bronchiectasis is estimated to be 310approximately 3%.5 The majority of the data indicates that bronchiectasis usually occurs in preschool children with a male preponderance (M:F = 2:1).2
 
ETIOPATHOGENESIS
 
Causes
Cystic fibrosis (CF) is the most common cause (Table 20.1) of clinically significant bronchiectasis in the Caucasian population.6 Postinfectious bronchiectasis is more common in developing countries like India.6 Primary ciliary dyskinesia (immotile cilia syndrome), alpha-1-antitrypsin deficiency, tracheobronchomegaly (Marnier-Kuhn syndrome)7 and bronchomalacia (weakness of bronchial wall cartilage) are other congenital disorders associated with bronchiectasis. Approximately half of the patients with primary ciliary dyskinesia have a triad of situs inversus, sinusitis and bronchiectasis (this is Kartagener syndrome).8 Williams-Campbell syndrome, in which there is an absence of annular bronchial cartilage, has been described with bronchiectasis.7
Table 20.1   Causes of bronchiectasis
No.
Etiology
Examples
1.
Infections
Measles, tuberculosis and non-tuberculous Mycobacteria, pertusis, adenovirus, aspergillosis
2.
Inherited/Syndromic
Cystic fibrosis (CF), primary ciliary dyskinesia/immotile cilia syndrome, alpha-1-antitrypsin deficiency, Marnier-Kuhn syndrome, Williams-Campbell syndrome, yellow-nail syndrome, Young syndrome, Marfan syndrome, Ehler-Danlos syndrome
3.
Immunodeficiency states
Severe combined immunodeficiency, hypogammaglobulinemia, Omenn syndrome, Hyperimmunodeficiency E or Job syndrome, chronic granulomatous disease, ataxia-telangiectasia, bare lymphocyte syndrome, neutrophil function abnormalities, human immunodeficiency virus (HIV) infection
4.
Aspiration
Impaired gag reflex, poor esophageal motility, esophageal atresia/fistula, cleft palate, foreign body aspiration
5.
Obstruction
Chronic obstructive pulmonary disease, bronchiolitis obliterans, foreign body, right middle lobe syndrome
6.
Systemic illnesses
Systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis
7.
Idiopathic
No etiology found even after a comprehensive evaluation
311Immunodeficiency states associated with severe combined immunodeficiency, hypogammaglobulinemia, Omenn syndrome, hyper-immunoglobulin E or Job syndrome, chronic granulomatous disease, ataxia- telangiectasia, bare lymphocyte syndrome, neutrophil function abnormalities and human immunodeficiency virus (HIV) infection are other conditions that can cause bronchiectasis. Infections especially pertussis, measles, adenovirus and chronic infections such as TB aspergillosis and non-tubercular mycobacterial infections are important causes of bronchiectasis. The cause is postinfective in at least 42% of all cases of bronchiectasis.9,10 Pre-existing pneumonia is a major causative factor in patients with non-CF bronchiectasis.4 However, widespread routine vaccination programs and antibiotic usage have decreased the incidence of postinfectious bronchiectasis. Aspiration syndromes due to impaired gag reflex, poor esophageal motility, esophageal atresia/fistula, cleft palate or a foreign body aspiration are the other causes of bronchiectasis. Chronic obstructive pulmonary disease, bronchiolitis obliterans and systemic autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and sarcoidosis have all been described to cause bronchiectasis. Other disease entities associated with bronchiectasis include right middle lobe syndrome (chronic extrinsic compression of right middle lobe bronchus by hilar lymph nodes) and yellows-nail syndrome (pleural effusion, lymphedema and discolored nails).7 Young syndrome (triad of chronic rhinosinusitis, bronchiectasis and infertility), Marfan syndrome, Ehler-Danlos syndrome are also reported with bronchiectasis.11 The association between asthma and bronchiectasis has been questionable. It has been postulated that inadequate control of asthma or persistent airflow narrowing from recurrent exacerbations was the precipitating cause of bronchiectasis in asthmatic patients. Despite the myriad etiologies of bronchiectasis, the cause remains unidentified in at least 30 to 50% patients constituting the “idiopathic” group of bronchiectasis. With improvement in diagnostic facilities, the cause is now being elucidated in an increasing number of patients from the “idiopathic” group.
 
Pathophysiology
Bronchi are dynamic structures, which widen and constrict during respiration. The two cardinal factors operating in the pathogenesis of bronchiectasis are obstruction and infection. Experimental occlusion or constriction of a bronchus in animals has been shown to result in bronchiectasis within few days or weeks and the speed of development is greatest when an infection is introduced beyond the blocked airway. Bronchial obstruction can occur as a result of tumor, foreign body, impacted mucus due to poor mucociliary clearance, external compression, bronchial webs and atresia.7 Infections due to Bordetella pertussis, measles, rubella, toga virus, respiratory syncytial virus and Mycobacterium tuberculosis induce chronic inflammation, progressive bronchial wall damage, and dilatation.7 The concept of “vicious” cycle put forth by Peter Cole and colleagues from the Brompton Hospital has been widely accepted and aids in understanding the key events in the pathogenesis of this illness.12 According to this theory, chronic bacterial endobronchial infection leads to inflammation and airway damage causing bronchial dilatation. The ensuing airway dilatation results in mucociliary 312stasis, which in turn promotes further bacterial infection, increased airway inflammation and more bronchial dilatation. Intrinsic to this theory is the fact that bronchial dilatation is both permanent and progressive in the absence of any treatment. The role of chronic infection and inflammation in the pathogenesis of bronchiectasis is highlighted further by the findings of increased concentrations of elastase13, interleukin-814, tumor necrosis factor15 and prostanoids16 in the sputum and bronchial mucosal biopsy specimens from patients with bronchiectasis. The development of bronchiectasis in congenital forms can be attributed to abnormal cartilage formation.7
Bronchiectasis can be focal or diffuse and the site of the lesion can often determine the etiology. Bronchiectasis is most commonly seen in the lower lobes, especially the left lower lobe the upper lobes being less affected, except in CF-induced bronchiectasis, probably because of enhanced mucociliary clearance assisted by gravity.17,18 Lower lobes of the lung are predominantly affected in “idiopathic” bronchiectasis, primary ciliary dyskinesia manifests as bronchiectasis affecting the middle lobe and hypogammaglobulinemia-related bronchiectasis is found mainly in lower/middle lobe or the lingular segment.19-21
Gross examination of the lung reveals dilated airways, sometimes as much as four times the normal size. The dilated airways can be followed directly out to the pleural surfaces.22 The gross appearance of bronchiectasis is classified by Reid as cylindrical, saccular or varicose.23 In cylindrical bronchiectasis, there is a diffuse, regular dilatation of the bronchi producing long, tube like enlargements with bronchial lumens ending abruptly due to mucus plugging. In saccular bronchiectasis, bronchial dilatation progresses resulting in ballooning of bronchi, which end in fluid/mucus-filled sacs. This is the most severe form of bronchiectasis. In the varicose form of bronchiectasis, the degree of dilatation is greater with local constrictions resembling varicose veins.7,22 The microscopic changes of bronchiectasis comprise loss of cilia, metaplasia of cuboidal and squamous epithelium, hypertrophied bronchial glands, lymphoid hyperplasia, along with vascular changes and fibrosis seen in chronic cases.22,24,25
 
CLINICAL FEATURES
Cough associated copious sputum production is the chief complaint in the majority of children presenting with bronchiectasis.2 Cough occurs in more than 90% patients; it is productive in 75 to 100% cases, the sputum being purulent/mucopurulent in 71 to 97% cases.26 Sputum production might not be apparent in young children with bronchiectasis as they tend to swallow the sputum.7 Sputum of patients with bronchiectasis often settles into three layers on standing.27,28 Hemoptysis in an infrequent symptom in children with bronchiectasis as compared to adults.29 Nevertheless, hemoptysis in children is seen more often with bronchiectasis than with any other pulmonary disease of childhood.27 Fever is the symptom in children who experience infective exacerbations such as a bronchopneumonia.7 Chest pain, anemia, anorexia, easy fatigability, night sweats and weight loss are some other clinical manifestations.26,27 Dyspnea in children 313with bronchiectasis can range from being completely absent in some patients to causing severe respiratory compromise in others. Some children experience breathlessness only during the course of an exacerbation.27 Wheeze is the only presentation in as much as 20% of children with bronchiectasis.30
On physical examination, clubbing of the fingers and toes is seen ranging from 3 to 51% of cases (Fig. 20.1).2,29 Respiratory system examination may show a barrel-shaped emphysematous chest and a shift of mediastinum to the affected side which indicates the presence of an underlying occluded bronchus or marked fibrosis.27 Auscultatory findings are not equivocal and can be unremarkable or can reveal extremely florid rales/rhonchi, indicating an underlying consolidation or an abscess.27 Persistent localized coarse creptations/rales may be heard on the affected lung segments.5,7 Evidence of tonsillitis, adenoiditis and pan-sinusitis may be found on examination of the upper airway in these children; these infected sites are a potential harbinger of pulmonary exacerbations in these children.27
 
DIAGNOSIS
In addition to children presenting with a chronic productive cough, the following should arouse a suspicion of bronchiectasis:26
  1. Children with a chronic moist cough, especially between common colds, which lasts for 8 weeks or longer.
  2. Asthma in children not responding to conventional therapy.
  3. Incomplete resolution of a pneumonia.
  4. Recurrent attacks of pneumonia.
  5. Pertussis—like illness not resolving in 6 months.
    Fig. 20.1: Note the clubbing in a case of bilateral bronchiectasis
  6. 314Persistent and unexplained lung signs.
  7. Respiratory symptoms in children with structural or functional disorders of the esophagus or the upper respiratory tract.
  8. Unexplained hemoptysis in a child.
 
Chest Radiograph
The findings can be non-specific and a normal X-ray chest does not rule out bronchiectasis.7,27 Typical findings are increase in size and loss of definition of bronchovascular markings, crowding of bronchi, loss of lung volume, parallel linear lines (“rail tracks”) and presence of cystic spaces with air-fluid levels (Fig. 20.2).7 “Honey-combing” seen particularly in the lower lobes in severe cases can be considered pathognomonic of bronchiectasis (Fig. 20.3).7,27 In cases with unilateral disease, a compensatory over-inflation of the uninvolved lung may be seen.7
 
High-resolution Computed Tomography of the Chest
Thin-section high-resolution computed tomography (HRCT) chest is now the gold standard diagnostic modality for bronchiectasis because it is non-invasive and offers excellent sensitivity and specificity.7 The HRCT can identify congenital lesions and location and extent of the disease process. The HRCT findings of bronchiectasis can be described as cylindrical—seen as “tram lines” or “signet ring” (dilated bronchus as compared to the adjacent pulmonary artery), varicose—seen as bronchi with “beaded contour” and cystic—seen as cysts in “strings and clusters” (Figs 20.4 and 20.5).7
Fig. 20.2: Chest radiograph. Note the bronchovascular markings and the ‘rail-road tracks’ (linear streaking) in the right paracardiac region
315
Fig. 20.3: Chest radiograph. Note the bilateral honeycombing (cystic pattern) in the lower lung fields
Fig. 20.4: High-resolution computed tomography (HRCT) scan of chest. Note the bilateral cystic bronchiectasis with distended bronchi and bronchial wall thickening
316
Fig. 20.5: High-resolution computed tomography (HRCT) scan of chest. Note the extensive bronchiectasis in right lower lobe
There is a correlation between HRCT findings of bronchiectasis with histopathological findings in the lung, in adults who underwent lobectomy as a result of severe bronchiectasis, HRCT was found to be sensitive in 87% cases.31 Similar data from pediatric studies is lacking. Bronchiectasis is included under the broad group of ‘chronic suppurative lung diseases in childhood’ and the proposed definitions for its components have also been based on HRCT of the chest. Three distinct entities have been described:4
  1. Prebronchiectasis: Chronic/recurrent bacterial or endobronchial infection associated with non-specific HRCT changes such as bronchial wall thickening. Prebronchiectasis may resolve, persist or progress to “HRCT bronchiectasis”.
  2. HRCT bronchiectasis: Clinical features associated with bronchial dilatation on HRCT chest. HRCT bronchiectasis, too, may revert to prebronchiectasis, persist or progress to “established bronchiectasis”.
  3. Established bronchiectasis: Irreversible condition with no resolution of HRCT findings within 2 years. The risk of anesthesia/sedation and a relatively high radiation dose might be a deterrent in performing HRCT scans in younger children.
 
Pulmonary Function Tests
Pulmonary function tests (PFTs) findings of bronchiectasis are non-specific and can be normal or show an obstructive, restrictive or a mixed pattern.7 Although PFT cannot be used as an independent diagnostic marker for bronchiectasis; it can assess functional impairment (due to the bronchiectasis) in older children.
 
Other Investigations for Etiology
It is extremely important to identify treatable causes of bronchiectasis and investigations should be directed to establish the cause as per the clinical scenario. 317Baseline immune function assessment requires a complete blood count, including a differential white blood cell count, serum immunoglobulins (IgG and its subclasses, IgA, IgE, IgM), HIV testing for at-risk children, antibody response to protein and polysaccharide antigens and neutrophil function tests.26 Erythrocyte sedimentation rate, Mantoux testing and sputum culture for mycobacteria26 is required to diagnose an underlying tuberculosis as a cause of bronchiectasis; sputum should also be cultured for bacteria. Sweat chloride test and mutation studies for CF, nasal cilia biopsy for primary ciliary dyskinesia, skin prick test to Aspergillus fumigatus and A. precipitins to diagnose allergic bronchopulmonary aspergillosis, etc. may be performed in a child if there is an underlying strong suspicion for these disorders. Bronchoscopic examination is indicated for a suspected foreign body and structural airway abnormality; it can also aid in providing material for microbiological culture. Fluoroscopic studies are advised to rule out aspiration syndromes as a cause of bronchiectasis.
 
TREATMENT
Early diagnosis and management of correctable causes of bronchiectasis helps to prevent the progression of disease and is important in the maintenance of pulmonary function. Early treatment also reduces the frequency of infective exacerbations in these children and improves the general quality of life by promoting overall growth and well-being. Regular chest physiotherapy and appropriate antibiotic treatment during exacerbations is the mainstay of management of bronchiectasis. Aims of therapy are to provide symptom-free days and better quality of life, to reduce ongoing damage to lung, to prevent complications and to identify use of surgical option.
 
Chest Physiotherapy
All children with bronchiectasis require a thorough evaluation by an experienced chest physiotherapist and the parents (or wherever possible the child) should be taught airway clearance exercises.26 Although physiotherapy forms the standard therapy in patients with CF32, studies demonstrating its effectiveness in non-CF bronchiectasis are lacking. Airway clearance breathing technique (ACBT) comprising postural drainage and vibration is a well-established method, especially in adults.33 Chest percussion, cough-assist devices, airway oscillation, i.e. flutter, etc. are other maneuvers that help in clearing airway secretions.34
 
Antibiotic Therapy
The presence of purulent/mucopurulent sputum or the isolation of an organism in it, alone does not warrant antibiotic therapy.26 Antibiotics are indicated for infective exacerbations presenting with acute deterioration (usually for several day) with worsening local symptoms and signs (cough, increased sputum production, change in the sputum viscosity, increasing sputum purulence with or without an increase in wheeze, dyspnea, hemoptysis) and/or evidence of a systemic upset (fever).26
318A sputum culture should be ideally performed prior to the commencement of antibiotics. In younger children who tend to swallow sputum, obtaining a sputum sample for analysis may be difficult and in cases with serious illness or those unresponsive to empirical therapy, a throat swab26 or a bronchoalveolar lavage35 may be done; the finding on a throat swab should be interpreted with caution due to the presence of commensals in throat.26 Empirical antibiotics should be started whilst awaiting the result of sputum culture and sensitivity; antibiotic sensitivity reports of previous sputum samples could also be used as a guide.26 In children with no previous bacteriology reports, oral amoxicillin or clarithromycin (in penicillin allergic patients) is the recommended first line therapy.26 Antibiotics can be modified subsequently on the sensitivity pattern of the isolated organism only if there is no clinical response to empirical drugs.26 Intravenous antibiotics are indicated in patients not responding to oral therapy—a more commonly observed phenomenon in children with Pseudomonas infection, in those with resistant organisms and unwell children requiring in patient care.26 The empirical antibiotics should cover organisms like Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, etc. Indications for hospitalization are:26
  1. Breathlessness with increased respiratory rate and work of breathing,
  2. Circulatory failure,
  3. Respiratory failure,
  4. Cyanosis,
  5. Temperature ≥ 38°C or
  6. Inability to take oral therapy. Antibiotics should be given for at least 10 to 14 days26,35; such short antibiotic courses ameliorate symptoms by reducing airway inflammation and improve the quality of life in these children.32 Most studies suggest a limited role of prolonged antibiotic therapy.36 Although, long-term antibiotic therapy may result in the development of antibiotic resistance; it should be considered in all children with severe disease or frequent exacerbations.26 Long-term use of oral quinolones is not recommended in children.26 Azithromycin used for 6 to 36 months in cystic fibrosis—related bronchiectasis initially improved lung functions and quality of life scores with reduced exacerbations; however, it did not show any sustained benefits.37,38 Recently, the use of long-term, low dose, oral azithromycin in difficult-to-control patients with non-cystic fibrosis bronchiectasis demonstrated a benefit on exacerbation frequency, sputum volume and microbiology and forced expiratory volume in 1 second (FEV1).39 Azithromycin is believed to have immunomodulatory effects and reduces bronchoalveolar lavage neutrophilia and interleukin-8 messenger ribonucleic acid (mRNA).40 Azithromycin has an anti-pseudomonal effect with a prokinetic action on the gut and has been associated with lower levels of aspiration markers.41 The role of nebulized long-term antibiotics such as gentamycin and tobramycin is perhaps useful in children with frequent exacerbations or a deteriorating bronchiectasis despite long-term oral antibiotic use and those with chronic Pseudomonas aeruginosa colonization of the airways.26 Few studies have shown a microbiological benefit with long-term inhaled to bramycin therapy.42,43 Further trials are needed 319to demonstrate the efficacy of these nebulised antibiotics in children whose airways are chronically colonized with organisms other than P. aeruginosa.26
 
Bronchodilators and Corticosteroids
Children with bronchiectasis may have asthma-like presentation. However, bronchodilators, either beta-2-agonists or anti-cholinergic agents should be used only if there is documented airflow reversibility with the use of these agents. They should be used as maintenance therapy only if there is symptomatic or pulmonary function testing (PFT) improvement.26 Inhaled steroids should not be used in patients with bronchiectasis, unless the child is suffering from asthma, which requires their use.26 There is no role of methylxanthines in the treatment of bronchiectasis.26
 
Mucolytics
There is no proven benefit till date in the use of mucolytics such as mannitol, carbocysteine and hypertonic saline in patients with bronchiectasis; however, they can be used depending on the merit of each case.26 Recombinant deoxyribonuclease, although effective in patients with CF, is shown to be associated with rapidly declining lung function, frequent exacerbations and hospitalizations in adults with bronchiectasis.44
 
Anti-inflammatory Agents
There is no evidence to suggest the use of leukotriene-receptor antagonists or other anti-inflammatory agents in the management of bronchiectasis.26
 
Long-term Oxygen and Non-invasive Ventilation
The indications of long-term oxygen therapy in bronchiectasis are similar to patients with chronic obstructive pulmonary disease (COPD). Non-invasive ventilation has shown to improve the quality of life in patients with chronic respiratory failure due to bronchiectasis and reduce the frequency of hospitalizations.26
 
Role of Surgery
Medical management suffices for most patients with bronchiectasis and surgery is required only in a minority of patients not responding to conservative therapy.6,26 Definite indications for surgery in the form of segmental or lobar resection, in children with bronchiectasis are described as:45
  1. Localized disease resulting in severe symptoms such as copious sputum, foul-smelling breath, severe cough or other symptoms that hamper the normal quality of life;
  2. Threatening hemorrhage from a demonstrated focal, segmental or lobar source;
  3. Significantly severe resectable disease associated with failure to thrive;
  4. Resectable disease of a demonstrated site of recurrent, acute lower respiratory infections. In young children, the disease process is often unstable and surgery 320should be deferred until the child is older (usually 6–12 years).45 Lung transplant may be rarely required in children with bronchiectasis.7
 
Management of Massive Hemoptysis
This requires urgent admission to a hospital; bronchial artery embolization and/or surgery is often required.26
 
Minimizing Further Lung Injury
Exposure of these children to environmental pollutants such as tobacco46 smoke and indoor biomass/wood-smoke47 increases the frequency of acute infective exacerbations. Therefore, measures to prevent such exposure, at home or outside, are needed to reduce further lung injury in these children. It is a known fact that an increased incidence of lower respiratory infections is associated with overcrowding, damp housing and inadequate water supply.48,49 Measures to improve the overall living conditions can therefore, minimize the lung injury caused by these infective episodes in children with bronchiectasis.49
 
Nutrition
Poor nutritional status, including macro-and-micro-nutrient deficiencies may have an adverse impact on the status of bronchiectasis by predisposing to frequent attacks of lower respiratory infections and TB; this holds true for children more than adults.35 Poor nutrition in children with CF-related bronchiectasis is associated with a decline in respiratory function.35 The diet in these children, therefore, should be wholesome with adequate vitamins (especially vitamin A) and mineral supplementation. Monitoring the growth (weight and height) is an important aspect in treatment. Breast-feeding protects infants from developing bronchiectasis and other forms of chronic suppurative lung diseases in future and should always be encouraged.50
 
Immunization
Apart from the routine childhood vaccines, all children with bronchiectasis should receive annual influenza virus vaccine and 5-yearly pneumococcal vaccination.26
 
Managing Comorbidities
Children with bronchiectasis may have additional comorbidities, which may be responsible for increased exacerbations.32 Maintenance of proper oral hygiene is essential as dental caries are associated with pulmonary disease severity.32 As previously highlighted, infections of the upper respiratory tract viz adeno-tonsillitis and pan-sinusitis should be adequately treated.
 
Monitoring and Follow-up
Parents should be educated about the child's illness and chest physiotherapy and advised to recognize early exacerbations and seek timely medical care; the need 321for a regular follow-up depending on the child's disease severity should also be emphasized. When the child is clinically stable, parents should be taught to keep a record of the child's sputum purulence and an estimate of 24-hour sputum volume. At every follow-up visit, an assessment of the child's general health and symptoms should be performed; parental record of sputum purulence and 24-hour sputum volume should be analyzed and, the number of infective exacerbations in the past year and the duration and frequency of antibiotic usage should be noted.26 An annual assessment of FEV1, forced vital capacity (FVC) and peak expiratory flow (PEF) should be performed, if possible, in older children.26 Repeat chest radiographs at follow-up visits should be done only if clinically indicated.26 An echocardiogram is recommended for all children with advancing disease to rule out the complication of pulmonary hypertension.32 A multi-disciplinary team comprising of a pediatric pulmonologist, chest physiotherapist and a dietitian should assess the child at each visit.
 
Prognosis
With the advent of better diagnostic and therapeutic techniques, an increasingly large number of patients are being diagnosed and treated early, resulting in an improvement in the overall prognosis.7 Complications of bronchiectasis have now become rare in this post-antibiotic era.51 The complications include lung and brain abscess, empyema, pyopneumothorax, bronchopleural fistula, hemoptysis, amyloidosis and in advanced cases-cor pulmonale.51 Untreated/progressive disease is potentially fatal owing to severe infectious exacerbations and/or respiratory failure. However, most patients can lead a normal life if provided with good medical care and support.51
 
SUMMARY AND CONCLUSION
Bronchiectasis is a chronic respiratory disorder of childhood resulting in significant morbidity and mortality. This condition is characterized by abnormal and sometimes permanent dilatation of the bronchi. Multiple etiologies (congenital and acquired) can result in bronchiectasis through a ‘vicious cycle’ of bronchial obstruction and infection. Cystic fibrosis (CF) is the leading of cause bronchiectasis in the developed world, while respiratory tract infections form the major cause in the developing nations. Chronic productive cough is the clinical hallmark in a child with bronchiectasis. Although chest radiographs have been widely used in the past, a high-resolution computed tomography (HRCT) scan of the chest now forms the gold standard for the diagnosis. Regular chest clearance through physiotherapy, antibiotics for infective exacerbations and definitive management of the underlying cause form the mainstay of treatment. With the advent of excellent antibiotics, the role of surgery is limited to cases with localized illness unresponsive to conventional therapy.322
 
ACKNOWLEDGMENT
The authors thank Dr Sanjay N Oak, Director, Medical Education and Major Hospitals of Municipal Corporation of Greater Mumbai and Dean, Seth GS Medical College and KEM Hospital, Mumbai for granting permission to publish this manuscript.
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Acute Otitis Media21

SA Jagdish Kumar
 
INTRODUCTION
Acute otitis media (AOM) is a common bacterial and/or viral childhood infection of the mucosal lining of the middle ear cleft which includes eustachean tube, middle ear proper and the mastoid air cells system in the mastoid process, zygomatic process and the petrous part of the temporal bone. It is a frequent indication for antimicrobial therapy in children, second only to the common cold (URTI) both in the developed and developing countries. It is most common from 6 months to 20 months of age and seen often up to early school age years.
It is also the leading cause of hearing loss in children. Development of speech and language depends on good hearing in children from birth to 2 years age.
AOM is under or overdiagnosed due to the difficulties in the ear examination of children, especially infants. Difficulties in diagnosis are due to the presence of cerumen (wax) in the external auditory canal (EAC), uncooperative, crying child, and an improper otoscope lighting. Nevertheless, it is significant for the prompt recognition and complete eradication of infection in the middle ear cleft as soon as possible. It is also important that the case of AOM has to be followed up till the tympanic membrane (TM) returns to complete normalcy by otoscopic examination. Mere disappearance of symptoms are not sufficient evidence of full cure. An incompletely treated AOM may lead to either otitis media with effusion (OME) or atelectasis, which is fully described below under clinical features.
 
DEFINITION
AOM is an acute inflammation of the middle ear cleft of rapid onset by bacterial and/or viral pyogenic organisms. It is essentially a self-limiting disease with spontaneous resolution in majority of cases even without treatment. It occurs in ears with intact tympanic membrane (TM) and also in TM with perforation or tympanostomy tubes inserted for OME . There are four different sub-groups:1
  1. Sporadic: Occurring with an episode of upper respiratory tract infection (URTI).
  2. Resistant AOM: Signs and symptoms beyond 3 to 5 days of antibiotic therapy.326
  3. Persistant AOM: Signs and symptoms persisting or recurring within 6 days of finishing antibiotic therapy.
  4. Recurrent AOM: Three or more episodes in 6 months or 4 to 6 episodes in 12 months.
Though sub-type 2 and 3 appear similar but there is minor difference and retained for the completeness as per the literature reviews.
Another variant includes, acute necrotizing otitis media seen in children suffering from measles, scarlet fever or influenza which cause immunodeficiency; and the infection is caused by virulent strains of beta-hemolytic streptococci in an immunodeficient child.
 
ETIOLOGY
With the present available evidence, AOM is caused both by bacteria and viruses in isolation or in combination. Other factors which predispose to infection are anatomical (cleft-palate); environmental (low socio-economic strata patients); altered host defense mechanism (AIDS) and genetic causes (cystic fibrosis, Kartagener's syndrome).
 
Viruses
Clinically AOM is commonly associated with viral URTI. In 60 to 90% cases of AOM, viruses have been isolated by PCR assays.2 In one study, 41% cases of AOM specific viruses causing URTI was responsible for both. Common viruses include respiratory syncitial virus (RSV), influenza A virus, parainfluenza virus human rhinovirus and adenovirus. They arrive middle ear passively or actively (e.g. RSV). Viruses reaching passively:3
  1. Impair local immune function
  2. Affect bacterial adherence in eustachian tube
  3. Change pharmacokinetics
  4. Affect host immunity.
All the above factors have been well documented. In a study of children caused by RSV, 62% developed AOM. Bacteria were isolated in all these children. Viral agents as cause of AOM, explain why antibiotics are ineffective in some cases and why cultures of middle ear fluid for bacteria are negative in these cases, which range from 7.2 to 39.3% according to different studies. There is good evidence to explain eustachean tube function getting affected by viruses.2 Viruses are said to alter the host's, cell mediated immunity, cause alteration of neutrophil functions besides increased susceptibility to bacterial infections.
Socioeconomically poor children, bottle fed children, repeated exposure to other children with infections at home or schools also influence the incidence.
 
Bacteria
Most common causative agents are pneumococci (30%); H. influenzae (20%); Moraxella catarrhalis (12%). In recurrent or resistant AOM–the common organisms 327are drug resistant pneumococci and beta-lactamase producing H. influenzae and Moraxella. Other organisms include Streptococcus pyogenes; Staphylococcus aureus (in HIV positive children); and sometimes Pseudomonas aeruginosa.
Reasons for high incidence in young children are:4
  • High incidence of URTI
  • Short, straight, immature ET (in infants)
  • Adenoid hypertrophy and/or adenoiditis.
  • Immature immune system.
Children are predisposed to otitis media because secretions from the nasopharynx can readily pass through the horizontal eustachian tube, introducing pathogens into the middle ear. Additionally, even a small amount of inflammation can obstruct an already small lumen of the child's ET, aggravating the infectious process.
 
Routes of Spread of Infection
  • Eustachian tube: Main route of infection. Shorter, straighter, patulous tubes and poor tubal muscular opening function are said to be the cause.
  • Hematogenous-very rare.
  • Through pre-exisiting perforations or ventilation tubes [grommets kept for OME which is also called “glue ear”]. This is commonly due to water entry through external auditory canal (EAC), after head bath or swimming in contaminated ponds and swimming pools which is common in the rural parts of the many developing countries.
 
Risk Factors1
  1. Genetic: There is growing evidence that recurrent AOM is genetically determined and there is familial association. Racial differences—AOM is common in American Indians, Eskimos, Australian aboriginals. Twin children studies, atopy, maternal blood group ‘A’, certain human leukocyte antigen (HLA) are some of the factors associated with recurrent AOM described in detail under recurrent AOM below.
  2. Immune factors: IgG2 deficiency, defective complement-dependent opsonization, aberrant expression of critical cytokines (TNF and Interleukins), over expression of mucin genes (MUC 5B gene), low CD4 counts in HIV positive cases are all suggestive of significant factors in recurrent AOM cases.
  3. Environmental factors: Poor socio-economic status, poorly ventilated housing, over crowding, unhygienic surroundings are associated with increased incidence of AOM.
  4. Syndromic association: Children with Down's syndrome, Turner's syndrome, Iron deficiency anemia suffer more often.
 
Epidemiology
Strangerup and Tos5 reported an incidence of 22% in first year of life, 15% in year two and 10% in year three, falling to 2% by year eight. Seventy-five percent children will have had at least one episode by the age of 9 years. Incidence is more in rainy 328and winter seasons due to increased incidence of URTI. In the first two years of life, AOM is bilateral in 80% cases, after 6 years it is unilateral in 86% children.
 
Pathology and Clinical Features
It is divided into five stages:
  1. Stage of tubal occlusion/hyperemia
  2. Stage of presuppuration/exudation
  3. Stage of suppuration
  4. Stage of resolution
  5. Stage of complication.
 
Stage of Hyperemia
Edema and hyperemia of Eustachian tube blocks the tube leading to absorption of air in the middle ear which results in retraction of the tympanic membrane (TM) due to negative middle ear pressure. Pus that forms in the middle ear can drain to either mastoid air cells or to nasopharynx through the Eustachian tube (ET) (Figs 21.1 to 21.3).
Symptoms: Ear ache, tugging/rubbing at the ear, fever, diminished hearing, restlessness.
Signs: Retracted and dull TM with loss of light reflex [light reflex (cone of light) is normally seen in the antero-inferior quadrant of the TM].
 
Stage of Presuppuration
Inflammatory exudates appear in the middle ear. The TM becomes congested. In infants TM is usually opaque and more horizontally disposed unlike in older children and adults, which is pearly gray and vertically disposed.
Symptoms: Ear ache is severe, disturbs sleep, causes refusal of feeds, with high fever and deafness.
Signs: The TM is congested, giving cart-wheel appearance initially and becomes uniformly red later.
 
Stage of Suppuration
Marked formation of pus in the middle ear causes bulging of the TM. As the ET is blocked it causes bulging of the TM.
Symptoms: Excruciating pain, vomiting (convulsions-may occur) and high fever.
Signs: On otoscopy, TM is seen bulging and red (see Figs 21.4 to 21.6) and sometimes there will be tenderness over mastoid due to mastoidism.
 
Stage of Resolution
In this stage, TM ruptures with release of blood stained pus.
Symptoms: Immediate relief of pain and fever, child feels better and hearing starts improving.329
Fig. 21.1: Anatomy of the ear. Note the pathway for pus in the middle ear in cases of AOM, going posteriorly towards mastoid air cells and towards nasopharynx through Eustachian tube anteriorly
Fig. 21.2: AOM stage 1, showing TM retraction and congestion in upper half of tympanic membrane
Sign: Pinhole perforation is seen with pus coming out through it. Blood tinged pus is seen in the EAC. “Light house sign”- seen on otoscopy [there will be flashes of light when the pus under pressure keeps coming out from the middle ear giving appearance similar to beams of light radiating from Light house tower near sea shore].330
Fig. 21.3: AOM stage 1, showing prominent radiating blood vessels (typical cartwheel appearance)
Fig. 21.4: AOM stage 2, showing bulging tympanic membrane due to collection of pus behind the tympanic membrane
 
Stage of Complication
If organisms are virulent and host defense is poor, instead of resolution, infection extends beyond the middle ear cleft [ME cleft includes ET, middle ear and mastoid air cells extending up to petrous part of the temporal bone].331
Fig. 21.5: AOM stage 2, showing uniform bulging of tympanic membrane due to pus in the middle ear, with yellow discoloration in anteroinferior quadrant
Fig. 21.6: AOM stage 2, showing severe bulging of tympanic membrane in posterior half which is about to rupture [going to stage 3, i.e. stage of suppuration]
332
 
DIAGNOSIS6
The following guidelines of the Dutch College of General Practitioners7 are helpful in the diagnosis, which are as below:
 
Symptoms
Local: Ear ache, impaired hearing, otorrhea, tinnitus, pulling or rubbing of the ear.
General: Fever, irritability, nocturnal agitation, anorexia, vomiting, diarrhea, pain abdomen. Pediatrician has to keep in mind AOM, in a child presenting with misleading gastrointestinal symptoms and signs.
Evidence of a congested reddish drum or bulging drum on otoscopy is a definitive and positive sign. Schwartz and Karma et al report that in AOM, TM is usually pink in most cases and reddish in 18 to 19% cases.8,9 Sometimes, presence of wax or debris prevents proper examination. It should be removed by oil soaked cotton swabs or by wax curette or by suction using micro tips by an experienced ENT surgeon. It should never be syringed as it causes severe pain. Crying also produces redness of the TM but the examination of the unaffected ear in an unilateral case of AOM will settle the diagnosis.
 
Differential Diagnosis1
Tonsillitis, rhinitis, sinusitis, temporo-mandibular joint disorders, Ramsay Hunt syndrome [facial palsy with rashes on the pinna] and bullous myringitis cause otalgia and have to be ruled out. Very rarely leukemia and Wegener's granulomatosis may have AOM as the first indication.
 
Course of the Illness
The otalgia reduces within 24 hours in two-thirds of children without treatment. Symptomatic relief is seen without treatment by day four to seven in 88% children as per some studies, and hence the dilemma of the treatment with antibiotics arises. The hearing loss may be greater than 20 dB, lasting for one month in 30% and for 2 months in 20% children.1
Hearing loss cannot be ignored as it affects speech and language development in young children below 2 years and affects the school performance in older children. Hence, there is dire necessity to treat all cases of AOM till the TM becomes normal and hearing is restored to full normalcy.
 
Complications
 
Extracranial Complications1
Acute mastoiditis: It is an extension of the infection of the middle ear to all the mastoid air cell system. It is a disease of the childhood. Symptoms are otalgia and irritability in most children. Fever and otorrhea are less common. On otoscopy, red bulging TM is commonly seen. Pinna is pushed forwards without the obliteration of the post aural groove differentiating it from cellulitis secondary to furuncle of 333the external auditory canal with tenderness under the cymba concha area of the pinna. This can develop within 2 days to 14 days after the onset of AOM, in spite of the antibiotic therapy as reported in 22 to 55% children in a study. In acute masked mastoiditis and subacute mastoiditis, otalgia and fever are present without the tenderness over the mastoid process. This cannot be ignored and it is due to use of antibiotics but in ineffective doses. Treatment is by hospitalization, intravenous antibiotics and analgesics. If there is no response and if there is “reservoir sign” which is a sign of acute coalescent mastoiditis with profuse purulent discharge through the perforation of the TM, surgical management [cortical mastoidectomy] is done under general anesthesia (GA).
 
AOM is a common complication of influenza in children (Fig. 21.7)
Fig. 21. 7: AOM as a complication of influenza, showing vescicles on the tympanic membrane
Acute sub-periosteal postaural abscess: There is formation of swelling behind the ear with in the sub-periosteal region due to bone erosion of the mastoid cortex and escape of pus from the mastoid cavity. This needs to be drained under GA.
Facial palsy: Lower motor neuron type of facial palsy can develop after an attack of AOM. Present incidence is 0.005%. Treatment is by surgery viz myringotomy and grommet insertion under general anesthesia along with intravenous antibiotics which is effective in 80% cases. However, cortical mastoidectomy is needed in 20% cases.
Labyrinthitis: Inner ear can be involved when the infection spreads through the round window membrane. It is of concern in children with cochlear implants, and congenital inner ear anomalies. Severe vertigo, nausea, vomiting, hearing loss are seen. Hearing loss can become permanent.
334Petrositis (Gradenigo's syndrome): Ipsilateral lateral rectus palsy with retro-orbital pain and otorrhea is due to involvement of 6th cranial nerve in the dorello canal in the petrous temporal bone. It is not seen nowadays.
 
Intracranial
The mortality due to intracranial complications has come down from 75% in preantibiotic era to 5%, now in the developed countries.
Persistent headache and fever are the most common symptoms:
  1. Perisinus or extradural abscess
  2. Meningitis
  3. Brain abscess
  4. Lateral sinus thrombosis.
 
Treatment
 
General Consideration
Antibiotics have to be used with caution due to increasing incidence of bacterial resistance. General considerations are : Children <6 months with presumed AOM, children between 6 months and 2 years age who are severely ill, temperature > 39°C, significant otalgia, toxic appearance and Children <2 years age with confirmed diagnosis are prescribed antibiotics. For children with non-severe AOM, observation for 2 to 3 days is advised.
In USA 40% of H. influenzae and almost all strains of M. catarrhalis are resistant to aminopenicillins. Fifty percent pneumococci are penicillin and macrolides resistant.3
 
Antibiotics
Minimum course is for 5 days according to recent studies.
  1. First line: Cotrimoxazole/Ampicilln/Amoxycillin.
  2. Second line: Amoxy-clavulunate, cephalosporins-cefuroxime (second generation), Cefixime, Ceftibuten (third generation) for minimum of 5 to 10 days till TM and hearing becomes normal. Early discontinuation of therapy with relief of ear ache and fever leads to OME or persistant AOM.
  3. Nasal decongestants: Oral nasal decongestants containing phenylephrine or pseudoephedrine, or topical nasal decongestants like oxy or xylometazoline nasal drops help relieve nasal congestion and edema of ET which promotes ventilation of middle ear.
  4. Analgesics and antipyretics: Paracetemol and Ibuprofen relieve pain and fever and are given in adequate doses.
  5. Mucolytic agents: These are useful in children with children with Down's, Kartagener's syndrome, etc.
 
Surgical Treatment
Incising the TM and letting out the pus from the middle ear by myringotomy under general anesthesia, is done only in the following situations:335
  1. Severe ear ache persisting for more than 72 hours.
  2. High fever.
  3. Toxic child.
  4. Poor response to antibiotic therapy.
  5. Newborns.
  6. Primary or secondary immunodeficiency.
 
ACUTE NECROTIZING OTITIS MEDIA
It is common in infants and young children.
 
Definition
It is a special variety of AOM seen in developing countries in children suffering from measles, scarlet fever, yellow fever, pneumonia, influenza and other febrile infections.
 
Etiopathogenesis
It is caused by virulent strains of β-hemolytic Streptococcus followed by infection with staphylococci, Pseudomonas aeruginosa.
There is rapid necrosis and sloughing of whole TM with its annulus, mucosa of middle ear, ossicular chain, and infection can spread to the mastoid air cells causing coalescent mastoiditis.
 
Symptoms
  1. Otalgia
  2. Profuse ear discharge, thin and fetid.
 
Signs
  1. Large central or subtotal perforation of TM [Fig. 21.8].
  2. Severe deafness-conductive hearing loss or mixed hearing loss due to associated labyrinthitis.
 
Course
Becomes CSOM with its resultant chronic hearing defect and morbidity of chronic ear discharge or develops secondary acquired type of cholesteatoma with serious prognosis unless promptly treated surgically by mastoidectomy.
 
Treatment
Effective antibiotic therapy based on C/S studies for minimum of 10 days.
 
Recurrent AOM
Some of the factors responsible for recurrent AOM10 are:
  1. Anatomic risk factors such as craniofacial anomalies, cleft palate, gastroesophageal reflux disease (GERD), and adenoidal hypertrophy.336
    Fig. 21.8: AOM sequel, showing subtotal perforation of pars tensa of tympanic membrane
  2. Functional risk factors such as cerebral palsy, other neurologic diseases, and immunodeficiency.
  3. Environmental risk factors such as bottle-feeding of infants (instead of breast-feeding); propping a bottle in a supine infant's mouth (resulting in milk reflux into the middle ear through the eustachian tube); passive smoking; under privileged socioeconomic status; and attendance in a child care facility.
In recurrent AOM, in 30 to 50% cases, repeat culture of the middle ear aspirates fail to show positive cultures implying that inflammation continues even after the eradication of the bacterial pathogens from the middle ear cavity.
Recurrent AOM is probably genetically determined as shown by studies of monozygotic and dizygotic twins through immune related mechanisms, human leukocyte antigen (HLA).11
Figure 21.9 depicts the appearance of the tympanic membrane in a child with recurrent otitis media.
 
Management1
 
Alteration of Risk Factors
  1. Avoid exposure to infected children in day care, schools.
  2. Bottle feed in semi-upright posture.
  3. Breast feeding for minimum 6 months age.
 
Medical Prophylaxis
  1. Amoxycillin—20 mg/kg for 3 to 6 months.
  2. Xylitol in chewing gum is said to reduce incidence, but there is no definite evidence.337
    Fig. 21.9: Recurrent AOM, showing bulging and prominent blood vessels in posterosuperior part of tympanic membrane
  3. Vaccination: It is based on the premise that, AOM incidence secondary to measles has become uncommon in the industrialized countries due to effective measles vaccination programme in children, suggesting usefulness of antiviral vaccines. Influenza ‘A’ vaccination reduces viral URTI and thus reduces AOM incidence. Three trials of influenza A vaccine reduced influenza associated AOM by 83 to 93%.12
    However, bacterial vaccines like pneumococcal vaccine, H. influenzae, Moraxella vaccine are still in experimental stage and can be used only for “At risk” children, like those awaiting cochlear implants. Hib conjugate vaccine up to 4 years age are recommended.
  4. Immunoglobulins: Useful in IgG2 deficient infants as shown in a Japanese study.
  5. Benign commensals: Spraying with α-steptococci into nose reduces recurrent AOM.
 
Surgical Prophylaxis
  1. Myringotomy and grommet insertion: It is done in failed cases of medical prophylaxis.
  2. Adenoidectomy and adenotonsillectomy: Beneficial for patients with failed medical prophylaxis cases.
 
Issue of Referral to ENT Specialist by a Pediatrician
There are three different categories of patients whom pediatricians might consider referring:
  1. A child who has an acute active ear infection and has undergone multiple trials of antibiotics on a broad spectrum, but continues to have acute otitis media that might need surgical drainage.338
  2. If a child has gone on to develop complications from an ear infection, such as mastoiditis, meningitis or facial nerve paralysis.
  3. A child with recurrent acute otitis media—four infections in a six-to-nine-month period. The criteria is less strict if the child is immunocompromised, displaying speech or language delays that may suggest a problem with hearing, developing multiple allergies to antibiotics or having severe complications from antibiotic therapy.
 
SUMMARY AND CONCLUSION
There are deficiencies in our current knowledge of both the diagnosis and etiology of AOM and uncertainty in management strategies. There are exciting new developments occurring in different modalities of treatment. AOM has to be treated with appropriate antibiotics whenever indicated and followed up till it is completely cured. Mere absence of symptoms is not an indication of cure. Follow up otoscopy is a must to prevent unnecessary complications/sequelae and to ensure complete restoration of normal functioning of the middle ear hearing mechanism.
REFERENCES
  1. Rea P, Graham J. Acute otitis media in children In: Gleeson M (Ed): Scott-Brown's Otorhinolaryngology, 7th edn. London: Hodder Arnold  2008:912-927.
  1. Heikkinnen T. The role of respiratory viruses in otitis media. Vaccine 2001;19:S51–55.
  1. Kerschner JE. Otitis media In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds): Nelson Textbook of Pediatrics, 18th edn. Philadelphia: Saunders/Elsevier  2008:2632-2646.
  1. Van Cauwenberge PB, De Moor SE, Dhooge I. Acute suppurative otitis media. In: Ludman H, Wright T (Eds): Diseases of the Ear, 6th edn. New Delhi: Jaypee  2006:354–360.
  1. Strangerup SE, Tos M. Epidemiology of acute suppurative otitis media. Am J Otolaryngol 1986;7:47–54.
  1. Browning GG. Acute otitis media in adults In: Gleeson M (Ed): Scott-Brown's Otorhinolaryngology, 7th edn. London: Hodder Arnold  2008:3385-3387.
  1. Gupte S, Pal M. ENT problems in pediatric practice. Asian Chron Child Hlth 2002;7:62–68.
  1. Schwarz RH, Stool SE, Rodrigues WT, Grundfast KM. Acute otitis media towards a more precise definition. Clin Pediatr 1981;20;549–554.
  1. Karma PH, Pentilla MA, Sipila MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media I: The value of different otoscopic findings. Intern J Pediatr Otorhinolaryngol 1989;17:37–49.
  1. Jafek BW, Murrow BW. Acute otitis media in children. In: ENT Secrets, 3rd edn. New York: Elsevier  2007.
  1. Casselbrant ML, Mandel EM. The genetics of otitis media. Curr Allergy Asthma Rep 2001;1:353–357.
  1. Giebink GS, Bakaletz LO, Barenkamp SJ, et al. Recent advances in otitis media: Vaccine. Ann otol, Rhinol Laryngol 2002;111:82–94.

Approach to the Child with Recurrent Respiratory Infections22

Bashir A Charoo, Javeed Iqbal Bhat
 
INTRODUCTION
Recurrent infections, especially acute respiratory infections, are important cause of mortality and morbidity in childhood. Around 6% of the children younger than 6 years of age present with recurrent respiratory infection (RRI). In the clinical practice, most of the children suffer from the recurrent infections of the upper airways, but in approximately 10 to 30%, the lower tract is also affected.1 There are two peaks of the incidence of RRI. In developed countries, up to 25% of children aged < 1 year and 18% of children aged 1 to 4 years experience RRI.2 Approximately 4 million children die due to acute lower respiratory tract infections annually. These infections are reported to be responsible for 28% of children deaths under 5 years of age. The causes of RRI are multiple, varying from simple viral infections to severe immunodeficiency disorders, the challenge for the clinician is to differentiate the child with immunodeficiency from the normal child who had more than the average number of viral infections or the child who has an underlying disease that mimics infection. Most often, these categories can be determined from the history, physical examination, and screening investigations.
 
DEFINITION
There is no clear consensus about definition of RRI. In case of otitis media, it is defined as 3 episodes within 6 months or 4 or more episodes within 1 year. Recurrent infectious rhinitis is usually defined as more than five episodes per year and recurrent pharyngitis and tonsillitis more than three episodes within 12 months.2,3 Pneumonia is clinically defined as a combination of respiratory symptoms (cough, dyspnea, or tachypnea) and signs (fever, crepitations, focally-reduced breath sounds, and wheeze). There are no guidelines, or universal agreement for the definitions of recurrent pneumonia. Suggested definitions include 2 episodes within the same year, or 3 or more episodes over any time period.4 For a child to be diagnosed with recurrent pneumonia there must be complete resolution of clinical and radiological findings between acute episodes. Every definition of RRI is arbitrary and too generic and restrictive. Rather than 341defining if a child has recurrent infections with an objective numeric evaluation, it is better to know:5
  • If the child generally feels good
  • If there are conditions that could be diagnosed and treated as a true disease
  • If the findings on the history and physical examination are suggestive of an immunodeficiency.
 
ETIOLOGY
The vast majority of acute upper respiratory tract infections are caused by viruses, such as rhinoviruses, coronaviruses, the respiratory syncytial virus, influenza and parainfluenza, and adenoviruses. Recurrent viral infections are part of the growing up process of any child. Although their immune and respiratory defenses are normal, many of these children are simply having the repeated viral respiratory tract infections. S. pneumoniae, H. influenzae, M.pneumoniae, C. pneumoniae, and M. catarrhalis are the most common non-viral pathogens for lower respiratory infections.6,7 In many cases, no pathogen can be identified. It is necessary to discriminate between those with simply-managed cause for their symptoms such as recurrent viral infections or asthma, from the children with more serious underlying pathology such as bronchiectasis or immune dysfunction. Many different disorders present this way, including cystic fibrosis, various immunodeficiency syndromes, congenital anomalies of respiratory tract, but in some children lung damage could follow a single severe pneumonia or can be the consequence of the inhalation of food or foreign body.
 
RISK FACTORS
Many factors increase the risk of RRIs in children (Box 22.1).
Child's age is an important risk factor for all respiratory infections. Young children are more vulnerable to recurrent respiratory infection due to many reasons like increased exposure to infectious agents during the first years of life especially when attending to preschool, general immaturity of the immune system of younger children, social and environmental factors,8 e.g. day-care attendance, family size, air pollution, parental smoking. Lower respiratory infections are more common in boys than girls, for unknown reasons.
342Infants born prematurely, particularly who develop chronic lung disease frequently develop RRI in early childhood and the mortality is higher than in term infants. Breastfeeding decreases the risk of RRI. The immunoprotective effect of breastfeeding against respiratory infections is most important in nonindustrialized countries, but is also evident in industrialized societies.9
Children with congenital anomalies, such as pulmonary sequestration, tracheoesophageal fistula, and congenital heart disease are more prone to develop RRI.
Cystic fibrosis is an important cause of recurrent and persistent chest infections. Infection in this group is not only more common but also more severe than in normal children, with a great risk of respiratory failure death.
Alterations in immune system and its function have been observed in some children with RRI. These include physical defenses, such as cough and mucociliary clearance, circulatory and resident cellular defenses, and a range of humeral and secretory mechanisms. Collectively, their function is to prevent the entry or to remove foreign material from the lung.
 
DIFFERENTIAL DIAGNOSIS
 
Childhood Asthma
About 30% of children with recurrent infections have atopic disease. Chronic allergic rhinitis may be mistaken for recurrent upper respiratory infections. Children with atopic disease often develop cough and wheezing following viral respiratory infections. These infections are frequently misdiagnosed as pneumonia or bronchitis rather than reactive airway disease, these episodes respond poorly to antibiotics; closer attention to history reveals that most of such children have characteristic trigger factors such as upper respiratory tract infections (URTIs), exercise, cold air, exposure to pets and aeroallergens. Family history of atopic disease is often present in these patients so is history of bronchodilator reversibility.
Atopy can favor RRI in children,10 this increased susceptibility to infection may be due to enhanced adherence of pathogens to inflamed respiratory epithelium or alteration to mucosal permeability.
 
Postinfectious Cough
Some children may continue with persistent cough for weeks to months following symptoms of an upper respiratory infection. It is commonly seen after Bordetella pertussis and Mycoplasma infections. While the pathogenesis of this condition is not exactly known, it has been thought to be due to the extensive disruption of epithelial integrity and widespread airway inflammation with or without transient airway hyper-responsiveness.11-13 Episodes of wheeze, cough and breathlessness, which may recur for months or years, are common in infants who have been admitted to hospital with an RSV bronchiolitis.14343
 
Tuberculosis
In a setting with a high incidence of TB and ongoing transmission, the most common clinical presentation of tuberculosis in children is likely to be pulmonary TB. The clinical picture of TB is very wide and can simulate several illnesses from a common cold to a chronic pneumopathy like asthma. Almost 17% of children with a TB who are admitted in hospitals present with wheezing, and can be misdiagnosed as asthmatics during an acute attack.15 Due to high prevalence of disease in developing countries pulmonary tuberculosis should always be kept in differential diagnosis in a child with an RRI, especially with history of contact, failure to thrive, weight loss, and other constitutional symptoms.
 
Inhaled Foreign Body
Foreign body inhalation should be considered in any young child, who develops a persistent productive cough, particularly with onset heralded by episode of choking. Some intrabronchial foreign bodies, notably peanuts evoke severe inflammation of the bronchial mucosa, which quickly leads to airway obstruction and distal infection even if foreign body has been removed.
 
Cystic Fibrosis
Cystic fibrosis is one of the important causes of recurrent respiratory infections in children. Majority of patients have associated malabsorption syndromes and failure to thrive due to pancreatic insufficiency. Viscid mucus in the small airways predispose to chronic airway infection. Majority of the cases are infected by Staphylococcus aureus, H. influenzae and Pseudomonas. It leads to progressive damage to the bronchial wall, bronchiectasis and eventually lung fibrosis.
 
Immunodeficiency Disorders
All people, especially children come across bacteria, fungi, viruses and other parasites everyday in a world full of microorganisms. Despite of the frequent everyday confrontation with microorganisms, infectious diseases are seen relatively rarely due to many systemic and local defense mechanisms of the host. Recurrent infections, especially recurrent sinopulmonary infections are seen clinically when there is deficiency or insufficiency at any step of this cascade.16,17 An immune defect should be considered in any child, who has respiratory infections that are unusually severe, recurrent, unresponsive to convential treatment or atypical. Common associated features include failure to thrive, severe atopic disease, such as eczema and occasionally autoimmune disease.
 
DIAGNOSTIC APPROACH
Pediatricians have first to determine whether the child presents with an underlying severe illness. The presence of infections with similar features, severity, and duration to those presented by children with ‘normal’ incidence of RI, the absence of systemic infections or illness caused by opportunistic agents, the absence of a 344failure to thrive, a family history negative for immunologic defects point towards a diagnosis of RRI.18 Careful history and clinical examination are very important to differentiate the child with more than average number of viral infections from the child with some serious underlying disease like cystic fibrosis, or some immunodeficiency disorder. For suspect cases, a complete blood count with differential is sufficient to exclude neutropenia and lymphocyte T defects. Total immunoglobulin levels are also important to evaluate the presence of a selective IgA deficiency.18 Which immune tests are performed will depend on the nature and severity of the respiratory symptoms. For example, in the child who has repeated episodes of cough with purulent sputum containing Streptococcus pneumoniae or H. influenzae, but who is otherwise well with no clinical or radiological evidence of lung damage, measurement of immunoglobulin and immunoglobulin subclass levels, and specific antibody levels against Pneumococcus, tetanus and Hib would be appropriate, as a specific antibody deficiency is the most likely diagnosis. By contrast, a child with severe opportunistic pneumonia demands a detailed assessment of cellular and humoral immune function.
A chest radiograph is the first-line investigation for evaluating children with a RRI. Hyperinflated lungs suggest asthma whilst air trapping in only one lung field suggests a foreign body. Widespread changes, such as bronchial wall thickening or inflammation involving several lobes suggests a systemic disorder such as cystic fibrosis, ciliary dyskinesia or an immunodeficiency disorder. A chest X-ray is also helpful to exclude other diagnoses like tuberculosis, lymphoma and bronchiectasis. Sinus radiographs are helpful in older children who present with nasal symptoms and wet cough, features that suggest allergic rhinosinusitis. Spirometry may be helpful in supporting the clinical diagnosis of cough variant asthma in older children (> six years old) who are able to perform the maneuver. Sweat testing to rule out cystic fibrosis, immune work-up and ciliary studies may be needed in children with recurrent chest infections.
A 24-hour esophageal pH study or flexible bronchoscopy may be required in a child with chronic cough in which the diagnosis is not clear-cut by history, physical examination or plain radiographs. If recurrent aspiration is suggested by the history, this may be detected by isotope milk scans. Incordinate swallowing, which is most commonly seen in children with severe neurodevelopmental problems, such as cerebral palsy or severe myopathies, should be assessed by barium swallow.
 
TREATMENT19,20
In order to overcome the mence of increasing antimicrobial resistance, there is need for a rational approach to management of recurrent respiratory infections in children. Antibiotics should be judiciously chosen depending on age, socioeconomic status, severity of infection and the type of organism anticipated and given in adequate doses and for proper duration.
Situation with highest risk for developing resistant bacteria are:
  • Failure of previous treatments,
  • Numerous previous antibiotic prescriptions, or
  • Low doses of antibiotics over a prolonged period.
345Preventive antibiotics my be considered in children who have at least three episodes of RTIs within a six-month period. These may be given for a consistent 3 to 6 month period following the last acute episode. Some physicians may prescribe them only in winter and spring when the risk for respiratory infections is high. The preventive regimen is one or two daily doses of amoxicillin, cotrimoxazole or sulfamethoxazole.
Subjects suffering from B cell immunodeficiencies who continue to experience recurrent infections despite intravenous immunoglobulin replacement treatment also should be considered for concomittant antibiotic therapy to avoid complications, such as chronic lung disease and bronchiectasis.
 
GROWTH MONITORING
Recurrent respiratory infections may predispose children to poor weight gain and growth failure. Understandably, monitoring of the height and weight should be performed frequently and appropriate nutritional interventions initiated early if problems arise. Recent approaches include the encouragement of breastfeeding, and respiratory syncytical virus immune globulin and methods of stimulating immunity, such as ribosomal immunotherapy.
 
PREVENTION
Simple precautions for prevention of RRI include:
  • Eating plenty of fruits and vegetables
  • Getting enough rest
  • Washing hands frequently
  • Avoidance of exposure to smoking, and
  • Promotion of brestfeeding.
Ordinary soap, rather than the so-called antibacterial soap, is sufficient. Common liquid dishwashing soaps are up to 100 times more effective than antibacterial soaps in killing respiratory syncytial virus—a well-known cause of pneumonia, bronchiolitis and other respiratory infections.19
In addition to the hygienic and dietary mesures, routine vaccines, including Hib, two vaccines that should always be given to children who are susceptible to recurrent respiratory infections are:
  • Pneumococcal vaccine
  • Influenza vaccine, annually, in advance of the influenza season.20
 
SUMMARY AND CONCLUSION
The child with recurrent respiratory infections poses one of the most difficult diagnostic challenges in pediatrics. The outcome may be anything from reassurance that the child is normal to the diagnosis of a life-threatening condition. One must attempt to co-relate the clinical profile with radiology and other laboratory tests. On most occasions, ignoring the clinical profile and depending heavily on investigations proves futile. In addition to the routine vaccine, including Hib, two vaccines that 346should always be given to children who are susceptible to recurrent respiratory infections are pneumococcal vaccine, and influenza vaccine, annually, in advance of the influenza season. Preventive antibiotics my be considered in children; who have at least three episodes of RTIs within a six-month period. Monitoring of the height and weight should be performed frequently and appropriate nutritional interventions initiated early if problems arise. Encouragement of breastfeeding, and respiratory syncytical virus immunoglobulin and methods of stimulating immunity, such as ribosomal immunotherapy figure among the new approaches.
REFERENCES
  1. Couriel J. Assessment of the child with recurrent chest infections. Br Med Bull 2002;61:115–132.
  1. Richard S. Recurrent respiratory infection in childhood. Pulmonology Today 2003;12:231–236.
  1. Richard S, Goldman EW. Acute respiratory infections: Epidemiology. Epidemiol Rev 2003;13:143–147.
  1. Wald ER. Recurrent and Nonresolving Pneumonia in Children. Seminars Resp Infect 1993;8:46–58.
  1. Don M, Fasoli L, Gregorutti, V, Pisa F, Valent F, Prodan M, & Canciani M. Recurrent respiratory infections and phagocytosis in childhood. Pediatr Intern 2007;49:40–47.
  1. Couriel JM. Lower respiratory tract infections in childhood. In: Ellis M (Ed). Infections of the Respiratory Tract. Cambridge: Cambridge University Press  1998:406-427.
  1. Heath PT. Epidemiology and bacteriology of bacterial pneumonias. Pediatr Respir Rev 2000;1:4–7.
  1. de Martino M, Balloti S. The child with recurrent respiratory infections: normal or not? Pediatric Allergy Immunol 2007;18:13–18.
  1. Beaudry M, Dufour R, Marcoux S. Relation between infant feeding and infections during the first six months of life. J Pediatr 1995;126:191–197.
  1. Daly KA, Hoffman HJ, Kvaerner KJ, et al. epidemiology, natural history, and risk factors: panel report from the ninth international conference on otitis media. Int J Pediatr Otorhinolaryngol 2010;74:281.
  1. Empey DW, Laitinen LA, Jacobs L, et al. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131–139.
  1. Little JW, Hall WJ, Douglas RG Jr, et al. Airway hyperreactivity and peripheral airway dysfunction in influenza A infection. Am Rev Respir Dis 1978;118:295–303.
  1. Corne JM, Holgate ST. Mechanisms of virus-induced exacerbations of asthma. Thorax 1997;52:380–389.
  1. Child HF, Couriel JM. Bronchiolitis and beyond: who will wheeze and why? Asthma J 1999;4:20–23.
  1. Gie RP, Beyers N, Schaaf HS, Nel ED, Smuts NA, van Zyl S, Donald PR. An evaluation of children with an incorrect initial diagnosis of pulmonary tuberculosis. S Afr Med J 1995;85:658–662.
  1. Finocchi, A, Angelini, F, Chini, L, Di Cesare, S, Cancrini, C, Rossi, P, Mosschese, V Evaluation of the relevance of humoral immunodeficiencies in a pediatric population affected by recurrent infections. Pediatr Allergy Immunol 2002;13:443–447.
  1. Quezada A, Norambuena X, Bravo A, Castro-Rodriguez JA. Recurrent pneumonia as warning manifestation for suspecting primary immunodeficiencies in children. J Investig Allergol Clin Immunol 2001;11:295–299.
  1. De Martino M, Galli L, Vierucci A. The child with recurrent respiratory infections. In: Aiuti F (Ed). Pathogenesis and Control of Viral Infections. New York: Raven Press  1989:225-231.
  1. Kilic SS. The evaluation of the child with recurrent respiratory tract infections. In: Gupte S, Gupte SB (Eds). Recent Advances in Pediatrics-14. New Delhi: Jaypee  2004:1–1.
  1. Gupte S, Pal M. Recurrent respiratory infections in childhood: Observation from north India. Bull Eur Fed Infect Dis 2002;6:73–79.

Surfactant Therapy23

B Vishnu Bhat, R Renitha
 
INTRODUCTION
Exogenous surfactant therapy is considered as one of the important achievement in the treatment of neonatal respiratory distress syndrome (RDS). It is one of the well studied therapies.
Surfactant is a complex mixture of lipids and proteins secreted by alveolar type II cells and it decreases the surface tension of the alveoli and prevents lung from collapsing during expiration.
Von Neergard was the first person to observe the surface properties of the lungs. In 1959, Avery and Mead1 reported that lung extracts from premature infants dying with hyaline membrane disease had high surface tension and suggested that surface active material was deficient in these infants. First report on artificial surfactant therapy in preterm infants was published in 1980 by Fujiwara et al.2 In this study ten preterm infants were treated with exogenous surfactant, which showed improvement in radiological appearance, arterial oxygenation, acid base balance and AaDO2.2 After that several studies have been published on surfactant therapy. This article will review the chemical composition, types and uses of surfactant.
 
COMPOSITION OF PULMONARY SURFACTANT
Pulmonary surfactant is a mixture of lipids and proteins. It is secreted by alveolar type II cells of the lung. It consists of 90% lipids and 10% proteins. Lipids consist of both saturated and unsaturated phospholipids and neutral lipids.3-5 Phospholipids of surfactant isolated from different species of animal are similar in composition. They include saturated and unsaturated phosphatidylcholine, phosphatidyl inositol, phosphatidyl glycerol. Phosphatidylcholine (PC) constitutes 70% of the lipid content, of which 60% is dipalmitolyl phosphatidylcholine (DPPC) and is the most important component which reduces the surface tension. Acidic phospholipids like phosphatidyl inositol, enhances the adsorption and film formation of DPPC.3,4
____________________________________________________________
Reproduced from Gupte S, Gupte SB (Eds): Recent Advances (Special Vol 21: Neonatal and Pediatric Intensive Care). New Delhi: Jaypee 2011:145-158.
349Surfactant contains about 10% protein. There are four different surfactant proteins. These include hydrophilic surfactant protein A (SP-A) and protein D (SP-D) and hydrophobic proteins protein B (SP-B) and protein C (SP-C).3-6
 
SYNTHESIS AND SECRETION OF PULMONARY SURFACTANT
Alveolar surface is formed by two types of cell–type I pneumocytes and type II pneumocytes. Synthesis of surfactant is the major function of type II pneumocytes. Other than synthesis of pulmonary surfactant, type II pneumocytes participate in repair of damaged areas and defense response by expressing various types of receptors like toll like receptors and production of cytokines and chemokines. Type II pneumocytes contains 0.1 to 2.4 μm diameter structures called lamellar bodies. Lamellar bodies, which are the storage of surfactant, are first observed at 22 weeks of gestation. They consist of highly packed concentric membrane lamellae, surrounded by a limiting membrane and contain surfactant phospholipids. Lamellar bodies express late endosomal and lysosomal markers. Though they have lysosomal markers and enzymes, they are not degradative, but are secretory organelles. Lamellar bodies are thought to be formed by redistribution of phospholipids within the late endosome termed multivesicular bodies (MVBs). An intermediate stage of fusion is known as composite bodies (CBs). Tubular myelin increases the adsorption of surfactant.6,7 Type II cells accumulate glycogen and serves as the carbon source for lipid synthesis. Many drugs given in antepartum increase the secretion of surfactant. Corticosteroids are the best studied drug among currently used. Aminophylline, isoxsuprine and epinephrine also was tried in previous years.8-11
 
Surfactant Phospholipid Secretion
Surfactant phospholipids are synthesized in endoplasmic reticulum (ER). From ER lipids are transported to lamellar bodies (LB) and then translocated across the LB limiting membrane.
Details of the transport of the lipids from ER to LB are not clear. Phosphatidyl choline transfer protein is expressed in lungs, which is highly specific for PC, but its function in vivo is not confirmed. Experimental animal which lacks this protein still has normal lamellar body formation.
Translocation of lipids across the limiting membrane is facilitated by ATP-binding cassette (ABC) family, predominantly ABC-A subfamily. ABCA3 isoform is highly expressed in type II pneumocytes and mutation of this protein resulted in decreased PC content in the surfactant and increased surface tension. ABCA3 mutation can also lead to abnormal processing and routing of SP-B and SP-C.7
 
Surfactant Protein Secretion
Secretion of surfactant proteins is a complex process. Hydrophobic proteins SP-B and SP-C are localized inside the LB and are co-secreted along with PC. Hydrophilic proteins SP-A and SP-D have LB-independent secretion. SP-B and 350SP-C are transported from endoplasmic reticulum to MVBs via Golgi apparatus and then to CBs and finally to LBs and are then secreted along with phospholipids. SP-B is synthesized as preproprotein. Processing of SP-B precursors occur in Golgi apparatus and MVBs. Mature SP-B fuse with MVBs and CBs and promote their fusion with lamellae of the mature LBs.6,7
SP-C is expressed exclusively in type II pneumocytes. SP-C also is synthesized as proprotein. Precursors are incorporated in the MVB membrane followed by relocation into lumen of MVBs and are then incorporated into LBs.6,7
Hydrophilic proteins SP-A and SP-D are collectin group of proteins. Secretion of these proteins is not well understood. Secretions of these proteins are constitutive and lamellar body independent. SP-D is also secreted from Clara cells.3,4,6,7
Following secretion of the surfactant, considerable proportion is recycled. Approximately 95% of the secreted surfactant is taken-up into type II pneumocytes by endocytosis from the alveolar lumen. SP-A helps in the reuptake of the surfactant. Internalized surfactant lipids are transported to LBs and secreted into the alveoli. Five percent of the surfactant secreted is degraded by alveolar macrophages.3,4,7
 
Regulation of Secretion
Regulation of secretion of the surfactant is by chemical and mechanical stimuli. A physiological stimulus for secretion of surfactant is direct mechanical stretching of alveolar type II cells during first breath. Stretching increases cytoplasmic calcium levels. Elevation of intracellular Ca triggers fusion of lamellar bodies to membrane, expansion of fusion pores and release of surfactant. Many agonists stimulate the secretion of the surfactant by stimulating protein kinases. These include protein kinase C (PKC), protein kinase A (PKA), and calcium/calmoduline dependent protein kinase (CaMK). Activation of PKC is the most potent stimulus. Simultaneous activation of different stimulus can lead to 12 to 15 fold increase in secretion of surfactant. Labor enhances both synthesis and secretion of surfactant. Maternal diseases that cause stress in the fetus will increase the catecholamine levels and increase the secretion of surfactant. This explains the low incidence of RDS in preterm intrauterine growth restricted neonates. Maternal diabetes and male gender are associated with decreased production of surfactant.7
 
SURFACTANT PROTEIN FUNCTIONS
Surfactant protein–A (SP-A): Surfactant protein A is most abundant protein of the surfactant system.16 It is primarily an innate host defense in airway and alveoli. It can bind to wide range of gram-positive and gram-negative organisms and it promotes phagocytosis by alveolar macrophages. It also increases the nitric oxide production in macrophages.4,12,13
Surfactant protein–B (SP-B): Surfactant protein B is most important surfactant protein required for the function of surfactant. It is essential for the tubular myelin formation and it also promotes the surface adsorption of the surfactant lipids over the alveoli. SP-B also helps in the processing and secretion of SP-C. Deficiency of 351this protein results in severe respiratory disease in newborn. Protein deficiency can be diagnosed by the presence of abnormal myelin formation and unprocessed SP-C.4,14-17
Surfactant protein–C (SP-C): Surfactant protein C is a hydrophobic protein secreted along with SP-B and surfactant lipids. SP-C promotes the film adsorption and increases the effectiveness of surfactant lipids. Lack of SP-C does not cause life threatening respiratory illness. They usually survive without apparent lung diseases. But there is increased incidence of interstitial lung disease later in life.4,16,17,19
Surfactant protein–D (SP-D): Surfactant protein D has similarities with SP-A. SP-D also binds to bacterial proteins and help in phagocytosis.4,17,18
 
EFFECTS OF SURFACTANT ON LUNG MECHANICS
In preterm lung deficient in surfactant, the opening pressure of alveoli is about 25 cm H2O. Some of the alveoli have an opening pressure more than 30 cm H2O, which is more than that required for the rupture of preterm lungs. The pressure required to open a lung unit depends upon the radius of the alveoli and surface tension of the meniscus of the fluid in the airway leading to that unit. Units with larger radius and lower surface tension open first. Surfactant treatment results in decrease in opening pressure. Subsequent inflation is more uniform as more units open at a lower pressure, which prevents overdistension of the already opened units. Surfactant increases the total lung volume and also stabilizes the deflating lung. Surfactant deficient lung collapses at low transpulmonary pressure; whereas surfactant treated lungs retain about 40% of the lung volume even on deflation to 5 cm H2O. There are also changes in dynamic lung mechanics after surfactant therapy. The time constant for deflation increases, resulting in less emptying of the lung. Thus, the functional residual capacity of surfactant treated lungs increases by two mechanisms, namely:
  1. Improved deflation stability, and
  2. Longer expiratory constant.3,20-26
 
TYPES OF SURFACTANT
Based on the source and components, surfactants are divided into two main groups. They are animal derived or natural surfactants and synthetic surfactants. Animal derived surfactants contain phospholipids and variable amounts of surfactant proteins SP-B and SP-C. Synthetic surfactants contain only surfactant lipids with no surfactant proteins. New generation synthetic surfactants contain PL and surfactant proteins (surfaxin and venticute). Surfaxin contains the KL4 peptide, which mimic SP-B and venticute contain recombinant form of SP-C. Table 23.1 gives the main characteristics of neonatal surfactants.21-24,27 352
Table 23.1   Main characteristics of surfactant used in neonates
Surfactant
Family
Main phospholipids
Proteins
PL
concentration
(mg/mL)
Dose
(mL/kg)
Exosurf
Synthetic
DPPC
No
13.5
5
Pumactant
Synthetic
DPPC, PG
No
40
1.2
Survanta
Animal derived
(bovine)
DPPC, PG
Some SP-B
and SP-C
25
4
Infrasurf
Animal derived
(bovine)
DPPC, PG
SP-B and SP-C
35
3
Curosurf
Animal derived
(porcine)
DPPC, PG
SP-B and SP-C
80
2.5
Alveofact
Animal derived
(bovine)
DPPC, PG
SP-B and SP-C
40
1.2
Surfaxin
Peptide containing
synthetic
DPPC, POPG
KL4
peptide
as SP-B
30
5.8
PL, phospholipids; DPPC, dipalmitoylphosphatidylcholine; PG, phosphatidylglycerol; POPG, palmitoyloleylphosphatidylglycerol; SP-B, surfactant protein-B; SP-C, surfactant protein-C.
 
SURFACTANT IN NEONATAL RESPIRATORY DISTRESS SYNDROME
After the initial studies by Avery and Mead many neonatologists tried using DPPC for RDS by various delivery methods including nebulized form and intravenous infusion, but were found to be ineffective. Fujiwara et al later found endotracheal instillation of exogenous bovine surfactant as an effective treatment for RDS. He found increase in PaO2 and decrease in oxygen supplementation few hours following administration of surfactant. Since, then surfactant therapy has been considered as the most effective therapy for RDS.2,30-34
 
Methods of Administration
Administration of surfactant differs according to the manufacturers. Transport of exogenous surfactant to distal airways consists of four different mechanisms:
  • The instilled surfactant may create a liquid plug that occludes the large airways but is forced to the peripheral airways by mechanical ventilation;
  • The bolus creates a deposited film on the airway walls, either from the liquid plug transport or from direct coating, which drains under the influence of gravity through the first few generations of airways;
  • In the smaller airways, surfactant forms a surface layer that spreads due to surface tension gradient, that is, Marangoni flows; and
  • The surfactant finally reaches the alveoli, where it is cleared according to first order kinetics. The pulmonary distribution of intratracheally instilled surfactant is determined by gravity. Changing the position of the chest did not 353have any influence on the distribution of surfactant. Thus, for most even distribution of surfactant in the two lungs, neonate should be kept in horizontal position.3,4,21,22,24,28,29
Survanta and curosurf are administered through a catheter inserted into the endotracheal tube. Exosurf should be administered through the side port adapter attached to the endotracheal tube. Slow infusion of exosurf using a microinfusion pump over a period of 10 to 20 minutes compared with the bolus administration showed slower infusion resulting in nonhomogenous distribution of surfactant. The side port administration and catheter administration seem to have similar outcome according to current studies.3,4,21,22,24,27
 
Pulmonary and Cardiac Effects of Surfactant Therapy
 
Immediate Pulmonary Effects
Administration of exogenous surfactant leads to rapid increase in oxygenation and decrease in ventilatory requirements. These changes are accompanied by increase in functional residual capacity, followed by a slow improvement in the lung compliance.21-23,35,36
 
Immediate Effects on Pulmonary Circulation
Some studies show that there is decrease in pulmonary artery pressure and increase in pulmonary blood flow.21-23,35,36
 
Radiological Changes
There is clearing of lung fields after the administration of the surfactant. Clearing can be uniform, patchy or asymmetrical.21-23 In a study done by Clark et al, 49% had no evidence of RDS after prophylactic surfactant, 30% had features of RDS, 14% had central clearing and 8% had disproportionate clearing.37 The most common X-ray finding is uniform clearing. Pulmonary interstitial emphysema had bad prognosis (Figs 23.1 and 23.2).38
 
Adverse Effects of Surfactant Therapy
Acute adverse effects immediately after the administration of surfactant include transient hypoxia and bradycardia due to obstruction of airways by the bolus dose of surfactant. Other adverse events include transient decrease in blood pressure, cerebral blood flow velocity, cerebral activity in electroencephalography and cerebral oxyhemoglobin concentration.
There is an increased incidence of pulmonary hemorrhage following surfactant therapy. The incidence was higher with natural surfactant (5–6%) than synthetic surfactant (1–3%).
Immune complex and antibodies were concerns when surfactant was initially used. However, immune complexes were noted both in neonates treated with surfactant and controls. The presence of immune complexes in controls may be the result of leakage of surfactant proteins through the damaged lungs. 354
Fig. 23.1: Chest radiograph showing bilateral white-out lung before surfactant instillation in RDS
Fig. 23.2: Clearing of lung after surfactant therapy in RDS
Organic solvent processing of phospholipids, terminal sterilization technique and screening of the animal sources have decreased the risk of transmission of infectious agents.21-23 355
 
CLINICAL TRIALS OF SURFACTANT THERAPY IN RESPIRATORY DISTRESS SYNDROME
 
Natural Surfactant Versus Synthetic Surfactant
Natural and synthetic surfactants have been used in the treatment of respiratory distress syndrome (RDS) and both are found to be effective in the treatment of RDS. Many trials have been conducted comparing the effectiveness of natural with synthetic surfactant. In a systematic review, it was found that risk of pneumothorax and deaths is less in neonates receiving natural surfactant. None of the natural surfactant has been shown to decrease the incidence of bronchopulmonary dysplasia compared with synthetic surfactant. Most of the studies compared natural surfactant with synthetic surfactant without proteins. A study by Sinha and collegues comparing surfaxin (synthetic surfactant with protein) with curosurf suggested that new generation synthetic surfactant seems to have some advantages over the older synthetic surfactant and are atleast as good as currently used animal derived surfactant.5,23,27,33,39
 
Comparison of Different Natural Surfactant
Cumulative analysis of comparison of survanta with infrasurf did not show any advantage favoring either surfactant in reducing mortality and oxygen requirement at 36 weeks of corrected gestation. There was fewer incidence of pneumothorax, faster reduction in oxygen supplementation and ventilatory support with infrasurf compared to survanta.
Comparison of curosurf with survanta showed significant survival advantage with higher dose of curosurf. There were no differences in incidence of pneumothorax and oxygen requirement at 36 weeks. Curosurf treated patient had rapid reduction of oxygen supplementation.27,40
 
Prophylactic Versus Rescue Therapy
Incidence of pneumothorax, pulmonary emphysema and neonatal mortality was less with prophylactic surfactant. These benefits should be weighed against the fact that the prophylactic use results in the treatment of many neonates who do not require treatment.27,33,41,42
 
Repeated dosing of Surfactant
Repeated administration of surfactant was associated with decreased the incidence of pneumothorax and decreased mortality.27,33,42
 
EXPANDED USE OF SURFACTANT
There are many evidences that surfactant may be useful in many other lung disorders. The respiratory disorders that are potentially benefited from surfactant therapy include the following43:
  • Meconium aspiration syndrome
  • Neonatal pneumonia356
  • Congenital diaphragmatic hernia
  • Pulmonary hemorrhage
  • Acute lung injury
  • Acute respiratory distress syndrome.
 
Meconium Aspiration Syndrome
Perinatal meconium aspiration causes severe respiratory distress in newborns. Meconium in lungs inactivates pulmonary surfactant. Fatty acids of meconium interfere with the monolayer formation of surfactant. Meconium also decreases SP-A and SP-C and decreases large aggregates of phospholipids. Surfactant is inhibited by meconium in a dose dependent pattern. Several studies have shown improved lung function with surfactant administration in meconium aspiration syndrome. In contrast to RDS, MAS require more than one dose of surfactant for the improvement in oxygenation. This is for ongoing inactivation of surfactant. Removal of meconium and inflammatory cells by bronchoalveolar lavage with animal-derived surfactant may be helpful in decreasing the ongoing inactivation. There was more rapid improvement in oxygenation and shorter duration of mechanical ventilation following lavage. Polymer-surfactant combination has been used to increase the resistance to inhibition by meconium. Polymixin B and other polymers, such as dextran, hyaluronan and polyethanol were used as the polymer. It was found that improved oxygenation and compliance with surfactant-polymer combination than surfactant alone.33,44-47
 
Neonatal Bacterial Pneumonia
Neonatal pneumonia and sepsis can cause impairment in surfactant function by several mechanisms. Inactivation of surfactant can occur with plasma derived proteins and blood products inside alveolar spaces, induction of bacterial secretion of phospholipases and injury to alveolar type II cells. Surfactant deficiency further worsens the infections, because SP-A and SP-D act as lung defenses against infections. SP-A and SP-D are collectin group of protein which bind to bacterial endotoxins and promote the phagocytosis of the organisms. Both proteins modulate the cytokine release by macrophages and neutrophils. Herting et al found that infants treated with surfactant had increased oxygenation after one hour of treatment. But currently there is no sufficient evidence to suggest that surfactant improves the long-term outcome of septic newborn.33,44,45,48
 
Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and pulmonary hypertension. Animal studies have shown improvement in lung function and oxygenation following surfactant administration. Many studies in humans have shown no improvement of lung function with surfactant. There is only limited experience of surfactant usage in CDH.33,44,45,49,50357
 
Pulmonary Hemorrhage
Pulmonary hemorrhage is one of the complications of surfactant therapy and is more common in patients with RDS and MAS. Hemoglobin and plasma protein are potent inhibitors of surfactant. This process is reversed by increasing the surfactant/inhibitor ratio by giving exogenous surfactant. Administration of exogenous surfactant in isolated pulmonary hemorrhage has shown to improve the oxygen index and lung compliance. Improvements were immediate and long lasting. Further investigation is required for regular use of surfactant in pulmonary hemorrhage.44,45,51,52
 
Acute Lung Injury and Acute Respiratory Distress Syndrome
Acute lung injury and acute respiratory distress syndrome (ARDS) is an overwhelming disease of inflammatory reaction of lung leading to severe pulmonary dysfunction. Endogenous surfactant system dysfunction occurs in multiple ways in ARDS. There is decrease in surfactant pool size because of acute severe injury of lung leading to injury of type II pneumocytes. There is also alteration in the composition of surfactant. There is a decreased level of saturated phosphatidylcholine and phosphatidylglycerol and increase in phosphatidyl inositol, spingomyelin and lysophosphatidylcholine. Decreased levels of SP-A and SP-B were also demonstrated. Further there is excessive inactivation of surfactant in ARDS. Exogenous surfactant administration seems to be promising treatment of ARDS. Many studies have shown rapid improvement in oxygenation and ventilatory supports after the administration of exogenous surfactant. There is also significant decrease in mortality in patients who received surfactant therapy.44,45,53-58
Surfactant has also been tried in conditions like brochiolitis, respiratory syncytial virus pneumonia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, lung transplantation, cystic fibrosis and otitis media.44
 
CONCLUSION
It is around 25 years after the introduction of exogenous surfactant therapy, but still many researches are being done in its therapy. Surfactant remains a hallmark treatment of RDS in preterm neonates and is now being investigated for other pediatric lung diseases. Further research is required for alternative route of administration of surfactant to avoid mechanical ventilation. Also further studies are required for the use of surfactant in other lung diseases.
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Pharmacotherapy of Respiratory Infections24

Novy Gupte
 
INTRODUCTION
Pharmacotherapy plays an important role in the management of respiratory infections, both acute and chronic.1 However, it is equally important to exercise due caution in the rational use of drugs, particularly antimicrobials in the wake of increasing antimicrobial resistance-a real challenge if we aim at controlling the infections in a concerted and effective manner.1,2
All this amply justifies renewed research endeavors aimd at development of higher antibiotics. Else, the medical profession may be left with no armamentarium to fight the microbial infections. In other words, we may have to revert back to the pre-antibiotic era with extremely high morbidity and mortality from infectious diseases. Understandably, the World Health Day theme for 7th April 2011: Antimicrobial Resistance Today, No Cure Tomorrow! was very timed.
 
ANTIBIOTICS1-7
 
Aminoglycosides
Aminoglycosides are of value in the treatment of gram-negative infections, including nosocomial infections. Usually, these are employed in combination with other antibiotics to enhance the coverage for gram-negative pathogens in serious infections such as bronchopneumonia in neonates and infants.
Aminoglycosides are potentially nephrotoxic and ototoxicity and may cause neuromuscular block.
 
Amikacin
Brand name: Amicin (Biochem), Mikicin (Aristo)
First semisynthetic aminoglycoside; derivative of kanamycin A; effective against gram-positive as well as gram-negative organisms—just like tobramycin.
Indications: Pneumonias caused by gram-negative pathogens (Extra-respiratory indications: Fulminant gram-negative infections (septicemia, pneumonia, meningitis, peritonitis, infected burns, postoperative sepsis), and gram-positive 362infections resistant to other aminoglycosides, e.g. nosocomial infections as in burns, in ICU, and in immunocompromised subjects).
Available as: Injections 100, 250, 500 mg/vial.
Dose: 15 to 25 mg/kg/day divided q 8 to 12 h.
ADRs: Nephrotoxicity, ototoxicity (mainly cochlear), neuromuscular blockade, hypersensitivity reactions like drug fever, rash, eosinophilia, tremors, nausea, vomiting, headache, overgrowth of nonsusceptible microorganisms.
Contraindications: Known hypersensitivity to aminoglycosides.
Precaution: Suitable reduction in dose must be made in renal insufficiency depending on creatinine clearance and BUN.
 
Gentamicin
Brand name: Garamycin (Fulford), Genticyn (Nicholas-Piramal).
An aminoglycoside; binds to 30s subunit of bacterial ribosome; induces translation misreading, freezing of initiation complex.
Indications: Pneumonias caused by gram-negative pathogens (Extra-respiratory indications: Life-threatening fulminant gram-negative infections, e.g. septicemia, meningitis, UTI).
Available as: Injection 40, 80 mg/mL.
Dose: 3 to 5 mg/kg/day (IV, IM) in first week of life and up to 7.5 mg/kg/day later in 2 to 3 divided doses in life-threatening situations. 0.8 to 1.2 mg/kg/day (IV, IM) in 2 to 3 divided doses for urinary tract infections.
ADRs: Nephrotoxic, hepatoxic, ototoxic, fever, rash, convulsions, joint pains, hypotension, purpura, anemia, granulocytopenia.
Drug interactions: Frusemide, ethacrynic acid, vitamin K, nephro- and ototoxic drugs, cephalosporins, penicillins, anesthetics, neuromuscular blocking agents. indomethacin.
Contraindications: Myasthenia gravis, previous toxic reaction in the form of nephro- or ototoxicity.
Precaution: Reduce frequency in renal impairment.
 
Kanamycin
Brand name: Kancin (Alembic)
Indications: Pneumonias and other severe respiratory infections caused by gram-negative pathogens resistant to safer aminoglycosides; a reserve drug for resistant tuberculosis (Extra-respiratory indications: Neonatal septicemia, urogenital, CNS, soft tissue and GIT infections due to Staphylococcus).
363Available as: Injection 0.5 and 1.0 g vials.
Dose: 10 to 15 mg/kg/day (IM) in 2 divided doses.
ADRs: Nephrotoxic, ototoxic, rash, fever, headache, paresthesia.
Drug interaction: Frusemide, ethacrynic acid, neuromuscular blocking agents, anesthetics.
Contraindications: Pregnancy, lactation.
Precaution: Myasthenia gravis, parkinsonism; monitor in renal impairment.
 
Netilmicin
Brand name: Netromycin (Fulford).
Available as: Ampoules: 10, 25, 50, 100 mg/mL Vials: 50, 200, 300 mg/vial, respectively.
Indications: Pneumonias and other severe respiratory infections caused by gram-negative pathogens (Extra-respiratory indications: Infections caused by gram negative bacilli (E. coli, Pseudomonas, Klebsiella); employed usually in combination with one of the penicillins or cephalosporins but not through the same syringe or infusion).
Dose: 5 to 7.5 mg/kg/day (IM, IV) q 8 hr. In infants, up to 10 mg/kg/day may be given.
ADRs: Nephrotoxicity (renal tubular dysfunction with loss of sodium, calcium and magnesium), ototoxicity, neuromuscular blockade with pancuronium.
Drug interactions: Frusemide, ethacrynic acid, cephalosporins, citrated blood, neuromuscular blocking drugs, anesthetics.
Contraindications: Renal insufficiency, pregnancy, lactation
Precaution: Myasthenia gravis, parkinsonism, dehydration, infant botulism, hypocalcemia; requires monitoring.
 
Streptomycin Sulfate
Brand name: Ambistryn-S (Sarabhai Piramal)
Indications: Tuberculosis; occasionally, pathogens susceptible to this drug only.
Available as: Injection 1 g vial. Syrup 0.28 g/teaspoonful. Tablet 0.2 g.
Dose: 20 to 50 mg/kg/day (IM).
1 to 2 mg/kg/day (IT),
100 mg/kg/day (O) in divided doses.
ADRs: Deafness, renal damage, allergic reactions, eosinophilia, fever, rash, CNS depression, blood dyscrasia.
364Drug interaction: Frusemide, ethacrynic acid, mannitol, other aminoglycosides, polymyxin B, colistin sulfate, cyclosporine, neuromuscular blocking drugs, anesthetics.
Contraindications: Disease of ear, especially suppurative otitis media (SOM), labyrinthitis.
Precautions: Impaired liver or kidney function, prematurity, impaired vestibular and auditory functions, pregnancy, lactation, myasthenia gravis.
 
Tobramycin Sulfate
Brand name: Tobraneg (Elder)
An aminoglycoside closely related to gentamicin, including antimicrobial spectrum except that it is 2 to 3 times more active in vitro against Pseudomonas aeruginosa.
Available as: Injection 20, 60, 80 mg vials
Ophthalmic solution/ointment
Indications: Fulminant gram-positive and gram-negative infections under aerobic conditions, including Pseudomonas aeruginosa in which this is the amiglycoside of choice.
Dose: Neonates under 7 days—4 mg/kg/day in 2 doses.
Neonates above 7 days—6 mg/kg/day in 3 doses.
ADRs: Anemia, granulocytopenia, thrombocytopenia, fever, rash, utricaria, gastrointestinal upset, headache, lethargy liver dysfunction.
Drug interactions: Likely to potentiate other nephrotoxic and ototoxic drugs.
Contraindications: Known allergy to aminoglycosides, pregnancy, lactation.
Precaution: Avoid its administration in conjunction with heparin, penicillin and cephalosporins; control blood levels and dosage in renal impairment.
 
β-Lactams
These antibiotics share the β-lactam ring structure, i.e. penicillins, cephalosporins, cerbacephems and carbapenemes. They work by inhibiting cell wall synthesis by the bacterial pathogens.
Bacteria often develop resistance to β-lactam antibiotics by synthesizing β- lactamase, an enzyme that attacks the β-lactam ring. To overcome this resistance, β-lactam antibiotics are often given with β-lactamase inhibitors (BLIs) such as clavulanic acid, sulbactam or tozabactam.20 Whereas clavulinic acid is a natural product, the other two are semisynthetic. Their own antibacterial effect is marginal. However, when administered in combination with a β-lactam drug (say, ampicillin, amoxycillin or cephalosporin), they exert a wide-spectrum of activity. Calculation of the dose needs to be based on the antibiotic rather than the total antibiotic- β-lactam complex.365
ADRs in the form of hypersensitivity are common to all members of the β- lactam group of antibiotics.
 
β-lactams Group 1: Penicillins
Penicillins is a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they were the first effective medicines against many previously serious diseases such as syphilis and Staphylococcus infections.
 
PENICILLINASE-SENSITIVE PENICILLINS
 
Procaine Penicillin
Indications: Moderately severe infections with gram-positive organisms.
Available as: Injection 4 lakh units/vial.
Dose: Under 4 years 2 lakh (IM) daily or twice a day.
Over 4 years 4 lakh (IM) daily or twice a day.
ADRs: β-lactam safety profile (rash, eosinophilia), allergy hypersensitive reactions in the form of rash, fever, bronchospasm, vasculitis, serum sickness, Stevens-Johnson syndrome and anaphylaxis. The clinical picture of anaphylaxis consists of sudden hypotension, bronchospasm with asthma, skin eruptions, diarrhea, nausea and vomiting.
 
Benzyl (Crystalline) Penicillin
Indications: Severe infection with gram-positive organisms.
Dose: 50 thousands to 4 lakh units/kg/day (IM, IV) in 4 divided doses. Higher limit is for severe infections like pyogenic meningitis or septicemia. For bacterial endocarditis, as much as 100,00,000 units/day.
ADRs: Beta-lactam safety profile (rash, eosinophilia), allergy. Hypersensitive reactions in the form of rash, fever, bronchospasm, vasculitis, serum sickness, Stevens-Johnson syndrome and anaphylaxis. The clinical picture of anaphylaxis consists of sudden hypotension, bronchospasm with asthma, skin eruptions, diarrhea, nausea and vomiting. Excessive dose may cause seizures.
 
Benzathine Penicillin
Brand name: Penidure 12 and 24 (Wyeth).
Indications: Rheumatic fever prophylaxis, syphilis, streptococcal infections, pyodrma, post-traumatic tetanus.
Available as: Vials 12 lakh (1.2 mega ) units.
366Dose: > 27 kg weight 1.2 mega units every 3 weeks.
< 27 kg weight 6 lakh units every 3 weeks.
ADRs: Beta-lactam safety profile (rash, eosinophilia), allergy.
Hypersensitive reactions in the form of rash, fever, bronchospasm, vasculitis, serum sickness, Stevens-Johnson syndrome and anaphylaxis. The clinical picture of anaphylaxis consists of sudden hypotension, bronchospasm with asthma, skin eruptions, diarrhea, nausea and vomiting.
Remarks: Pendidure LA-6 which was available earlier stands withdrawn now.
 
Oral Penicillin
Brand name: Pentids (Sarabhai Piramal)
This is an acid-resistant penicillin administred orally.
Indications: Mild to moderate gram-positive infections; also some gram-negative (N. gonorrhoeae, N. meningitidis) infections.
Available as: Tablets 2, 4, 8 lakh units.
Dose: 50 thousand units/kg/day in divided doses.
ADRs: β-lactam safety profile (rash, eosinophilia), allergy. Hypersensitive reactions in the form of rash, fever, bronchospasm, vasculitis, serum sickness, Stevens-Johnson syndrome and anaphylaxis. The clinical picture of anaphylaxis consists of sudden hypotension, bronchospasm with asthma, skin eruptions, diarrhea, nausea and vomiting. Seizures with overdose.
 
PENICILLINASE-RESISTANT (SEMISYNTHETIC) PENICILLINS
The noteworthy feature of these semisynthetic penicillins is the side chains that protect the β-lactam ring from the on slaught of enzyme, penicillinase. These are the drug of choice for penicillinase-producing Staphylococcus aureus, provided that the pathogens are not methicillin-resistant. The most important member of this class is cloxacillin. Others, say oxacillin, nefcillin, dicloxacillin, flucloxacillin, etc. are not marketd in India.
 
Cloxacillin
Brand name: Bioclox (Biochem)
Indications: Staphylococcal infections
Available as: Capsules 250, 500 mg.
Suspension 125 mg/measure.
Injection 250, 500 mg/vial.
Dose: 50 to 200 mg/kg/day (O, IV) in 4 divided doses. The higher limit is in case of staphylococcal meningitis.
367ADRs: GIT upset, rash, rise in SGOT, superadded infections with gram-negative bacteria and fungi.
Contraindications: Hypersensitivity to penicillins, asthma, hay fever, urticaria.
Precaution: Oral administration 1 hour before or 2 hours after food.
 
BROAD-SPECTRUM (MODIFIED OR AMINO) PENICILLINS
 
Amoxycillin
Brand name: Novamox (Cipla), Flemoxicin (East India), Wymox (Wyeth).
Indications: Respiratory infections caused by pneumococci, streptococci, H. influenzae, E. coli, gonorrhea. (Extra-respiratory indications: Genitourinary, gastrointestinal, soft tissue, ENT infections).
Available as: Capsule 250, 500 mg, Tablet 125, 250 mg. Syrup 125, 250 mg/teaspoonful. Drops 100 mg/mL.
Dose: 20 to 50 mg/kg/day, divided q 8 to 12 h.
ADRs: Diarrhea, vomiting, maculopapular rash, urticaria, rise in SGOT.
Drug interaction: Probenecid.
 
Amoxycillin-Clavulanate
Brand name: Augmentin (GSK), Acuclav (Macleods).
Indications: Beta-lactam (amoxycillin) beta-lactamase inhibitor (clavulanate or clavulanic acid as potassium salt) for boosting amoxycillin activity against penicillinase producing bacteria such as S. aureus, Streptococcus pneumoniae, H. influenzae, M. catarrhalis, E. coli, Klebsiella, B. fragilis.
Available as: Tablets 375 mg (amoxycillin 250 mg, clavulanate 125 mg); 625 mg (amoxycillin 500 mg, clavulanate 125 mg); 1000 mg (amoxycillin 875 mg, clavulanate 125 mg).
Syrup amoxycillin 200 mg, clavulanate 28.5 mg/teaspoonful.
Injection (IV) 300 mg (amoxycillin 250 mg, clavulanate 50 mg); 600 mg (amoxycillin 500 mg, clavulanate 100 mg); 1.2 g (amoxycillin 1000 mg, clavulanate 200 mg).
Dose: 20 to 45 mg/kg/day (O) divided q 8 to 12 h.
In AOM, give higher dose 80 to 90 mg/kg/day.
30 mg/kg (IV) every 8 hours; may give 6 hours in more serious infections. (Calculations are based on amoxycillin).
ADRs: Diarrhea, vomiting, maculopapular rash, urticaria, rise in SGOT.
Drug interaction: Probenecid.
368Contraindication: Hypersensitivity.
Precaution: Reduce dose and frequency in renal impairment.
 
Ampicillin
Brand name: Roscillin (Ranbaxy), Campicillin (Cadila Pharma), Synthocilin (PCI).
Indications: Respiratory infections (Extra-respiratory indications: Genitourinary, gastrointestinal, soft tissue, ENT, etc. infections due to gram-negative as well as gram-positive organisms).
Available as: Tablet 125, 250 mg. Capsule 250 mg, 500 mg.
Syrup 125, 250 mg/teaspoonful. Injection (IM, IV, IT) 250, 500 mg.
Dose: 50 to 400 mg/kg/day in 4 divided doses, the upper limit being the recommendation for very severe infections such as pyogenic meningitis and septicemia.
ADRs: Hypersensitivity reactions, rash, GIT upset, convulsions, eosinophilia, superadded infection with Pseudomonas and Candida due to change in the normal flora of the GIT, mild hepatic dysfunction, agranulocytosis.
Contraindications: Hyprsensitivity.
Drug interactions: Probenecid, anticoagulants, allopurinol, urine glucose determinations.
Precaution: Monitor blood, liver and kidney function when therapy exceeds 10 days. Avoid in infectious mononucleosis, renal impairment and lymphatic leukemia.
 
Ampicillin-Sulbactam
Combination of a beta lactam, ampicillin, and a beta-lactamase inhibitor, sulbactam.
Brand name: Sulbacin (Unichem).
Indications: Beta-lactam (ampicillin) + beta-lactamase inhibitor (sulbactam) for boosting ampicillin activity against penicillinase-producing bacteria such as S. aureus, S. pneumoniae, H. influenzae, M. catarrhalis, E. coli, Klebsiella, B. fragilis.
Available as: Injection: Ampicillin 1g, sulbactam 500 mg/vial.
Dose: 100 to 200 mg/kg/day (IM, IV) divided q 4 to 8 h.
Calculations are based on ampicillin component.
ADRs: Diarrhea, especially pseudomembranous colitis, C. difficile-associated diarrhea (CDAD), skin, rash, hypersensitivity.
Contraindication: Hypersensitivity.
Drug interaction: Probenecid.369
 
EXTENDED-SPECTRUM PENICILLINS
 
Piperacillin
Brand name: Zosyn (Wyeth)
Indications: Many gram-positive and gram-negative infections, including infections caused by E. coli, Enterobacter, Serratia, Pseudomonas, Bacteroides.
Available as: Injection (IV, IM) 1, 2, 4 g. Also in combination with beta-lactamase inhibitor, tazobactam.
Dose: Generally, 50 to 300 mg/kg/day (IV, IM) in 3 to 4 divided doses (upper limit for serious infections).
Neonate < 7 days 150 mg/kg/day (IV) q 8 to 12 hr
  • 7 days 200 mg/kg/day q 6 to 8 hr
    Infants and children 200 to 300 mg q 4 to 6 hr
    Cystic fibrosis 350 to 500 mg/kg/day (IV)
ADRs: Beta-lactam safety profile (rash, eosinophilia, transient rise in liver enzymes).
Drug interaction: Probenecid.
Precaution: Renal excretion; inactivated by penicillinase.
 
Ticarcillin
Brand name: Ticar (Wolters Kluwer).
Indications: Severe infections caused by E. coli, Enterobacter, Serratia, Pseudomonas, Bacteroides.
Available as: Injection 3.1 g.
Dose: Neonates < 7 days/>2000g 150 mg/kg/day (IV) q 8 to 12 hr (2–3 divided doses)
  • 7 days/> 20000 g 225 mg/kg/day (IV) q 8 hr
  • 7 days/< 1200 g 150 mg/kg/day (IV)
  • 7 days 1200 to 2000 g 225 mg/kg/day (IV) q 8 hr
Infants and children 200 to 400 mg/kg/day (IV) q 4 to 6 hr
Cystic fibrosis 400 to 600 mg/kg/day (IV).
ADRs: β-lactam safety profile (rash, eosinophilia)
Drug Interaction: Probenecid.
Precaution: Renal excretion; inactivated by penicillinase. Monitor LFT.
 
Ticarcillin with Clavulanic Acid
Brand name: Timentin (GSK).
370Indications: Severe infections caused by E. coli, Enterobacter, Serratia, Pseudomonas, Bacteroides, Acinetobacter, and H. influenzae, especially in subjects with impaired/suppressed host defenses.
Available as: Injection 3.1 g (ticarcillin 3 g, clavulanic acid 100 mg).
Dose: To be calculated with respect to ticarcillin. Neonates < 7 days/>2000 g 150 mg/kg/day (IV) q 8 to 12 hr (2–3 divided doses)
  • 7 days/> 20000 g 225 mg/kg/day (IV) q 8 hr
  • 7 days/< 1200 g 150 mg/kg/day (IV)
  • 7 days 1200 to 2000 g 225 mg/kg/day (IV) q 8 hr
Infants and children 200 to 400 mg/kg/day (IV) q 4 to 6 hr
Cystic fibrosis 400 to 600 mg/kg/day (IV).
ADRs: Hypersensitivity reactions, GI disturbances, pseudomembranous colitis, S. difficile-associated diarrhea (CDAD), bleeding diathesis, hypokalemia, hypernatremia, CNS, hepatic and renal disturbances, superinfections.
Contraindications: Hypersensitivity, moderate or severe renal dysfunction, pregnancy, lactation.
Drug interaction: Probenecid, methotrexate, oral contraceptives, may causefalse positive Coomb's test.
Precaution: Renal excretion; inactivated by penicillinase. Monitor LFT.
 
ANTIPSEUDOMONAS (CARBOXY AND UREIDO) PENICILLINS
 
Carbenicillin
Brand name: Carbelin
Indications: Pseudomonas and indole-positive Proteus infections.
Available as: Injection 1 g vial.
Dose: Neonates: < 7 days and 2000 g 225 mg/kg/day (IM, IV) in 3 divided doses. > 2000 g 300 mg/kg/day (IM, IV) in 4 divided doses. > 7 days 300 to 400 mg/kg/day (IM, IV) in 4 divided doses.
Children: 400 to 600 mg/kg/day (IM, IV) in 4 to 6 divided doses, the higher range being for Pseudomonas infections.
ADRs: These are generally on the same lines as in case of injectable penicillin. Others include local pain, local phlebitis, abnormalities of coagulation leading to bleeding, hypokalemia.
Contraindication: Known penicillin allergy.
Precaution: The vials should be stored in a cool dry place below 5°C temperature. Do not mix in the same syringe with gentamicin to prevent inactivation of the latter.371
 
Piperacillin
Brand name: Zosyn (Wyeth).
It is far more (around 8 times) active than carbencillin in its pseudomonal potency.
For details, see under “Extended Spectrum Penicillins”.
372
 
Ticarcillin
Brand name: Ticar (Wolters Kluwer)
Its psedomonal activity is greater than carbencillin.
For details, see under “Extended Spectrum Penicillins”.
 
β-Lactams Group 2: Cephalosporins
Cephalosporins, are the most widely used antibiotics at present, have a structure similar to that of penicillins, except that its beta-lactam ring is a 6-member ring whereas penicillin has a 5-member ring structure. They are relatively resistant to beta-lactamase produced by the pathogens.
Cephalosporins are divided into 5 generations. Higher the generation, greater the activity against gram-negative pathogens with simultaneous fall in activity against gram-positive pathogens.
 
Cefaclor
Brand name: Keflor (Ranbaxy)
A semisynthetic broadspectrum second generation cephalosporin; bactericidal.
Indications: Particularly useful in beta-lactamase producing organisms like H. influenzae and B. catarrhalis causing upper and lower respiratory infections.
  • Otitis media caused by S. pneumoniae, H. influenzae, B. catarrhalis, S. pyogenes, S. aureus.
  • URI, including pharyngitis and tonsillitis, caused by S. pyogenes. Other ENT infections like rhinosinusitis, acute laryngitis, epiglottitis, otitis externa caused by S. pneumoniae, S. aureus and S. pyogenes.
  • LRI caused by S. pneumoniae, H. influenzae, B. catarrhalis, S. aureus, gram-negative bacilli like E. coli, Klebsiella and Proteus.
Extra-respiratory indications: Skin infections caused by S. aureus and S. Pyogenes, UTI caused by E. coli, Proteus mirabilis, Klebsiella sp, S. aureus, gonococcal urethritis).373
Available as: Capsules 250 mg.
Suspension 125 g/teaspoonful, drops 100 mg/mL
Dose: 20 to 40 mg/kg/day (maximum 1 g) in 3 divided doses.
ADRs: Infrequent and minor.
Hypersensitivity reaction: Morbiliform eruptions, pruritus, urticaria, serum sickness-like reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis.
CNS: Reversible hyperactivity nervousness, insomnia, confusion, hypertonia, dizziness, somnolence.
GIT: Nausea, vomiting and diarrhea, pseudomembranous colitis, transient hepatitis.
Kidneys: Reversible interstitial nephritis.
Hemopoietic: Transient lymphocytosis, leukopenia, neutropenia, thrombocytopenia, eosinophilia.
Renal: Raised BUN and serum creatinine.
Liver: Raised SGOT, SGPT and alkaline phosphatase.
Drug interaction: Probenicid.
Contraindication: Known allergy to cephalosporins.
Precaution: Avoid in preterm infants and infants < 1 month of age, and in penicillin allergy.
 
Cefadroxil
Brand name: Lydroxil (Hetero), Odoxil (Lupin).
First generation ceophalosporin active against Staphylococcus aureus, Streptococcus, E. coli. Klebsiella and Proteus.
Indications: Majority of gram-positive and gram-negative, penicillin-sensitive as well as penicillin-resistant pathogens: URI, including tonsillitis and pharyngitis (Extra-respiratory indications: UTI, skin infections).
Available as: Dry syrup 125, 250 mg/teaspoonful. Tablets/Capsules 250, 500, 1000 mg.
Dose: 30 mg/kg/day in 2 divided doses.
ADRs: Nausea, vomiting, diarrhea, dysuria, pseudomonas colitis, hypersensitivity reactions, allergies, genital pruritis/moniliasis, vaginitis, moderate neutropenia (transient).
Drug interactions: Probenicid, false positive Coomb's test or Clintest.
Contraindications: Known allergy to cephalosporins/penicillin group of antibiotics.
Precautions: Exercise restraint in penicillin-allergic subjects. Observe for ideosyncracy. Use caution in renal impairment; modify dose according to creatinine clearance.374
 
Cefazolin
Brand name: Azolin (Biochem).
First generation cephalosporin active against Staphylococcus aureus, Streptococcus, E. coli, Klebsiella and Proteus, not effective in Pseudomonas.
Indications: Most serious gram-positive and negative infections, including penicillin-resistant ones, but excluding Pseudomonas.
Dose: 25 to 100 mg/kg/day (IM, IV) in 2 to 4 divided doses.
ADRs: Hypersensitivity reactions like drug fever, rash, pruritis, eosinophilia, and rarely, anaphylaxis and brochospasm, vomiting, anorexia, hepatotoxicity with transient rise in SGOT, SGPT and alkaline phosphatase, nephrotoxicity (transient rise in BUN), pain over injection site, thrombophlobitis, oral thrush.
Drug interactions: Loop diuretics, probenicid, aminoglycosides.
Contraindication: Known hypersensitivity to cephalosporin.
Precaution: Reduce dose in impaired renal function. In mild, moderate and severe impairment, the dose should be 60 and 10% of the usual dose. Only one dose may be given.
Avoid in premature infants under 1 month.
 
Cefdinir
Brand name: Sefdin (Unichem)
Extended-spectrum semisynthetic cephalosporin
Indications: Community-acquired pneumonia (CAP), acute exacerbation of chronic bronchitis, acute bacterial sinusitis (Extra-respiratory indications: Uncomplicated skin infections).
Available as: Capsules 300 mg
Suspension 125 mg/5 mL
Dose: 14 mg/kg/day (maximum 600 mg/day) in one or two daily doses.
ADRs: Nausea, diarrhea, including Cl difficile-assiociated diarrhea (CDAD) or constipation, indigestion, anorexia, headache, abdominal pain, superinfection, pseudomembranous colitis, dizziness, drowsiness, weakness, rash, serum sickness-like reactions, anaphylaxis.
Drug interaction: Probenicid, antacids, iron supplements.
Contraindication: Hypersensitivity to cephalosporins.
Precaution: Avoid under 6 months of age.
Reduce dosage in renal insufficiency, i.e when creatinine clearance < 60 mL/min.
Administer at least 2 hr apart consumption of antacids and iron-containing products which are known to remarkably cut down its absorption. 375
 
Cefepime
Brand name: Ceficad (Cadila Pharma).
Extended-spectrum fourth generation cephalosporin active against several gram-positive as well as gram-negative bacteria; even several multidrug resistant (MRD) pathogens may be responsive to it.
Indications: Most serious gram-positive and negative infections, including MRD states.
Available as: Injection.
Dose: 100 to 150 mg/kg/day (IV, IM) in 2 to 3 divided doses.
ADRs: Nausea, diarrhea, superadded vaginal candidiasis, injection site reactions, pseudomembranous colitis, headache, fever, rash encephalopathy.
Drug interaction: Probenicid, nephrotoxic agents (aminoglycosides, potent diuretics).
Precautions: Beta-lactam safety profile (rash, eosinophilia).
Monitor renal parameters since it is renally eliminated.
 
Cefixime
Brand name: Cefinar (Zydus-Alidac)
Third generation cephalosporin active against most bacteria (including Salmonella typhi), except Staphylococcus and Pseudomonas. CNS penetration inadequate.
Available as: Tablets 50, 100, 200 mg
Suspension 50 mg/teaspoonful.
Indications: Most bacteria (including Salmonella typhi), except Staphylococcus and Pseudomonas.
Dose: Usually, 8 mg/kg/day in 2 divided doses. In enteric fever, double the dose is required.
ADRs: GIT upset. Also, see Box 24.1.
Drug interaction: Probenicid.
Contraindication: Known cephalosporin allergy.
Precaution: Avoid in CNS infections and known penicillin allergy.
 
Cefoperazone
Brand name: Magnamycin (Pfizer)
Third generation cephalosporin effective against gram-positive and gram-negative bacteria, including pseudomonas (weak antipseudomonal activity).
Indications: Serious gram-positive and gram-negative bacterial infections, inclu-ding Pseudomonas.
376Available as: Injection 250 mg, 500 mg, 1 g, 2 g.
Dose: 100 to 150 mg/kg/day (IM, IV) divided q 8 to 12 h.
ADR: Gastrointestinal upset, rash, urticaria, fever, reversible neutropenia.
Drug interaction: Disulfiram-like reaction with alcohol.
Precaution: Avoid in severe biliary obstruction, hepatic disease and coexisting renal dysfunction.
 
Cefoperazone-Sulbactam
Brand name: Magnex (Pfizer)
A combination of the third generation cephalosporin (cefoperazone) and the potent beta-lactamase inhibitor (sulbactam) in 1:1 ratio.
Indications: Most serious infections caused by gram-positive, gram-negative and anaerobic organisms.
Available as: Injection 1 g, 2 g vial (half cefoperazone and half sulbactam).
Dose: 50 to 80 mg/kg/day with reference to cefoperazone (IM, IV) in 2 to 4 divided doses. The neonates should receive the lower limit of dose in 2 divided doses.
ADRs: Gastrointestinal upset, rash, urticaria, fever, reversible neutropenia, transient abnormality of liver function tests.
Contraindication: Known hypersensitivity to cephalosporins.
Drug interactions: Disulfiram-like reaction with alcohol.
Caution: Avoid in significant biliary obstruction, hepatic dysfunction and renal dysfunction.
 
Cefotaxime
Brand name: Claforan (Aventis) Omnatax (Nicholas-Piramal)
A third generation cophalosporin, resistant to beta-Lactamase.
Indications: Fulminant and life-threatening infections (gram-positive and negative, anaerobes), especially where inactivation by beta-lactamases is suspected.
Available as: Injection 250 mg, 1 g vial.
Dose: 50 to 200 mg/kg/day (IM, IV) in 2 to 4 divided doses. In preterm infants, do not exceed 50 mg/kg/day.
ADRs: Hypersensitivity reactions like anaphylaxis, bronchospasm, urticaria, rash, fever, and eosinophilia, adenopathy, pseudomembranous colitis.
Contraindications: Allergy to penicillin.
Precaution: Never dissolve the drug in soda bicarbonate solution.
Do not store above 25°C.
In renal impairment (creatinine clearance less than 5), reduce dose by half.377
 
Cefpodoxine Proxetil
Brand name: Cepodem (Stancare)
Third generation cephalosporin active against most bacterial infections, except Pseudomonas.
Available as: Tablets 100, 200 mg
Suspension 50, 100 mg/teaspoonful.
Indications: Most bacterial infections, except Pseudomonas.
Dose: 10 mg/kg/day in 2 divided doses.
ADRs: See Box 24.2.
Contraindications: Known cephalosporin allergy.
Drug interaction: Probenicid; antacids and H-2 receptor antagonists are likely to cut down its absorption.
Precaution: Avoid in CNS infections and known penicillin allergy.
 
Cefprozil
Brand name: Refzil-O (Ranbaxy).
Second generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, M. catarrhalis, Klebsiella and Proteus. No effect of food on bioavailability.
Indications: Susceptible bacterial infections (vide infra).
Available as: Tablets 250, 500 mg
Suspension 125 mg, 250 mg/teaspoonful.
Dose: 30 mg/kg/day in 2 to 3 divided doses.
ADRs: See Box 24.1.
Caution: Beta-lactam safety profile (rash, eosinophilia).
Monitor renal parameters.
 
Ceftazidime
Brand name: Fortum (GSK).
Indications: Serious gram-negative hospital infections and most gram-positive infections, including Pseudomonas.
Available as: Injection 250, 500, 1000 mg/vial.
Dose: Under 2 months 25 to 60 mg/kg/day (IM, IV) in 2 divided doses.
Above 2 months 30 to 100 mg/kg/day (IM, IV) in 2 to 3 divided doses.
ADRs: Pain over injection site, phlebitis/thrombophlebitis, rash, fever, pruritus, anaphylaxis, thrombocytopenia, slight increase in hepatic enzymes.
378Contraindications: Known hypersensitivity to cephalosporins.
Precaution: Impaired renal failure, when GFR is below 50 mL/min, reduce dose.
 
Ceftibuten
Brand name: Procadex (Ranbaxy).
Indications: A third generation cephalosporin indicated in a wide range of infections except group B. Streptococcus (GBS), Staphylococcus, Enterococcus, Listeria spp. Bacteroide spp. and Clostridium spp; (Extra-respiratory indication: Effective in enteric fever).
Available as: Dry powder 90 mg/teaspoonful.
Caps 400 mg.
Dose: 9 mg/kg once a day.
ADRs: Gastrointestinal disturbances, rash, headache, dizziness, blood dyscrasias, enzyme abnormalities, colitis, seizures.
Contraindications: Known allergy to cephalosporins.
Precaution: Avoid in infants under 6 months, penicillin hypersensitivity, renal impairment and gastrointestinal disease.
 
Ceftriaxone
Brand name: Monocef (Aristo)
A third generation cephalosporin.
Indications: Life-threatening gram-positive and negative infections, including penicillin-resistant Staphylococcus and many strains of Pseudomonas aeruginosa, and some anaerobic bacteria.
Available as: Injection 250, 500, 1000 mg/vial.
Dose: 20 to 80 mg/kg/day (IM, IV) in 1 or 2 doses.
ADRs: Pain, induration and tenderness at the injection site, thrombophlebitis at IV site, pruritus, fever chills, eosinophilia, thrombocytosis, leukopenia, anemia, neutropenia, lymphopenia, thrombocytopenia, diarrhea, nausea, vomiting, alkaline phosphatase bilirubin SGOT and SGPT rise, BUN rise, creatinine elev, casts in urine, headache, dizziness, moniliasis, vaginitis pseudomembranous colitis.
Contraindication: Known allergy to cephalosporins.
Precautions: Give cautiously to subjects with known penicillin allergy.
Do not mix with other antimicrobial agents.
Give cautiously in subjects with GI dis.379
 
Cefuroxime
Brand name: Supacef (GSK)
Second generation cephalosporin, resistant to gram-negative beta-lactamase.
Indications: Life-threatening gram-positive and gram-negative infections, including penicillin-resistant Staphylococcus aureus strains.
Available as: Injection 250, 750 mg/vial.
Dose: 15 to 150 mg/kg/day (IM, IV) in 2 or 3 divided doses.
ADRs: Rash, gastrointestinal upset, anemia, eosinophilia, transient rise in serum bilirubin in liver disease, pain at IM injection site.
Contraindication: Known allergy to cephalosporins.
Precaution: Take special care in subjects with known anaphylaxis to penicillin, or when the drug is needed to be given in higher doses in conjunction with frusemide or some other potent diuretic.
 
Cefuroxime Axetil
Brand name: Altacef (Glenmasrk), Ceftum (Glaxo)
An oral prodrug of Cefuroxime (see above).
Indications: Useful in a wide range of gram-positive and gram-negative infections, including beta-lactamase producing organisms.
Available as: Captabs 125, 250, 500 mg
Suspension 125 mg/5 mL
Dose: 25 to 50 mg/kg/day in 2 divided doses.
ADRs: See Cefuroxime.
Contraindications: See Cefuroxime.
Precaution: See Cefuroxime.
 
Cephalexin
Brand name: Sporidex (Ranbaxy), Sepexin (Hetero).
First generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella and Proteus.
Indications: Respiratory infections (Extra-respiratory indications: genitourinary, skin and soft tissue, ENT infections, osteomyelities, septicemia, bacterial endocarditis).
Available as: Caps 250, 500 mg. Dry syrup 125 mg/teaspoonful.
Dose: 50 to 100 mg/kg/day in 2 to 4 divided doses.
ADRs: Nausea, vomiting, diarrhea, allergic skin reactions, eosinophilia, positive Coombs’ test, overgrowth of nonsusceptible organisms.
380Drug interaction: Probenicid.
Precaution: Beta-lactam safety profile (rash, eosinophilia).
 
Ceftobiprole Medocaril
It is an injectable anti-MRSA cephalosporin antibiotic in development. It acts by destroying the bacterial cell wall. This new cephalosporin is in phase III clinical trial for complicated skin and soft tissue infections as well as nosocomial pneumonia caused by resistant strains of MRSA, enterococci, and Streptococcus pneumoniae, especially ventilator-associated pneumonia (VAP).
 
Group 3: β-Lactams: Non-penicillin, Non-cehalosporin β-lactams
Monobactams are β-lactams with only one ring. Their spectrum resembles that of aminoglycosides. The protype is aztreonam.
Carbapenems are characterized by a high resistance to hydrolysis of β-lactamases and possess a broad spectrum of antibacterial activity. In most cases they are considered to be preparations of reserve. The drugs in this group are imipenem-cilastatin and meropenem.
 
Aztreonam
Brandname: Azenam (Aristo)
Indications: Gram-negative infections of lower respiratory tract, including pulmonary infectionsin cystic fibrosis; (Extra-respiratory indications: septicemia, meningitis caused by H. influenzae type b (Hib) and N. meningitidis, pylonephritis, cystitis, asymptomatic bacteriuria, gonorrhea adjunct to surgery in management of infections).
Available as: Injection 500 mg, 1 g, 2 g vial.
Dose: 30 to 50 mg/kg/dose (IM, IV) every 6 to 8 hours.
ADRs: Vomiting, diarrhea, skin rash, injection site reactions, pseudomembranous colitis (PMC), C. difficile-associated diarrhea (CDAD), superinfection, blood dyscrasias, elevation in liver enzymes (aminotransferases), serum creatinine.
Drug interactions: Frusemide, probenicid, aminoglycosides, cefoxitin, imipenem.
Contraindications: Pregnancy, lactation.
Precautions: Monitor renal and hepatic function, particularly in high-dose or prolonged therapy.
Special remarks: In view of absence of crossreactivity with by and large all other β-lactams (ceftazidine may well be excluded), it can be employed in subjects with allergy to penicillins or cephalosporins. 381
 
Imipenem-Cilastatin
Brand name: Cilanem-500 (Ranbaxy)
Indications: A broadspectrum beta-lactam antimicrobial for aerobic as well as anaerobic extended-spectrum beta-lactamase-producing (ESBL) bacterial infections (both gram-positive and gram-negative).
Available as: Injection 500 mg each of imipenem and cilastatin.
Dose: 15 mg/kg/dose (IV infusion) every 6 hourly with a maximum of 2 g/day.
ADRs: Local and allergic reactions, phlebitis, GI upset, rash, fever, blood dyscrasias, hepatic dysfunction, renal dysfunction, CNS disturbances, hearing loss, seizures, confusion, dizziness, somnolence, hypotension, perverted taste, superinfections, pseudomembranous colitis, Cl difficile-associated diarrhea (CDAD).
Drug interaction: Probenicid, valproic acid, ganciclovis, divalproex sodium, estrogen contraceptives.
Contraindications: < 3 months, lactation.
Precautions: Penicillin, cephalosporin or other allergy, colitis, concomitant use with valproic acid, CNS disorders, renal impairment, meningitis, brain abscess, granulocytopenia, prolonged use, pregnancy.
 
Moropenom
Brand name: Meronem (Astra-Zeneca), Meroza (Zydus Alidac).
An ultra-broadspectrum parenteral antibiotic of the carbapenem group.
Indications: Anerobic, aerobic and faculitative gram-positive and gram-negative microorganisms, e.g. pneumonia (Extra-respiratory indications: septicemia, bacterial meningitis, febrile neutropenia; skin and soft tissue, gastrointestinal and urinary tract and other intra-abdominal infections; cystic fibrosis with superimposed bacterial infections).
Available as: Injection 500 mg, 1 g.
Dose: Complicated skin infections: 10 mg/kg/dose IV every 8 hourly.
Sepsis and intra-abdominal infections: 20 mg/kg/dose IV every 8 hourly
Bacterial meningitis: 40 mg/kg/dose IV every 8 hourly.
ADRs: Injection site inflammation, pain; nausea, vomiting, diarrhea/constipation, rash, headache; rarely, neuropathy; hepatic and renal dysfunction; thrombocytosis/thrombocytopenia, anemia, eosinophilia; Cl. Difficile-associated diarrhea (CDAD).
Contraindications; Known hypersensitivity.
Drug interactions: Probenecid, valporic acid; nephrotoxic agents.
Precautions: Lactating mothers, hepatic/renal impairment; seizure disorder, pretreatment skin test in penicillin-allergic children. Monitor hepatic, renal and hemopietic function during long-term use.382
 
MACROLIDES
Macrolides are antibiotics with a complex cyclic structure. They exert bacteriostatic action.
Macrolides are indicated for the treatment of gram-positive cocci and intracellular pathogens (mycoplasma, chlamydias). They are considered to be less toxic antibiotics.
 
Azithromycin
Brand name: Aziwok (Wockhardt), Azithral (Alembic)
A macrolide with very long half life, thereby imparting it the uniqueness of once daily dosing.
Indications: Respiratory infections with Staphylococcus aureus, Streptococcus, H. influenzae. (Extra-respiratory indications: Staphylococcus aureus, Streptococcus, H. influenzae. V. cholera, Compylobacter, Mycoplasma, Legionella; Salmonella typhi, Chlamydia trachomtis elsewhere; nontuberculous mycobacterium disease {especially M. avium complex (MAC)} in combination with other antibiotics).
Available as: Tablets 200, 500 mg
Suspension 100, 200 mg/teaspoonful
Dose: Routine -10 mg/kg as a single dose on first day followed by 5 mg/kg OD for next 4 days or
10 mg/kg/day OD for only 3 days
30 mg/kg as single dose therapy
In case of Group A Streptococcus (GAS) pharyngitis: 12 mg/kg/day OD for 5 days
In case of cholera, 20 mg/kg as a single dose once only.
In case of enteric fever, 20 mg/kg/day for 1 to 2 weeks.
In nontuberculous mycobacterial (NTM) infection such as MAC, 5 mg/kg/day. The duration of therapy is not yet clearly specified. But it has got to be a prolonged therapy, usually 1 year. More experience is needed in this respect.
ADRs: Mild GIT upset, reversible rise in liver enzymes, allergic reactions, pseudomembranous colitis, photosensitivity and other dermatosis, exacerbation of myasthenia gravis.
Drug interaction: Antacids, digoxin, carbamazepine, phenytoin, theophylline, fluconazole, cyclosporin, anticoagulants.
Precaution: Renal and hepatic dysfunction.
 
Clarithromycin
Brand name: Claribid (Pfizer).
Indications: A macrolide antibiotic indicated in treatment of upper and lower respiratory infections (mild to moderate) (Extra-respiratory indications: skin 383infections due to susceptible bacteria, say H. influenzae, M. catarrhalis, M. pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, C. trachomatis, Legionella spp; nontuberculous mycobacteria).
Available as: Tablets 250, 500 mg. Suspension 75 mg/5 mL.
Dose: 15 mg/kg/day in 2 divided doses.
In nontuberculous mycobacterial (NTM) infection such as MAC, 7.5 mg/kg/day. The duration of therapy is not yet clearly specified. But it has got to be a prolonged therapy, usually 1 year. More experience is needed in this respect.
ADRs: Gastrointestinal upset, allergic reactions.
Drug interactions: Theophylline, digoxin, rifampicin, carbamazepine, phenobarbital, phenytoin, midazolam, sdium valproate, oral anticoagulants, cisapride, primozole, ergot derivatives, drugs metabolized by P450, statins, warfarin, colchicines, quinidine, cyclosporin, bromocriptine, zidovudine.
Contraindications: Hepatic dysfunction, hypersensitivity to clarithromycin, erythromycin, azithromycin or clarithromycin.
Precautions: Renal/hepatic impairment, arrhythmias, QT interval prolongation, pregnancy, lactation.
 
Erythromycin
Brand name: Ersafe (USV), Erythrocin (Pfizer), Eltocin (Ipca).
A bacteriostatic antimicrobial most active against gram-positive pathogens, Cornybacterium diphtheria and Mycoplasma pneumoniae.
Indications: Respiratory infections, especially pharyngitis, tonsillitis, sinusitis, pneumonia; M. Pneumoniae (Extra-respiratory indications: soft tissue and wound infections; pertussis; diphtheria carriers. Also employed for promoting GI motility and feeding intolerance in preterms; cholera, comylobater jejuni infection)
Available as: Tablets 100, 250 mg. Suspension 100 mg/teaspoonful.
Dose: 30 to 50 mg/kg/day (O) in divided doses.
ADRs: GIT upset, abdominal pain, hypersensitivity reactions, eosinophilia, hepatic dysfunction.
Drug interaction: Antacids (containing Mg, Ca, Al); Carbamazepine, theophylline, digoxin, oral anticoagulants, terfenidin, cyclosporine, tacrolimus, astemizole (same as in case of erythromycin, operates by antagonizing hepatic CYP450, 344 activity.
Contraindications: Impaired liver function; concomitant cisapride, pimozide, pophyria.
Precaution: Renal impairment; cholestatic jaundice: immediate the drug must be discontinued. 384
 
Roxithromycin
Brand name: Roxid (Alembic).
Indications: Respiratory infections, especially pharyngitis, tonsillitis, sinusitis, pneumonia; M. Pneumoniae.
Available as: Tablets 50, 150 mg.
Syrup 50 mg/5 mL.
Dose: 5 mg/kg/day (O) q 12 hr.
ADRs: Nausea, vomiting, diarrhea, pseudomembranous colitis, superinfection, rash, transient rise in liver transaminase.
Drug interactions: Theophylline, digoxin, warfarin, ergot alkaloids, midazolam, cyclosporin, disopyramide.
Contraindications: Severe liver dysfunctions, ergotamine-like agents.
Precaution: Renal or hepatic insufficiency, pregnancy, lactation.
 
Telithromycin (Ketek)
A structural derivative of macrolide erythromycin, it is the first ketolide antibiotic to enter clinical use.
It is a ketolide antibiotic which blocks bacterial protein synthesis. It is uniquely designed to combat DRSP. Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Moraxella catarrhalis are susceptible to telithromycin. It also is active against some of the atypical respiratory pathogens such as Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. However, it does not cover MRSA, GRE, or any enteric gram-negative bacteria.
Indications: It is indicated for treating upper and lower respiratory infections, such as acute sinusitis, chronic bronchitis, and community-acquired pneumonia.
Available as: Tablets 300, 400 mg.
Dose: 10 to 15 mg/kg with a maximum of 800 mg per day administered in 2 divided doses for 5 days for chronic bronchitis or sinusitis. For community-acquired pneumonia, same dose should be administered daily for 7 to 10 days.
Dosage of telithromycin has not been established for patients with severe renal impairment.
ADRs: Diarrhea, nausea, vomiting, headache, dizziness, and persistent unpleasant taste. Antibiotic-associated pseudomembranous colitis (PMC) due to clostridium overgrowth in the bowel, and prolongation of QT interval, transient vision disturbances.
Contraindications: Myasthenia gravis, liver and renal dysfunction, QTc prolongation.
385Drug interaction: Phenobarbital, phenytoin, carbamazepine may cause subtherapeutic levels of telithromycin. Digitalis, theophylline, metaprolol and oral contraceptive levels may also be affected by telithromycin.
Precautions: Because telithromycin is metabolized mainly by the liver, dosage adjustment may be necessary in patients with liver impairment. Special attention is needed when ketoconazole, itraconazole, anti-lipidemic statins, midazolam, and cisapride are administered concomitantly with telithromycin because these drugs have direct hepatic effects.
 
LINOCOSAMIDES
Lincosamides include natural and semi-synthetic antibiotics that possess a narrow spectrum of action. They are used to treat infections caused by gram-positive cocci, both aerobes and anaerobes.
 
Lincomycin HCl
Brand name: Lynx (Wallace).
Indications: Serious infections due to susceptible strains of streptococci, pneumococci and staphylococci.
Available as: Capsules 250, 500 mg.
Syrup 125 mg/5 mL
Injection 300 mg/mL.
Dose: 30 to 60 mg/kg/day (O) in 3 divided doses.
10 to 20 mg/kg/day (IM, IV) in 2 or 3 divided doses. IV dose need to administered as 10 mg/ml solution over a span of 1 to 4 hours.
ADRs: Vomiting, persistent diarrhea, altered taste or smell, overgrowth of yeast, urticaria, superadded infection, abdominal pain, muscle pain, pruritus, hepatotoxicity. C. difficile-associated diarrhea/colitis (CDAD).
Drug interactions: Neuromuscular blocking drugs.
Contraindications: Hypersensitivity to lincomycin or clindamycin.
Precautions: Asthma, allergy, gastrointestinal disease.
 
Clindamycin
Brand name: Dalacin injection (Pfizer), Dalcap (Unichem).
A semisynthetic derivative of lincomycin, effective in serious staphylococcal infections involving bones and joints, peritonitis, endocarditis prophylaxis.
Indications: Gram-positive aerobes and anaerobes; serious infections caused by MRSA; invasive GAS infections in combination with a beta-lactam; anaerobic infections. (Extra-respiratory indications: acne (topical preparation).386
Available as: Injection 150 mg/mL
Capsules 75, 150, 300 mg
Suspension 75 mg/5 mL
Topical
Dose: Under 7 days and weight under 2000 g to 10 mg/kg/day in 3 divided doses.
Under 7 days and over 2000 g to 15 mg/kg/day in 3 divided doses.
Children 20 to 45 mg/kg/day in 3 to 4 divided doses.
ADRs: Nausea, diarrhea, C. difficile-associated diarrhea (CDAD), pseudomembranous colitis (infrequent in children but common in adults), rash, liver dysfunction, neutropenia, eosinophilia, agranulocytosis, thrombocytopenia, abscess at injection site.
Drug interaction: Neuromuscular-blocking agents.
Contraindications: Diarrheal state.
Precautions: Renal or hepatic dysfunction. Discontinue therapy in case of development of persistent diarrhea or colitis. Administer slowly IV over 30 to 60 min.
 
QUINOLONES AND FLUOROQUINOLONES
Approved for clinical use since the beginning of 1980s, they are characterized by a broad spectrum of antibacterial action (including staphylococci), bactericidal activity and good pharmacokinetic characteristics. Nalidixic acid is a quinolone whereas others are fluroquinolones.
 
Ciproflaxacin
Brand name: Cifran (Ranbaxy), Ciplox (Cipla), Ciprobid Zydus-Alidac)
A high-performance quinolone active against Pseudomonas aeruginosa, Serratia, Enterobacter, Shigella, Salmonella, Compylobacter, Neisseria gonorrhoeae, H. influenzae, M. catarrhalis, Staphylococcus aureus (selected) and Streptococcus.
Indications: Infections of respiratory tract (Extra-respiratory indications: Infections of the urinary tract, gastrointestinal tract, respiratory tract, bones and joints, skin; serious life-threatening infections, e.g. septicemia, resistant enteric fever; hospital-acquired infections; prevention of sepsis in immunocompromised hosts).
Available as: Tablets 250, 500 mg.
Injections 1,2 mg/mL.
Dose: 15 to 30 mg/kg/day (O) in 2 divided doses, 5 to 10 mg/kg/day (IV) in 2 divided doses.
ADRs: Tendonitis, gastrointestinal intolerance (nausea, vomiting, diarrhea), anorexia, abdominal pain, flatulence, pseudomembranous colitis; dizziness, 387headache, insomnia, confusion, agitation, tremors, ataxia, seizures, hallucinations, visual disturbances, migraine, deafness; rash, pruritus, drug fever, anaphylaxis, Stevens-Johnson syndrome, photosensitivity, eosinophilia; hepatitis, raised SGOT, SGPT, alkaline phosphatase, serum bilirubin; crystalluria, nephritis, transient renal failure, raised blood urea, creatine, crystalluria, hematuria, anemia, thrombocytopenia, thrombocytosis; thrombophlebitis, superinfections.
The joint destruction (encountered in juvenile animals) is not seen in humans.
Drug interactions: Antacids (containing Mg, Ca, Al), Carbamazepine, theophylline, digoxin, oral anticoagulants, terfenidin, cyclosporine, tacrolimus, astemizole (same as in case of erythromycin; operates by antagonizing hepatic CYP activity.
Contraindications: Hypersensitivity to quinolones; children and growing adolescents, except when benefits overweigh risk, tendon disorders, concurrent use of tizanidine.
Precautions: Avoid the drug 1 to 2 hours before and 4 hour after the antacids.
Avoid with theophylline and nonsteroidal anti-inflammatory drugs (NSAIDs).
Avoid in epileptics.
Monitor drug dose in case of renal disease, creatinine clearance under 30 mL/min.
 
Ofloxacin
Brand name: Tarivid (Aventis)
A new fluorinated quinolone.
Indications: Infections of lower respiratory tract (Extra-respiratory indications: Genitourinary tract, gastrointestinal tract, skin and soft tissue; peritonitis, gonorrhea).
Available as: Tablets 200, 400 mg.
Dose: 4 to 16 mg/kg/day as a single dose or in 2 divided doses.
ADRs: Anorexia, epigastric pain, nausea, vomiting, diarrhea; transient rise of SGOT, SGPT, serum creatinine, bilirubin; anemia, thrombocytopenia, leukopenia, agranulocytosis.
Drug interactions: Antacids (magnesium and aluminium), iron, sucralfate, NSAIDs, theophylline, warfarin, insulin, oral hypoglycemic, drugs metabolized by CYP450, probenicuid, cimetidine, furosemide, methotrexate, anticoagulants, steroids, Phenobarbital, anesthetics, hypotensive drugs.
Contraindications: Hypersensitivity to quinolones; epilepsy. Hypersensitivity reactions; vasculitis, edema face, glottis or tongue, dyspnea, shock; sleeplessness, headache, hallucination, visual disturbances, smell and taste disturbances, psychotic reactions.
Precaution: Avoid in children below 12 years except in desperate situations.388
 
Pefloxacin
Brand name: Pefbid (Alembic), Pelox (Wockhardt).
Indications: Severe infections in adolescents caused by sensitive gram-negative bacteria and staphylococci.
Available as: Tablets 400 mg
IV infusion: 400 mg/100 mL.
Dose: 12 mg/kg/day (O) q 12 hr or IV infusion.
ADRs: Epigastric discomfort, nausea, vomiting, tendinitis (even rupture of tendon), muscular pains, articular pains, headache, vigilance disorders, thrombocytopenia.
Drug interaction: Antacids; enhances risk of theophylline toxicity; chloride solutions.
Contraindications: Allergy to quinolones.
Precaution: Avoid in respiratory infections, exposure to ultraviolet light.
 
Sparfloxacin
Brand name: Sparx (Wockhardt)
Indications: Gram-positive and gram-negative pathogens
Available as: Tablets 100, 200 mg
Dose: 4 mg/kg/day (O) OD or 2 divided doses
ADRs: Nausea, diarrhea, heartburn, anorexia, rash, tendinitis/ruture, eosinophilia, thrombocytopenia, fall in hemoglobin, WBC and RBC.
Drug interactions: Erythromycin, phenothizines, digoxin, tricyclic antidepressants, etc.
Contraindications: Hypersensitivity, G-6-PD deficiency, pregnancy, lactation.
Precautions: Avoid sunlight exposure; avoid in hypokalemia, hypomagnesemia, seizure disorder, arrhythmias.
 
Levofloxacin
Brand name: Levoflox (Cipla), Leeflox (Centaur), Lomflox (Ipca).
A levo isomerof ofloxacin.
Indications: Gram-positive and gram-negative infections; MDR-TB.
Available as: Tablets 250, 500 mg
Injection 500 mg/100 ml IV infusion.
Dose: 10 to 15 mg/kg OD or in 2 divided doses.
389ADRs: Nausea, diarrhea, dizziness, headache, photosensitivity, peripheral neuropathy (paresthesia, hypoesthesia, dysesthesia, weakness), rupture of tendons.
Drug interactions: Antacids, sucralfate, probenecid.
Contraindications: < 8 years, hypersensitivity, lactation, pregnancy.
Precaution: Avoid in children < 8 years, severe renal impairment; avoid exposure to sunlight; discontinue in case of hypersensitivity, photosensitivity, neuropathy.
 
TETRACYCLINES
Tetracyclines, the bacteriostatic antibiotics, have broadspectrum of activity against both gram-positive and gram-negative bacteria, rickettsia as also some parasites. These drugs exhibit their antimicrobial effect by binding to the bacteria l305 ribosomal subunit, thereby inhibiting protein translation.
Generally speaking, tetracyclines should be avoided in children <8 years in view of the risk of dental staining, enamel hypoplasia and abnormal bone growth.
 
Oxytetracycline
Brand name: Terramycin (Pfizer).
Indications: Respiratory tract infections (Extra-respiratory indications: systemic infections (genitourinary, ENT, venereal, soft tissue, etc.). brucellosis, Chlamydia, Mycoplasma, Rickettsia; acne vulgaria).
Available as: Capsules 250 mg.
Injection 50 mg/mL
Dose: 25 to 50 mg/kg/day (O) in 4 divided doses.
15 to 25 mg/kg/day (IM) in 2 divided doses.
10 to 15 mg/kg/day (IV) in 2 divided doses.
ADRs: Dental discoloration and enamel hypoplasia, retardation of bone growth rate, especially in fibula, photosensitivity, GI upset, pseudotumor cerebri, allergic reactions, superinfections; rarely hepatotoxicity and blood dyscrasias.
Drug interactions: Antacids, milk, mineral supplements, oral contraceptives.
Contraindications: Children <8 years, hypersensitivity, renal impairment, pregnancy, lactation.
Precautions: Hepatic impairment, myasthenia gravis, SLE, porphyria.
 
Tetracycline Hydrochloride
Brand name: Hostacycline (Aventis), Resteclin (Srabhai Piramal).
Brand name: Biodoxi (Biochem).
390Indications: Respiratrory tract infections (Extra-respiratory indications: Systemic infections in relation to genitourinary, ENT, venereal, soft tissue, etc. brucellosis, Chlamydia, Mycoplasma, Rickettsia; acne vulgaris).
Available as: Tablets/capsules 100 mg. Suspension 25 and 50 mg/teaspoonful.
Dose: 5 mg/kg/day (O) on divided doses on first day. Then 2.5 mg/kg/day once daily.
ADRs: Dental discoloration and enamel hypoplasia, retardation of bone growth rate, especially in fibula, photosensitivity, GI upset, pseudotumor cerebri, allergic reactions, superinfections, Cl difficuile-associated diarrhea (CDAD; rarely hepatotoxicity and blood dyscrasias.
Drug interactions: Antacids, milk, mineral supplements, oral contraceptives.
Contraindications: Children <8 years, hypersensitivity, renal impairment, pregnancy, lactation.
Precautions: Hepatic impairment, myasthenia gravis, SLE, porphyria; avoid exposure to sunlight/UV rays.
 
Minocyclin
Brand name: Cynomycin (Wyeth).
Indications: Exacerbation of chronic bronchitis (Extra-respiratory indications: brucellosis meningococcal carrier state, Chlamydia, Mycoplasma and Rickettsia, pleural effusion secondary to cirrhosis or malignancy; acne vulgaris).
Available as: Capsules 50, 100 mg.
Dose: Initially 4 mg/kg (O) followed by 4 mg/kg/day in 2 divided doses.
ADRs: Hypersensitivity reactions, GI upset, vestibular disorders, impaired hearing, pseudotumor cerebri, superinfections, rise in BUN, blood dyscrasias, autoimmune hepatitis, buccal mucosal discoloration, Cl difficuile-associated diarrhea (CDAD); rarely pericarditis, myocarditis, vasculitis, hepatotoxicity, renal failure, pancreatitis, interstitial nephritis, SLE, hyperpigmentation.
Drug interactions: Antacids, mineral supplements, penicillins, ergot alkaloids, digoxin, urinary alkalinizers, methoxyflurane, oral anticoagulants.
Contraindications: Children < 8 years, lactation, pregnancy, renal failure.
Precaution: Renal impairment: Monitor serum creatine and blood urea levels.
Hepatic impairment: Monitor for hepatitis, SLE or unusual pigmentation every 3 months in long-term therapy. Continue therapy for 2 days after symptomatic control. 391
 
GLYCOPEPTIDE ANTIBIOTICS
Available for clinical use since 1960s, glycopeptides are used in the treatment of nosocomial infections caused by gram-positive microorganisms as also for the treatment of MRSA, MRSE, and enterococcal infections.These drugs are bactericidal, acting by inhibition of cell wall biosynthesized. Their antibacterial activity is limited to gram-positive pathogens, including S. aureus, coagulase-negative staphylococci, Pneumococcus, Enterococcus, Bacillus and Cornybacterium.
First generation glycopeptides antibiotics are vancomycin and teicoplanin. Second generation glycolpeptide antibiotics are dalbavancin (dabtomycin) and oritavancin.
 
Vancomycin
Brand name: Vancocin (Astra-Zeneca).
First generation complex glycoprotein antibiotic, the glycopeptide inhibiting synthesis of cell wall in gram-positive bacteria.
Available as: Injection 500 mg vial.
Dose: Severe infections
Children 45 to 60 mg/kg/day in 2 to 3 divided doses (IV slow)
Adolescents 0.5 g 6 hourly or 1 g 12 hourly (IV slow)
Neonates < 1200 g < 7 days—15 mg/kg/day
OD (Slow IV)
> 1200 g < 7 days—30 mg/kg/day in 2 divided
doses (IV slow)
< 1200 g > 7 days—15 mg/kg/day OD (IV slow)
> 1200 g > 7 days—30 to 45 mg/kg/day in
2 to 3 divided doses.
ADRs: Anaphylactoid reaction, flushing, nephrotoxicity, ototoxicity, neutropenia, nausea, chills, pyrexia, rash, eosinophilia, phlebitis. Rapid infusion may lead to sudden, profound fall in blood pressure, flushing, and itching (the so-called “red man syndrome”).
Drug interaction: Neurotoxic and nephrotoxic agents and anesthetics.
Contraindication: Renal and auditory diseases.
Precautions: Avoid combining with aminoglycoside since the combination is likely to boost the nephrotoxicity of each drug. Reduce dose in renal insufficiency. Monitor blood levels.
 
Teicoplanin
Brand name: Targocid (Sanofi-Aventis)
A newer first generation glycopeptide antibiotic.
392Indications: Resistant gram-positive bactria only; more effective than vancomycin against enterococci (enterococcal endocarditis) and equally active against MRSA. It may be effective in some VRSA.
Available as: Injection 200, 400 mg/vial for reconstitution.
Dose: Children ≥ 2 months severe infection or neutropenic: 10 mg/kg IV 12 hourly for 1st 3 doses then 10 mg/kg daily IV/IM. Moderate infection: 10 mg/kg 12 hourly IV for 1st 3 doses then 6 mg/kg daily IV/IM.
Neonate Single loading dose: 16 mg/kg. Maintenance: 8 mg/kg IV infusion over 30 mins daily.
ADRS: Gastrointestinal upset in the form of nausea, vomiting and diarrhea, anaphylaxis, rashes, uticaria, fever, granulocytopenia; rarely hearing loss and histamine—release reactions.
Drug interactions: Nephrotoxic drugs like aminoglycosides, frusemide, cyclosporine, amphotericin B.
Contraindications: Hypersensitivity, Pregnancy, lactation.
Precautions: Renal insufficiency; concurrent administration with drug having oto- and nephrotoxicity.
 
OXAZOLIDINONE ANTIBIOTICS
Oxazolidinones are up-to-date group of antibiotics. They are primarily used in the therapy in the therapy of infections caused by multiresistant gram-positive cocci.
 
Linezolid
Brand name: Linox (Unichem)
This is the first commercially available oxazolidinone antibiotic. It is usually reserved for the treatment of serious gram-positive bacterial infections where older antibiotics have failed due to antibiotic resistance, i.e. methicillin or penicillin resistance. It is very expensive. It was approved by Food and Drug Association (FDA) for clinical use in 2000. Repeated studies have shown that linezolid is superior to vancomycin in treating multiresistant Staphylococcus aureus (MRSA) infections. Linezolid has out-performed glycopeptides in both HA-MRSA and CA-MRSA infections. However, reports of resistance and treatment failures have appeared.
Its mechanism of action is unique in as much as that it is the first synthesized antibiotic that acts by inhibiting the initiation of bacterial protein synthesis.
Antibacterial spectrum, in addition to MRSA, includes other gram-positive pathogens like E. faecium, S. agalactiae, S. pyogenes and Streptococcus pneumoniae. It is only bacteroistatic against most enterococcus species. Against gram-negative pathogens, it is ineffective.
393Indications: MRSA, VRE, coagulase-negative staphylococci, penicillin-resistant pneumococci. It is recommended for pneumonia (both community acquired and nosocomial) caused by drug-resistant Streptococcus pneumoniae (DRSP).
Others: surgical site infections, complicated skin and soft tissue infections, and diabetic foot infections; septicemia, osteomyelitis, endocarditis.
Availability: Tablet 400, 600 mg
Oral suspension powder (after reconstitution 100 mg/5 mL)
Injection in an inactive medium for intravenous injection, 200 mg/100 mL, 400 mg/200 mL, 600 mg/300 mL.
Dose: 10 mg/kg (O, IV) q 12 hr for 10 to 14 days. IV administration should be through infusion over a period of 30 to 120 minutes.
ADRs: Rash, anorexia, diarrhea, nausea, constipation, headache, and fever. Occasionally, severe allergic reaction, or tinnitis, or pseudomembranous colitis (PMC), lactic acidosis; anemia, thrombocytopenia and myelosuppression may occur.
Drug interaction: Probenicid.
Contraindications: Known hypersensitivity to linezolid, concurrent administration with phenelzine, isocarboxazid; lactation.
Precaution: Its administration with pseudoephedrine and foodstuffs containg tyramine should be avoided since it is a monoamine oxidase inhibitor (MAOI).
 
Dalfopristin-Quinupristin
Brand name: Synercid (Rhône-Poulenc Rorer)
This dual drug is a prototype of the group Streptogramins which is highly useful for esistant gram-positive infections. Quinupristin and dalfopristin are both streptogramin antibiotics, derived from pristinamycin. Quinupristin is derived from pristinamycin IA and dalfopristin from pristinamycin IIA. They are combined in a weight-to-weight ratio of 30% quinupristin to 70% dalfopristin.
Indications: MRSA, coagulase-negative Staphylococcus, penicillin-susceptible and penicillin-resistant Pneumococcus, vancomycin-resistant E. faecium ( not E. faecalis).
Available as: IV Injection 150 mg quinupristin and 350 mg dalfopristin.
Dose: VRE 7.5 mg/kg q 8 hr IV, preferably through central catheter to prevent venous irritation and phlebitis.
Skin infections 7.5 mg/kg q 12 hr IV.
ADRs: Local pain, edema, phlebitis, nausea, diarrhea, arthralgia, myalgia.
Contraindications: Known hypersensitivity to the two components or to other streptogramins (e.g. pristinamycin or virginiamycin).
394Drug interactions: A potent inhibitor of cytochrome P450 (CYP3A4), thereby enhancing the effects of terfenadine, astemizole, indinavir, midazolam, Ca channel blockers, warfarin, cisapride and cyclosporin.
Precautions: Use in children > 12 years, preferably >16 years for which it stands approved. Avoid in CNS infections for which it is not yet approved.
 
SULFONAMIDES
 
Sulfamethoxazole with Trimethoprim
Brand name: Septran (GSK), Bactrim (Piramal Health).
Indications: Respiratory infections (Extra-respiratory indications: GIT, urinary tract, ENT, skin/soft tissue infections; typhoid and paratyphoid fevers; nontuberculous mycobacteria; Pneumocystis cainii superinfection in HIV/AIDS)
Available as:
Adult Tablet
160 mg trimethoprim, 800 mg sulfamethoxazole.
80 mg trimethoprim, 400 mg sulfamethoxazole.
Pediatric Tablet
20 mg trimethoprim, 100 mg sulfamethoxazole.
Suspension
40 mg trimethoprim, 200 mg sulfamethoxazole/5 mL
Injection (5 ml)
80 mg trimethoprim, 400 mg sulfamethoxazole.
Dose: 4 to 10 mg/kg/day (O, IV) in terms of trimethoprim.
ADRs: Gastric upset, nausea, vomiting, glossitis, anorexia, malaise, skin rash, crystalluria, rarely blood dyscrasias.
Drug interactions: SMZ- Protein displacement with warfarin, phenytoin, methotrexate. TMP – Phenytoin, cyclosporin, rifampicin, warfarin.
Contraindications: Sulfonamide allergy and neonatal period; also any individual with G-6-PD deficiency; premature infants for first 3 months.
Precaution: The injectable cotrimoxazole should never be given directly. The drug should be diluted in normal saline or 5% dextrose in a proportion of its 5 mL (1 ampoule) to 125 mL of infusion. The rate of infusion should be about 2 to 6 mL/minute. Infusion solution must be used within 6 hours of preparation.
 
Sulfisoxazole
Brand name: Gantrisin (Roche).
Indications: Otitis media,chronic bronchitis (Extra-respiratory indications: lower urinary tract infection due to susceptible pathogens).
Available as: Tablets 500 mg
Suspension 500 mg/5 mL.
Dose: 5 to 60 mg/kg/day in 2 divided doses.
395ADRs: Nausea, vomiting, crystalluria, rash, Stevens-Johnson syndrome, renal and hepatic impairment.
Drug interaction: Protein displacement with warfarin, phenytoin and methotrexate.
Contraindications: Hypersensitivity to sulfonamides or chemically related drugs (e.g. sulfonylureas, thiazide and loop diuretics, carbonic anhydrase inhibitors, sunscreens containing PABA, local anesthetics); hypersensitivity to salicylates; porphyria; children younger than 2 months of age; pregnancy at term.
Precaution: Avoid in renal disease.
 
MISCELLANEOUS ANTIBACTERIAL DRUGS
 
Chloramphenicol
Brand name: Chloromycetin (Parke-Davis), Paraxin (Nicholas)
Originally obtained from Streptomyces venezuelae in 1947, now it is entirely a synthetic product.
Indications: Respiratory infections, especially those caused by H. influenzae). (Extra-respiratory indications: Typhoid fever; and other severe infections).
Available as: Capsules/dragees/tablets 250, 500 mg. Suspension 125 mg/teaspoonful. Injection 250 mg/mL.
Dose: 50 to 100 mg/kg/day (O, IM, IV) in divided doses, 25 mg/kg/day (O, IM, IV) in first 2 weeks of life when it is best avoided on account of the risk of developing gray baby syndrome.
ADRs: Bone marrow depression (parenteral chloramphenicol is relatively less dangerous than oral chloramphenicol as regards bone marrow depression), allergic reaction, GIT upset, peripheral neuritis, retrobulbar neuritis.
In preterm newborns, it may rarely cause gray baby syndrome which is acardiovascular collapse characterized by appearance of symptoms like vomiting or regurgitation, refusal to suck and abdominal distention. These occur after 2 to 3 days of continued therapy. In another day or so the infant develops ashen-gray color, cyanosis, and becomes limp. Prognosis is extremely poor with very high fatality.
This condition is due to a lack of glucoronidation reactions occurring in the baby, thus leading to an accumulation of toxic chloramphenicol metabolites.
The UDP-glucuronyl transferase enzyme system of infants, especially premature infants, is immature and incapable of metabolizing the excessive drug load. Insufficient renal excretion of the unconjugated drug makes its own contribution.
Drug interactions: It inhibits metabolism of tolbutamiide, chlorpropramide, warfarin, cyclophosphamide and phenytoin. Such drugs as phenobarbital, phenytoin, and rifampicin enhance its metabolism, thereby contributing to failure of adequate response.
396Contraindications: Hematologic disorders.
Precaution: Monitor blood counts; void in minor infections that can be treated with other antimicrobials.
Special remarks: Having had only limited prescriptions over the past couple of decades on account of emergence of resistance, antimicrobial sensitivity to chloramphenicol is now bouncing back.
 
Rifampicin
Brand name: R-cin (Lupin), Rifamycin (Biochem), Siticox (Sarabhai)
This drug acts through inhibition of bacterial RNA polymerase.
Indications: Second agent (synergistic) for S. aureus infections; elimination of nasopharyngeal colonization in carriers of H. influenzae type b (Extra-respiratory indications: N. meningitidis resistant to penicillin and sulfas; tuberculosis, leprosy).
Available as: Capsules 150, 300, 450, 600 mg.
Syrup 100 mg/teaspoonful.
Dose: 10 to 20 mg/kg/day (O) as a single daily dose before food.
ADRs: Nausea, hypersensitivity reactions, hepatic dysfunction, orange-red staining of saliva, sputum, sweat, urine and stool, GIT upset, heartburn, rash, drowsiness, headache, confusion, numbness, cramps, visual disturbances, eosinophilia, thrombocytopenia.
Drug interactions: Phenytoin, steroids, narcotics, alcohol, digoxin, hypoglycemic, oral contraceptives, disulfiram.
Contraindication: Optic neuritis, jaundice.
Precaution: Impaired liver and renal function.
 
ANTITUBERCULOUS DRUGS7,8-19
The fundamental principles of antituberculous therapy is to employ multiple drugs for obtaining a relatively rapid cure and safeguard against the secondary drug resistance in the course of treatment. The extent of tuberculous disease, the host and likelihood of drug resistance influence the choice of antituberculous regimen.
Antituberculous drugs are categorized in 3 groups (Box 24.3).
 
GROUP 1: ANTITUBERCULOUS FIRST LINE DRUGS
 
Isoniazid {Isonicotinic acid (INH)}
Brand name: Isokin (Pfizer), Ipcazide (Ipca).
Indications: Tuberculosis.397
Available as: Tablets 50, 100, 300 mg.
Liquid 50, 100 mg/teaspoonful.
Dose: 5 to 10 mg/kg/day (O) as a single dose or in 2 to 3 divided doses.
ADRs: Weight gain, constipation, euphoria, pellagra-like dermatosis, peripheral neuritis, convulsions, hepatotoxicity.
Contraindication: Liver disease.
Drug interactions: Alcohol, antacids, carbamanzepine, ketoconazole, phenytoin, rifampicin, valproate.
Precaution: Monitor hepatic and ocular function.
 
Pyrazinamide
Brand name: PZA-Ciba (Novartis), P-Zide (Cadila Pharma), Pyzina (Lupin).
Indications: Standard/first line antituberculous drug.
Available as: Tablets 500 mg, 750 mg, 1 g.
Syrup 250 mg/5 mL.
Dose: 20 to 35 mg/kg/day (O) as a single dose; maximum dose 2 g daily.
ADRs: Nausea, vomiting, hepatotoxicity (especially in diabetics and alcoholics), hyperuricemia, gout, anorexia nervosa, arthralgia, myalgia, rash, dysuria, sideroblastic anemia; rarely blood dyscrasias and photosensitivity.
398Drug interactions: Uricosurics, probenicid, sulfinpyrazione.
Contraindications: Gout, hepatic dysfunction; lactation.
Precaution: Monitor with LFT, blood uric acid estimation regularly.
 
Ethambutol
Brand name: Combutol (Lupin).
Indication: Tuberculosis.
Available as: Tablets 200, 400, 500 and 800 mg.
Dose: 15 to 25 mg/kg/day (O) in a single dose.
ADRs: Drowsiness, GIT upset, rash, headache, dizziness, euphoria, swelling of tongue, hepatic and renal dysfunction, leukopenia, bone marrow depression, aggravation of grand mal attacks, visual disturbances.
Precaution: Avoid in preschoolers in view of difficulty in evaluating their vision.
 
Rifampicin
Brand name: R-cin (Lupin), Rifamycin (Biochem), Siticox (Sarabhai).
Indications: Tuberculosis (Other indications: leprosy; carriers of N. meningitidis resistant to penicillin and sulfas.
Available as: Capsules 150, 300, 450, 600 mg.
Syrup 100 mg/teaspoonful.
Dose: 10 to 20 mg/kg/day (O) as a single daily dose before food.
ADRs: Nausea, hypersensitivity reactions, hepatic dysfunction, orange-red staining of saliva, sputum, sweat, urine and stool, GIT upset, heartburn, rash, drowsiness, headache, confusion, numbness, cramps, visual disturbances, eosinophilia, thrombocytopenia.
Drug interactions: Phenytoin, steroids, narcotics, alcohol, digoxin, hypoglycemic, oral contraceptives, disulfiram.
Contraindication: Optic neuritis, jaundice.
Precaution: Impaired liver and renal function.
 
Streptomycin
Brand name: Ambistryn-S (Sarabhai-Piramal).
Indication: Tuberculosis.
Available as: Injection 750 mg, 1 g/vial.
Dose: 15 to 20 mg/kg/day (IM) for 3 months.
399ADRs: Ototoxicity, nephrotoxicity, anaphylaxis, fever, rash, urticaria, angioneurotic edema, eosinophilia, hemolytic anemia, blood dyscrasias, azotemia, muscle weaknss, amblyopia.
Drug interactions: Diuretics (especially frusemide), mannitol, other aminoglycosides, ethacrynic acid, polymyxin B, colistin, cyclosporin, anesthetics, neuromuscular blocking agents.
Contraindications: Hypersensitivity, vestibular damage, suppurative otitis media (SOM).
Precaution: Impaired hepatic and kidney function, prematurity, impaire vestibular/auditory function, myasthenia gravis, pregnancy, lactation.
 
GROUP 2: ANTITUBERCULOUS SECOND LINE DRUGS
 
Ethionamide
Brand name: Ethide (Lupin).
Indication: Tuberculosis when other drugs are ineffective or contraindicated.
Available as: Tablets 250 mg.
Dose: 10 to 20 mg/kg/day with a maximum of 500 to 750 mg daily (O) in 2 to 3 divided doses.
ADRs: Nausea, vomiting, diarrhea, anorexia, salivation, abdominal pain, icterus, rash, acne, alopecia, mental changes, peripheral neuritis, photosensitivity.
Contraindications: Hepastic damage, pregnancy.
Caution: Monitor LFT periodically.
 
Cycloserine
Brand name: Cyclorine (Lupin).
Indication: Second line drug for resistant TB; in combination with other ATT.
Available as: Capsules 250 mg.
Dose: 10 mg/kg/day in 2 divided doses; may be increased to 15 to 20 mg/kg/day in 2 divide doses after 2 weeks.
ADRs: Headache, dizziness, vertigo, drowsiness, depression, tremors, seizures, psychosis, rash, liver dysfunction, megaloblastic anemia.
Drug interaction: Alcohol.
Contraindications: Severe renal impairment, epilepsy, alcohol dependence, psychotic states, porphyria.
Precaution: Reduce dose in impairment; discontinue in case of allergic rash or CNS toxicity; monitor blood, renal and liver function status periodically. 400
 
Kanamycin
Brand name: Kancin (Alembic).
Indications: Tuberculosis as a second line drug. Also, neonatal sepsis, urogenital, respiratory, CNS, soft tissue and GIT infections due to Staphylococcus.
Available as: Injection 0.5 and 1.0 g vials.
Dose: 10 to 15 mg/kg/day (IM) in one or 2 divided doses.
ADRs: Nephrotoxic, ototoxic, rash, fever, headache, paresthesia.
Contraindications: Pregnancy, lactation.
Drug interaction: Fruswemide, ethacrynic acid, neuromuscular blocking agents, anesthetics.
Precaution: Myasthenia gravis, parkinsonism, monitor in renal impairment.
 
Para-amino Salicylic Acid
A structural analog of para-aminobenzoic acid (PABA), acting by competitively inhibiting the synthesis of folic acid as do the sulfonamides.
Indication: Resistant tuberculosis as a second line drug in combination with other ATT.
Available as: Generic sodium para-amino salicylic (PAS) 80 g/100 g granules; 4 g packets.
Dose: 200 to 300 mg/kg/day (O) in 3 to 4 divided doses, essentially after food. The granules are best mixed with a liquid and swallowed whole.
ADRs: GI disturbances, weight loss, hepatotoxicity, hypersensitivity; hypokalemia, hematuria, albuminuria, crystalluria.
Drug interaction: May decrease the absorption of rifampicin; on the other hand, its adverse effects are potentiated when given along with ethionamide.
Precaution: Liver insufficiency; monitor for weight loss and liver and renal function.
 
GROUP 3: ANTITUBERCULOUS RESERVE DRUGS
 
Ciprofloxacin
Brand name: Cifran, Ciplox, Ciprobid
A high-performance quinolone active against Pseudomonas aeruginosa, Serratia, Enterobacter, Shigella, Salmonella, Compylobacter, Neisseria gonorrhoeae, H. influenzae, M. catarrhalis, S. aureus (selected) and Streptococcus.
Indications: Resistant tuberculosis as a reserve drug in combination with other ATT. Also, infections of the urinary tract, gastrointestinal tract, respiratory 401tract, bones and joints, skin; serious life-threatening infections, e.g. septicemia, resistant enteric fever; hospital-acquired infections; prevention of sepsis in immunocompromised hosts.
Available as: Tablets 250, 500 mg. Injections 1,2 mg/mL.
Dose: 15 to 30 mg/kg/day (O) in 2 divided doses, 5 to 10 mg/kg/day (IV) in 2 divided doses.
ADRs: Tendonitis, gastrointestinal intolerance (nausea, vomiting, diarrhea), anorexia, abdominal pain, flatulence, pseudomembranous colitis; dizziness, headache, insomnia, confusion agitation, tremors, ataxia, seizures, hallucinations, visual disturbances, migraine, deafness; rash, pruritus, drug fever, anaphylaxis, Stevens-Johnson syndrome, photosensitivity, eosinophilia; hepatitis, raised SGOT, SGPT, alkaline phosphatase, serum bilirubin; crystalluria, nephritis, transient renal failure, raised blood urea, creatine, crystalluria, hematuria, anemia, thrombocytopenia, thrombocytosis; thrombophlebitis, superinfections.
The joint destruction (encountered in juvenile animals) is not seen in humans.
Drug interactions: Antacids (containing Mg, Ca, Al), sucraflate, theophylline, probenecid, warfarin, cyclosporin.
Contraindications: Hypersensitivity to quinolones.
Caution: Avoid the drug 1 to 2 hours before and 4 hours after the antacids.
Avoid with theophylline and nonsteroidal anti-inflammatory drugs (NSAIDs).
Avoid in epileptics.
 
Levofloxacin
Brand name: Levoflox (Cipla), Leeflox (Centaur), Lomflox (Ipca).
A levo isomer of ofloxacin.
Indications: Resistant tuberculosis (MDR-TB) as a reserve drug in combination with other ATT. Gram-positive and gram-negative infections.
Available as: Tablets 250, 500 mg
Injection 500 mg/100 mL IV infusion.
Dose: 10 to 15 mg/kg OD or in 2 divided doses.
ADRs: Nausea, diarrhea, dizziness, headache, photosensitivity, peripheral neuropathy (paresthesia, hypoesthesia, dysesthesia, weakness), rupture of tendons.
Drug interactions: Antacids, sucralfate, probenecid.
Contraindications: < 8 years, hypersensitivity, lactation, pregnancy.
Precaution: Avoid in children < 8 years, severe renal impairment; avoid exposure to sunlight; discontinue in case of hypersensitivity, photosensitivity, neuropathy manifestations. 402
 
Amikacin
Brand name: Amicin (Biochem), Mikicin (Aristo).
First semisynthetic aminoglycoside; derivative of kanamycin A; effective against gram-positive as well as gram-negative organisms—just like tobramycin.
Indications: Tuberculosis (third line, i.e. reserve drug) in combination with other ATT. Also, fulminant gram-negative infections (septsis, pneumonia, meningitis, peritonitis, infected burns, postoperative sepsis), and gram-positive infections resistant to other aminoglycosides, e.g. nosocomial infections like in burns, in ICU, and in immunocompromised subjects.
Available as: Injections 100, 250, 500 mg/vial.
Dose: 15 to 25 mg/kg/day divided q 8 to 12 h.
ADRs: Nephrotoxicity, ototoxicity (mainly cochlear), neuromuscular blockade, hypersensitivity reactions like drug fever, rash, eosinophilia, tremors, nausea, vomiting, headache, overgrowth of nonsusceptible microorganisms.
Contraindications: Known hypersensitivity to aminoglycosides.
Precaution: Suitable reduction in dose must be made in renal insufficiency depending on creatinine clearance and BUN.
 
Ampicillin
 
Imipenem-Cilastatin
Brand name: Cilanem-500 (Ranbaxy).
Indications: Multidrug resistant tuberculosis (MDR TB) as reserve/third line drug along with other ATT. Being a broadspectrum beta-lactam antimicrobial, also employed for aerobic as well as anaerobic extended-spectrum beta-lactamase-producing (ESBL) bacterial infections (both gram-positive and gram-negative).
Available as: Injection 500 mg each of imipenem and cilastatin.
Dose: 15 mg/kg/dose (IV infusion) every 6 hourly with a maximum of 2 g/day.
ADRs: Local and allergic reactions, phlebitis, GI upset, rash, fever, blood dyscrasias, hepatic dysfunction, renal dysfunction, CNS disturbances, hearing loss, seizures, confusion, dizziness, somnolence, hypotension, perverted taste, superinfections, pseudomembranous colitis, Cl difficile-associated diarrhea (CDAD).
Drug interaction: Probenicid, valproic acid, ganciclovir, divalproex sodium, estrogen contraceptives.
Contraindications: < 3 months, lactation.
Precautions: Penicillin, cephalosporin or other allergy, colitis, concomitant use with valproic acid, CNS disorders, renal impairment, meningitis, brain abscess, granulocytopenia, prolonged use, pregnancy.403
 
ANTIVIRAL DRUGS7,15-20
 
Amantadine
Brand name: Amantrel (Cipla)
A M2-inhibitor antiviral, a tricyclic amine, acting by blocking M2 protein ion channel. It changes pH of lysozymes.
Indications: Influenza A (both prevention and treatment); also herpes zoster, parkinsonism, drug-induced extrapyramidal reactions
Available as: Oral formulation: Capsules 100 mg.
Syrup 50 mg/teaspoonful
Dose: 4 to 8 mg/kg/day (O) q 8 to 12 hr with a maximum of 150 mg/day and 200 mg/day before and after 10 years of age, respectively, for 2 to 7 days.
ADRs: Transient insomnia, nervousness, light headedness, drowsiness, pedal edema, livedo reticularis due to vasoconstriction.
Contraindication: Gastric ulceration, epilepsy, nursing and pregnant mothers, hypersensitivity to amantadine.
Precaution: Avoid its use in view of widespread resistant strains as per recommendations of CDC.
 
Oseltamivir
Brand name: Antiflu (Cipla), Fluvir (Hetero), Tomiflu (Roche)
This antiviral agent is a neuraminidase inhibitor. Oseltamivir is not a substitute for early vaccination on an annual basis.
Indications: Treatment of uncomplicated acute illness due to influenza infection in patients aged 1 year and beyond who have been symptomatic for up to 48 hours.
Prophylaxis of influenza in patients older than 1 year.
Available as: Capsules 75 mg.
Powder for oral suspension, to be constituted with water (12 mg/mL; available in glass bottles containing 25 mL of suspension).
 
Dosage
Treatment: Optimal dose for adolescents and adults 75 mg BID for 5 days. Pediatric patients who cannot swallow, should receive the oral suspension.
1 to 12 years:
< 15 kg
30 mg
15 to 23 kg
45 mg
23 to 49 g
60 mg
>40 kg
75 mg
All twice daily for 5 days
404It should preferably be administred within 48 hours after the onset of symptoms; most effective if initiated as soon as possible (< 24 hours). The drug is generally well-tolerated.
Prophylaxis: Optimal dose for adolescents and adults 75 mg once daily for 10 days or up to 6 weeks during an epidemic. Pediatric patients who cannot swallow, should receive the oral suspension.
1 to 12 years:
<15 kg
30 mg
15 to 23 years
45 mg
23 to 49 kg
60 mg
>40 kg
75 mg
All once daily for 10 days or up to 6 weeks during an epidemic.
Special dosage: Patients with a serum creatinine clearance between 10 and 30 mL/min are treated with 75 mg once daily for 5 days; the prophylactic dose is 75 mg every other day or 30 mg oral suspension every day. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.
ADRs: Nausea and vomiting which are generally mild to moderate in degree and usually occur on the first 2 days of treatment; GI bleeding, hemorrhagic colitis, respiratory infection, dizziness, fatigue, headache, insomnia, seizures, vertigo, delirium, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares.
Drug interactions: Chlorpromazine, methotrexate, phenylbutazone; do not administer live attenuated influenza vaccine (LAIV) within 2 weeks prior or 48 hours after treatment.
Contraindication: Children < 1 year age.
Precaution: Patients should be instructed to begin treatment with oseltamivir as soon as possible after the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible following exposure.
  • Renal and hepatic impairment, hemodialysis, chronic cardiorespiratory disease, repeat courses, pregnancy and lactation.
  • Transient gastrointestinal disturbance may be reduced by taking oseltamivir after a light snack.
  • Co-administration with food has no significant effect on the peak plasma concentration and the AUC.
  • Oseltamivir is not a substitute for an influenza vaccine. Patients should continue receiving an annual/seasonal vaccine according to the relevant national or local recommendationas.
 
Rimantidine
Brand name: Flumadine.
Action: A M2 inhibitor.
405Indications: Prophylaxis of influenza A infection. Treatment must be initiated within 48 hours after the onset of symptoms.
Doses: 100 mg BID. A dose reduction to 100 mg daily is recommended in patients with severe hepatic dysfunction, renal failure (CrCl ≤ 10 mL/min) and in elderly nursing home patients.
Children less than 10 years of age should receive 5 mg/kg but not exceeding 150 mg.
Children 10 years of age or older should receive the adult dose.
Drug interactions: No significant interactions.
ADRs: Gastrointestinal symptoms like nausea, vomiting, diarrhea, dyspepsia, CNS disturbances like insomnia, dizziness, tinnitus, ataxia, skin rash.
Precaution: A dose reduction to 100 mg daily is recommended in patients with severe hepatic dysfunction, renal failure (CrCl ≤ 10 mL/min) and in old age. Avoid it suse in view of widespread resistance.
 
Zinamivir
Brand name: Relenza.
A neuraminidase inhibitor. Neuraminidase glycoprotein is essential in the infective cycle of influenza viruses. It simulates sialic acid, the natural substrate of neuraminidase.
Indications: Treatment of uncomplicated influenza (A and B) symptomatic over up to 2 days.
 
Dosage
Treatment: 10 mg BID twice daily (2 consecutive days).
Prophylaxis: Not yet approved.
ADRs: A good safety profile and the overall risk for any respiratory event is low. Adverse events include bronchospasm, especially in the setting of underlying airways disease, allergic reactions, including oropharyngeal edema; arrhythmias, syncope, seizures.
Drug interactions: No clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies.
Precaution: Not to be recommended for the treatment of patients with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) in which risk of bronchospasm is significant.
 
Ribavirin
Brand name: Ribavin (Lupin).
Indications: A semisynthetic nucleoside antiviral drug, particularly useful in respiratory syncytial virus (RSV), hepatitis influenza virus and herpes simplex 406virus. In practice, primarily used for treatment of acute bronchiolitis from RSV, especially when the infant is critically ill or has underlying high risk condition such as prematurity, chronic lung disease (cystic fibrosis) and congenital heart disease (CHD).
Available as:
Aerosol capsules 100 mg, 200 mg.
Syrup 50 mg/5 mL.
Dose: 10 mg/kg/day continuous aerosolization for 12 to 18 hours daily for 3 to 7 days.
ADRs: Hemolysis, anemia, flu-like symptoms, dizziness, weight loss, alopecia, rash, diabetes, pancreatitis, hyperuricemia, thrombotic thrombocytopenic purpura, thyroid disorders, dental and periodontal disorders, vision disorders, optic disk changes, including papilledema and retinal detachment; psychiatric problems, cardiac arrest, hypotension.
Drug interactions: Alcohol, nucleoside reverse transcriptase inhibitors (NRTIs), stavudine, zidovudine, didanosine, peginterferon alfa 2a.
Contraindications: Pregnancy since it is teratogenic drug; hypersensitivity to ribavirin or any component of the product.
Precaution: Avoid in asthma; closely monitor renal, cariac, hematologic and biochemical parameters before and at 2 to 4 weeks intervals during therapy.
 
SUMMARY AND CONCLUSION
The choice of an antimicrobials, the most important tool for treatment of respiratory infectious diseases, is based on factors in relation to the patient and the microbial pathogen, especially pharmacodynamics and pharmacokinetics and adverse reactions of the drug.
Multidrug therapy rather than monotherapy is important in treating mycobacterial infections for rapid cure and prevention of development of drug resistance during the course of treatment. Choice of regimen depends on the extent of disease, the host and the likelihood of emergence of secondary drug resistance.
Right indication, dose and duration are important in antimicrobial therapy to give the optimal results. Irrational antimicrobial therapy is a key factor in promoting resistant pathogens. While prescribing an antimicrobial, it is important to bear in mind its antimicrobial spectrum, proper indication, dosage, ADRs, drug interaction, contraindications and precautions/cautions.
Unlike antibiotics, antiviral pharmacotherapy is difficult in view of the fact that the drug may simultaneously interfere with the normal cellular metabolism in the patient, causing adverse effects. Ideally, antivirus drugs should target virus-specific steps, namely cell penetration, uncoating, reverse transcription, virus assembly or maturation and virus-directed enzymes in the infected host cells. For best outcome, antiviral therapy should be started during the course of the incubation period, meaning thereby that it is more prophylactic than curative.
407Emergence of resistance to both antibiotics and antiviral drugs is on increase. Irrational antimicrobial therapy is a key factor in promoting resistant pathogens. While prescribing an antimicrobial, it is important to bear in mind its antimicrobial spectrum, proper indication, dosage, ADRs, drug interaction, contraindications and precautions/cautions.
A multipronged strategy is warranted, including rational therapy and efforts at development of newer antimicrobials, to fight against development of resistant strains.
REFERENCES
  1. Gupte S, Gupte N. Pediatric Drug Directory, 8th edn. New Delhi: Jaypee  2013. Bowlware KL, Stoll T. Antibacterial agents in pediatrics. Infect Dis Clin North Am 2004;18:513–531.
  1. John E. Pharmacologic Therapy in Pediatric Pulmonology. London: Smith and Smith;  2009.
  1. Pong AL, Bradley JS. Guidelines for the selection of antibacterial therapy in children. Pediatr Clin North Am 2005;52;869–894.
  1. Bowlware KL, Stoll T. Antibacterial agents in pediatrics. Infect Dis Clin North Am 2004;18:513–531.
  1. Prajapati BS, Prajapati RB, Patel PS. Chemoprophylaxis in pediatric practice. In: Gupte S, Sobti PC, Gupte SB (Eds): Recent Advances in Pediatrics-18: Hot Topics. New Delhi: Jaypee  2009:387–403.
  1. Bruton LL, Laza JS (Eds). Chemotherapy of microbial diseases. In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 11th edn. Mcgraw-Hill  2008.
  1. Seth V, Kabra SK. Management of tuberculosis. In: Seth V, Kabra SK (Eds): Essentials of Tuberculosis in Children, 4th edn. New Delhi: Jaypee  2011: 4
  1. Indian Academy of Pediatrics. Consensus Statement of Childhood Tuberculosis (2010 IAP Working Group on Tuberculosis). Indian Pediatr 2010;27:41–55.
  1. Starke JR, Munoz FM. Tuberculosis (Mycobacterium tuberculosis). In: Kliegman RM, Behran RE, Jenson HB, Stanton BF (Eds): Nelson Textbook of Pediatrics, 18th edn. Philadelphia: Saunders  2008:1240–1244.
  1. Revised National TB Control Program (RNTCP). Available at: http://www.tbcindia.org/RNTCP.asp. Accessed on: 8 September 2010.
  1. World Health Organization (WHO). Guidelines for the Programmatic Management of Drug-resistant Tuberculosis. Geneva: WHO  2008.
  1. Moadebi S, Harder CK, Fitzgerald MJ, et al. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs 2007;67:2077–2099.
  1. World Health Organization (WHO). Guidance for National Tuberculosis Programs on the Management of Tuberculosis in Children. Geneva: WHO  2006.
  1. Chen SF, Schleiss MR. Principles of antiviral therapy. In: Kliegman RM, Behrmam RE, Jenson HB, Stanton BF (Eds): Nelson Textbook of Pediatrics, 18th edn. Philadelphia: Saundrs  2008:1327-1331.
  1. De Clerk E. Antiviral drugs in current clinical use. J Clin Virol 2004;30:115–133.
  1. Kimberlin DW. Antiviral therapies in children: Has their time arrived ? Pediatr Clin North Am 2005;52:837–867.
  1. Littler E, Oberg B. Achievements and challenges in antiviral drug discovery. Antivir Chem Chemother 2005;16:155–168.
  1. Gupte S, Gupte N. Perspectives in influenza. Gurgaon (NCR): Macmillan  2011.
  1. Gupte S, Gupte N. A-Z Influenza. New Delhi: Macmillan  2013.

Pharmacotherapy of Asthma25

Novy Gupte
 
INTRODUCTION
The major goals for therapy in pediatric asthma are:
  • To control asthma by reducing impairment through prevention of chronic and troublesome symptoms (say, coughing or breathlessness in the daytime, in the night, or after exertion)
  • To reduce the need for a short-acting beta-2-agonist (SABA) for quick relief of symptoms (not including prevention of exercise-induced bronchospasm)
  • To maintain near-normal pulmonary function
  • To maintain normal activity levels (including exercise and other physical activity and attendance at work or school)
  • To satisfy patients’ and families’ expectations for asthma car.
Preventing recurrent exacerbations of asthma and minimizing the need for emergency visits and hospitalizations, and preventing progressive loss of lung function leads to a fall in “risk”. Preventing reduced lung growth and providing optimal pharmacotherapy with minimal or no adverse effects is particularly important, in pediatric practice.
The goal of long-term therapy is to prevent acute exacerbations.1,2 The patient should avoid exposure to environmental allergens and irritants that are identified during the evaluation.
The goals of pharmacotherapy of asthma are to prevent as well as to control bronchoconstriction resulting from activation of mast cells, infiltration of eosinophils and T-helper 2 (TH2) lymphocytes.2-5
 
ADRENALINE (EPINEPHRINE)
A sympthomimetic agent.
Indications: Bronchial asthma (Other indications: cardiac arrest, cardiac asthma, severe bradycardia).
Available as: 1 in 1,000 aqueous solution, 1 mg/mL.
410Dose: For relief of bronchospasm, 0.01 mL/kg/dose (IM, SC) with a maximum of 0.5 mL/dose. Repeat every 10 to 20 minutes for 3 or 4 times, or every 3 to 4 hours as per the situation (prn).
ADRs: Nausea, vomiting, anxiety, restlessness, tachycardia, angina, tremors, cold extremities, gagrene.
Precaution: Avoid its use in nervous or anxious patients, or those having hypertension, hyperthyroidism, ischemic heart disease, or in conjunction with trichorethylene, halothane, cycloproyone, or monoamine oxidase inhibitors.
 
AMINOPHYLLINE
Indications: Bronchodilator (Other indication: neonatal apnea).
Available as: Tablet 100 mg, 200 mg.
Injection 25 mg/mL.
Dose: 4 to 6 mg/kg/dose (IM, IV); 12 mg/kg/day (IM, IV) in 3 or 4 divided dose; 10 mg/kg/dose (O), to be repeated every 6 to 8 hours.
An alternative and better method for controlling the acute attack of bronchial asthma consists in giving 4 to 6 mg/kg of aminophylline in over 15 minutes as an intravenous infusion. Then, continue giving 0.6 to 1 mL/kg every hour as a constant infusion.
For apneic attacks in newborn, the dose is 4 to 6 mg/kg/day (O) in 4 divided doses.
ADRs: Restlessness, palpitation, dizziness, nausea, hypotension, shock, cardiac arrest, sudden death (usually secondary to very rapid injection).
Caution: ECG monitoring desirable.
 
CROMOGLYCATE DISODIUM
Brand name: (Cremolyn Ifiral, Intal)
Indication: Prophylaxis of acute asthmatic attack. It reduces airway hyperactivity and inhibits mast cell degranulation (blocking mediator release).
Available as: Rotacap 20 mg.
Dose: Inhalation of 1 rotacap TDS for 4 to 6 weeks.
Repeat course after 3 to 6 months.
ADRs:Transient bronchospasm.
Precaution: Avoid in children below 5 years.
Keep a specific bronchodilator injection handy for use in the event of bronchospasm developing as a side effect of cromoglycate.411
 
MONTELUKAST
Brand name: Romilast, Montair, Ventair.
A singular leukotriene receptor blocker, employed as an “add-on” therapy in moderate asthma (chronic/recurrent).
Indications: For prevention and treatment of chronic/recurrent/persistent bronchial asthma (Other indications: also in nasobronchial allergy).
Available as: Tablets 4, 5, 10 mg.
Dose:
2 to 5 years: 4 mg (O) OD in the morning
6 to 14 years: 5 mg OD in the morning
15 years and above: 10 mg OD in the morning.
Drug interactions: Phenobarbital, phenytoin, rifampicin, drugs metabolized by CYP2C8 such as rosiglitazone.
ADRs: Headache, dizziness, dyspepsia, fatigue; raised liver enzymes.
Contraindications: Pregnancy.
Precaution: For best outcome, it should be administered in the evening. Do not employ as a substitute for oral or inhaled steroid therapy.
 
MAGNESIUM SULFATE
Indication: Acute severe asthma (Other indications: acute severe malnutrition).
Available as: Injection 1, 10, 25, 50% 1 mL ampoule.
Dose: 25 mg/kg IV infusion in about 30-min.
ADRs: Hypermagnesemia, hypotension, respiratory depression, diarrhea.
Contraindications: Severe renal impairment, heart block, myocardial disease.
Precautions: Renal insufficiency, concurrent therapy with digoxin.
Antidote: IV calcium gluconate.
 
ORCIPRENALINE SULFATE
Brand name: Alupent.
Indications: Bronchial asthma.
Available as: Injection 1 mL containing 0.5, 1.0 mg. Syrup 2 mg/mL. Tablets 10, 20 mg.
Dose: 0.02 mg/kg/dose (IM), 2 to 3 mg/kg/day (O) in 4 divided doses.
ADRs: Palpitations, restlessness, finger tremors, nausea sleep disturbances, headache, flushing, allergic reactions, extrasystoles.
412Precaution: Avoid concurrent use of sympathomimetics or MAO inhibitors.
Contraindications: Thyrotoxicosis.
Antidote: A betablocker agent.
 
SALBUTAMOL
Brand name: Asthalin, Bronkotab, Bronkosyrup, Brethmol, Salbetol.
Indications: Bronchial asthma; other lung conditions accompanied by significant bronchospasm.
Available as: Tablets 2, 4 mg. Syrup 2 mg/teaspoonful.
Dose: 0.2 to 0.4 mg/kg/day q 8 hr.
ADRs: Fine tremors (most remarkable in hands) tachycardia, headache, tenseness, restlessness, arrhythmias, hypokalemia, hypoxemia, ventilation-perfusion mismatch; metabolic effects ( high free fatty acid, glucose) following large systemic doses.
Caution: Long-term use may cause tolerance ( desensitization, subsensitivity).
 
TERBUTALINE SULFATE
Brand name: Bricanyl, Bronkine.
Indications: Bronchospasm as in bronchial asthma.
Available as: Tablets 2.5 and 5 mg. Suspension 1.5 mg/teaspoonful. Injection (SC) 0.5 mg/mL.
Dose: 0.2 mg/kg/day (O), 0.005 mg/kg/dose (SC). IV infusion may be given in difficult cases.
ADRs: Nervousness, muscle tremors, headache, tachycardia, palpitation, drowsiness, nausea, vomiting and sweating. These side effects are usually mild, their frequency reducing with continued therapy. No or little cardiac side effects since it has selective action on beta-2 receptors in bronchial muscles and relatively slight effect on beta-1 receptors in the heart.
Caution: As with all sympathomimetic stimulants, it should be used with special caution in patients with hypertension, coronary artery disease, CCF, hyperthyroi-dism on diabetes mellitus.
Contraindications: Thyrotoxicosis, known hypersensitivity to sympathomimetic amines, arrhythmias.
 
THEOPHYLLINE
Brand name: Etophylate, Broncordil, Deriphyllin.
Indications: Bronchospasm. (Other indications: apnea of prematurity).
413Available as: Tablets 100, 200 mg. Elixir 30, 125 mg/teaspoonful. Injection 110 mg/mL.
Dose: 10 to 20 mg/kg/day (O) in 2 to 3 divided doses. 5 mg/kg/dose (IM, IV, SC).
ADRs: GIT upset, hypotension, cardiovascular collapse, increased gastric and urine excretion, irritability, tremors, convulsions.
Precaution: Reduce dose by 50% in viral illness, high fever (>102°F), cor pulmonale, concurrent administration of drugs like macrolids, quinolones, cimetidine, verapamil, ibuprofen.
 
ZAFIRLUKAST
Brand name: Zuvair.
Indications: Add-on therapy in persistent asthma showing poor response to conventional therapy; asthma prophylaxis.
Available as: Tablets 10, 20 mg.
Dose: 10 mg BD.
ADRs: Headache, dizziness, GI upset, dyspepsia, fatigue; raised liver enzymes.
Drug Interactions: Warfarin, theophylline, aspirin, erythromycin, smoking.
Contraindication: Pregnancy, lactation; hepatic/renal impairment.
Precaution: Administer on empty stomach.
 
INHALATION THERAPY
 
 
Beclomethasone Dipropionate
Brand name: Beclate Inhalor, Beclatye nasal spray.
Indications: Persistent asthma (Other indications: allergic and vasomotor rhinitis, nasal polyposis-sheer symptomatic).
Dose:
  1. Metered Dose Inhaler
    Mild asthma 200 to 400 mcg/day in 2 to 4 divided doses
    Moderate asthma 400 to 800 mcg/day in 2 to 4 divided doses
    Severe asthma 800 to 1000 mcg/day in 2 to 4 divided doses
    The inhalation therapy needs to be continued for 10 to 12 weeks.
  2. Nasal Spray
    50 mcg dose of spray OD or BD.
ADRs: Hoarseness, superadded fungus infection (candidiasis) involving mouth and throat.
Caution: Mouth and throat wash after every inhalation/spray.414
 
BUDESONIDE
Brand name: Pulmicort inhaler.
Indications: Persistent asthma, croup.
Dose
Mild asthma 100 to 400 mcg/day in 2 divided doses.
Moderate asthma 400 to 600 mcg/day in 2 divided doses.
Severe 600 to 800 mcg/day in 2 divided doses.
 
IPRATROPIUM BROMIDE
Ipravent respirator solution for nebulization.
Brand name: Duolin Meter dose inhaler.
Dose: 1 to 2 puffs TDS.
For nebulization: 250 mcg, diluted in 2 mL saline, administered over 10 minutes every 20 minutes X 3 doses. This should be followed by 250 mcg nebulization over 2 to 4 h.
 
SALMETEROL
Brand name: Salmeter, Serobid MDI.
A beta-2-agonist.
A long-acting bronchodilator meant for use >4 years of age.
Indications: Exercise-induced asthma, nocturnal asthma.
Dose: 50 to 100 mcg/day.
ADRs: Palpitations/tachycardia, headache, tremors.
Precaution: Avoid in children < 4 years.
 
TERBUTALINE
Brand name: Bricanyl MDI, Bricanyl nebulizing solution.
Availability:
MDI 250 mcg/metred dose
Nebulizing solution 10 mg/mL.
Dose: Inhalation: 1 to 2 puffs 3 to 4 times daily.
Nebulization: < 20 kg weight 2.5 mg
20 kg weight 5 mg. 415
 
SUMMARY AND CONCLUSION
Pharmacotherapy in asthma may be by oral, parenteral or inhalation routes, depending on the drug employed and the merits of the case. Short-acting beta-2 agonists are the most effective and most commonly used bronchodilators in the therapy of asthma. They relax constricted smooth muscles and, thus, cause immediate reversal of airway obstruction. Additionally, they also prevent bronchoconstriction, thereby providing bronchoprotection. Inhaled beta-2- agonist should be regarded as the bronchodilator treatment of choice in asthma. Cromolyn sodium prevents bronchoconstriction but has no bronchodilator effect. It is ineffective during acute attack. Antileukotrienes predominantly prevent bronchoconstriction but my have some bronchodilator effect. Corticosteroids act through their anti-inflammatory property in removing the bronchial obstruction.
REFERENCES
  1. Barnes PJ. Pulmonary pharmacology. In: Brunton L, Chabner B, Knollman B (Eds). Goodman and Gillmn's The Pharmcological Basis of Therpeutics, 12th edn. New York: McGrw-Hill  2011:1031-1065.
  1. Gandhi JP, Barnes. Asthma therapy in childhood. Asthm Update 2011;6:45–49.
  1. Medscape. Pediatric asthma abd treatment. Available at: http://emedicine.medscape.com/article/1000997-treatment. Accessed on: 12 December 2012.
  1. Batemn ED, Hurd SS, Barnes PJ, et al. Globl strategy for asthma management and prevention. Eur Resp J 2008;31:143–178.
  1. Berger W. Aerosol devices and asthma therapy. Curr Drug Deliv 2009;6:38–49.
Index
Page numbers followed by f refer to figure and t for table, respectively
A Acid aspiration Acinetobacter spp , Acquired immunodeficiency syndrome Acute bronchiolitis , life-threatening events lower respiratory tract infections lung injury , , , otitis media , phase reactants respiratory distress syndrome , , , , , failure failure, signs and symptoms of infections infections in under subperiosteal postaural abscess upper respiratory tract infections Adaptive aerosol delivery Adenosine triphosphate Adrenaline Adult respiratory distress syndrome Advantages and disadvantages of various aerosol devices Aerosol delivery therapy Airway pressure release ventilation Airway/lung dysfunction Alveolar atelectasis in RDS Amantadine American-European conference consensus criteria Amikacin , Amino penicillins Aminoglycosides Aminophylline Amoxycillin , Amoxycillin-clavulanate Ampicillin , Ampicillin-sulbactam Amyloidosis Anatomy of ear Angiotensin II receptor blockers Ankylosing spondylitis Annual influenza vaccine Anorexia nervosa Antegrade aspiration Antenatal steroids Antibiotic therapy , in aspiration pneumonia Antibiotics , for community-acquired pneumonia for etiologic pathogens in community-acquired pneumonia Antibiotic-β-lactam complex Anticholinergics Antidepressants Antigens of flu virus Anti-inflammatory agents drugs therapy Antimicrobial in hospital-acquired pneumonia therapy Antinuclear antibody Antipseudomonas Anti-TB treatment Antituberculous drugs first line drugs reserve drugs second line drugs Antiviral agents for treatment of influenza in children drugs , , Anxiety Approach in noncardiogenic edema Approach to child with acute respiratory failure pneumonia in community ARDS, etiology of Arterial blood gas analysis Arthralgia Aspects of drugs used in bronchial asthma Aspergillus fumigatus Aspiration pneumonia - risk factors for syndromes Assessment of fetal lung maturity severity of illness Asthma , and depression on cardiovascular system ATP-binding cassette Auxillary spacing devices Availability of vaccines in India A-Z pneumonias Azithromycin Aztreonam B Bactec radiometric system Bacteria , B-adrenergic bronchodilators Barriers for injectable antibiotics in severe pneumonia Beclomethasone dipropionate Behçet disease Benzathine penicillin Benzodiazepines Benzyl penicillin Beta-lactams , Biliary tract Bin tissues Biomarkers in aspiration Bird-like voice Blood culture gas analysis , management , glucose lactate level pressure Bordetella pertussis , , , Brand names Breath actuated meter dose inhaler Breathing retraining exercises Broad-spectrum penicillins Bronchial asthma etiology of risk factors for Bronchiectasis Bronchiolitis obliterans Bronchoalveolar lavage Bronchodilator , therapy Bronchopneumonia , , , right Bronchopneumonias Budesonide C C. pneumoniae Carbapenems Carbenicillin Carboxy penicillins Cardiogenic pulmonary edema , , Cardiopulmonary disease Categories of antituberculous drugs Causes of high sweat chloride Causes for community-acquired pneumonia Causes of ARDS/ALI in children bronchiectasis cardiogenic pulmonary edema low sweat chloride CDC criteria for VAP Cefaclor Cefadroxil Cefazolin Cefdinir Cefepime Cefixime Cefoperazone Cefoperazone-sulbactam Cefotaxime Cefpodoxine proxetil Cefprozil Ceftazidime Ceftibuten Ceftobiprole medocaril Ceftriaxone Cefuroxime axetil Celiac disease Cephalexin Cephalosporins Chemoprophylaxis Chest computed tomography physiotherapy , radiograph , , bilateral white-out lung X-ray with reticulogranular infiltrates in RDS Cheyne-Stokes respiration Child with flu recurrent respiratory infections Childhood asthma severity assessment Chlamydia , , pneumoniae , , trachomatis Chloramphenicol Chlorofluorocarbons Cholinesterase inhibitors Chronic cardiorespiratory disease health problems lung disease , obstructive pulmonary disease pneumonia , rhinosinusitis Churg-Strauss syndrome Chylous effusions Ciprofloxacin , Clarithromycin Classic infection control measures Classical stages of lobar pneumonia Classification of pneumonias respiratory failure Clearing of lung after surfactant therapy in RDS Clindamycin Clinical pulmonary infection score , Closure of patent ductus arteriosus Cloxacillin Clubbing in case of bilateral bronchiectasis Clues in chest X-ray for likely pathogen or type of pneumonia Combination vaccines Common disease causing mutation Community-acquired pneumonia , , Complete blood count , Complications of flu pertain to ear influenza in children vaccine-preventable diseases Composite bodies Composition of pulmonary surfactant Conditions associated with aspiration Confirmed serotypes of influenza type virus Congenital diaphragmatic hernia heart diseases , , pneumonia respiratory associated malformations Conjugate vaccine , Connective tissue diseases Continuous rotational therapy Coronary heart disease Corticosteroid treatment Corticosteroids , Corynebacterium diphtheriae Cost of reducing pneumonia deaths Cough , hygienically or difficult breathing Course of illness Criteria for defining HAP hospitalization Cromoglycate disodium Crying child Crystalline penicillin Cyclophosphamide Cycloserine Cystic fibrosis , , , , , , gene modifier D Defective clearance of airway secretions Dehydration Deoxyribonucleic acid Depending upon severity Depression affects asthma outcome negatively Developing near-fatal asthma Diagnostic tapping of pleural fluid Diet in comorbidities Differences between transudates and exudates Different natural surfactant, comparison of Diffuse aspiration bronchiolitis Direct aspiration Disease burden , Disseminated intravascular coagulation DNA testing Dobutamine Dopamine Dosage schedule of first-line antitubercular drugs , Dose of oseltamivir Dried powder inhaler , Drugs Dynamic hyperinflation Dyselectrolytemia Dysphagic aspiration Dyspnea in neonate, differential diagnosis of E Earache Echocardiography Effects of surfactant on lung mechanics Electrolyte balance panel ELISA tests for detection of anti-TB antibodies Empyema thoracis , , Encountered in lobar Endoscopy and lavage End-stage lung disease Enteral nutrition Enterobacteriaceae Epinephrine Erythromycin Essential fatty acid deficiency Established bronchiectasis Ethambutol , , Ethionamide Etiology of ARDs Eustachian tube Evidence of lung disease Expectorants Extended drug resistant Extended-spectrum penicillins External auditory canal Extracorporeal life support membrane oxygenation , , support Extrapulmonary ards F Facial palsy , Factors inflowing aerosol therapy False-negative sweat test Family and asthmatic child Fatal asthma First dose of antibiotics Five generations of cephalosporins Flu vaccine gold standard and best preventive modality against flu virus types Fluid , balance Flu-like symptoms Flu-proofing child Foreign body in airway Functional residual capacity Fungal G Gas exchange abnormalities Gastric lavage Gastroesophageal reflux , disease , Gastrointestinal disorders Genetics Genitourinary Gentamicin Geometric standard deviation Glomerular basement membrane Glycopeptide antibiotics Goodpasture disease Gout Gradenigo's syndrome Growth hormone monitoring H H. influenzae , , , , , type B influenza H. pertussis , Haemophilus influenzae , , , , , , , B and Pneumococcus Haemophilus pneumoniae Hard facts about pneumonias Helium-oxygen Hemagglutinin Hematological disorders Hemodynamic edema , Hemoglobin Hemoptysis Henoch-Schönlein purpura Hepatopulmonary syndrome Hepatotoxicity Hib vaccine , High altitude pulmonary edema , , High frequency oscillatory ventilation , High-risk children Hospital-acquired pneumonia , HRCT bronchiectasis Human immunodeficiency virus Humidified oxygen Hyaline membrane disease , Hydrocarbon aspiration Hydrofluoroalkanes Hyperlucent lung syndrome Hypersensitivity reaction Hypertonic saline nebulization Hypoxemic respiratory failure I Imipenem-cilastatin , Immediate effects on pulmonary circulation pulmonary effects Immunization , Immunodeficiency disorders Immunoglobulins Increased negative interstitial pressure Increased respiratory drive Indications for tracheal intubation Indrawing of lower chest wall, retractions Infant mortality rate Influenza complications vaccine Inhalation therapy , Inhaled foreign body nitric oxide β2-agonists Initial management in NICU Intensive care unit Intercostal water seal drainage placement Interferon-gamma release assays Intramuscular antibiotics , Intrapleural fibrinolytics Intravenous and subcutaneous β2-agonists Invasive hemodynamic monitoring ventilation Inverse ratio ventilation Ipratropium bromide Isolation of flu virus M. tuberculosis Isoniazid , , Isonicotinic acid J Johanson criteria for VAP Juvenile dermatomyositis rheumatoid arthritis , K Kanamycin , Kidneys Klebsiella pneumoniae L Labyrinthitis Lactate dehydrogenase Lake louise criteria Left lower lobe pneumonia ventricular dysfunction Legionella pneumophila Levofloxacin , Levosimendan Life-threatening asthma attacks Light house sign Limitation of conventional flu vaccines Lincomycin HCL Linezolid Linocosamides Lipoid pneumonia Lithium Live attenuated influenza vaccine Liver disease function tests Lobar pneumonia , , , left pneumonis Long-term oxygen Loop diuretics Low birth weight Lower lung fields respiratory infections in children tract infections , tidal volume Lung abscess protective strategies Lungs in respiratory distress syndrome Lymphangioleiomyomatosis Lysosomal storage diseases M M. avium M. catarrhalis M. intracellulare M. pneumoniae , M. tuberculosis bacilli Macleod syndrome Macrolides Magnesium sulfate , Malignant pleural effusions Malnutrition syndrome Management issue in rural health care Management of acute aspiration chronic aspiration illness , massive hemoptysis pleural space infection in children Manifestations of CF Mantoux test , Mean mass aerodynamic diameter Measles vaccine Mechanical ventilation , Mechanism in acute and chronic stress of development of pneumonia Meconium aspiration syndrome ileus Medications used in bronchial asthma Meniscus sign Methicillin-resistant Staphylococcus aureus Methicillin-sensitive Staphylococcus aureus Methylxanthines Microorganisms causing ventilator- associated pneumonia Microvascular injury Miliary tuberculosis Minimizing further lung injury Minocyclin Miscellaneous antibacterial drugs Modified penicillins Molecular methods for identification of M tuberculosis Monobactams Montelukast Moraxella catarrhalis Moropenom Morphine sulfate Mortality Mucolytics , Multidrug resistance Multivesicular bodies Myalgia Mycobacteria Mycobacterium tuberculosis , , Mycophenolate mofetil Mycoplasma , , , infections pneumoniae , , , , N N. meningitidis Nasal polyps National Family Health Survey Natural surfactant versus synthetic surfactant Nausea Nebulized epinephrine Neonatal bacterial pneumonia intensive care unit pneumonia , respiratory distress syndrome Nephrotic syndrome Nesiritide Netilmicin Neurofibromatosis Neurogenic pulmonary edema , , Neurological disorders Neuromuscular disorder New development in influenza vaccine Newer culture techniques Nitroglycerine Nonacid aspiration Noncardiogenic pulmonary edema Noncehalosporin β-lactams Noninvasive mechanical ventilation monitoring, pulse oximetry positive pressure ventilation , ventilation , Nonpenicillin Nonsevere pneumonia Nontuberculous mycobacteria Norepinephrine Normal defense mechanisms of body against aspiration Nosocomial pneumonia Noteworthy complications of CF Novel therapies Nucleotide-binding domains Nutrition , Nutritional factors O Obesity Ofloxacin Oral antibiotics , penicillin Orciprenaline sulfate Oseltamivir Other neonatal pneumonias Oxazolidinone antibiotics Oxygen , saturation therapy , , Oxytetracycline P P. aeruginosa Pancreas Pancreatic disorders Panic cycle, cognitive behavioral explanation disorder , Para-amino salicylic acid Paranasal sinuses Parapneumonic effusions Partial liquid ventilation pressure of carbon dioxide Pathogen causing pneumonia Pathophysiology of ARDS Peak expiratory flow Pediatric flu , clinical features of Pediatric intensive care unit , , Pefloxacin Penicillinase-resistant penicillins Penicillinase-sensitive penicillins Penicillins Permissive hypercapnea , Persistent pneumonia , and recurrent pneumonia Pertussis Petrositis syndrome Pharmacotherapy of asthma Phosphatidylglycerol Phosphodiesterase inhibitors Photopheresis Physical rehabilitation Piperacillin , Pleural effusion fluid analysis Pneumatocele complicating staphylococcal pneumonia Pneumococcal conjugate vaccine pneumonia vaccine vaccination vaccine , , Pneumococcus , Pneumocystis carinii , , Pneumonia in various age groups major categories of risk factors for specific features Polyarteritis nodosa Polymerase chain reactions , Polysaccharide vaccine , Positive end expiratory pressure , , , Postinfectious cough Prebronchiectasis Predisposing factors for staphylococcal pneumonia Pressurized metered dose inhaler Prevention of low blood sugar relapse Procaine penicillin Prognosis of patients in status asthmaticus Pro-kinetic drugs Prophylactic versus rescue therapy Protected specimen brush Protein kinase A C Protein structure Proteus vulgaris Proton pump inhibitors Protozoal Pseudomonas , aeruginosa , , , infection Psychological aspects of bronchial asthma Psychosocial consideration in CF Psychosomatic theory of asthma Pulmonary and cardiac effects of surfactant therapy ARDS aspiration syndromes capillary wedge pressure complications and treatment edema function tests , lymphangioleiomyomatosis Pulse oximetry Purified protein derivative Pyrazinamide , , Q Quinolones and fluoroquinolones R Ramsay Hunt syndrome Rapid breathing, trachypnea respiratory rate Recurrent lobar pneumonia pneumonia , , differential diagnosis for Renal function tests Repeated dosing of surfactant Replication of flu virus Resolving lobar pneumonia Respiratory distress syndrome , , manifestations of systemic disease pump dysfunction support syncitial virus , Reye's syndrome Rhinitis Rhinorrhea with nasal obstruction Rhinosinusitis Ribavarin , Ribavirin therapy in severe bronchiolitis Ribonucleic acid Rickettsial Rifampicin , , , Right parahilar pneumonia in immunocompromised adolescent female sided whiteout lung in supine film Rimantidine Role of appetite stimulants pyridoxine surgery Routes of infection in VAP spread of infection Roxithromycin Ryle's tube S S. aureus , S. pneumoniae , , , , , Salbutamol Salmeterol Salt depletion Sarcoidosis Saybolt seconds universal units School-related actions in influenza prophylaxis Scleroderma Scorpion envenomation Secondary scoliosis Sedation during ventilation Selection of antibiotics Semisynthetic penicillins Serum albumin electrolytes Severe pneumonia Sildenafil Single and multidose DPIs Sinusitis Situations predisposing to complicated flu Sjögren syndrome Small particle aerosol generator Smear for acid-fast bacillus Sneeze discretely Social distancing interventions for flu prevention Solid aspiration Some aerosol devices Soothing throat Sparfloxacin Special considerations for treatment of avian flu Specific antimicrobials entities Spleen Sputum collection Stage of hyperemia presuppuration resolution suppuration Standard antituberculous drugs Staphylococcus aureus , , , , , , , , , pneumoniae spp Starling's forces Status asthmaticus Steroid therapy Steroids Stevens-Johnson syndrome Strategies limiting airway colonization Streptococcus pneumoniae , , , , , , , , , pyogenes , Streptomycin , , sulfate Stress and autonomic dysregulation endocrinal imbalance immunomodulations Sulfamethoxazole with trimethoprim Sulfisoxazole Sulfonamides Supplemental oxygen Supplementation with vitamins and micronutrients Surfactant in neonatal respiratory distress syndrome phospholipid secretion protein A B C D functions secretion therapy adverse effects of in respiratory distress syndrome, clinical trials of used in neonates, characteristics of Suspecting tuberculosis in children, guidelines for Sweat glands Swyer-James syndrome Symptoms of mild asthma Synthesis and secretion of pulmonary surfactant Systemic lupus erythematosus scleroderma T Takayasu arteritis Teicoplanin Telithromycin, ketek Temporo-mandibular joint disorders Terbutaline sulfate Tetracycline hydrochloride Tetracyclines Theophylline , Theoretical model of NBD1 Therapy targeted respiratory system Ticarcillin , with clavulanic acid Tobramycin sulfate Tolvaptan Tonsillitis Tracheobronchial suctioning Transesophageal echocardiography Transfusion of blood and blood products Transudate versus exudates Traumatic pleural effusions Treatment for acute asthma severe asthma Treatment of life-threatening complications of CF underlying cause Triggers for bronchial asthma Trivalent inactivated influenza vaccine Tubercular pleural effusions Tuberculin skin test Tuberculosis in children Tumor necrosis factor-α , Tympanic membrane Types of aspiration flu vaccine PMDIS available in market surfactant tuberculosis in children Typical cartwheel appearance U Ultrasonic nebulizer , Ultrasonography of chest Unique peculiarities of pediatric influenza Upper esophageal sphincter respiratory tract infection involvement Ureaplasma urealyticum Ureido penicillins V Vaccination , recommendations in India Vancomycin Various organisms contributing to occurrence of ARIS therapies targeting ARDS Vasculitis Ventilation strategies Ventilation-associated pneumonia Ventilation-perfusion relationships and blood gas abnormalities Ventilator-associated pneumonia Ventilator-induced lung injury Viral testing Viruses , Vitamin A Vomiting W Weaning from mechanical ventilation Wegener granulomatosis Wheeze , WHO recommendations for HP avian flu in children X X-ray of chest in brochiolitis Z Zafirlukast Ziehl-Neelsen stain Zinamivir