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Asthma in Children
© 2011, Jaypee Brothers Medical Publishers (P) Ltd.
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher.
First Edition: 2011
Typeset at JPBMP typesetting unit
Printed at Rajkamal Electric PressFOREWORD
Increasing prevalence of asthma in recent time has been accompanied by an unprecedented research into pathogenesis and management by this disabling disorder. Children are no more silent sufferers of this disease which is a manifestation respiratory allergy. Guidelines based on current best evidence form the basis of directions to treat asthma today. However, a large number of doctors managing children with asthma in India are still unaware of the recent advances that have occurred in delineating the basic pathogenesis of this diseases.
Though a perfect cure is still elusive, asthma can be very effectively controlled leading to excellent quality of life of these patients. This book edited by Dr Meenu Singh, who has been my student and a fellow faculty member seems to fill this gap in knowledge. The book will serve as a good reference for practising and academic physician dealing with children with asthma by providing evidence-based management strategies. The book also throws ample light on the pathophysiologic basis on the steps in management. The chapters include besides background on increasing prevalence asthma, pharmacological aspects, drug therapy, scientific basis of immunotherapy as well as strategies to improve adherence to treatment. I hope that this book makes a rich contribution to improved asthma care in India.
Professor Lata Kumar
md fiap facaai
Former Head, Department of Pediatrics
Indian College of Allergy, Asthma and Applied
A child with asthma is a child first
A verdict from the doctor that your child has asthma comes as a jolt to the parents and the family. Due to persistent symptoms of cough and wheezing which are considered “cold” in Indian folklore all things considered cold are stopped for the child. No cold drinks, no white foods like banana, rice and several other things.
I do not know the rationale behind all this but it really affects the quality of life of the child. Generally, he is not sent to excursions or picnics with the fear that his problem may get worse. Soft toys and pets are literally banned.
Though apparently innocuous this takes its toll on child's psychology and his self confidence. To top it all the feeling and stigma of a disease which is incurable and the taboo of giving steroid increases the malady. Sometimes, the family lives in incessant fear of catastrophe.
However, we as doctors and parents must realize that a child with asthma is a child first and only then he is a patient. He has his aspiration and dreams which need to be fulfilled. The family which is yet to come to terms with the diagnosis of asthma needs counseling and support. I should avoid giving too complicated treatment advice and difficult to accomplish dietary advice. After proper history and allergy testing it is possible to discern the known allergens and pathogens and only those should be avoided rather than a blanket ban on everything.
Schools must take an initiative to make these children feel as normal as possible. Educational institution must be well equipped to deal with all kind of emergencies that can happen to them. The children can carry with themselves a card bearing the diagnosis and treatment which can be referred to in case of any emergency. The treatment does not finish with prescription. It needs active efforts on the part of the doctor and parents to develop a partnership to offer the best care to the child.
The chapters in the book provide an insight into the pathophysiological basic of asthma and the latest evidence-based management and counseling strategies to treat this disease.
Words cannot express the stream of gratitude felt towards people and institutions responsible for creation of this work. First and foremost are my teachers Prof BNS Walia, Prof ON Bhankoo and Prof Lata Kumar who have shaped me as pediatric pulmonologist. Further refinement is attributed to Prof Geoffrey Kurland at Children's Hospital of Pittsburgh who trained me as fellow in Pediatric Pulmonology. Dr Lata Kumar has a special place as an asthma educator and researcher as she founded the Allergy and Asthma Clinic at PGIMER where I have honed my skills as clinician and researcher. Prof SK Jindal, the Chief of Pulmonary Medicine at PGIMER has added another perspective by being a strong motivator to work in the respiratory field and included me in all WHO sponsored activities for asthma management guidelines.
We are part of a larger world of Indian Academy of Pediatrics who gave us an opportunity to express our opinions in a consensual manner and frame guidelines for managing asthma in children. Extreme gratitude needs to be expressed towards families with children with asthma who chose us as their clinicians and repose their faith in us for bringing their children for follow-up without fail so that this chronic disorder can be effectively controlled.
No new treatments can be discovered unless active researchers put their mind into action. The tireless labour of my Ph D scholars and research officers who have provided their working hands to convert ideas into action is immensely acknowledged. A special thanks to my research collaborators who provided unstinted support for research activities on asthma. Individuals cannot flourish unless they are supported by their institutions. PGIMER has the distinction of having a very constructive leadership and camaraderie. Hence, I dedicate this work to my institution.
A worldwide increase in the prevalence of asthma has been reported in recent years. With an increase in prevalence comes an increased burden of disease in terms of morbidity, mortality and compromised quality of life. The economic burden in terms of utilization of healthcare resources and limitation of the earning capacity of the individuals and families is an added problem. Various indicators such as disability adjusted life years and healthy life years have been used to define the economic burden. The data from Asian countries regarding these parameters in scarce, underlining the need of systematic studies in these countries, especially those that are resource poor. The present review highlights the varying prevalence of asthma in Asia and assesses the likely economic burden for the future.
It is estimated that as many as 300 million people of all ages and all ethnic backgrounds suffer from asthma and the burden of this disease to government, healthcare systems, families and patients is increasing worldwide.1
An estimation of the burden of asthma is needed to raise awareness among public health and government officials, healthcare workers and the general public towards the prevalence of asthma which is increasing. A management programme should be based on the best-available scientific evidence to provide effective medical care for asthma, tailored to local healthcare systems and resources. Asthma has become more common in both children and adults around the world in recent decades. The increased prevalence of asthma has been associated with an increase in atopic sensitization and other allergic disorders such as eczema and rhinitis. The rate of asthma increases as communities adopt Western life styles and become urbanized. With the projected increase in the urban proportion of the world's population from 45% to 59% in 2025, there is likely to be a marked increase in the number of individuals with asthma world-wide. It is estimated that there may be an additional 100 million people with asthma by 2025. The South Asian region of the world, with several developing countries, abounds in people with asthma who do not have access to basic asthma medications or medical care. Increasing the economic wealth and improving the distribution of resources between and within countries represent important priorities to enable the provision of the better health care. The burden of asthma in many countries is of sufficient magnitude to warrant its recognition as a priority disorder in government health strategies. The objectives of this article is to review the disease burden in countries in South Asian region in terms of prevalence, economic impact and effects on quality of life in order to prioritise resource allocation. Particular resources need to be provided to improve the care of disadvantaged groups with high morbidity, including certain racial groups, those who are poorly educated, live in large cities or are poor. Resources also need to be provided to address preventable factors that trigger exacerbations of asthma, such as air pollution.
• Prevalence of Asthma In Asian Countries
The prevalence of asthma symptoms has been assessed by the International Study of Asthma and Allergies in Childhood (ISAAC) in several Asian Countries using a standardized questionnaire. The results of the ISAAC study suggest substantial worldwide variations in the prevalence of symptoms of allergic rhinoconjunctivitis, asthma ad atopic aczema. As part of the ISAAC study, prevalence surveys were conducted among representative samples of school children for locations in Europe, Asia, Africa, Australia and North and South America.2 In total 257,800 children aged 6–7 years from 91 centres in 38 countries and 463,801 children aged 13–14 years from 155 centres in 56 countries were surveyed. Written symptom questionnaires translated from English into the local language were self completed by the 13–14 year olds and completed by the parents of the 6–7 year olds. Within each age group the global pattern was broadly consistent across each of the symptom categories. The lowest prevalence of asthma was found in parts of Eastern Europe and South and Central Asia. In Asia, the prevalence ranged for 1.5% in Nepal to 6.2% in Hong Kong and the United Arab Emirates. High prevalence was reported from centres in several regions. These differences, if real, may offer important clues to environmental influences on allergy and underline the need for planned allocation and distribution of resources. Another survey estimated the prevalence of childhood asthma in urban areas in China in order to assess the influences of asthma on patients social lives and their families.3 A nationwide randomized survey, covering 43 cities in 31 provinces, on the prevalence of childhood asthma was carried out by the National Paediatric Cooperative Group of Asthma Research from June to October
2000 on a population of 437,873 children aged 0 to 14 years. Patients who had asthma, infantile asthma, cough variant asthma and questionnaire asthma were chosen as subjects. In total 10,065 subjects were screened as asthma associated by means of parental questionnaire, physical examination and case history review. Among them, 7401 (73.53%) children aged 3 years or more and 1109 (11.02%) infants and young children aged less than 3 years were diagnosed as asthma, 785 (7.80%) as cough variant asthma and 770 (7.65%) as questionable asthma. The average prevalence of accumulated asthma of the 0–14 year old asthma population (including asthma in older children and infants) was 1.97%. the male/female ration was 1.75:1.43 cities, with the highest rate in Chongquing (4.63%) and the lowest rate in Xining (0.25%). Overall, within (0.99%) an higher prevalence in south China (1.54%): the highest prevalence was seen in East china (2.37%), where 4670 (70%) children experienced asthma onset before 3 years of age. The current 2-year prevalence of Urban Chinese children was 1.54%. Thirty six of the 43 cities had received a similar asthma prevalence survey 10 years previously, which allowed a longitudinal comparison for 6370 patients (95.47%) family members work was affected because of their asthma attacks. One-third of the patients had used inhaled corticosteroids. In about two thirds of patients the diagnosis of asthma was correct. Only one third of patients with cough variant asthma were diagnosed correctly compared with their early diagnosis. Sixteen percent of patients had not been diagnosed as having asthma previously. Asthma prevalence has increased over the last 10 years, especially in the older age group. The survey inferred that there have been certain improvements in the accuracy of diagnosis and in the practice of steroid inhalation therapy in paediatricians in different cities.
The ISAAC study noted significant variation in prevalence in different parts of India with a range of 0.5–18% in 12-month prevalence of self - reported asthma symptoms from written questionnaire.4 A 20 to 60 fold difference in the prevalence of symptoms was found between various centres involved in this study. Although prevalence data of allergic disease in India in scarce, the little data that are available suggest that patterns differ in different areas. A study of 271 children from rural areas of Tamil Nadu reported a prevalence of breathing difficulty at any time in the past of 9%.5 In another study in rural areas of North India, the prevalence if chronic cough among children aged 1–15 years (n=2275) was 1.06% and two-thirds were due to asthma.6 Such variable patterns also exist across urban regions.7 Prevalence rates ranging from 1.9 to 15.7% have been reported.8 Such national variation, with almost 10–15 fold difference in the prevalence of allergic disorders, is probably unique to India. In a recently conducted study at our centre under the aegis of the Asthma Task Force of the Indian Council of Medical Research, a survey was conducted on 10,028 school children (10–15 yeas of age) belonging to 39 randomly selected schools for the diagnosis of asthma and other atopic disease in Chandigarh, India. A total of 536 children were found to have a current clinical diagnosis of asthma, allergic rhinitis or eczema. The prevalence of asthma was 3.3%. These findings were similar to the ISAAC surveys conducted at our centre.
Most urban areas in South Asia have high pollution indices, characterized by narrow streets, heavy traffic, smog, umplanned city architecture and the use of kerosene or wood as household fuel. However, some urban areas in South Asia are clean and modern, with concrete housing vehicle emission regulations and the use of smoke free household fuel. A study was conducted to compare the prevalence of wheeze in 13–14 year olds between two South Asia cities (Galle, Sri Lanka and Chandigarh, India) representing each of the above archetypes.9 The validated one page ISAAC questionnaire for 13–14 year olds was used for the study. Of 1814 distributed questionnaires. 1737 (95.8%) were completed correctly and returned. Crude prevalence rates and odds ratios (OR with 95% two sides confidence intervals (CI) for comparison of prevalence rates were calculated. The prevalence rate for wheezing in Galle (28.7%) was higher than that in Chandigarh (I 2.5%). The ORs for prevalence for Galle vs Chandigarh were: 2.3 (95% CI 1.8–2.9) for lifetime wheezing; 2.1 (95% CI 1.6–2.7) for wheezing in the previous year. 4.8 (95% CI 3.5–6.7) for exercise-related wheeze; and 1.7 (95% CI 1.2–2.3) for physician diagnosed wheeze, thus demonstrating significant differences in wheeze prevalence between the two cities (P<0.05). The numbers of 13–14 year olds experiencing less than 12 wheezing episodes per year or sleep disturbance due to wheeze of less than one night per week were also significantly higher for Galle than Chandigarh. Hence, a higher prevalence of wheeze was noticed in 13–14-year-old children living in an old-fashioned, congested city than in a clean, modern city in South Asia. Although reported countrywide prevalence of current asthma is lowest in Nepal, a high proportion of children in Nepal have allergic symptoms and positivity to skin tests. Two hundred and ninety-three ‘normal’ school children between 5 and 15 years of age living in the hills of Eastern Nepal were tested by the skin-prick method for sensitivity to six allergens: Dermatophagoides pteronyssinus, Aspergillus fumigatus, Cladosporium herbarum, Penicillium notaturn, mixed pollens and mixed threshings. These children were questioned and examined for symptoms and signs relating to allergic disease. Of these children, 20% were skin-prick positive to at least one of the allergens and 20% had symptoms of allergic disease. However, there was no relationship between the symptoms and the skin-prick test results.10 No relationship was found between the skin-prick test results and any of the following: the length of time a child was breast fed; the age of the child; and month of birth. Nineteen percent of boys and 11% of girls admitted to smoking cigarettes. Pakistan and Bangladesh have shown a relatively high prevalence of asthma. According to one report, up to 4% of children attending outpatient departments in Pakistan suffer from bronchial asthma. In the ISAAC survey, the reported prevalence of asthma in Bangladesh and Pakistan was 3.8% and 4.3%, respectively. Table 1 gives the prevalence of current asthma in various South Asian countries in relation to the population and population density of these countries to assess the burden of disease in tenns of the affected population and available resources.
• Morbidity and Health Care Utilisation
We compared the healthcare utilisation and work days lost for individuals with and without asthma in Chandigarh, India. Individual data on self-perceived asthma problems, self-reported utilisation of outpatient care and official data on inpatient care and work days lost were obtained from our Allergy and Asthma Clinic. Independent t-tests were performed to compare average differences in primary care visits, emergency room visits. days in hospital and work days lost for parents and patients. Compared with the general population individuals with asthma were found to make outpatient department visits and emergency visits and be hospitalised according to the following ratios: 3.1/1.0. 7.9/ 1.0 and 9.3/ 1.0/year, respectively. For work days lost, the ratio was 3.9/1.0. All differences were statistically significant. The self-reported data provided evidence of the burden of asthma to individuals and society. There is a great degree of variability in the healthcare standards in various private and government-funded facilities in India. General private practitioners deliver a large proportion of health care at a relatively higher cost. Hence generalisation of the estimation of expenditure is flawed due to a lack of uniformity in the cost structure of healthcare services.
An attempt was made to audit hospital admissions due to asthma in Pakistan.11 However, the authors concluded that the data available were inadequate and more documentation was required to improve the basic clinical management of individuals with asthma.
• Quality-of-life Issues
Asthma is known to reduce the quality of life of its sufferers. Most studies relating to quality of life come from the developed world. Appropriate measures to estimate quality of life in developing countries with diverse cultural beliefs, values and convictions are practically non-existent. Some attempts have been made in this direction but the wider applicability of these measures needs to be validated.12 Asthma education and quality of life in the community have been studied in the South Asian population residing in the UK.13 It was evaluated whether asthma morbidity in minority groups can be reduced by preventative healthcare measures delivered in the relevant ethnic dialects. Clinical outcomes and quality of life from a community-based project investigating white European (W/E) and Indian subcontinent (ISC) ethnic groups with asthma living in deprived inner city areas of Birmingham, UK were reported. Six hundred and eightynine asthmatic subjects (345 W/E, 344 ISC) of mean (SD) age 34.5 (15) years (range 11–59) and mean forced expiratory volume less than 80% predicted were interviewed in English Punjabi Hindi or Urdu. Subjects randomised to the active limb of a prospective, open, randomised, controlled, parallel group, 12-month follow-up study underwent individually based asthma education and optimisation of drug therapy with 4-monthly follow up (active intervention), Control groups were only seen at the beginning and end of the study. Urgent or emergency interactions with primary and secondary health care (clinical outcomes) and both cross-sectional and longitudinal data from an Asthma Quality of Life Questionnaire (AQLQ) were analysed. Clinical outcomes were available for 593 subjects. Fewer of the active intervention group consulted their general practitioner (GP) (41.8% vs 57.8%, OR 0.52, 95% CI 0.37-0.74) or were prescribed antibiotics (34.9% vs 5 1.2%, OR 0.51, 95% CI 0.36-0.72). However, by ethnicity, statistically significant changes only occurred in the W/E group with fewer also attending accident and emergency departments and requiring urgent home visits. Active intervention reduced the number of hospital admissions (10 vs 30), GP consultations (341 vs 476), prescriptions of rescue oral steroids (92 vs 177) and antibiotics (220 vs 340) but significant improvements by ethnicity only occurred in the active W/E group. AQLQ scores were negatively skewed to the higher values. Regression analysis showed that lower values were associated with ISC ethnicity. Longitudinal changes (for 522 subjects) in the mean AQLQ scores were small but statistically significant for both ethnic groups, with scores improving in the active group and worsening in the control group. It was concluded that active intervention only improved clinical outcomes in the W/E group, AQLQ scores, although lower in the ISC group, were improved by active intervention in both ethnic groups.
It is estimated that asthma accounts for about one in every 250 deaths worldwide. Comparison of asthma mortality between different countries has been made using asthma mortality rates in the 5–34-years age group because the diagnosis of asthma mortality is firmly established in this age group. Many deaths are preventable as they are due to suboptimal long-term medical care and delay in obtaining help during the final attack. Standardised data on deaths due to asthma are not available in most South Asian countries. We have had more than 7000 patients with asthma registered in our Allergy and Asthma Clinic since 1973 who come from different parts of the country: the majority come from the Northern region. Not a single death has been recorded in any of these patients who have had variable periods of follow-up.
• Disability Adjusted Life Years
Disability-adjusted life years (DALYs) is a measure of the burden of disease that assesses the years of healthy life lost due to disease or illness. DALYs combine information about morbidity and mortality in terms of healthy years lost. The calculation of disease-specific health loss in DALY s is the sum of years of life lost (YLLs) and years lived with disability (YLDs) weighted for severity. Each state of health is assigned a disability weighting by an expert panel on a scale from zero (perfect health) to one (death). To calculate the burden of a disease the disability weighting is multiplied by the number of years lived in that health state and is added to the number of years lost due to that disease. The number of DALYs lost due to asthma worldwide has been estimated to be about 15 million/year Worldwide, asthma accounts for around 1% of all DALYs lost, which reflects the high prevalence and severity of asthma. Asthma was the 25th leading cause of DALYs lost worldwide in 2001. The number of DALYs lost due to asthma is similar to that for diabetes, liver cirrhosis or schizophrenia. The burden of disease in terms of DALYs has not been calculated for most Asian countries: however some indirect attempts have been made. While developing a draft measure of the burden of diseases in Sri Lanka using DALYS.14 computation was done for 100 disease categories identified to reflect the disease pattern in Sri Lanka. Factors that were considered for the calculation of DALYs were incidence, degree of disability, duration of illness and age at onset. Injuries, ischaemlc heart disease, asthma, disease of the pulmonary circulation and burns contribute to 55% of the burden of disease in Sri Lanka. The highest burden was due to non-communicable diseases. as their duration and degree of disability are high. YLDs contribute nearly two-thirds of the DALYs worldwide and are particularly important in developing countries where infant and child mortality is still high. These were estimated for India under the global burden of disease study in 1990. A study estimated different causes of YLDs in rural areas of India. Pneumonia was the top cause responsible for YLDs; heart attacks bronchitis and asthma had lower YLDs.15 For children living in developing countries. A study has identified the major causes of ill health that are Inadequately covered by established health programmes.16 Injuries and non-communicable diseases notably asthma, epilepsy, dental caries, diabetes mellitus and rheumatic heart disease have been identified as growing in significance. In countries where resources are scarce, it is to be expected that increasing importance will be attached to the development and implementation of measures against these problems. This study evaluated the major causes of ill health that are not covered by global health programmes among children in developing countries. Assessments were based on a set of death and disability estimates. Causes of death were classified as: (1) infectious, maternal, perinatal and nutritional conditions: (2) non-communicable diseases: or (3) injuries. DALYs were used in estimates of disease burden. Childhood disease burden In 1990 among regions, age groups and sex were compared using DALYs/1000 population and presented in table form. Among childhood disease burdens infectious, perinatal and nutritional disorders ranked first (72%), followed by non-communicable diseases including asthma (15%) and injuries (13%); these values are significantly higher in developing countries than in developed regions. This study has special relevance for South Asia where programmes directed against infectious, nutritional and perinatal disorders need to be applied to the control of non-communicable diseases. The importance of community involvement, family education and social marketing needs emphasising in the formulation and implementation of these control measures. In the last decade a number of quantitative epidemiological studies of specific diseases have been undertaken in developing countries. This allows for the first time, estimation of the total burden of disease (mortality and morbidity) attributable to use of solid fuels in adult women and young children who jointly receive the highest exposures because of their household roles. Few such studies are available to date for adult men or children over 5 years of age. A paper has evaluated the existing epidemiological studies and applied the resulting risks to Indian households dependent on such fuels (>75%).17 Allowance was made for the existence or improved stoves with chimneys and other factors that may lower exposure. Attributable risks were calculated in reference to the demographic conditions and patterns of each disease in India. Sufficient evidence was available to estimate risks most confidently for acute respiratory infections chronic obstructive pulmonary disease and lung cancer. Estimates for tuberculosis asthma and blindness were of intermediate confidence. Estimates for heart disease had the lowest confidence. Insufficient quantitative evidence is currently available to estimate the impact on adverse pregnancy outcomes (e.g. low birth weight and stillbirth). The resulting conservative estimates indicate that 400,000–550,000 premature deaths can be attributed annually to use of biomass fuels in these population groups due to respiratory diseases including asthma.
• Economic Costs
Patients with difficult-to-treat or suboptimally controlled asthma consume a disproportionate share of asthma healthcare resources.18 Treatment strategies that minimise exacerbations may decrease the need for unscheduled medical services reduce emergency department visits and minimize asthma-related hospitalisations. Poor control of symptoms is a major issue that can result in adverse clinical and economic outcomes. Prescribing costs are the most obvious visible expense in asthma care but these are only the tip of the iceberg. We need to take all factors into account when considering the overall cost of asthma treatments and recognise that treatment which results in better asthma control may reduce both direct and indirect costs. To assess this accurately health economic evaluations need to be undertaken in relevant settings on representative populations. They need to use appropriate measures of asthma outcome. Drug related costs need to take into account savings made by decreased costs of other prescribed medication and patient factors. We need information that is applicable to the types of patients we see in the real world to make proper cost analyses. Such information can come from good-quality randomised trials, retrospective analysis of research databases and observational studies, or using primary care clinical and prescribing databases.19 Asthma self-management training can significantly affect the health status and resource use of patients with chronic asthma.20 A randomised controlled trial on chronic asthmatic patients was conducted in a tertiary care centre in India. The intervention group (153 patients) received four training sessions in addition to the regular care provided to the control group (150 patients). Health status and resource use were measured at baseline and over a 1-year follow-up period. The intervention group had significantly better health status (measured by breathing ability) fewer productive days lost and lower resource use (hospitalisations and emergency room visits) than the control group. Total annual costs (direct and indirect) were also lower, although physician costs were not included in the assessment. It was concluded that the incorporation of asthma self-management training as part of clinical management of asthma can result in improvements in health status and reductions in hospital use.
- MasoliM, FabianD, HoltS, BeasleyR. The global burden of asthma: executive summary of the GINA Dissemination Committee Report Allergy 2004;59:469–78.
- ChenYZ. National Cooperation Group on Childhood Asthma [A nationwide survey in China on prevalence of asthma in urban children (in Chinese”). Zhonghua Er Ke Za Zhi 2003;41:123–27.
- The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma allergic rhinoconjunctivitis and atopic eczema: The International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998;12:315–35.
- ChakravarthyS, SinghRB, SwaminathanS, VenkatesanP. Prevalence of asthma in urban and rural children in Tamil Nadu. Nael Med J India 2002;15:260–63.
- SinghD, AroraV, SobtiPc. Chronic and recurrent cough in rural children In Ludhiana. Punjab. Ind Pediatr 2002;39:23–29.
- ParameshH. Epidemiology of asthma In India. Ind J Pediatr 2002; 69:309–12.
- GuptaD. AggarwalAN. KumarR. Jindal SK Prevalence of bronchial asthma and association with environmental tobacco smoke exposure in adolescent school children in Chandigarll. North India. J Asthma 2001;38:501–07.
- MistryR, WicckramasinghaN, OgstonS, SinghM, DevasiriV, MukhopadhyayS. Wheeze and urban variation in South Asia. Eur J Pediatr 2004;163:145–47.
- HopeRA, BanghamCR. The prevalence of immediate positive skin tests in Nepalese children. Clin Allergy 1981;II:263–71.
- KhanJA Saghir 5, Ta.5umG. HusainSF. An audit on hospital management of bronchial asthma J Pak Med Assoc 1995;45: 298–300.
- SinghM, MathewJL, MalhiP, NaiduAN, KumarL Evaluation of quality of life in Indian children with bronchial asthma using a disease specific and locally appropriate questionnaire. Acta Pediatr Scand 2004;93:554–55.
- WijewardeneK. SpohrM. An attempt to measure burden of disease using disability adjusted life years for Sri Lanka Ceylon Med J 2000;45:10–115.
- IndrayanA, WysockyMJ, KumarR, ChawlaA, SinghN. Estimates of the years of life lost date to the top nine causes of death in rural areas of major states in India in 1995. Notl Med J Ind 2002;15:7–13.
- DeenJL, VosT, HuttlySR, TullochJ. Injuries and noncommunicable disease emerging health problems of children, in indeveloping coutries. Bull World Health Organ 1999;77:518–52–1.
- SmithKR. National burden of disease in India from Indoor air pollution. Proc Notl Acad So USA 2000;97:13286–93.
- BootmanJL, CrownWH LuskinAT. Clinical and economic effects of suboptimally controlled asthma Manag Care interface 2004;17:31:36.
- GhoshC, RavindranP, Josh,M, SteamsSc. Reductions In hospital use from Self management training for chronic asthmatics. Soc Sci Med 1998;48:1087–93.
- ClelandJ, ThomasM, PriceD. Pharmacoeconomics of asthma treatment, Exp Opin. Pharmacother 2003;4:311:18.
Allergic asthma is a disease characterized by intermittent airway obstruction that causes difficulty in breathing and, in the most severe cases, death from asphyxiation. Ultimately, airway obstruction is mediated by hyperresponsive bronchial smooth muscle, secreted airway glycoproteins, and inflammatory debris produced by airway goblet cells and other cells, as well as edema or swelling of the airway wall. Although the precise basis for the development of airway inflammation in patients with asthma is not fully defined, recent developments in experimental models have helped us understand some basic mechanisms that take place in at least some forms of asthma. Mouse models are not exact replica of human asthma; however, they have helped to understand some of the basic mechanisms involved in the production of this disease.1 Observations from mouse models of allergic asthma support many existing paradigms, although some novel discoveries in mice are yet to be verified in humans.
• Gross Features
Most of the classic descriptions of the pathologic patterns of asthma have been derived from autopsy studies.2–4 These studies based on individuals who died in status asthmaticus describe overinflation of the lungs and mucus plugs occluding medium-sized bronchi, small bronchi, and bronchioles. In recent articles, however, there are descriptions derived from bronchoscopic biopsies.5–13 These studies have provided a bronchoscopic and pathologic description of early and mild forms of the disease. It is well known that overinflation is seen in asthmatic patients. This gross appearance is seen in individuals who die in status asthmaticus, but the lungs may appear normal between attacks. The lungs fill the chest cavity during status asthmaticus and do not collapse when the pleural space is opened. Overdistention must be distinguished from emphysema because emphysema implies destruction of alveolar parenchyma, which rarely occurs in asthmatic patients, most likely because the asthmatic attacks are intermittent. In contrast, bronchiectasis can be seen as a complication of asthma and has been described in 15% to 20% of patients.2–4
• Microscopic Features
Airways of asthmatic patients may be normal or they may show only mild histologic changes between asthmatic attacks. Mucous plugs made of heavily viscous inspissated mucus fill both bronchi and bronchioles. These plugs appear to be produced by both submucosal gland hypertrophy and goblet cell hyperplasia. It has been reported that the proportion of both mucin and goblet cells in the epithelium may be up to 3 times higher in asthmatic patients than in controls.14
• Airway Remodeling
A series of progressive structural changes of the airways is known as airway remodeling. These changes most likely occur as a result of repeated episodes of inflammation with production of matrix proteins and growth factors by inflammatory cells.15 It is also possible that repeated damage to the epithelium, with subsequent repair, may lead to airway remodeling.16 It is conceivable that airways that undergo significant remodeling may not respond to bronchodilators because of reduced elasticity, increased muscle mass, and mucosal edema.17
• AIrway Epithelium
A number of well-known changes occur in the airway epithelium of asthmatic patients. Goblet cell hyperplasia is a common histopathologic finding, although not specific for asthma.18, 19 Other common findings are the presence of mucus plugs20 and squamous metaplasia. Areas of denuded epithelium are seen occasionally. It has been proposed that patients with significant epithelial desquamation present with persistent rather than intermittent asthma12 as a result of direct exposure of nerve endings to factors that would trigger the inflammatory response; whorls of detached epithelium may form Creola bodies and Curschmann spirals. The airway wall can be thickened from edema, an increase in smooth muscle, and an increase in the size of the submucosal mucous glands. Airways are infiltrated by eosinophils. Mucus may contain many eosinophils with Charcot-Leyden crystals.21
• Reticular Basement Membrane
Light microscopy has revealed that what has been interpreted in the old literature as basement membranes are usually thicker in asthmatic individuals than in nonasthamtic individuals.2, 8 However, in a manner reminiscent of the situation seen by the pathologist in collagenous colitis, what light microscopic studies refer to as “basement membrane thickening” has been determined by ultrastructural and immunohistochemical studies to be deposition of types III and V collagen as well as fibronectin beneath the true basement membrane that is usually of normal thickness.8 The mechanism of production of this reticular basement membrane is controversial but it has been suggested that activated eosinophils are involved through the production of cytokines such as transforming fibroblast growth factor (TGF-β), which is a potent profibrotic cytokine.22 In some studies, basement membrane in central airways from nonasthmatic individuals measures between 6 and 10 mm, but in asthmatic patients it ranges from 11 to 22 mm.23
• Bronchial Submucosal Glands
Bronchial submucosal glands are increased in size in individuals with asthma, but at some stage, patients with chronic bronchitis also show increased bronchial submucosal glands, which is the basis for the Reid index in chronic bronchitis.24–27 In fact, increased bronchial submucosal glands apparently are found in individuals with recent onset of asthma rather than in patients with long-standing asthma.28
• Smooth Muscle
Patients dying of status asthmaticus have a 2-fold to 3-fold increase in the amount of airway smooth muscle, especially in the medium-sized bronchi. This finding has been well documented by several morphometric studies.29–31 Smooth muscle thickness in asthmatic patients appears to increase with age.32 It has been proposed that myofibroblasts play a role in this smooth muscle thickening and also in the reticular basement membrane thickening because of the production and deposition of fibronectin in the bronchial mucosa.33 Presence of myofibroblasts has been associated with local expression of TGF-β produced by eosinophils and fibroblasts;34 some studies show that basal TGF-β1 levels in the airways are elevated in atopic asthma. The TGF-β1 is upregulated 24 hours after allergen stimulation.35 It is thought that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-β1 plays an important role in airway wall remodeling in asthma.
• Immune Responses In Asthma
Asthma is a chronic inflammatory condition, and evidence of inflammation can be observed in mild, moderate, and severe disease. However, the relative magnitude, type of inflammatory cells, and site of the inflammatory infiltrate may differ among patients. Many cells are involved in the immune and inflammatory responses to allergens in asthma; these include T cells, eosinophils, mast cells, and neutrophils. The role of the activated T lymphocyte in controlling and perpetuating chronic inflammation in asthma has received much attention.36 In some studies, T cell activation can be related to measures of asthma severity, such as the degree of airway narrowing or airway hyperresponsiveness (AHR), as well as the bronchial eosinophil response.37 The association between tissue eosinophilia and asthma is strong, but the degree of tissue eosinophilia varies with each case and with the duration of the terminal episode.38–39 Dendritic cells and their subtypes are key antigen-presenting cells that respond rapidly to antigenic challenge with kinetics similar to those of neutrophils.40 They form an interface between innate and adaptive immunity and orchestrate both primary and secondary immune responses.41 They are present throughout the respiratory tree and number approximately 500 cells per mm2 within the epithelium.42 Inflammatory cells and immune responses are regulated by a number of immune mediators that are secreted from inflammatory and structural cells. In this review, we focus on cytokines and chemokines and their possible role in the immunobiology of asthma.
• Cytokines and Chemokines
Cytokines are a family of small glycosylated proteins that are involved in cell-to-cell signaling, cellular growth, differentiation, proliferation, chemotaxis, immunomodulation, immunoglobulin isotype switching, and apoptosis. The actions of cytokines are mediated through specific cytokine receptors on the surfaces of target cells. Although cytokines usually have effects on adjacent cells, they can act at a distance and can have effects on the cells producing the cytokines themselves. Many of these cytokines exhibit pleiotropy and have overlapping functions, making their individual roles in the pathogenesis of asthma and allergic disease difficult to differentiate. Among these cytokines are T cell-derived molecules such as the so-called T helper-1 (Th1) cells [interleukin (IL)-2, interferon (IFN)-g, and IL-12], Th2 cells (IL-4, -5, -9, -13, and -25), Th3 or T regulatory cytokines (IL-10) and transforming growth factor beta (TGF-β)], and Th-17 cells (IL-17A and -17F), all of which are involved in the regulation of cell-mediated and humoral immunities. Although the distinction between Th1 and Th2 cells in humans is not as clear as in mice, there is overwhelming evidence in the literature supporting the notion that allergic inflammation is driven by an imbalance between Th1 and Th2 cytokines, favoring the Th2 arm of the immune response. Recently, Th-17-associated cytokines were also implicated in asthma immunobiology
• IG E and Cytokines
A central mediator in atopic asthma is the IgE antibody, which is produced by sensitized allergen-specific B cells. Allergens are antigens that can (a) elicit hypersensitivity or allergic reactions and (b) increase IgE levels in the serum in susceptible subjects subsequent to stimulation. By presenting the allergen fragments in conjunction with the major histocompatibility complex (MHC), B cells can activate specific Th2 cells to produce numerous cytokines, leading to further B cell activation and antibody release. IgE antibodies bind to the high-affinity IgE receptor Fc epsilon receptor I (FceRI) that is present on mast cells, eosinophils, and basophils, thereby sensitizing these cells to antigen exposure. Subsequently, cross-linking of adjacent IgE-FceRI complexes by allergens triggers (a) the degranulation of cytoplasmic vesicles containing histamine and (b) the de novo formation of eicosanoids and reactive oxygen species. This results in smooth muscle contraction, mucous secretion, and vasodilatation, all of which are hallmarks of asthma. IgE-producing B cells play a critical role in allergic inflammation; consequently, factors responsible for their activation-namely IgE-associated cytokines such as IL-4, IL-9, and IL-13.
• Eosinophils and Asthma
Eosinophils are prominent in allergic airway disease and are still considered by many to be the hallmark of asthma. Otherwise, eosinophils form part of the host defense against parasitic infestation. The biological activity exerted by these cells is largely attributable to their release of prestored granular proteins, including eosinophil cationic protein, eosinophil peroxidase, and major basic protein. These potent cytotoxic proteins have been found in high concentrations in the sputum of asthmatic patients and are thought to play an important role in the epithelial damage observed in asthmatic patients. In addition to cytotoxic proteins, eosinophils can synthesize and release oxygen radicals and lipid mediators (e.g., LTB4, LTC4, and PAF), as well as numerous cytokines (e.g., IL-1, -2, -3, -4, -5, -6, -10, -12, and -13; TNF-α and GMCSF) and chemokines (e.g., IL-8, RANTES, and MIP-1a)
• Airway Remodeling
It has long been known that architectural and structural changes occur in the airways of asthmatic patients. These changes include collagen (type III and IV) and fibronectin deposition, increased thickness of subepithelial basement membrane, goblet cell hyperplasia, increased ASM mass and size, angiogenesis, and fibrosis, all of which collectively contribute to the phenomenon known as airway remodeling. The functional consequences of airway remodelling include persistent AHR and mucous hypersecretion, which contribute to increased susceptibility to asthma exacerbations. The mechanisms involved in airway remodeling are poorly understood, but research in the past three to five years suggests that the balance between matrix metalloproteinases and tissue inhibitors of metalloproteinases may play a role in this process. Moreover, the increase in Airway Smooth Muscle content, along with a change in the phenotype of fibroblasts to contractile myofibroblasts, may explain the permanent reduction in airway caliber, which is steroid insensitive and typical in patients with severe forms of the disease. The predominant remodeling-associated cytokines include TGF-β, PDGF, IL-6, IL-11, IL-13, IL-17, and IL-25.
• Immunomodulatory Cytokines
It is now generally accepted that adult atopic disease is characterized by the expression of T cell immunity to common airborne environmental allergens, which is polarized toward the Th2-cytokine profile; in nonatopics, Th1- skewed immunity is observed. As a result, shifting the balance from Th2 to Th1 immunomodulatory cytokines such as IL-10, IL-12, and IFN-γ may be important for the treatment of allergic inflammation. IL-10 is primarily known as an inhibitory cytokine; however, it can exert both immunosuppressive and immunostimulatory effects. IL-10 was originally identified as a product of murine Th2 cells, but in humans IL-10 is produced by Th0, Th1, and Th2 cells and also by activated monocytes, mast cells, and macrophages.43 IL-10 curtails the effects of proinflammatory cytokines (e.g., TNF-a, IL- 1b, IL-6, IL-8, and MIP-1a) released during an allergic reaction. In addition, IL-10 can inhibit eosinophil survival and migration by preventing the release of chemoattractants such as RANTES and IL-8 from human ASM cells.44 Its other actions include downregulation of the IL-4-induced isotype switching of activated B cells45, which prevents IgE synthesis. IL-10 may inhibit Th2- driven inflammation, and it is also known to inhibit the differentiation of Th1 cells, thereby preventing the release of IFN-γ and IL-2. Other members of the IL-10 family of cytokines are IL-19, IL-20, IL-22, and IL-24. Like IL-10, they are considered to be anti-inflammatory cytokines and are produced by a variety of cell types, including monocytes, keratinocytes, mast cells, and lymphocytes. IFN-γ is the most important cytokine in cell-mediated immunity; it controls the balance of Th1/Th2 development. IFN-γ is produced by Th1 cells and has an inhibitory effect on Th2 cells. IFN-γ inhibits allergic responses by preventing isotype switching of IgE and IgE production in B cells.46 The main sources of IFN-γ are Th1 cells. However, IFN-γ can also be produced by cytotoxic T cells and natural killer (NK) cells. Importantly, IFN-γ stimulates monocytes, NK cells, and neutrophils to increase their cytokine production, phagocytosis, adherence, respiratory burst, and NO production, thereby promoting cell-mediated cytotoxic responses at the site of inflammation. IL-12 is produced by antigen-presenting cells including B cells, monocytes, macrophages, Langerhans cells, and dendritic cells, as well as neutrophils and mast cells. IL-12 promotes T cell differentiation toward a Th1-mediated response by stimulating NK and T cells to produce IFNγ while suppressing the expansion and differentiation of IL-4 secreting Th2 cells.47 The biologically active form of IL-12 is a heterodimer consisting of the p40 subunit and the p35 subunit, which are expressed by different genes. The effects of IL-12 have been extensively studied in small animal models of allergic inflammation and consistently demonstrate that this cytokine is involved in reduction of allergen-specific IgE, abolition of AHR, and airway eosinophilia.48, 49 However, this effect of IL-12 is critically dependent on the timing of its administration. The most effective protection against allergen-induced inflammation is observed when IL-12 is administered early in the active sensitization process and thus when it can act in synergy with IL-18.50 IL-18, also known as IFN-g-inducing factor, is a potent inducer of IFN-γ production by T cells, NK cells, and B cells.51
Chemokines are small cytokines (8-10 kDa) involved primarily in a process called chemotaxis, whereby they attract and regulate leukocyte trafficking into the tissues by binding specific seven-transmembrane-spanning G proteincoupled receptors. To date, more than 40 chemokines have been described and have been classified into four subclasses according to their structure: CXC, CC, C, and CX3C. The two main groups are CXC (a chemokines) and CC (b chemokines). CXC chemokines include IL-8 and IP-10, which primarily target neutrophils. Eotaxin, RANTES, MCP-1-MCP-4, macrophage inhibitory protein (MIP)-1a, and MIP-1b are typical CC chemokines, which target monocytes, T cells, and eosinophils. For this reason, CC chemokines are thought to have the greatest relevance in the pathogenesis of asthma. Although the primary role of chemokines is chemotaxis, chemokines have a variety of other functions, including direct effects on T cell differentiation. MIP- 1a, MIP-1b, and RANTES can promote the development of IFN-γ-producing Th1 cells by stimulating IL- 12 production from antigen-producing cells. However, MCP-1, MCP-2, MCP-3, and MCP-4 can increase T cell production of IL-4 and can decrease antigen-producing cells' production of IL-12, resulting in a Th2 phenotype.
• Asthma, Infection and Immune Responses
The reasons for the increasing prevalence of allergic respiratory diseases in developed countries and in undeveloped countries that develop a Western lifestyle remain unclear. For many years, lower respiratory tract infections in early life have been recognized as primary triggers of asthma exacerbations in young children. Using both epidemiological and virology data, prospective studies have convincingly shown that viral and not bacterial respiratory infections precipitate reactive airway symptoms.52 It is now believed that the development of bacteria-induced, non-wheezing lower respiratory tract infection in childhood may protect against the development of atopy and asthma in later life. Microbial exposure helps to skew the immune response away from allergic phenotype and toward the normal adult nonatopic immune response.53 The longer the immune system takes to adapt postnatally to its functionally mature state, the greater is the risk for allergic sensitization.54 The hygiene hypothesis suggests that decreasing levels of exposure to infections and/or commensal microbial stimuli in developed countries, particularly during the induction of primary Th1/Th2 responses to allergens in early life, may be responsible for the increased prevalence of asthma. There is ample epidemiological evidence to support this hypothesis.55 The reported increase in atopy inversely correlates with a steady decline in the extent to which people in Western societies are exposed to infectious diseases such as whooping cough, measles, tuberculosis, and influenza.56 Bacterial lipopolysaccharide (LPS) or endotoxin has been suggested as a potential mediator of these effects. LPS is a major component of the outer membrane of ubiquitous gram-negative bacteria. Gram-negative infections make up a significant proportion of clinical respiratory tract infections among children in early life; thus, there is ongoing and chronic environmental exposure to gram-negative organisms and their components/products. In common house dust, LPS makes up a significant proportion of dust weight, and a significant correlation has been reported between domestic LPS exposure and clinical severity of asthma in adults.57 Toll is a Drosophila receptor that is involved in antifungal immune responses. Toll like receptors (TLRs) are a large family of evolutionarily conserved receptors from Toll that sense invasion by microorganisms through the recognition of specific pathogen-associated molecule patterns and that produce immediate innate responses. To date, 10 TLRs (TLR1- 10) have been identified in humans and in mice.54 TLRs are single-transmembrane-domain receptors that have a cytoplasmic signaling portion homologous to the IL-1 receptor. Although the TLRs differ in their extracellular domain structure, similar cytoplasmic domains allow TLRs to use the same signaling molecules. Different TLRs recognize different ligands. TLR3 is a cell-surface receptor for doublestranded RNA; hence, it may be implicated in viral recognition. TLR5 is specific for bacterial flagellin, whereas TLR9 is a receptor for unmethylated CpG motifs, which are abundant in bacterial DNA. In mammals, TLR4 is the principal receptor responsible for LPS induced signal transduction.58 Recognition of LPS by TLR4 is aided by two accessory proteins: CD14 and MD-2. TLR4 is expressed at particularly high levels by cells of the innate immune system, such as monocytes, dendritic cells, macrophages, and endothelial cells.59–62 TLR4 expression is thought to be related to LPS sensitivity,63 and it was recently demonstrated in murine macrophages that TLR expression and function decline with age.64, 65
Bronchial asthma is a complex, chronic disease of the airways that is characterized by reversible AHR, airway remodeling, and inflammation. These pathological and physiological changes occur even in mild asthmatics and can be detected in asthmatic children. Within the past decade, one of the most striking advances in study of asthma has been the recognition that cytokines and chemokines play an integral role in orchestrating, perpetuating, and amplifying the underlying processes of this disease. Only by understanding the immunobiology of asthma can one begin to provide a rational basis of novel drug design and make progress in identifying those individuals at risk for this disease.
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Pediatric asthma is a major global health problem, which exerts a substantial burden on the family, healthcare services and on the society as a whole. Although the first symptoms of asthma can occur at any age, recurrent episodes of wheezing and airway obstruction manifest before the age of 6 years in most patients. This suggests that asthma, at any age, is likely to originate in childhood or earlier, therefore, observation in children and models of early life or infant airway injury and repair will provide important clues to the inception and pathogenesis of this disorder. It is believed that the expression of the asthmatic phenotype is dependent upon two major factors: a genetic predisposition and environmental interactions. It is the combination of these inferences that ultimately determines whether asthma develops and what time these processes manifest. There is an inverse association between infectious burden in early life and the development of atopy and asthma. Children who have frequent respiratory infections and pneumonia have a lower prevalence of asthma. Such findings suggest that increased exposure to infections in infancy may protect against the development of asthma. Several investigators have proposed the “hygiene hypothesis” as a mechanism by which these protective effects are produced. The hygiene hypothesis postulates that reduced exposure to environmental influences (such as infections) that produce a Th1 type immune response has led to a persistence of “fetal” immune responses that are Th2 skewed and that persistence of Th2 type responses has led to increased, susceptibility to allergic disease. During early childhood there is a transition from the fetal Th2 cytokine phenotype to the adult Th1 cytokine phenotype. The timing of this transition is influenced by both environmental and genetic factors. Microbial exposure is thought to be the major environmental trigger for the maturation of immune responses in the newborn.1 Moreover, there are indications that exposure to an environment with a high bacterial load is particularly important in the first year of life in order to acquire protection from asthma and other allergic diseases. Keeping, this in mind, this follow up study of infants, has been designed to study the effect of bacterial infections on the neonate immune response.
• Increasing Prevalence of Asthma
The continuous increase in asthma can not only be due to the genetic defects but may be due to the environmental factors. Viewing the neonatal immune system and exposure to infections we need to know how infections in infancy can delay the adverse effects of immune responses. The Th2 biased immune response of the neonate switches to Th1 response with time by various harmful and harmless exposures to microbes. But with increasing cleaner environments and thus decreased exposures the switch does not take place at the appropriate time during infancy, and results in the persistence of Th2 responses which leads to the fatal allergic reactions. Evidence from the ISAAC study showed that the distribution of childhood asthma varies between global populations from less than 2% to approx 33% of the population. Furthermore, the prevalence also appears to vary within countries. Prevalence has been recorded to be 17–30% in the UK, New Zealand, and Australia, whereas low prevalence (1-7%) areas include Eastern Europe, China and South Asian countries. For example across India it ranges from less than 5% to approximately 20%.2 This variation has been attributed to the healthcare in the western world, which leads to a diminished or different exposure to infection early in life. This exposure renders the immune system susceptible to an atopic response3 which also includes childhood respiratory disease, allergen exposure, dietary changes4 and socioeconomic differences.5 Till date, there have been few studies on the role of natural killer cells and other components of the innate immune response, in this regard, but this should be studied in both animal model and in humans. Taking into account the complexity of asthma, the cost of time and money as well as the problems faced by the asthma patients one has the reason to justify the extensive efforts put by the researchers to relieve the suffering caused by these disorders. The immune system serves to protect the host from infection and cancer but some of the inappropriate responses of the immune system can lead to variety of diseases. The common dysfunctions of the immune system are allergies and asthma, and both of them are serious health problems. Exposure to the antigen or allergen triggers an IgE mediated release of molecules that cause symptoms ranging from sneezing and dermatitis to inflammation of the lungs in an asthmatic attack.
Asthma has puzzled medical scientists for centuries. It's an inflammatory disease of the lung characterized by acute nonspecific airway hyper responsiveness in association with chronic pulmonary inflammation. It has been found that altered smooth-muscle responses cause increased airway resistance and increased responses to nonspecific stimuli which results in a phenomenon known as airway hyperactivity. Moreover interactions between eosinophils, mast cells, T cells, B cells and IgE antibodies result in airway inflammation.6 Asthma is the most common chronic disease in children in developed countries. Pediatric asthma is a major global health problem, which exerts a substantial burden on the family, healthcare services and on society as a whole. Till now asthma prevalence studies lack consistency, which is possibly because of the ill defined diagnostic criteria and non standardized study protocol.7
• Role of Immunity and Allergy
One of the striking advances in the last decade has been the recognition that cytokines and chemokines play a critical role in orchestrating, perpetuating and amplifying the inflammatory response leading to the pathophysiology of asthma.8 The inflammation characteristics of asthma are different from other respiratory infections. Subsets of T-helper (Th) lymphocytes have been defined and are distinguishable by a differing pattern of cytokine release. Th1 type cells stimulate the recruitment and activity of macrophages and mononuclear phagocytes and are involved in the cellular immunity activated by microbial antigens typically resulting in IgG antibody production without an increase in IgE.9 They produce interleukin (IL)-2, interferon (IFN)-γ and tumor necrosis factor. Th2 responses are important in the allergic response and asthma, producing the cytokines IL-4, −5, −6, −10 and −13 and are involved in the humoral immune response with elevated IgE levels and eosinophil.9 Complex antagonistic interrelationship exists between the two subsets and the cytokine milieu. Th2 cytokines play an important role in the pathophysiology of allergic diseases, including asthma and have shown to be very useful therapeutic targets in the future management of allergic diseases. Considering this several approaches inhibiting these cytokines are now being tested in clinical trials or are in active development.8 Soluble interleukin (IL)-2 receptor levels are raised in children with asthma, suggesting that activated T cells are important in childhood asthma. Current data supports the predominance of a T helper 2 phenotype in allergic asthma.10 Allergens induce CD4+ T helper cells to produce type-2 (Th2) cytokines such as IL-4, IL- 5, IL-6, IL-10 and IL-13. IL-5 attracts and activates eonsinophils while IL-4 is essential for B cell isotype switching to Ig E. CD 8 + T cells may lead to Ig E class switching via IL-13 rather than IL-4. These events lead to eosinophilic bronchitis, mucus-hyper secretion and bronchial smooth muscle contraction.11 However, some studies suggest that T helper type 1 (Th 1) cytokines such as IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-γ) and IL-15 may promote allergic inflammation as well12,13. Leukocyte migration is essential for immune surveillance of the body's tissues, and for focusing immune cells to sites of antigenic challenge. The control of leukocyte migration depends on the combined actions of the various adhesion molecules, as well as a vast array of chemotactic cytokines (chemokines) and their receptors. The chemokine receptors comprise two groups, th e CC receptors 1 to 8 (CCR 1-8) that bind CC chemokines, and the CXC receptors 1–4 (CXCR 1–4), which bind CXC chemokines14,15. In general, the CC chemokines and their receptors effect the migration of monocytes, eosinophils, basophils and T cells,16 whereas CXR1 and CXCR2, which are two IL-8 receptors, effect the migration of neutrophils.14 Many recent findings indicate that chemokine receptors are differentially expressed on memory T cells depending on their polarization17,18 with Th 1 lymphocytes expressing CCR5 and CXC3, and Th2 lymphocytes CCR3, CCR4, and CCR8. As a consequence, selective chemotactic stimuli contribute to the differential positioning of Th1 and Th2 cells within tissues17,19. These results indicate that differential expression of chemokine receptors in Th1 versus Th2 system can serve as markers of these responses and tools to modulate polarized versions of T cell-dependent immunity. The decline in infectious diseases is due in part to the development of better sanitation and a cleaner living environment. Lately, various scientists have proposed a theory known as the Hygiene Hypothesis as the cause of increasing asthma prevalence. According to this theory the society has been too successful in its fight against infectious organisms and has eliminated contact with many harmless bacteria and microbes that actually help the immune system build its defenses against more toxic infections. The immune system consists of two basic parts: Th1 lymphocytes, which are specialized white blood cells that directly attack infected cells, and Th2 lymphocytes, which try to prevent foreign organisms from invading cells. Researchers speculate that newborn's bodies primarily rely on Th2 response and the Th1 system can only develop by being exposed to “practice” infections with microbes that cause no harm. Martinez and Holt, 1999 have proposed that the hygiene hypothesis postulates that reduced exposure to environmental influences (such as infections) that produce a Th1-type immune response has led to a persistence of “fetal” immune responses that are Th2 skewed and that persistence of Th2 type responses has led to increased susceptibility to allergic disease.20 Studies indicate that exposure to an environment with a high bacterial load is particularly important in the 1st yr of life in order to acquire protection from asthma and other allergic diseases.21 Moreover, in humans there is an association between protection against allergy and the presence of antibodies specific for orofecal microbes but not the presence of antibodies against airborne viruses.22 Pregnancy is considered as a Th2 state and there is some evidence that the neonatal immune response is biased toward theTh2 type. When a mother is pregnant, her pregnancy is controlled by cytokines, and requires a suppression of her immune system with a predominance ofTh2 cytokines in order not to reject the baby. A “Thl” driven immune system would treat the baby as a graft from the father, thereby leading to miscarriage. After the Th2-skewed baby is born, the mother's immune system changes back to normal very quickly and breast milk quickly starts the process of changing the baby's balance towards Thl dominance. Microbial infections early in infancy can protect the baby from the development of atopy and asthma later, as the stimulus for normal postnatal maturation of the immunoinflammatory response may be provided by microbial stimulation.23,24 The first year of life is the time when the “difference” between “vaccine” and “natural” immunity is important. The portal of entry of antigens and switching pathways of the Th1 system from Th2 type teach and mature the immune system which in turn help to prevent both allergy development and auto-immune diseases. Cytokines, which protect the fetus from cytokine immune responses, could also affect the development of the fetal immune system. High levels of Th2 like cytokines could reduce secretion of IFN γ and other Th1 cytokines from the fetus, which could bias the developing neonatal immune system towards production of Th2 like cytokines and promote allergy. This concept is supported by studies of cytokine productions from neonatal T cells, which have generally been found to produce relatively low levels of IFN γ and to overproduce Th2 like cytokines. Michel et al (1992) has reported that lipopolysaccharide inhalation (20mg) could induce a local bronchial inflammation as well as a systemic inflammatory response in asthmatic subjects.25 Endotoxins are very potent proinflammatory substances26 present in a variety of domestic25 and occupational dusts.27 The mechanism by which endotoxin exposure may protect against the development of atopic immune responses and diseases are not fully understood. It has been suggested that by the time a child reaches school age, high levels of environmental exposures to endotoxin have resulted in a marked suppression of the capacity for the cytokine production in response to activation of the innate immune system. Studies have indicated that exposure during the first year of life to stables and other aspects of farm life that are likely to reflect exposure to microbial products has a strong protective effect against the occurrence of asthma and atopy at school age. It is currently accepted that respiratory viral infections are important “trigger factors” in the development of allergic respiratory diseases, particularly asthma.28 Unlike viral infections, bacterial infections do not generally trigger asthma and in fact, early exposure to bacterial products may protect the individual from development of atopy and asthma later in life.23 This mechanism further contributes to the variations in the frequency of atopy and asthma that have been reported between first- and second-world countries and points to an inverse relationship between disease prevalence and socioeconomic status. Various workers have demonstrated different kinds of cytokine productions at the time of birth and on acquiring infection during infancy. Karlsson et al. (2002) have demonstrated that gram positive bacterial strains induce high levels of IL-12 in both cord cells and adult cells, where as gram negative bacterial strains are poor inducers of IL-12.29 Apart from the genetic parameters environmental influences are also important determinant in the development of an atopic or asthmatic phenotype. Primary exposure to environments those rich in airborne antigens like house dust mite and orally encountered antigens (Bjorksten et al. 1998) can lead to atopy in genetically affected individuals. The effects of air pollutants, lifestyle factors and urbanization on the development of atopy and asthma are controversial. The environmental factors, which account for atopy and asthma include urban versus rural settings, dietary factors, exercise patterns, experienced infections, or the use of antibiotics which might influence deviation of the immune system away from Th2 responses and towards Th1 responses. Infants who are exclusively breast-fed appear to have decreased risk for development of food allergy than infants who are not breast-fed or who have other food exposures. Moreover urbanization is thought to be a key feature in the development of asthma and atopy. Also decreased incidence of infection and frequent use of antibiotics may also contribute to the development of atopy. Immunization conveys the same immunity to a specific disease as catching the disease does. It's the same immune mechanism and results in the same immune response. Natural immunity does provide higher levels of protective antibodies than vaccination, but the type of protection is the same. However, relying on the natural immunity only, means risking the neonate's life and leaving a chance for the disease to develop with severe complications. It was observed by Ota et al., (2002) that Mycobacterium bovis, Bacillus Calmettle Guerin (BCG)3 vaccination induces a potent Th1-type immune response at birth in humans as in mice.30 Today it is the time when scientists are trying to eradicate diseases right from the root with the help of DNA based medicines. Apart from the mutations in interleukin region, there are studies, which strongly suggest that adenosine plays an important role in the pathogenesis of disorders like asthma, COPD and the intestinal disorders.31 Adenosine is a purine nucleoside that is produced by dephosphorylation of 5' AMP by the membrane associated enzyme 5 nucleotidase and is liberated intracellularly by cleavage of the high energy bonds of adenosine triphosphate, adenosine diphosphate and cyclic 5' AMP. Adenosine release was originally demonstrated during myocardial hypoxia,32 although there is now evidence that all cells are capable of producing adenosine in times of energy deficit. Adenosine can be released by lung tissue in times of hypoxia, such as after allergen induced bronchoconstriction, when the circulating levels of adenosine have bee shown to be 3 times the base line concentrations. Adenosine is a potent mediator of mast cell degranulation and thus may contribute to the inflammatory changes observed in asthma. On the other hand, adenosine inhibits eosinophil degranulation. A3 receptors have been recently identified on human eosinophils. Recent studies have revealed that mice, which accumulate high levels of endogenous adenosine owing to a deficiency of the adenosine catabolizing enzyme, adenosine deaminase, develop a pulmonary phenotype with mast cell mediated inflammation resembling the symptoms of asthma.31 Such evidence along with the observations that patients suffering from asthma have elevated pulmonary adenosine levels as well as augmented expression of adenosine receptors, suggest that increased adenosine signalling could be an important feature of asthma and chronic obstructive pulmonary disease.
Also there are a number of studies which demonstrate that IL-13 is overproduced in asthma and has implicated IL-13 in the pathogenesis of the Th2 inflammation and airway remodeling that is characteristics of this disorder.33 Blackburn et al. (2003) have demonstrated that adenosine accumulation, down regulation of ADA, and adenosine receptor alterations play important roles in the pathogenesis of IL-13 induced phenotypes in the lung. They also demonstrate that adenosine is a potent stimulator of IL-13, which highlights a pathway where IL-13 and adenosine can stimulate one another. In contrast, there are studies which report the occurrence of feedback loops-T cell inactivation mediated by increased levels of adenosine33 may dampen the IL-13 inflammatory program. Moreover adenosine also plays a major role in surfactant secretion. Surfactant secretion is known to be regulated by interplay of adenosine A1 and A2 receptors, with, A1 receptors inhibiting surfactant secretion and A2 receptors enhancing it.34 The role of the neutrophil in moderate to severe asthma, and the established role for the adenosine A1 receptor in neutrophil adherence to endothelium proposed neutrophil chemotoxis as an additional rationale for developing A1 receptor specific therapeutics. Studies have indicated that the interactions of the environmental factors and genetic disorders lead to allergy and asthma. Further these interactions lead to allergy depending on the age at which these interactions occur. Moreover in neonates the Th2 biased immune response switches to Th1 response with time by various kinds of exposures to microbes.
To conclude, the Hygiene Hypothesis is being proposed as the cause of increasing asthma prevalence which states that the society has been too successful in its fight against infectious organisms and has eliminated contact with many harmless bacteria and microbes that actually help the immune system build its defenses against more toxic infections. Early environmental exposures may in fact be critical for the development of the immune system. Determining which environmental exposures early in life lead to protective immunity and which are potentially detrimental is an area of active research. Till date, in this regard, there have been few studies on the role of natural killer cells and other components of the innate immune response. Understanding the immune response to allergens and infections in early life may allow us to develop strategies for preventing childhood asthma.
- TangMimi LK. Is prevention of childhood asthma possible? Allergens, infections and animals. MJA 2002;(177)(6 Suppl):S75–S77.
- ISAAC (International study of asthma and allergies in childhood) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjuctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225–32.
- BlackPN, SharpeS. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10:6–12.
- LewisSA, BrittonJR. Consistent effects of high socioeconomic status and low birth order, and the modifying effect of maternal smoking on the risk allergic disease during childhood. Respir Med 1998:92:1237–44.
- GrunigG. IL-13 and adenosine: partners in a molecular dance? J Clin Invest 2003;112:329–31.
- Mutius. The burden of childhood asthma. Arch Dis Child 2000;82(112–115).
- BarnesPJ: Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160;S72–S79.
- MosmannTR, RLCoffman. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties (Review). Annu Rev Immunol 1989;7:145–73.
- DelPrete GF, De CarliM, D'EliosMM, et al. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol 1993;23:1445–49.
- KayAB. T cells as orchestrators of the astmatic response. Ciba Found Symp 1997;206:56–67 [Medline].
- KrugAB, MaddenJ, RedingtonAE, et al. T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol 1996;14:319–26.
- HesselEM, Van OosterhoutAJ, Van ArkI, et al. Development of airway hyperresponswiveness is dependent on interferon-gamma and independent of eosinophil infiltration. Am J Respir Cell Mol Biol 1997;16:325–34.
- Chemokines:Mackay CR. what chemokine is that? Curr. Biol 1997;7:R384–R386.
- QinSG, LaRosaJJ, CampbellH, Smith-HeathN, Kassam, X. Shi L Zeng, ECButcher, CRMackay. Expression of monocyte chemoattractant protein-1 and interleukin- 8 receptors on subsets of T cells: Correlation with transendothelial chemotactic potential. Eur J Immunol 1996;26:640–47.
- SallustoF, CRMackay A.Lanzavecchia. 1997. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cell. Science 277:2005.
- GerberBO, MPZanni, MUguccioni, MLoetscher, CRMackay, WJPichler, NYawalkar, MBaggiolini, BMoser. 1997. Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinoophils. Curr. Biol. 7:836.
- MantovaniA. The chemokine and system: redundancy for robust outputs. Immunol. Today 1999;20:254.
- MartinezFD, HoltPG. Role of microbial burden in aetiology of allergy and asthma. Lancet 1999;354(Suppl II):S II 12–5 II 15.
- Braun,Riedler JC Fahrlander, WEder, MSchreuer, MWaser, SMaisch, DCarr, RSchierl, DNowak, Evon Mutius. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129–33.
- MatricardiPM, FRosmini, SRiondino, MFortini, LFerrigno. Exposure to food borne and orofecal microbes versus, airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 2000;320:412–17.
- HoltPG. Environmental factors and primary T-cell sensitization to inhalant allergens in infancy: reappraisal of the role of infections and air pollution (Review). Pediatr. Allergy Immunol 1995;6:1–10.
BjorkstenB, KjellmanNIM, ZeigerRS. Development and prevention of allergic disease in childhood. In: Allergy, Principles and Practice, Vol I (MiddletonE, ReedC, EllisEF, AdkinsonNF, YunginerJW, BusseWW, eds). St. Louis, MO: Mosby, 1998; 28–39. 32. MentzerRM, RubioR, BeeneRM. Release of adenosine and hypoxic canine lung tissue and its possible role in pulmonary circulation. Am J Physiol 1975;229:1625–31.
- MichelO, GinanniR, DuchateauJ, VertongenF, Le BonB, SergyselsR. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy 1991;21:441–48.
- MorrissonDC, UlevitchRJ. The effects of bacterial endotoxins on host mediation systems. Am J Pathol 1968;93:527–617.
- Donham,K., Haglind,P., Peterson,Y., Rylander,R., Belin,L. Environmental and health studies of farm workers in Swedish swine confinement buildings. Br J Ind Med 1989;46:31–37.
- BusseWW, 1994. The role of respiratory infections in airway hyperresponsiveness and asthma. Am. J. Respir. Crit. Care Med 150:S77–S79.
- Karlsson,H., Hessle,C. and Rudin.A (2002). Innate immune responses of human neonatal cells to bacteria from the normal gastrointestinal flora. Infection and immunity. 70(12):6688–96.
- OtaMOC, VekemansJ, HaueterSES. Influence of Mycobacterium bovis Bacillus Calmette Guerin on antibody and Cytokine Responses to Human Neonatal vaccination. The Journal of Immunology (168):919–25.
- BlackburnMR, et al. Metabolic consequences of adenoisine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation and airway obstruction. J Exp Med 2000;192:159–70.
- ChiramonteMG, DonaldsonDD, CheeverAW, and WynnTA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper Type 2-dominated inflammatory response. J Clin Invest 1999;104:777–85.
- GieseM, GorbanLJ, DouglassJS, RooneySA, Adenosine. A receptor mediated phosphatdylcholine secretion in type II pneumocytes. Am J Physiol 1991;260 L52–L60.
Asthma is a chronic inflammatory disease of the airways1 that, if untreated or inadequately treated, can dramatically impair quality of life and can be lifethreatening. The rationale behind treatment of asthma is that emergency treatment is more expensive than planned treatment and that guideline determined asthma care can be more cost effective.1 Asthma is a reversible airway disease and patient may exhibit normal lung function between exacerbations but a component of chronic inflammation also goes on leading to chronic impairment in pulmonary function in the long run. The current therapy in asthma controls the symptoms but does not modify the disease. Expert panel guidelines by the National Heart, Lung and Blood institute recognise inhaled corticosteroids (ICS) as the preferred treatment for initiating therapy in children with persistent asthma. Treatment with inhaled corticosteroids (ICS) improves lung function and reduces asthma symptoms. For children who remain symptomatic despite treatment with low dose ICS, the preferred treatment is addition of long acting β2 agonist (LABA) to low dose ICS rather than an increase in the dose of ICS. This approach further improves lung function and quality of life in patients with moderate to severe persistent asthma. The medications can be delivered via a number of different types of inhaler devices; these differ in the efficiency with which they deliver the drug to the lower respiratory tract. There are currently three commonly used ICS available as licensed preparations in India for children aged under 12 years: beclometasone dipropionate (BDP), budesonide (BUD) and fluticasone propionate (FP). Two of the ICS are available as licensed preparations in combination with LABA: FP used in combination with salmeterol/formoterol (SAL) and BUD used in combination with formoterol fumarate (FF).
The principal advantage of combining ICS and LABA in one inhaler is the simultaneous delivery of two effective inhaled therapies. This may lead users to better adhere to dosing regimens, especially given concerns over the use of LABA therapy without a regular background steroid as β2-agonists do not have any substantial anti-inflammatory properties they can, in the worst case, mask asthma deterioration, placing patients at increased risk of a severe, potentially life-threatening exacerbation. Combination inhalers, containing both an ICS and a LABA, are included in the current GINA clinical guidelines for the management of asthma.1 Combination inhalers are preferred to two separate inhalers as they probably improve compliance with the ICS component.2, 3 Previous assessments have considered the addition of any LABA to any ICS when the dose of ICS is increased or when the study drugs are titrated according to symptoms. ICS and LABA is the recommended therapy for children with moderate persistent asthma. Although the LABAs commonly used in combination preparations have a similar duration of effect of around 12 hours or more, salmeterol and formoterol also have differing pharmacological properties. 4, 5 Some differences exist also between fluticasone and budesonide despite the shared anti-inflammatory effect.6, 7
• Definition of Asthma
According to National Asthma Education and Prevention Program (NAEPP), working definition of asthma is, “Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. In susceptible individual, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.2 Asthma constitutes about 1% of total global disease burden. Global prevalence of asthma, which is on the increasing trend, is 4.8 – 13.2%.3 According to WHO, 15 million DALYS (disability adjusted life years) are lost annually due to asthma. The prevalence of asthma in India is 3.3%.9 The increased prevalence of asthma has been associated with an increase in atopic sensitization and other allergic disorders such as eczema and rhinitis. Recent studies have demonstrated that asthma can be associated with impaired lung growth during childhood and a progressive decline in pulmonary function in adulthood, and hence the need to establish early treatment of childhood asthma. The clinical manifestations of asthma and underlying airway inflammation though variable; reflect the different aspects of the disease, as acute vs. chronic inflammation corresponding to intermittent vs. persistent asthma.
• Management of Asthma
As per GINA (Global Initiative for Asthma) guidelines there are five essential components of asthma management and prevention program:
- Develop patient/doctor relationship
- Identify and reduce exposure to risk factors
- Assess, treat and monitor asthma
- Manage airway exacerbations
- Special consideration
• Goals of Long Management of Asthma
- Achieve and maintain control of symptoms
- Maintain normal activity levels including exercise
- Maintain pulmonary functions as close to normal levels as possible
- Prevent asthma exacerbations
- Avoid adverse effects from asthma medications
- Prevent asthma mortality
• Asthma Symptom Score
Different studies have used various parameters for symptom scores. The Grampian study included sleep disturbances and restriction of activity. Woolcock et al included daytime and night-time symptoms and rescue salbutamol use. Greening et al included cough, breathlessness, wheeze. Whereas Gallant2 et al included breathlessness, cough, rescue salbutamol use, night time symptoms. In our clinical studies, asthma symptom score consists of 6 items to be scored namely history of day time cough, history of nocturnal cough, wheezing, difficulty in breathing and use of rescue salbutamol and limitation of activity. A score of zero will be given for absence and one for the presence of each of the items. Thus the total score could vary from 0 to 42. Well constructed symptom based management plan has been shown equivalent to objective measurement especially in mild asthma.
• Medications in Asthma
Medications in asthma can be classified as controllers or relievers. Controllers are anti-inflammatory drugs (steroidal or non-steroidal) taken daily on long-term basis, to keep the disease under control (minimizing exacerbations, symptoms and the need of reliever medications). Of all the anti-inflammatory drugs, the most potent are inhaled corticosteroids (ICS). The other drugs which can be used are systemic corticosteroids, inhaled long acting b2 agonists (LABA), leukotriene receptor antagonists (LTRA), theophylline, cromolyn and nedocromil, and other systemic steroid sparing drugs. Relievers are medications used on an as per needed basis that act quickly to reverse bronchoconstriction and relieve its symptoms. They include rapid-acting inhaled β2-agonists, inhaled anticholinergics, short-acting theophylline, and short-acting oral β2 agonists. Rapid-acting inhaled β2-agonists are the medications of choice for relief of bronchoconstriction in both adults and children of all ages.
• Controller Medications In Moderate Persistent Asthma
• Inhaled Corticosteroids
Inhaled corticosteroids are currently the most effective anti-inflammatory medications for the treatment of persistent asthma. Studies have demonstrated their efficacy in reducing asthma symptoms, improving quality of life, improving lung function, decreasing airway hyper responsiveness, controlling airway inflammation, reducing frequency and severity of exacerbations and reducing asthma mortality.1 However, they do not cure asthma, and when they are discontinued deterioration of clinical control follows within weeks to months in a proportion of patients. The side effects of ICS are limited to a small, transient reduction in growth velocity.10 Although anti-inflammatory drugs are the mainstay of therapy in persistent asthma, many patients continue to have troublesome symptoms, exacerbations and compromised lung function despite use of ICS therapy. Theses patients require either • Medium to high dose ICS (or) addition of • LABA (or) LTRA to ICS Addition of LABA (or) LTRA to ICS acts to decrease dose of ICS and thereby decreasing the long term systemic steroid induced side effects on growth and bone mineral density.12 Long acting b2 agonists (LABA): includes:
These drugs should not be used as monotherapy as they have no role in controlling airway inflammation. Addition of long-acting inhaled β2 agonists to a daily regimen of ICS improves symptom scores, decreases nocturnal asthma, improves lung function, decreases the use of rapid-acting inhaled β2 agonists, reduces the number of exacerbations, and achieves clinical control of asthma in more patients, more rapidly, and at a lower dose of ICS than ICS given alone.13–15 Studies show that when compared to a therapy with an ICS above combination with LABA addresses inflammation and smooth muscle dysfunction, the 2 main components of asthma. In addition, salmeterol possesses several non bronchodilator properties that may contribute to its therapeutic effects. For example, salmeterol has demonstrated inhibitory effects in vascular permeability; platelet-activating factor induced eosinophil accumulation, and the release of mast cell mediators from the lung. In vitro also it has demonstrated ability to prime the glucocorticoid receptor for activation of corticosteroids. These findings suggest that the above combination has as broad scope of activity in treatment of asthma. The side effects expected with this combination include oropharyngeal candidiasis, tachycardia, and tremors.
Leukotriene modifiers: includes
- LTRA - leukotriene receptor antagonists (montelukast, pranlukast, and zafirlukast) and
- 5-lipoxygenase inhibitor (zileuton)
• Pharmacological and Pharmaco-dynamics of Combination Therapies for Asthma Management
• LABA Component
In LABA component, mechanism of action is bronchodilation through β2 receptor stimulation which leads to increased cAMP formation in bronchial smooth muscle and their relaxation.
Comparison of Formoterol and Salmeterol
- Formoterol delivers increased efficacy as rapidly as salbutamol and terbutaline with a duration of action in excess of 12 hours compared to salmeterol which has lower intrinsic efficacy and slower onset of effect.
- Formoterol exhibits a dose-response curve with increasing doses providing greater bronchoprotective and bronchodilator effects while there is no evidence of a dose-response relationship for salmeterol above 50 mg twice daily.4
- Adequate water solubility and moderate lipophilicity of formoterol ensures rapid diffusion to β2-adrenoceptors on the airway smooth muscle cells and a rapid bronchodilator effect while salmeterol diffuses more slowly to the β2-adrenoceptors because of its high lipophilicity, and this may explain the slower onset of action.
- The systemic activity of formoterol is short-lived, comparable with that reported for salbutamol or terbutaline Consequently, the risk of a longer duration of systemic side effects with formoterol is minimal. In contrast, the systemic effect of salmeterol is long-lasting and repeated dosing increases the risk for persistence of b2-agonist related adverse systemic side effects.5
- Corticosteroid component: These acts by reducing bronchial hyperactivity, mucosal edema and by suppressing inflammatory response to antigen-antibody reaction or other trigger stimuli.
- Comparison of Budesonide and Fluticasone.
- Budesonide and fluticasone both have anti-inflammatory effect on airway tissues when given via inhalation but fluticasone has approximately 2:1 potency v/s budesonide in vitro.
- The absorption of budesonide into airways tissue is not affected by lung function, with comparable plasma concentrations achieved following pulmonary delivery in healthy and asthmatic individuals. Unlike budesonide, the absorption of fluticasone is affected by lung function with markedly lower plasma concentrations achieved in asthmatic individuals compared with non-asthmatics.6
- A dose-response relationship has been demonstrated for budesonide and an increase in the dose and frequency of budesonide administration has been shown to be beneficial in quickly reducing inflammation and bronchoconstriction in patients with unstable asthma.7
- Once absorbed intracellularly, budesonide undergoes reversible conjugation with intracellular fatty acids, which prolongs its retention within the airways - its principle site of therapeutic action - and its duration of action in contrast to budesonide, fluticasone does not undergo the intracellular esterification process and consequently is not as well retained within the airway tissue. The pharmacodynamic differences described above between formoterol/salmeterol and budesonide/fluticasone impact on the clinical use of the two products, with the pharmacological and pharmacodynamic properties of budesonide/formoterol allowing for the use of the combination as both maintenance and reliever therapy.
• Clinical Effectiveness of Combination Therapy
For both the budesonide/formoterol and salmeterol/fluticasone combinations, the addition of a LABA to the ICS component for patients not adequately controlled on ICS alone has been shown to produce greater improvements in pulmonary function and symptomatology and reduction in the exacerbation rate than higher doses of ICS alone.11, 12 O'Byrne et al13 reported the results of a one-year trial in which patients with mild persistent asthma were stratified according to whether they were currently receiving an ICS or not.
Among 698 patients who were initially corticosteroid- free, treatment with budesonide plus formoterol resulted in comparable reductions in the risk of severe exacerbations and symptom-free days as budesonide alone (60% and 48%, respectively) and an improvement in lung function. For patients already receiving an ICS, addition of formoterol proved more effective than doubling the ICS dose alone, reducing the risk for severe exacerbations by 43% and reducing the number of poorly controlled days by 30%. In a separate study, the addition of formoterol to ongoing budesonide therapy reduced the rates of severe and mild asthma exacerbations by 63% and 62%, respectively, compared with a reduction of 49% and 37% for the same dose of budesonide alone Similar beneficial effects have been reported when salmeterol was added to ICS therapy. The beneficial effect of adding salmeterol to fluticasone has also been compared with an increased dose of fluticasone alone in patients with moderate to severe asthma, with marked improvements in lung function and symptom control.11
Having established the efficacy of the fixed-dose budesonide/formoterol and salmeterol/fluticasone combination therapies in the treatment of uncontrolled asthma, several studies have performed direct comparisons between the two as part of their design.
The 6-month COMPASS study recruited adults and adolescents who were symptomatic on their existing ICS dose alone during a two-week run-in and randomised 1105 patients to fixed-dose budesonide/ formoterol (640 mg/day; BDP equivalent 1000 mg/day) and 1123 patients to fixed-dose salmeterol/ fluticasone (500 mg/day; BDP equivalent 1000 mg/day). The effects of both fixeddose regimens were similar for all of the efficacy parameters except for a statistically significant increase in asthma-related hospital admissions/ emergency room treatments with salmeterol/fluticasone.14 The much smaller comparator study by Aalbers et al.15 also found similar efficacy and levels of well controlled asthma (primary endpoint) with the same fixed-doses of budesonide/formoterol and salmeterol/fluticasone combination therapies. In a third study, a large 24-week double-blind study (EXCEL).16 comparing the same fixed-dose of budesonide/formoterol (400/12 mg twice daily [metered dose]; BDP equivalent 1000 mg/day) and fixed-dose salmeterol/fluticasone (50/250 mg twice daily; BDP equivalent 1000 mg/day) in adults with asthma, Dahl and colleagues reported that both regimens produced equal improvements in well-controlled asthma and lung function, and similar reductions in the overall asthma exacerbation rate, which was the primary variable. The published study attempted to suggest that fixed-dose salmeterol/fluticasone was superior to budesonide/formoterol in reducing the rate of moderate/severe exacerbations using post hoc analyses on the last 8 weeks of the study but the weaknesses in this post hoc analysis and failure to fully report the most severe exacerbations by treatment group, which were reduced in the budesonide/formoterol group, have been highlighted in the literature. In a meta-analysis of the effectiveness of fixed dose maintenance therapy including all of the above studies with either budesonide/formoterol or salmeterol/fluticasone there were no differences between the fixed dose ICS/ LABA combinations apart from one, the increased risk of severe exacerbations resulting in emergency treatment, which were consistently higher in all three studies in patients receiving salmeterol/fluticasone with an overall 49% increase that was statistically significant.16, 17 Meta-analyses focusing on hospital admissions due to exacerbations reported reduction in the risk of asthma-related hospitalisations/ER visits with budesonide/formoterol versus salmeterol/fluticasone is supported by other independent meta-analyses of fixed-dose combinations versus ICS alone that have excluded studies with the potential for LABA monotherapy. Jaeschke and coworkers  analysed data from clinical studies including formoterol with ICS in patients with asthma and found that the addition of formoterol resulted in a 41% reduction in asthma-related hospitalisation admissions versus a similar or higher dose of ICS alone, whereas a separate meta-analysis of 52 studies in which salmeterol was added to ICS therapy found no change in the risk of hospitalisation admissions.18 The greater reduction in the risk of asthma related hospitalisation/emergency room visits seen with fixed-dose budesonide/formoterol compared with fixed-dose salmeterol/fluticasone is most likely due to the different pharmacology of the LABAs as discussed above; that is, the greater intrinsic activity and bronchoprotective effect of formoterol compared with salmeterol during periods with severe exacerbations ensures that this LABA provides greater protection from severe exacerbations. Some differences exist also between fluticasone and budesonide despite the shared anti-inflammatory effect and so a systematic exploration of the relative efficacy of these different drug combinations is justified. The evidence in the Cochrane review indicates that differences in the requirement for oral steroids and hospital admission between BUD/F and FP/SAL do not reach statistical significance. However, the confidence intervals do not exclude clinically important differences between treatments in reducing exacerbations or causing adverse events. The width of the confidence intervals for the primary outcomes justify further trials in order to better determine the relative effects of these drug combinations.
- BatemanED, HurdSS, BarnesPJ, BousquetJ, et al Global strategy for asthma management and prevention. GINA executive summary. Eur Respir J 2008;1:143–78.
- National Asthma Education Prevention Program Expert Panel Report 3: Guidelines for diagnosis and management of asthma. Summary report 2007. J Allergy Clin Immunol 2007;120:114S–138S.
- NICE Technology Appraisal Guidance 138, 2008. Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over. Available at www.nice.org.uk/TA138.
- PalmqvistM, IbsenT, MellenA, LotvallJ. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med Volume 160, Number 1, July 1999;244–49.
- GuhanAR, CooperS, OsbourneJ, LewisS, BennettJ, TattersfieldAE. Systemic effects of formoterol and salmeterol: a dose–response comparison in healthy subjects. Thorax 55(8):650–56.
- HarrisonTW, TattersfieldAE. Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects. Thorax 2003;58(3):258–60.
- ToogoodJH, BaskervilleJC, JenningsB, LefcoeNM, JohanssonSA. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid budesonide. J Allergy Clin Immunol 1982;70(4):288–98.
- SinghM. The Burden of asthma in children: AnAsian perspective. Pediatr Respir Reviews 2005;6:14–19.
- WarnerJ, LicolaizikW, MarchantJ. The systemic effects of inhaled corticosteroids. JAllergy Clin Immunol 1989;83:220–25.
- HeynemanCA, CraftsR, HollandJ, ArnoldAD. Fluticasone versus salmeterol/low-dose fluticasone for long-term asthma control. Ann Pharmacother. 2002;36:1944–49.
- GreeningAP, IndPW, NorthfieldM, ShawG. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344(8917):219–24.
- O'ByrnePM, BarnesPJ, Rodriguez–RoisinR, RunnerstromE, SandstromT, SvenssonK, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164(8 Pt 1):1392–97.
- KunaP, PetersMJ, ManjraAI, JorupC, NayaIP, Martinez-JimenezNE, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007;61(5):725–36.
- AalbersR, BackerV, KavaTT, OmenaasER, SandstromT, JorupC, et al. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Current Medical Research and Opinion 2004;20(2):225–40.
- DahlR, ChuchalinA, GorD, YoxallS, SharmaR. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Respiratory Medicine 2006;100(7):1152–62.
- NelsonHS, BeasleyR, YanceySW, KralKM, EdwardsLD, SuttonLB, et al. No increase in asthma-related hospitalizations following the addition of salmeterol to an inhaled corticosteroid in patients with asthma: A meta–analysis. Am J Respir Crit Care Med 2007;175:A59.
Asthma is a chronic inflammatory disorder of the airways, causing recurrent episodes of wheezing, breathlessness, chest tightness and cough. Increase in prevalence in many countries over the recent decades, highlights the need for a greater understanding of the risk factors for asthma. Many causes have been postulated and dietary change is one of several causal factors implicated in this trend. In the past two decades the evidence base on the relation between diet and asthma has increased substantially. Asthma is a multifactorial disease with a large series of causative, inducing, triggering and aggravating factors, each of which help shape the disease phenotype in the single patient by interacting with the expression of his/her unique genetic background at a given age. Because asthma is the result of interaction between genetic and environmental factors, increasing prevalence is certainly the result of changes in environmental factors. The hypothesis made to explain the epidemic trend fall into two main groups: one that points to increasing exposure to aggressive factors, and the other that implicates decreasing exposure to protective factors. The most cited aggressive factors are airborne indoor or outdoor pollutants, high salt intake, indoor allergens, drugs and vaccines. The proposed protective factors are antioxidants, microbial burden and physical exercise. This increasing prevalence has affected both rural and urban communities, suggesting that local environmental factors such as exposure to allergens or industrial air pollutions are not the sole cause.1 In the last few years, nutrition has represented an important conditioning factor of many cardiovascular, gastro-intestinal and chronic pulmonary diseases. So it has been hypothesized that dietary constituents influence the immune system and thus, may also be actively involved in the onset of asthma and other allergic diseases.2 The possible role of diet in the development of asthma can be described as follows: first, a food allergen can cause asthma. Second, there is role of breast-feeding for prevention of asthma later in life. Third, a low intake of anti oxidative dietary constituents might be a risk factor for asthma.3 Moreover, role of cations such as sodium, potassium and magnesium has been described in development of asthma. Finally, intake of fatty acids especially the role of omega-3 and omega-6 fatty acids plays a beneficial and detrimental role respectively in cause of asthma.
• Additives and Preservatives as Etiological Agent
It is reported in the United States that about 6-8% of infants and about 1.5% of adults are allergic to food.4 Food is very important cause of asthma but is often overlooked, as usual skin tests are often negative and history is often not helpful. Children are more sensitive to foods than adults. Deaths in children, adolescents, and adults who ingested foods to which they were highly allergic have been reported.5,6 These deaths are often caused by “hidden” ingredients in the food to which the individual is allergic. Sulfites and sulfating agents such as sulfur dioxide, sodium bisulfite, potassium bisulfite, sodium metasulfite, potassium metasulfite, sodium sulfite – both occurring naturally or used in food processing, have been found to trigger asthma. Egg is one of the most allergenic of all foods, and minute amounts of egg can result in asthma symptoms within minutes, including anaphylaxis. This is also seen after contact with egg through non-oral routes.7 Reactions may occur first time in a child who is given egg. Although ovalbumin, ovomucoid, and ovotransferrin have been identified as the major allergens in egg white, 10 other unnamed allergens of lesser importance have been identified. These allergens are also present in egg yolk but in lesser quantities. Some preservatives and additives may provoke asthma. Examples of such provoking compounds are - preservatives e.g. sulfur dioxide and sodium benzoate, colourants (natural or synthetic) e.g. tartrazine, flavour enhancers e.g. monosodium glutamate and salicylates e.g. aspirin like substances found in many foods. It has been postulated that asthma associated with chewing betel-nuts is chemically mediated by cholinergic stimulation.8 Children sensitive to food have higher rates of hospitalization due to asthma. In addition, children sensitive to food require more steroid medications to manage their asthma symptoms. Presence of food sensitization may be a useful marker for identifying children with more severe asthma. In an Indian study, it was found that deterioration in asthma can be prevented by specific food avoidance in many patients.9 The only proven treatment for food allergy is strict elimination of the relevant offending allergen(s). It should be noted here; however that elimination diet may lead to unwanted side effects such as malnutrition and eating disorders. But if successful, the food induced symptoms will certainly disappear. The diet revision should be complete and comprehensive to resolve them. It can be presumed that symptomatic reactivity is lost over time. Approximately, one third of children and adults lose their clinical reactivity after 1–2 years of allergen avoidance.
• Anti Oxidants
The epithelial lining of the respiratory system, by virtue of its large surface area and its role in gas exchange and host defense, is vulnerable to oxidant damage. The toxicity of oxidants which are directly inhaled such as cigarette smoke and air-pollution or generated through inflammatory process such as in response to allergen and viral infection, is normally balanced by the protective activity of an array of endogenous antioxidant defense system which may be functionally dependent on adequate supply of nutritional antioxidants. Reactive oxygen species, released from eosinophils, alveolar macrophages, and neutrophils, seem to play a key role in asthma. They may directly contract airway smooth muscles; stimulate histamine release from mast cells and mucus secretion. Asthma is, therefore, also associated with oxidative-antioxidative imbalance. Antioxidant status may affect asthma risk by influencing the development of the asthmatic immune phenotype, the asthmatic response to antigen provocation, or the inflammatory response during and after asthma attack. Antioxidants such as vitamin-A/β-carotene, vitamin-C, vitamin-E and selenium are important dietary constituents which may prevent oxidative injury. Therefore, they may reduce inflammation caused by allergen exposure.
Vitamin-C: Vitamin-C is the most extensively investigated among antioxidants and has been shown to be associated with a reduced risk of asthma. Lower plasma and leukocyte concentration of vitamin-C has been associated with a high prevalence of asthma in adults and in children,11 increased respiratory symptoms, reduced pulmonary functions10,12 and increased airway responsiveness. Supplementation with vitamin-C has been shown to decrease asthma severity and frequency, exercise induced bronchospasm and airway responsiveness to methacholine. A 100 mg increase in vitamin-C intake per day is associated with an approximately 10–50 ml increase in forced expiratory volume in one second (FEV1). Vitamin-C is a free radical scavenger present in intracellular and extracellular lung fluids and protects against endogenous as well as exogenous oxidants. It is the most abundant antioxidant substance present in the extracellular fluid in the lung and contribute to the regeneration of membrane bound oxidized vitamin-E to function again. Vitamin-C is known to have a general antihistamine effect. It also inhibits the prostaglandins production. Most of the exacerbations of asthma in children have been associated with upper respiratory tract viral infections, especially rhinovirus. There are suggestions that vitamin- C supplementation may affect the susceptibility to common cold in subjects with low intake of vitamin-C. Moreover, vitamin-C reduces the duration of episodes and the severity of symptoms of the common cold. Natural sources of vitamin-C are citrus fruits and red and yellow pepper.
Vitamin-E: Vitamin-E effects have been studied and there is evidence of beneficial effects of vitamin-E on asthma. There is evidence of an inverse association between vitamin-E intake and both allergen skin sensitization and total serum Ig-E levels in adults.13 High vitamin-E intake is associated with reduced asthma incidence. Vitamin-E is present in extracellular lung fluid and lipid membrane, where it converts oxygen radicals and lipid proxy radicals to less reactive forms. Thus vitamin- E is a membrane stabilizer and principle defense against oxidant induced membrane injury by breaking the lipid peroxidation chain reaction. Vitamin-E seems to suppress neutrophil migration and inhibits Ig-E production. It may be immunomodulatory and also able to influence T-helper cell development in direction of Th1, subtype.14
Vitamin-A and b -Carotene: Vitamin-A and b-carotene have protective effect in asthma.15 Vitamin-A derivatives of retinol influence the development, maintenance, differentiation, and regeneration of lung epithelial cells and may play a central role in the development of airway disease. Vitamin-A/ ²-carotene are lipid soluble and acts by their antioxidant action that helps to prevent membrane lipid oxidation.
Other Vitamins: Asthmatics are typically deficient in vitamin-B complex (especially vitamin-B6 and B12) and folic acid and supplementing these subjects with multivitamins can help to reduce asthma symptoms. A deficiency of vitamin-B6 has been found in many asthma patients. This may be due to the fact that the medications in many asthma inhalers interfere with the absorption of vitamin-B6 by the body. In mild to average cases, the addition of vitamin-B6 supplement to the diet appears to lessen the occurrence of asthma attacks.16,17 It has been found in a study that vitamin-B12 taken in large doses can decrease likelihood that asthmatics react to foods with sulfites.
• Flavones and Flavanoids
Flavones and flavanoids are naturally occurring antioxidants found particularly in fruits and red wine, which may account for protective effect associated with these fruits. These are also mast cell stabilizer. In a study, whole blood levels of antioxidants carotenoids, lycopene, lutein, ²-cryptoxanthin, ±-carotene and ²-carotene were measured and found to be significantly lower in asthma patients than in controls.
• Fruits and Vegetables
Several studies have demonstrated a reduced risk of asthma in relation to a high fruit intake. High intake of fruits is associated with a reduced risk of decline in FEV1, over a time. The FEV1 in subjects with a high intake of fruits (once per week or more) is about 80–100 ml higher than in subjects with a low intake (less than once per week).18,19 In an Indian study, it was suggested that eating vegetables and fruits are protective for asthma/wheeze. Fruits and vegetables are better than vitamins pills. In a study it was found that daily intake of fruits and vegetables in infancy decrease the risk of asthma more than that by the intake of extra vitamins and cod liver oil supplements. It has also been found that fruits, rather than vegetables are more constantly related with increased level of lung functions. This may be explained by the fact that fruits are high in vitamin-C, which may be more important dietary antioxidant.
Selenium: Among minerals, selenium has been most strongly associated with asthma. Studies have demonstrated decreased selenium intake and decreased serum levels in patients with asthma. Selenium deficiency may greatly increase the risk of asthma.20,21 Selenium functions as a cofactor for the antioxidant enzyme glutathione peroxidase, which is proposed to counter oxidation and to reduce the synthesis and release of leukotriene B4, an inflammatory mediator. Selenium may also, along with vitamin-C, attenuate the activation of nuclear factor kappa-b, a transcription factor that upregulates inflammatory cytokines associated with the asthmatic immune response.22
Magnesium: Magnesium has several biological effects of potential relevance to asthma, including bronchodilatation when given intravenous in acute severe asthma.23 There is also strong evidence of protection by dietary magnesium against asthma. In a study, reduced magnesium intake was found to be associated with brittle asthma.24 These effects of magnesium are mediated by its properties of smooth muscle relaxation and mast cell stabilization. Milk and other dairy products, whole grains, nuts, legumes, leafy green vegetables are good sources of magnesium.
Sodium: It has been shown that bronchial reactivity to histamine is related to 24 hours urinary sodium excretion. Bronchial reactivity appears to increase with greater salt intake. Studies have linked increasing dietary salt intake with worsening asthma symptoms and increased bronchodilators use.25,26 Following sodium restriction in three double blind clinical trials, improvements were noted in airway responsiveness, FEV1 and asthma symptoms. Research suggests that the effects of sodium are limited to individuals with asthma. Dietary sodium may increase airway reactivity and cause bronchoconstriction through potentiation of the electrogenic sodium pump in the membrane of the airway smooth muscles.
Trace Minerals: There are evidences linking copper, zinc and manganese with asthma. Copper and zinc have role in antioxidant defense as cofactor in superoxide dismutase. Zinc is an essential trace mineral for most immune mechanisms in the body to function, including lymphocyte (T-cell) function.27 Zinc deficiency may also lead to an enhanced Th2 immune response. Manganese has been found deficient in bronchial biopsies of asthmatic patients, indicating manganese replenishment could help in treatment of asthma.28
• Role of Fatty Acids
Dietary fatty acids have important role in asthma.29,30 Intake of omega-3 fatty acids is potentially beneficial and of omega-6 fatty acids is detrimental to asthma. Reduced omega-3 fatty acid/omega-6 fatty acid ratio leads to high chances of asthma. Mechanisms of action proposed for dietary polyunsaturated omega-6 and omega-3 fatty acids include modification of gene expression, signal transduction pathways and production of eicosanoids, the prostaglandins and leukotrienes which are potent inflammatory mediators. Well studied beneficial effect of fish in asthma is attributed to the presence of omega-3 fatty acids in fish oil. Fish oil contains eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA) which are competitive substrates for arachidonic acid for generation of inflammatory mediators. In humans, the principal substrate for eicosanoid production is arachidonic acid, an unsaturated fatty acid. The production of eicosanoids by inflammatory cells begins with the release of arachidonic acid from membrane phospholipids by phospholipase enzymes, and subsequent metabolism by cycloxygenase or lipoxygenase, enzymes and subsequent prostaglandin or leukotriene products. The derivatives of arachidonic acid (an omega-6 fatty acid) are leukotriene B4 (LTB4), a potent neutrophil chemoattractant and a pro-inflammatory mediator and cysteinyl series of LT (LTC4, D4, E4) which produce potent smooth muscle contraction and bronchoconstriction. In contrast, EPA and DHA (omega-3 fatty acids), as well as inhibiting arachidonic acid metabolism, is a substrate for the less active prostanoids (e.g. thromoxane A3) and LT (LTB5) and so has the potential to reduce airway inflammation, severe bronchoconstriction and airway hyper responsiveness. EPA also reduces the production of cytokine- tumor necrosis factor- ± (TNF-²) which increases airway responsiveness. On the other hand, omega-6 fatty acids such as linoleic acid, may influence the development of allergic sensitization by increasing the formation of prostaglandin E2 (PGE2), thus promoting Th2 lymphocyte response and Ig-E generation. Fish oil may therefore alleviate certain inflammatory respiratory diseases, preserve normal airway resistance, and modulate allergic sensitization.
• Amino Acids
Among amino acids, of particular interest are the amino acids: cystine, methionine, glycine and glutamic acid, which collectively contribute to glutathione metabolism32 which is an important antioxidant that may influence susceptibility to asthma. Cystine, is of particular interest, as it may be converted to reduced form of cysteine by macrophages, which thus increases intracellular glutatione. Arginine, the precursor for nitric oxide, which has been shown to be elevated in asthma and glutamine, which has powerful antibacterial properties in vivo are also of interest. In addition, phenylalanine is potentially important since uncontrolled phenylketonuria is associated with increased plasma Ig-E and atopic dermatitis. Studies have drawn attention to tryptophan, where the metabolic pathways may differ in asthmatic subjects as compared to control subjects, as demonstrated by elevated urinary kynurenic acid and xanthenuric acid excretion in children with asthma.33 In a study, there was strong inverse relationship between fasting plasma glycine level and asthma risk. It is therefore, possible that changes in the pattern of amino acids intake arising from an overall increase in the proportion of protein from animal sources may have contributed to the rise in asthma prevalence that has occurred in the most developed countries.
• Breast Feeding
The plasticity of the immune system in early life suggests that it will be dietary influences at this stage that will have the greatest impact. Indeed, early exposure to cow's milk protein has been linked to the development of atopy and asthma. Studies indicate that prolonged and exclusive breast feeding significantly decreases the risk of asthma and other allergic diseases among children.35,36 Guidelines recommend that exclusive breast feeding for the first 6 months with introduction of solids thereafter decreases the chance to develop asthma or eczema than when fed solids earlier. Recent WHO feeding guidelines propose the introduction of solids after the sixth months following exclusive breast feeding for the prevention of asthma and atopy.34 Even introduction of milk other than breast milk before the age of 4 months of age has been found a significant risk factor for all asthma and atopy related outcomes in children aged 6 years. Incidence of allergy to cow's milk has been estimated to be from 0.3% to 7% in general infants and from 14% to 30% in “Suspected allergic” infants. In general, cow's milk has been designated the food allergen most commonly affecting children. It has been recommended that if breast feeding is not possible;consider supplementing infants with omega-3 fatty acids, lactobacillus probiotics and protein hydrolyzed formula. In nut shell breast feeding was found to be protective for asthma. This protective effect may operate through several mechanisms. These include the exclusion of milk other than breast milk (and its potentially allergic components) from the infant's diet, and the provision of immunomodulatory, anti-inflammatory, nutritional, or other components in human milk. Several lines of evidence suggest that maternal dietary antioxidant intake during pregnancy may have relevant antenatal influence. Maternal vitamin-E intake during pregnancy has the potential to influence postnatal susceptibility to asthma and atopic diseases by modulating fetal and neonatal Th-cell response during initial encounter with allergens. Similarly, maternal fish oil intake during pregnancy may protect offspring from asthma.
• Intestinal Flora and Probiotics
Evidence that the gut microflora may be associated with the development of atopy comes from studies comparing Estonian infants with Swedish infants. Estonian infants have a low prevalence of atopy and display greater gut colonization with lactobacillus and Eubacteria, whereas Swedish infants, who have a higher prevalence of atopy, display greater levels of Clostridium difficile.37 Furthermore, iso-caproic acid, a compound associated with C. difficile, has been detected almost exclusively in allergic infants, and the levels of other compounds associated with Lactobacillus flora were higher in non-atopic infants. Thus it has been suggested that promotion of Lactobacillus and other potentially beneficial gut micro-organisms may protect against the development of atopic disease. Breast feeding promotes gut colonization with bifidobacterium and thus reduces chances of atopy and/or asthma. Another method with potential to enhance the numbers of potentially beneficial organisms in the gut is the use of probiotics. Dietary supplementation with probiotics has shown encouraging results in asthma. In a double blind, randomized, placebo controlled trial, lactobacillus (given prenatally to mothers and then postnatally for 6 months to their infants) resulted in 50% reduction in the rate of atopic eczema at the age of two years.38 Thus, the role of probiotics can be considered to prevent asthma. A key factor with probiotic intervention is that it does not cause any harm. Indeed, probiotics certainly result in a more friendly gut flora, witch may have other beneficial effect on health apart from reducing rates of atopic diseases. The probiotics may provide a natural means of beneficially modulating the immune system. However, the mechanism remains unclear and more data needs to be available before conclusion can be made on their ability to impact on the development of the other allergic disease including asthma.
Summary: Nutrients or nutrient groups implicated in the etiology of asthma and their postulated mechanism of effect Nutrient(s) Activity and potential mechanisms of effect Vitamin A, C, E Antioxidant; protection against endogenous and exogenous oxidant inflammation Vitamin C Prostaglandin inhibition Vitamin E Membrane stabilization, inhibition of IgE production Flavones and flavonoids Antioxidant; mast cell stabilization Magnesium Smooth muscle relaxation, mast cell stabilization Selenium Antioxidant cofactor in glutathione peroxidise Copper, Zinc Antioxidant cofactors in superoxide dismutase n-3 fatty acids Leukotriene substitution, stabilization of inflammatory cell membranes Polyunsaturated and trans Increased eicosanoid production fatty acids (n6) Sodium Increased smooth muscle contraction.
- BurneyP, ChinnS, RonaRJ. Has the prevalence of asthma increased in children? Evidence from the national study of health and growth 1973-86. BMJ 1990;300:1306–10.
- KankaanpaaP, SutasY, SalminenS, LichtensteinA, IsolauriE. Dietary fatty acids and allergy. Ann Med 1999; 31: 282–7. 5. Monteleone Ca, ShermanAR. Nutrition and asthma. Arch Intern Med 1997;157:23–24.
- PrechtD, Molkentinj. Trans fatty acids: implications for health, analytical methods, and incidence in edible fats and intake. Nahrung 1995;39:343–74.
- LessofMH, WraithDG, MerrettTG. Food allergy and intolerance in 100 patients, local and systemic effects. Q J Med 1980;49:259.
- SampsonHA, MendelsonL, RosenJP. Fatal and near fatal induced anaphylaxis. N Engl J Med 1992;327:380–84.
- YungingerJW, SweeneyKG, SturnerWQ. Fatal food induced anaphylaxis. JAMA 1988;260:1450–52.
- HillDJ. Clinical recognition of the child with food allergy. Ann Allergy 1987;59:141–45.
- TaylorRFH, Al-JaradN, JohnLME. Betel-nut chewing and asthma. Lancet 1992;339:1134.
- NessAR, KhawKT, BinghamS. Vitamin C status and respiratory function. Eur J Clin Nutr 1996;50:573–79.
- OlusiSO, Ojutiku00, JessopWJ. Plasma and white blood cell ascorbic acid concentrations in patients with bronchial asthma. Clin Chim Acta 1979;92:161–66.
- SchwartzJ, WeissST. Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I) Am J Clin Nutr 1994;59:110–14.
- FogartyA, LewisS, WeissS, BrittonJ. Dietary vitamin E, IgE concentrations, and atopy. Lancet 2000;356:1573–74.
- WangY, HuangDS, EskelsonCD. Long term dietary vitamin E retards development of retrovirus-induced disregulation in cytokine production. Clin Immunol 1994;72:70–5.
- BrittonJR, PavordID, RichardsKA. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 1995;151:1383–87.
- WeirMR. Depression of vitamin B6 levels due to theophylline. Ann Allergy 1990;65:59–62.
- SurS, CarnaraM, BuchmeierA. Double blind trial of pyridoxine (vitamin 136) in the treatment of steroid dependent asthma. Ann Allergy 1993;70:141–52.
- NjaF, NystadW, LodrupCarisen KC, HethevikO, CarisenKH. Effects of early intake of fruit or vegetables in relation to later asthma and allergic sensitization in school-age children. Acta Paediatr 2005;94(2):147–54.
- GillilandFD, BerhaneKT, LiYF, GaudemanWJ, McCannellR, PetersJ. Children's lung function and antioxidant vitamin, fruit, juice, and vegetable intake. Am J Epidemio 12003;158:576–84.
- Selenium.Sunde R. In: StipanukM, editor. Biochemical and physiological aspects of human nutrition. Saunders; Philadelphia: 2000.
- JeongDW, YooNM, KimTS, KimJH, KimIY. Protection of mice from allergeninduced asthma by selenite: prevention of eosinophil infiltration by inhibition of NF-kappa B activation. J Biol Chem 2002;277:17871–76.
- RoweBH, BretzlaffJA, BourdonC, BotaGW, CamargoCAJ. Magnesium sulphate for treating exacerbations of acute asthma inthe emergency department (Cochrane Review). In: The CochraneLibrary, Issue l. 2004. John Wiley and Sons, Ltd. Chichester, UK:
- BakerJC, TunnicliffeWS, DuncansonRC, AyresJG. Dietary antioxidants and magnesium in type 1 brittle asthma: a case control study. Thorax 1999; 54: 115–18.
- CareyOJ, LockeC, CooksonJB. Effect of alterations of dietary sodium on the severity of asthma in men. Thorax 1993;48:714–18.
- TribeRM, BartonJR, PostonL. Dietary sodium intake, airway responsiveness, and cellular sodium transport. Am J Respir Crit Care Med 1994;149:1426–33:
- SprietsmaJE. Modern diets and diseases: NO-zinc balance. Under Thl, zinc and ni trogen monoxide (NO) col lectively protect againstviruses, AIDS, automimmunity, diabetes, allergies, asthma, infectious diseases, altherosclerosis and cancer, Med Hypotheses 1999;53:6–16.
- CampbellM: Low levels of manganese in bronchial biopsies from asthmatic subjects. J Aller Clin Immunol 1992;89(1, Part II):332749.
- HoltzmanMJ. Arachidonic acid metabolism. Implications of biological chemistry for lung function and disease: Am Rev Respir Dis 1991;143:188–203.
- BroughtonKS, JohnsonCS, PaceBK. Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production. Am J Clin Nutr 1997;65:1011–17.
- RahmanI, MacNeeW. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16:534–54.
- WarrakiS, El-GammalM, El-AsmarM, WahbaN. Serum kynurenine in bronchial asthma and chronic bronchitis. Chest 1970;57:148–50.
- Anon. News in brief: WHO recommends exclusive breast feeding for first six months. BMJ 2001;322:126.
- SaarinenUM, KajosaariM. Breastfeeding as prophylaxis against atopic diseases, prospective follow-up study until 17 years. Lancet 1995;346:1065–9.
- GdalevichM, MimouniD, MimouniM. Breast feeding and the risk of bronchial asthma in childhood: a systematic review with metaanalysis of prospective studies. J Pediatr 2001;139:261–66
- BjorkstenB, NaaberP, SeepE, MikelsaarM. The intestinal microflora in allergic Estonian and Swedish 2-year old children. Clin Exp Allergy 1999;29:342–46.
- KalliomakiM, SalminenS, ArvilommiH. Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet 2001;357:1076–79.
According to International Consensus report from National Heart Lung and Blood Institute NIH, USA (1997) asthma is defined as “a chronic inflammatory disorder of airways in which many cells play a role. In susceptible individuals this inflammation causes symptoms which are usually associated with wide spread but variable airflow obstruction that is often reversible either spontaneously or with treatment, and it also causes an associated increase in airway responsiveness to a variety of stimuli.”1 Drug treatment of asthma is directed towards treating bronchial inflammation and relieving bronchoconstriction. Although inhaled corticosteroids are the cornerstone for anti inflammatory therapy, several newer immunomodulatory agents are in the horizon for treating bronchial asthma. Newer inhaled corticiosteroids are also being tested in children and will be available for clinical use soon.
I. NEWER INHALED CORTICOSTEROIDS (ICS)
Inhaled corticosteroids are currently the most effective agents used to treat chronic asthma. However systemic side-effects limit the dose in which inhaled steroids can be administered for long term therapy. Adrenal suppression, abnormalities of glucose metabolism growth impairment, cataract formation are some of the dreaded side-effects of high dose inhaled steroids taken over a prolonged period. The major aim in development of novel steroids is to have high topical activity but no or significantly low systemic bioavailability. Some of the newer steroids that have been developed are as follows.
• On Site Activated Steroid: Ciclesonide
Ciclesonide is a newly developed inhaled steroid that is undergoing evaluation in children which has on site activation. It is a new generation, non halogenated, glucocorticoid with high local anti-inflammatory properties. It has essentially no bioavailability. It is an ester prodrug which is not directly active and has no binding affinity for glucocorticoid receptors. Binding affinity of activatecd ciclesonide is about 100 times its unbounded form. Pharmakokinetically, the onsite activated drug concept leads to blunted and delayed peak concentrations of the active metabolite of this drug. Activated ciclesonide is very rapidly metabolized to inactive breakdown products.2
Soft Steroids: A soft drug is active by itself, has therapeutic efficacy at the site of application and is rapidly and predictably inactivated during its systemic uptake and distribution. A soft ICS should have sufficient metabolic stability for inducing the desired anti inflammatory effect at the airways and the lung target but during its systemic uptake and distribution it has to be inactivated by further metabolic routes, in addition to hepatic CYP 450.3
Loteprednol etabonate: Loteprednol etabonate (LE) is a soft drug which is being tested for respiratory use. So far it has been used for ophthalmic indications. Lactone Derivatives: These are a novel class of soft GCSs that have recently been developed. These drugs have stability in their target organ but high lability in blood.
II. ANTI-IGE ANTIBODY
A century has passed since it was first recognized that a soluble factor in serum is capable of transferring wheal and flare reactions to intradermal injection of allergen, but it was not until 1968 that IgE was recognized as the antibody responsible.4 With the demonstration of a strong association between increased serum levels of IgE and bronchial hyperreactivity and skin test reactivity to allergens, IgE came to be regarded as playing a central role in the pathogenesis of diseases associated with immediate hypersensitivity reactions, like anaphylaxis, allergic rhinitis and asthma.5 The mechanisms by which IgE plays this central role are thought to depend on its binding to high-affinity receptors (FceRI receptors) on mast cells and basophils, and perhaps also to low affinity receptors (FceRII receptors) on macrophages, dendritic cells, B lymphocytes, and other cells. On exposure to a specific allergen, allergen molecules crosslink adjacent Fab components of IgE on the cell surface, activating intracellular signal transduction. In mast cells, this cascade leads to the release of histamine, tryptase, and other preformed mediators. Antigen-antibody bridging also leads to the synthesis and realease of other chemicals, including prostaglandin D2, leukotrienes, and cytokines like TNF-α and IL-4 and IL-5. These compounds in turn cause vascular leakage, smooth muscle contraction, mucus secretion, and the attraction and activation of lymphocytes, eosinophils, neutrophils and other inflammatory cells.6 Considering this pivotal role of IgE in asthma anti IgE has found its place in new drug development.7
• Clinical Trials
Omalizumab: is a recombinant humanized monoclonal antibody which specifically binds to the Ce3 domain of immunoglobin E, the site of high affinity IgE receptor binding. It is indicated in allergic rhinitis and asthma. Improvements in asthma symptoms and health-related quality-of-life, and a significant reduction in the frequency of asthma exacerbations were seen in allergic asthmatic patients treated with omalizumab. Omalizumab was also effective in the treatment of children with allergic asthma demonstrating improvements in health-related quality-of-life and significant dosage reductions of inhaled corticosteroids. Administration of omalizumab to patients with allergic rhinitis resulted in a rapid dose-dependent suppression of serum free IgE levels. Omalizumab significantly improved health-related quality-of-life and nasal symptoms in patients with seasonal allergic rhinitis. Antihistamine requirements were also significantly reduced following treatment. Adverse events were infrequent in clinical trials of omalizumab, and not significantly different from placebo. The most frequent drug-related event was mild to moderate urticaria. Dosage and administration in clinical trials
Allergic asthma: 150–300mg every 4 wks or 225–375mg every 2 wks (dependent on bodyweight and baseline IgE).
Allergic rhinitis: 300mg every 3–4 wks (frequency dependent on baseline IgE)
Route of administration- Subcutaneous
III. SOLUBLE CYTOKINE RECEPTORS AS THERAPEUTIC AGENTS8
Interleukin 4 receptor (IL-4R) on the cell surface is a hetorodimeric complex consisting of a specific high-affinity α-chain that binds to IL-4 and a second chain that can be either the common γ-chain shared with multiple cytokine receptors or the IL-13 receptors-chain. Soluble forms of α-chain IL-4R occur naturally in patients with allergic inflammation and may represent an autoregulatory pathway for IL-4 inhibition. By acting as a decoy to bind to circulating IL-4 and neutralize its activity, its high specificity and affinity make it ideal as an IL-4R.
• Clinical Studies with soluble IL-4R
The promising data in preclinical studies led to preliminary investigations where IL-4R proved safe and effective in the treatment of patients with asthma.9 IL-4R was associated with statistically significant improvement in asthma symptom score and β2-agonist use. Scores on the third section of the AQLQ (patient's perception of general health and physical functioning) worsened in the placebo group and improved in the IL-4R 1.5-mg group (p>0.05). Methacholine testing showed decreased sensitivilty in 6 out of 8 patients tested in the 1.5-mg group. Exhaled NO scores were significantly improved among patients receiving IL-4R, demonstrating an anti-inflammatory effect.
IV. INTERLEUKIN-5 ANTAGONISM
IL-5 inhibitors are being developed as specific anti-eosinophil directed therapies for the treatment of asthma and other allergic diseases. Strategies include blocking receptor binding, inhibiting release of cytokines from T cells, and using blocking monoclonal antibodies directed against IL-5. Several preclinical studies have been completed using monoclonal antibodies directed against IL-5, with promising results in terms of beneficial effects on airways hyperresponsiveness (AHR) and tissue eosinophilia. More recently, anti-IL-5 monoclonal antibodies have been administered to patients with mild allergic asthma using an allergen challenge model. Anti-IL-5 causes clear and longterm reduction in both blood and sputum eosinophils with no significant effect on either AHR or the late asthmatic reaction to inhaled allergen. Thus, IL-5 is an attractive target for antieosinophil-directed therapy, and further studies are ongoing to assess the efficacy of anti-IL-5 monoclonal antibodies in asthma.
• Clinical Studies
There is limited experience with anti-IL-5 monoclonal antibody treatment in human trials. Despite significant reductions in blood and sputum eosinophils, there was no detectable effect on the allergen-induced LAR or AHR to histamine.10 This provides the noval insight that eosinophils may not be a prerequisite for the LAR and AHR, and has relevance to the pathogenesis and treatment of asthma. The limited effects on the LAR and AHR following anti- IL-5 treatment may be due to the involvement of residual eosinophils as well as a number of other cell types such as allergen-specific T cells and mast cells. This has led to a questioning of the role of the eosinophil in human allergen challenge models of asthma, and in clinical asthma.11 A large-scale clinical study on the effect of multiple doses of anti-IL-5 on bone marrow, blood, skin and lung tissue eosinophils will provide further insight into the role of eosinophils in the clinical pathogenesis of allergy and asthma.
Rationale of interleukin 10 (IL-10) in asthma. It has been shown that asthmatics have a low basal IL 10 production which increases considerably after treatment. Hence it is speculated that some of the thrapeutic effects of inhaled corticosteroids may be due to IL 10 stimulation. Genotyping of asthmatic patients has suggested that there are polymorphisms in the promoter region of the IL-10 gene-showing an association of low IL 10 and greater asthma severity and IgE production.
V. PHOSPHODIESTERASE 4 INHIBITORS
Among its myriad of biological actions, the second messenger cAMP relaxes airway smooth muscle, suppresses the actions of immune and inflammatory cells, and modulates pulmonary nerve activity. Thus, increasing cAMP content in these tissues should be of substantial benefit in the treatment of pulmonary disorders such as asthma.12 PDE4 is a major cAMP-metabolizing enzyme in immune and inflammatory cells, airway smooth muscle and pulmonary nerves. Hence PDE4 inhibitors produce a wide range of pharmacological actions that, if replicated in the clinic, may be beneficial in the therapy of asthma. These include anti-inflammatory effects, bronchodilation, and modulation of pulmonary nerves. Indeed, initial clinical data on these agents are encouraging, and suggest that PDE4 inhibitors may have broad utility in the treatment of pulmonary disease. However, full knowledge of the therapeutic value of this novel compound class awaits the outcome of long-term clinical trials. There are strong therapeutic rationales for the use of PDE4 inhibitors in asthma. PDE4 inhibitors are pluripotent anti-inflammatory agents, with actions against eosinophils, T lymphocytes, monocytes and macrophages, and neutrophils. These agents also suppress pulmonary edema and have the unique capacity to inhibit the activity of excitatory (contractile) nonadrenergic noncholinergic nerves, while simultaneously potentiating inhibitory (relaxant) nonadrenergic noncholinergic nerves. Their ability to suppress airway smooth muscle mitogenesis hints that PDE4 inhibitors may impact the airway remodelling that occurs in severe, long-standing asthma.13,14 The principal toxicological observation with both selective PDE4 and nonselective PDE inhibitors is a focal, necrotizing vasculitis in rodents. The relationship between this and the testicular and thymic atrophy also observed in rats is currently under investigation.
VI. LONG-ACTING β2– AGONISTS
The LABAs salmeterol and formoterol have both prolonged airway smooth muscle effects and non-bronchodilator activity. They have a complementary mode of action to the topical anti-inflammatory effects of corticosteroids, and inhibit mucosal oedema, increase mucociliary transport and reduce respiratory tract infection. In asthma, LABAs are currently positioned as ‘add-on’ therapy, where combination with inhaled steroids results in better lung function and symptom control, decreased rescue medication and fewer exacerbations.
• Interactions with Corticosteroids
In addition to the well-documented increase in β2-adrenoceptors induced by corticosteroids, LABAs, such as salmeterol, increase steroid-dependent translocation of the glucocorticoid receptor from the cell cytosol to the nucleus, via a possible mitogen-activated protein kinase (MAPK)- mediated phosphorylation mechanism, leading to a ‘priming’ of the receptor. This complementary mechanism of action of the LABAs is reflected in vitro, for example, as an increase in steroid-induced eosinophil apoptosis, additive inhibition of cellular cytokine and chemokine release, and potentiation of respiratory mucosal cytoprotection. In asthmatic patients, the additional of salmeterol to low-dose inhaled steroids decreases the number of eosinophils and reduces mast cells and CD4+ T cells in airway tissue], and significantly inhibits the degree of angiogenesis occurring as part of the remodelling process. These effects were not observed with higher doses of corticosteroids, and may contribute to the increased clinical efficacy with LABA/steroid combination therapy.
• Clinical Use in Bronchial Asthma
In addition to their long-acting bronchodilator activity, LABAs have been shown to produce a clinically relevant reduction in inhaled steroid dose, and salmeterol, unlike salbutamol, significantly decreases exacerbations in patients with moderate to severe disease. However, the most important role for LABAs in asthma is as an ‘add-on’ combination therapy with inhaled steroids. This concept was first developed by a multi-centre study in the UK in asthmatics not controlled on low-dose steroid. Treatments were divided into one group, where the dose of inhaled steroid (beclomethasone dipropionate) was increased 2.5-fold, whilst the other had salmeterol (50 g b.d.) added to their existing steroid. In terms of lung function and symptoms, the salmeterol combination group improved more than the increased steroid group.
The FACET study evaluated the risk that a LABA, although improving lung function, may be suppressing symptoms of underlying inflammation and increasing the risk of exacerbation of asthma. After stabilizing over 4 weeks on budesonide 1,600mg daily, 800 symptomatic patients were given either lowdose (200 mg/day) or high-dose (800 mg/day) budesonide with or without formoterol (12 mg b.d.) for 1 year. The rate of exacerbations was reduced not only by incresing the inhaled steroid dose, but also by the addition of the LABA. Further evaluation showed that lung function deteriorated prior to severe exacerbations after treatment with LABA or steroids, suggesting that there was no masking of inflammation in the clinical setting. A meta-analysis (MIASMA) which compared the addition of salmeterol to at least doubling the dose of inhaled steroid has been performed. The analysis on nine parallel-group trials of at least 12 weeks in 3,685 patients showed that not only did salmeterol give better lung function, symptom control and less need for rescue medication than increased inhaled steroid, but there were also fewer exacerbations.15 Other therapeutic agents, such as theophylline and leukotriene receptor antagonists (LTRA), have been compared with LABAs as an alternative to increased doses of inhaled steroids.16 The addition of theophylline has also been shown to be beneficial, although a meta-analysis of LABAs versus theophylline by the Cochrane Airways Group showed that salmeterol was more effective with less adverse events17 than the LTRA, montelukast added to low-dose beclomethasone dipropionate (400 g/day) in incompletely controlled asthmatics produced an increase in morning FEV1 from baseline in the order of 5%. This modest effect was confirmed in two other comparator studies with zafirlukast, where the LABA, salmeterol, was at least twice as effective in increasing lung function, decreasing symptoms and reducing rescue bronchodilator use.
VI. LEUKOTRIENE INHIBITORS
The leukotrienes (LTs) are eicosanoids derived from membrane constituent arachidonic acid. The cysteinyl LTs LTC4, LTD4 and LTE4 are potent airway smooth muscle constrictors with a much longer duration of action than other smooth muscle constrictors.18 Several potent and selective anti-LTs have been developed, which have demonstrated the critical role of cysteinyl LTs in asthma pathobiology. The anti-LTs have now been extensively evaluated in clinical trials in patients with persisting asthma, several of which are available to treat the disease. It is theoretically possible to inhibit the production of the LTs by inhibition of any of the enzymes in their biosynthetic pathway. However, as of this time, the only enzyme that has been selectively inhibited in human studies is 5-lipoxygenase. It has also been possible to interrupt LT formation by preventing the binding of arachidonic acid to the 5-lipoxygenase-activating protein19 Cysteinyl leukotrienes are products of the 5-LO pathway. They are potent mediators of allergic bronchospasm and inflammation. Considerable effort in the pharmaceutical industry has focussed on the development of agents that modulate their synthesis or actions. Recently, three selective antagonists of the cysLT1 receptor have been launched for the treatment of asthma. This review summarizes the discovery and development of this new class of asthma therapy.
Zafirlukast, Montelukast and Pranlukast In the 1990s, the leukotriene approach moved from concept to proof. This was based on the successful development and subsequent launch of three cysteinyl leukotriene antagonists: zafirlukast; montelukast and pranlukast, Longer-term studies of leukotriene antagonists in asthma have confirmed the acute improvement in FEV1 is maintained in trials of 6-to 13-weeks duration and there is no evidence for development of tolerance. These effects are associated with improvements in a variety of symptom scores (e.g. total asthma symptoms, night time awakenings and morning asthma symptoms) as well as decreased use of inhaled β2-agonists. Symptom improvements have been demonstrated in 3-month studies of zafirlukast or montelukast. These improvements are generally in the range of 25-50%, although the magnitude of the changes depends on the symptoms which are measured as well as the severity of the asthma. Direct comparison with pranlukast is more difficult since the majority of the studies have been carried out in Japan with somewhat different protocols. However, a 4-week study in the USA with pranlukast has reported improvement in symptoms of a magnitude similar to those described above for zafirlukast and montelukast. A reduction in asthma exacerbations (measured as requirement for oral steroids to treat asthma attacks) was reported in a 3-month study of montelukast in asthma. This has been confirmed in a meta-analysis of five clinical trials of at least 3 months’ duration with zafirlukast. Although the definition of exacerbation varied in the individual trials, the overall reduction in asthma exacerbations shown in this analysis was approximately 50%. Single-Isomer β-Agonists. Studies differentiating the biological activities of R- and S-albuterol have suggested that the S-isomer has properties which are inappropriate for an asthma medication. Recently, R-albuterol (levalbuterol) has become available and seminal studies have demonstrated that the removal of S-albuterol from racemic albuterol creates a more efficacious therapeutic effect for mild persistent to acute asthma.20 In pediatric patients, levalbuterol achieved dose-related improvements in FEV1. Removal of the S-albuterol allowed for a reduction in the dose of R-albuterol so that 0.63 mg offered comparable efficacy to the bronchodilation effects of 2.50 mg racemic albuterol, resulting in a reduction in β-mediated side effects, such as nervousness, tremor and tachycardia. A study of the single-isomer β-agonist levalbuterol for effective bronchodilation in the treatment of acute asthma in the emergency department revealed significant improvements in discharge rate in comparison to the reported discharge rates of racemic albuterol.21, 22
• PHARMACOGENOMICS FOR ASTHMA
Respirable antisense oligonucleotides (RASONs): are a new, drug class targeting respiratory disease. Lung represents a unique target for antisense intervention. The lining surfactant is composed of zwitterionic lipids that are cationic at lung pH. Cationic lipids improve the uptake of antisense oliginucleotides into cells. Surfactant secretion is known to be regulated by an interplay of Adenosine A1 and A2 receptors with A1 receptors inhibiting surfactant secretion and A2 receptors enhancing it. Recent evidence indicated that surfctant secretion is diminished in asthma and may contribute significantly to bronchial hyperresponsiveness. The upregulaton of A1 receptor in asthma may therefore be responsible for loss of surfactant providing a further impetus to develop agents capable of attenuating A1 receptor function. The lung represents unrespirable antisense oligonucleotides functionally, but not genetically, ablate gene expression by blocking the template function of target respiratory messenger RNAs by as yet incompletely defined mechanisms The first respirable antisense oligonucleotide, EPI-2010, has now reached clinical trials. It has shown intriguing initial indications of efficacy and the potential to be the first once-per-week asthma preventation. Respirable antisense oligonucletides are capable of addressing targets, have proven to be intractable to traditional ‘small molecule’ approaches, against which newer monoclonal antibody strategies may also not be optimal. The target properties of respiratory messenger RNAs are strikingly different from those of respiratory protein enabling respirable antisense oligonucleotides to offer the potential of longer duration of effect, increased specificity of effect, and lack of systemic side effects compared with either traditional small molecule protein antagonists or monoclonal antibodies.
- National Heart Lung and Bloood Institute, Expert Panel Report Guidelines for the diagnosis and management of asthma. National Institutes of Health, Bathesda HD, Publication No. 1997: 95–3659.
- BodorN buchwaldP: soft drug design. General Principles and recent applications. Med Res Rev. 2000: 20:58–101.
- BennichHH IshizakaK JohanssonSGO et at: Immunoglobulin E a new class of human immunoglobulin. Bull World Hlth Org 1968: 38:151–52.
- BurrowsB MartinezFD HalonenM et al: Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl j Med 1989: 320:271–77.
- SearsMR BurrowsB FlanneryEM et al: Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 1991: 325:1067–71.
- MilgromH FickRB SuJQ et al: Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999: 341:1966–73.
- BensonM StrannegardIl WennergrenG StrannegardO: Cytokines in nasal fluids from school children with seasonal allergic rhinitis. Pediatric Allergy Immunol 1997: 8:143–49.
- BorishL NelsonH LanzM ClaussenL WhitmoreJ AgostiJ et al: Recombinant human interleukin-4 receptor in moderate astopic asthma: A randomized double-blind, placebo-controlled pilot study. Am J Respir Crit Care Med 1999: 160:1816–23.
- LeckieMJ ten BrinkeA LordanJ KhanJ DiamantZ WallsCM CowleyD HanselT DjukanovicR SterkPJ HolgateS BarnesPJ: SB 240563, a humanised anti-IL-5 monoclonal antibody: initial single dose safety and activity in patients with asthma. Am J Respir Crit Care Med 1999: 159:A624.
- CollinsPD MarleauS Griffiths-JohnsonDA JosePJ WilliamsTJ: Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp med 1995: 182:1169–74.
- TorphyTJ BarnetteMS UnderwoodDC GriswoldDE ChristensenSB MurdochRD NiemanRB ComptonCH: Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: From concept to clinic. Pulm Pharmacol Ther 1999: 12:131–35.
- PanettieriRA EszterhasA CieslinskiLB TorphyTJ: Ariflo® (SB 207499) modulates human airway smooth muscle cell proliferation induced by mitogens. Am J Respir Crit Care Med 2000: 161:A697.
- ShrewsburyS PykeS BrittonM: A meta-analysis of incresing inhaled steroid or adding salmeterol in symptomatic asthma (MIASMA). BMJ 2000: 320:1368–73.
- EvansDJ TaylorDA ZetterstromO Fan ChungK O’ ConnorBJ BarnesPJ: A comparison of low dose inhaled budesonide plus theophylline and high dose inhaled budesonide for moderate asthma. N Engl J Med 1997: 337:1412–18.
- WilsonAJ GibsonPG CoughlanJ: Long-acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2000: 1:1–11.
- LynchKR O’ NeillGP LiuQ ImDS SawyerN MettersKM et al: Characterization of the human cysteinyl leukotriene CysLTI receptor. Nature 1999: 399:789–93.
- DrazenJM IsraelE O’ ByrnePM: Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999: 340:197–206.
- GawchikSM SaccarCL NoonanM RaesnerDS DeGrawSS: The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999: 103:615–21.
- TattersfieldAE PostmaDS BarnesPJ SvenssonK BauerC-A, O’ ByrnePM LofdahlC-G, PauwelsRA UllmanA: Exacerbations of asthma: A descriptive study of 425 severe exacerbations. Am J Respir Crit Care Med 1999: 160:594–99.
Respiratory allergies include allergic rhinitis, sinusitis and asthma. Increasing attention has been devoted to the relationship between rhinitis and asthma, (i.e. between the upper and the lower respiratory airways) that was first noted in epidemiological studies1 and later supported by clinical observations. The atopic march2 refers to the natural history of allergic or atopic manifestations characterized by a typical sequence of clinical symptoms and conditions appearing during a certain age period and persisting over a number of years. In general the clinical features of atopic eczema occur first and precede the development of asthma and allergic rhinitis. The “hygiene hypothesis” proposes that the increase in allergic diseases reflects a decrease in infections during childhood. Clinical trials also suggest that the exposure to microbes through the gastrointestinal tract powerfully shapes immune function. Intestinal microbiota differs in infants who later develop allergic diseases, and feeding probiotics to infants at risk has been shown to reduce their rate of developing eczema. This has prompted studies of administering probiotics in prevention as well as treatment of respiratory allergy. We hereby discuss the status of probiotics in respiratory allergy.
• Burden of Respiratory Allergy
Approximately 300 million people worldwide currently have asthma, with prevalence increasing globally by 50% every decade.3 Prevalence is high (>10%) in developed countries and, although data are still missing, rates are increasing in developing regions as they become more westernized.3 Globally, the economic costs associated with asthma exceed those of tuberculosis and HIV/AIDS combined.4 Developed economies can expect to spend 1 to 2% of their health-care budget on asthma.3 Rhinitis often coexists with asthma (upto 78% of asthma patients have AR, and 38% of patients with AR have asthma). The aggravation of AR coincides with exacerbation of asthma; accordingly, treatment of nasal inflammation reduces bronchospasm, asthma-related emergency department visits, and hospitalizations.
• Scientific Basis for Use of Probiotics in Allergic Diseases
• Microbes, Development of Immunity and Atopy
Infants are born with a “Th2 bias” in immune function, and the cell-mediated immunity, necessary for effective defense against intracellular pathogens, requires production of Th1 cytokines.5 The capacity to induce protective Th1 immune responses develops early in life, primarily over the first year, but appears to be delayed in children predisposed to atopy.6 In fact, Th2 polarization appears to be more prominent and to persist until a greater age in such children.7 Knowing that Th1-dependent immune function matures through infancy, and that the maturity of this function may affect the risk of developing allergic diseases, invites speculation as to how maturation of immune function might be accelerated. Clues as to a possible approach can be inferred from close consideration of the hygiene hypothesis. The “hygiene hypothesis” for the increase in prevalence of allergic diseases This was first put forward by Strachan when he noted an inverse association between family size and the rate of allergic disease, with the greatest protection being associated with the number of older siblings.8 Strachan proposed that the development of allergic disease is prevented by infections in early childhood, and the rise in prevalence is a consequence of the smaller family size and greater hygiene of modern Western societies. Subsequent studies have confirmed a negative association between the risk of developing allergic disease and sibling rank, and have further shown a positive association with higher socioeconomic status.9 This idea, that exposure to nonpathogenic microbes might play a role in preventing the development of asthma and other allergic diseases, was greatly advanced by studies of stool flora in infants from populations with different rates of allergic disease.10–13 Collectively, these studies demonstrate the importance of gut microbial community, and suggest that differences in microbial community composition and increased abundance of specific bacterial species correlate with development of atopy.
• Rationale Behind Using Probiotics in Respiratory Allergy
• Mechanism of Action
Probiotics are “live micro-organisms administered in adequate amounts which confer a beneficial physiological effect on the host”.14 There are a number of possible means by which probiotics may improve health, one of which is the immunomodulation of local immunity (that maintains gut wall integrity)15 and systemic immunity (that enhances non-specific and specific arms of the immune system).16–19 Interfering in the gut flora through ingestion of live microbiota (probiotics), could favour the correct maturation of the immune system, and reduce development of allergy in childhood and later life. It has been seen that the risk of asthma and allergy is lower in children raised in households with domestic animals20,21 or in bedrooms with high levels of endotoxin.22 Especially compelling is the finding that the risk of asthma and allergy is lower in adults with serologic evidence of infection with microbes transmitted by the “feco-oral” route.23 Taken together, these observations suggest a protective effect of microbial exposure on development of respiratory allergy.
• Difficulties in Treatment of Respiratory Allergy
There is currently no cure for these diseases, though a wide range of treatment modalities have been used to control symptoms. Recently, anti-IgE antibody (omalizumab), immunotherapy24,25 anti TNF-a and vitamins have been tried. Many of these treatment modalities do not act through modification of actual inflammatory pathways which underlies the pathophygiologic basis of these diseases. The treatment regimens can be time consuming and expensive for those affected and their families, and there is need for new treatment modalities which are effective, cheap and simple to administer. For individuals with persistent or severe disease, the treatment options are limited.
• Inference from Clinical Trials
A recent meta-analysis26 done on preventive role of probiotics in allergic diseases involving 1549 infants, has shown that there is insufficient evidence to recommend probiotics for prevention of allergic diseases (asthma, rhinitis, eczema, food allergy), although there was a beneficial effect on eczema found on sub-group analysis. They inferred that studies using L. rhamnosus have been the most homogenous in reporting beneficial outcomes. There has been no meta-analysis done on role of probiotics in treatment of allergic respiratory diseases. Evidence from Randomized controlled trials (RCTs) (Table 7.1), have shown variable results. There have been nine good quality RCTs done on role of probiotics in treatment of respiratory allergies. Study done by Giovannini27 showed that the probiotics group is having longer time free from and lower cumulative number of episodes of asthma/rhinitis. But on separating the two outcomes, they found no statistical difference between probiotics and placebo group in asthmatic children, but the annual number of rhinitis episode was lower in children with rhinitis. Similarly studies done by others29,33,34 have shown beneficial effects of probiotics on symptom-medication score of allergic rhinitis. Among these 9 RCTs, 2 studies did not find any beneficial effects of probiotics in allergic rhinitis/asthma. One study28 did not find any beneficial effect on allergic nasal and lung symptoms induced by birch-pollen and another32 found no difference in mean daily peak flows or changes in spirometric values or lung function tests in adults with moderate asthma. Three studies reported on quality of life score (PRQLQ), with two30,31 showing improvement of PRQLQ in rhinitis patients and another32 showing no improvement in asthma patients. All these trials have used different doses and durations as well as different strains of probiotics. The studies on asthma have used only Lactobacillus (sp; acidophilus, rhamnosus, casei) as the probiotic strain; whereas studies on allergic rhinitis have used Bifidobacterium (sp; longum) as well as Lactobacillus strains. It has been hypothesized that some probiotic strains and/or their fermentation products are responsible for improvement of allergic rhinitis34 and the immunostimulatory effect of Lactobacillus may be dose dependant.36 Whatever the dose and duration of probiotics was used in these studies, no beneficial effect was found in subjects with asthma. None of these studies have reported any significant adverse events related to probiotics.
The administration of living organisms, even if considered normal and non-pathogenic as probiotics, must be regarded as potentially dangerous in individuals with primary or acquired immunodeficiency. Anecdotal cases of severe infections or fatalities linked to bifidobacteria or lactobacilli have been reported. Thus, meningitis caused by bifidobacterium was described in an infant treated with probiotics37 and a patient became fatally septicaemic with a vancomycin resistant strain of Lactobacillus rhamnosus contained in a live yogurt.38 While rare, Lactobacillus is recognized as a potential cause of endocarditis,39 even in the absence of probiotic supplementation. Experts estimate that the risk of developing an infection from a Lactobacillus probiotic is “neglible,” happening in less than 1 case per 1 million users of probiotic supplements.40 Like lactobacillemia, biofidobactermia is extremely rare and, when reported, is usually associated with problems during pregnancy or delivery.39
Presently there are no reports of bifidobacterial sepsis occurring in conjunction with probiotic use.41 Instead of infections, the most common adverse effects associated with lactobacilli and bifidobacterial probiotics are transient flatulence and bloating. It is said that these temporary symptoms are a “die-off” effect as probiotic bacteria crowd out and eliminate pathogenic intestinal bacteria. Overall, it appears that probiotics are safe for most individuals, even when compared with the host's own commensal flora. However, as probiotic supplementation does involve ingestion of live micro-organisms, caution is warranted, particularly in people with central venous catheters and compromised immune systems, including transplant recipients.
While there is no doubt that symptom control of respiratory allergic diseases are achieved through judicious use of anti-allergy medications, probiotics are increasingly recognized as safe and effective adjuncts for treating respiratory allergy. Moreover, clinical trials have shown that they are useful in allergic rhinitis, though there is doubtful/no role in mild and moderate asthma. Large clinical trials with evaluation of clinically relevant outcomes are needed before probiotics are recommended for use in allergic respiratory diseases.
- PassalacquaG, CanonicaG W. Impact of rhinitis on airway inflammation: biological and therapeutic implications. Respir Res 2001;2:320–23.
- WeinbergEG. The Atopic March. Current Allergy and Clinical Immunology, March 2005;18(1):4–5.
- World Health Organization. WHO factsheet 206: bronchial asthma. Available at: http://www.who.int/mediacentre/factsheets/fs206/en. Accessed October 23, 2008.
- PrescottSL, MacaubasC, HoltBJ, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998;160:4730–37.
- HoltPG, CloughJB, HoltBJ, et al. Genetic risk for atopy is associated with delayed postnatal maturation of T cell competence. Clin Exp Allergy 1992;22:1093–99.
- PrescottSL, MacaubasC, SmallacombeT, et al. Reciprocal age-related patterns of allergen-specific T cell immunity in normal vs atopic infants. Clin Exp Allergy 1998;28:39–44.
- StrachanDP. Hay fever, hygiene, and household size. BMJ 1989;299:1259–60.
- StrachanDP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 2000;55:S2–10.
- SeppE, JulgeK, VasarM, NaaberP, BjorkstenB, MikelsaarM. Intestnal microflora of Estonian and Swedish infants. Acta Pediatr 1997;86:956–61.
- BjorkstenB, NaaberP, SeppE, MikelsaarM. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999;29:342–46.
- KalliomakiM, KirjavainenP, EerolaE, KeroP, SalminenS, IsolauriE. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clinical Immunol 2001;107:129–34.
- ReidG, SandersME, GaskinsHR, et al. New scientific paradigms for probiotics and prebiotics. Journal of Clinical Gastroenterology 2003;37(2):105–18.
- PerdigonG, AlvarezS, RachidM, AgueroG, GobbatoN. Immune system stimulation by probiotics. Journal of Dairy Science 1995;78(7):1597–606.
- ArunachalamK, GillHS, ChandroRK. Enhancement of natural immune function by dietary comsumption of Bifidobacterium lactis (HN019). European Journal of ClinicalNutrition 2000;54(3):263–67.
- GillHS. Stimulation of the immune system by lactic cultures. International Dairy Journal 1998;8:535–44.
- SchiffrinEJ, RocharF, link-AmsterH, AeschlimannJM, Donnet-HughesA. Immuno-modulation of human blood cells following the ingestion of lactic acid bacteria. Journal of Dairy Science 1995;78:491–97.
- SheihYH, ChiaryBL, WangLH, LiaoCK, GillHS. Systemic immunity-enhancing effects in healthy subjects following dietary consumption of the lactic acid bacterium, lactobacillus rhamnosus HN001. Journal of the American College of Nutrition 2001;20(Suppl 2):149–56.
- OwnbyDR, JohnsonCC, PetersonEL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002; 288: 963–972.
- RiedlerJ, Braun-FahrlanderC, EderW, et al. Exposure to farming in early life and development of asthma and allergy: A cross-sectional survey. Lancet 2001;358:1129–33.
- Braun-FahrlanderC, RiedlerJ, HerzU, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869–77.
- PifferiM, BaldiniG, MarrazziniG, et al. Benefits of immunotherapy with a standardized Dermatophagoides pteronyssinus extract in asthmatic children: A threeyear prospective study. Allergy 2002;57:785–90.
- Di RienzoV, MarcucciF, PuccinelliP, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy 2003;33:206–10.
- OsbornDA, SinnJK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No: CD006475.
- GiovanniniM, AgostoniC, RivaE, et al. A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus casei in pre-school children with allergic asthma and/or rhinitis. Pediatric Research 2007;62(2):215–20.
- HelinT, HaahtelaS, HaahtelaT. No effect of oral treatment with an intestinal bacterial strain, Lactobacillus rhamnosus (ATCC 53103), on birch-pollen allergy:a placebo-controlled double-blind study. Allergy 2002;57:243–46.
- TamuraM, ShikinaT, MorihanaT, et al. Effects of probiotics on allergic rhinitis induced by Japanese cedar pollen: Randomized double-blind, placebo-controlled clinical trial. Int Arch Allergy Immunol 2007;143:75–82.
- PengG-C, HsuC-H. The Efficacy and safety of heat-killed Lactobacillus paracaseifor treatment of perennial allergic rhinitis induced by house-dust mite. Pediatr Allergy Immunol 2005;16:433–38.
- WangMF, LinHC, WangYY, HsuCH. Treatment of perennial allergic rhinitis with lactic acid bacteria. Pediatr Allergy Immunol 2004;15:152–58.
- Ishida,Y Nakamura,F Kanzato,H et al. Clinical effects of Lactobacillus acidophilus strain L-92 on perennial allergic rhinitis: A double-blind, placebo-controlled study. J Dairy Sci 2005;85:527–33.
- Xiao,JZ Kondo,S Yanagisawa,N et al. Effect of probiotic Bifidobacterium longum BB536 [corrected] in relieving clinical symptoms and modulating plasma cytokine levels of Japanese cedar pollinosis during the pollen season. A randomized double-blind, placebo-controlled trial. J Investig Allergol Clin Immunol 2006;16(2):86–93.
- TrappCL, ChangCC, HalpernGM, KeenCL, GershwinME: The influence of chronic yogurt consumption on populations of young and elderly adults. Int J Immunother 1993;IX:53–64.
- HatakkaK, SavilahtiE, Po“nka”A, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. BMJ 2001;322:1327–29.
- HataD, YoshidaA, OhkuboH, MochizukiY, HosokiY, TanakaR. Meningitis caused by bifidobacterium in an infant. Pediatr Infect Dis 1988;7:669–71.
- BartonLL, RiderED, CoenRW. Bacteremic infection with Pediococcus: vancomycin-resistant opportunist. Pediatrics 2001;107:775–76.
- AdamsMR. Safety of industrial lactic acid bacteria. J Biotechnol 1999;68:171–87.
- BorrielloSP, HammesWP, HolzapfelW, et al. Safety of Probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003;36:775–80.
- BoyleRJ, Robins-BrowneRM, TangMLK. Probiotic use in clinical practice: What are the risks? Am J Clin Nutr 2006;83:1256–64.
There has been an increasing prevalence of asthma in the past decade both globally as well as in our country and with that has come the recognition of the magnitude of morbidity it entails.1,2 Missed school days, increased hospitalizations, retarded growth and even death may result from a deficient management of these children. In any chronic disease the effectiveness of therapy depends on ‘how good’ is the treatment and ‘how well’ the patient takes it. Effective treatment options (inhaled medications) are now available which when properly used help in decreasing morbidity associated with asthma and improving the quality of life of the children. However there is a big barrier from the prescription pads to therapeutic effectiveness in the patient. This is largely because the patient does not take the medication the way we would like him to, or in short is non-adherent. Since the outcome of treatment plans works only as well as the patient adherence to therapy, it is worthwhile to look at how well the patient is following what we tell him. Adherence to medication can be defined as the degree to which use of medication by the patient corresponds with the prescribed regimen.3 The term adherence and compliance are used interchangeably in medical parlence. However these are not synonymous. The term ‘adherence’ suggests a more active role for the patient than the word ‘compliance’ which implies that the patient passively submits to the prescribers authority and is obedient with a treatment regimen. Adherence on the other hand, implies a choice made voluntarily by a patient to closely follow a treatment plan. Adherence is influenced by diverse and complex factors including the eccentricities of human behavior and is difficult to predict even in the same patient at different times. Often physicians underplay the importance of adherence assuming it to be a problem of the poor, uneducated or with intense psychosocial dysfunction and are notoriously poor at identifying non-adherence.
• Extent of The Problem
It is conservatively estimated that 50% of medication dependent patients of chronic diseases do not follow prescribed regimens.4 Studies in asthma using electronic monitoring devices attached to MDIs record rate of medication use of about 50% only.5,6 In UK Coutts et al examined patient adherence to antiinflammatory therapy using electronic monitoring and noted under use of inhaled corticosteroids on 55% of study days.5 In another similar study by these authors in preschool children, complete adherence was seen only on half of the study days and only 77% of prescribed doses were taken over the 2 month period.6 In a survey of patients with asthma attending our clinic some form of non adherence was seen in upto 68% of cases (Table 8.1).
• Forms of Non-adherence
Adherence in asthma alternates even in the same individual between fully adherent when symptomatic to non-adherent when asymptomatic. Adherence pattern also differs at different times for different drugs. Non-adherence may be in form of not fulfilling prescriptions, omission of doses, incorrect medication, incorrect dosages or schedules, premature discontinuation of drugs, not following advice to avoid allergens and sub optimal inha lation technique.4,7,8
Erratic non-adherence. Doses are missed because of forgetfulness, changing schedules or busy lifestyles.
Unwitting non-adherence Some patients may be in advertently non-adherent because they have failed to understand fully the specifics of therapy or necessity for adherence.
Intelligent non-adherence. Sometimes patients alter, discontinue or even fail to initiate Inhaled corticosteroids (ICS) treatment. Patients who feel better may decide that they no longer need to take prescribed medications.3 Patterns of non adherence like drug holidays (a period of 3 or more drug free days often associated with interruptions of daily habits like weekends or holidays) and white coat compliance (improvement in compliance several days before a scheduled medical visit) have been described.8
We did a study to find out types of non adherent behavior in patients attending our outpatient and asthma clinic and found all types of non adherent behavior is rampant.
• Consequences of Non Adherence
Unrecognized non adherence decreases the effectiveness of asthma therapy. Non-adherence can result in an increased rate of illness exacerbation, hospitalization, emergency department visits and asthma related deaths.9,10 Further if non-adherence goes unnoticed, medical decisions may be compromised and patient may be exposed to potentially detrimental and costly changes in therapeutic regimen, e.g. the treating physician may hike the dose of the drugs, add a new drug or order fresh investigations to look for alternate causes in view of persisting symptoms.9
• Factors Determining Adherence
Adherence to medication in asthma also seems to be related to wide range of diverse factors like age and sex of the patient, financial status of the family, cultural beliefs, educational level of the parents. Duration of disease and disease severity are also important in determining the adherence to asthma treatment. Milgrom et al demonstrated that “prednisolone” bursts were more common in poorly adherent patients.11 Shrunk et al followed adherence in patients enrolled for CAMP trial and found adherence problems to be greater in patients who had been longer in the trial.12 Adherence behavior is also affected by patient's perception of his or her disease and parental concerns about safety of corticosteroids.13 Type of medication used, dosing schedule, improvement of symptoms with medication also affect adherence to asthma therapy. Patient education about nature of disease and medications also improves adherence to asthma treatment.
• Adherence in Pediatric Population
Few other concerns arise about adherence in children. Since the responsibility of giving medication lies with the parents, Children from troubled families may find it difficult to adhere to therapies. At on older age the adolescent may be rebellious and detest medication. They may feel stigmatized and conceal medication.
• Promoting Adherence
• 1. Clinician Patient Relationships
Nothing is more important in promoting adherence to medication than a sound patient clinician relationship.14 The key to establishing this relationship is open communication, which clinicians foster by demonstrating attentiveness, giving encouragement, active conversation, and eliciting and allaying patient concerns. By using these open communication skills and listening carefully, the clinician may uncover personal beliefs or concerns that may affect adherence.15 If the patient knows, likes and trusts his doctor he or she is most likely to be motivated to be adherent to the therapeutic regimen. In present day management of asthma a great emphasis is placed on patient education and self-management strategies but none of these are likely to succeed unless the patient - physician relationship is maintained. Education and communication is not merely a lecture or hand out, but a dialogue, a two way process between doctor and the patient.16 Asking about patient concerns showing empathy, demonstrating technique, giving feedback and giving suggestions about setting priorities in treatment will all help convince the patient that the patient is committed to the partnership effort and help improve adherence.16 The concept of partnership between patient and physician is a therapeutic and professional relationship specifically designed to promote adherence of the patient to the medical regimen that will result in optimal control of disease. It makes patient an active participant in deciding treatment plans.15
• 2. Prescribing Strategies
Most individuals will prefer not to take any medication. I f medication is needed they will take the least amount and for the shortest period possible. Medication, which needs to be taken once or twice daily, is better adhered to patients' preference also needs to be kept in mind when prescribing. Adolescent boys would not like to carry along a MDI with spacer but might adhere if a dry powder inhaler that can be securely pocketed is prescribed. Also in the context of developing countries cost may be important issue that can limit adherence.17
• 3. Patient education
Patient education aims to alleviate patients and caregivers' concerns and provides knowledge and skills about asthma. The basis of this approach is the belief that patients who are more knowledgeable about their disease and the treatments being used are more motivated and more likely to adhere to an asthma treatment plan. Issues, which need to be a part of these education plans should be addressed with the patient and his/her family, should include information on nature of the disease, nature of treatment and how to use treatment.18 Patients need to be educated on possible allergens and triggers and how to suitably modify treatment to avoid these. Recognition and management of exacerbations and development of self-monitoring and self-assessment skills.18 An individualized asthma action plan needs to be discussed and negotiated with the patient. Information about the basic pathophysiology of asthma is the foundation of patient education. Patients should be informed as far as possible in their own language that asthma is a chronic disease and inflammation is the primary mechanism that occurs in asthma attack. All asthma patients and there family members should know the symptoms of asthma and should be able to determine when these symptoms worsen. Patients who are able to monitor response to therapy may be more inclined to be adherent to asthma treatment. PEFR monitoring is a technique that may be used, however it is essential that patient be adequately instructed on how to use this device. Patients should also be made familiar with environment control strategies. In addition to assisting patients in establishing priorities and explaining how to implement environmental controls, the clinician should explain the rationale for these measures. Additionally patients may be informed about the immediate and delayed responses to these allergens. Last but not the least patients should be educated about their medication; the information should encompass mechanism of action, expected outcome of treatment, importance of correct technique, common and serious adverse effects of each medication. It is very important that the patient understands which medications are prescribed for immediate relief and which are for long-term control. Further since adherence with medications that do not have a immediate benefit is poor, the long-term benefits of controller medication should be emphasized. Because parents may have concerns regarding long-term use of corticosteroids, special effort must be made to address them.13
Written instructions which are culturally appropriate and suited to patient's literacy level should be a core part of every interaction with the patient.18 In patient encounters, the clinician's presentation style should be altered as needed to address patient age, education level, culture and ethnicity. A one to one verbal communication with the patient, including demonstration of recommended devices is an important component of patient education. Ideally the patient should be provided the opportunity to demonstrate their skills and understanding of these devices after the education session. Informational audiotapes, videos and computer software may be used as adjunct to patient education.19 Educational efforts should also be individualized to the patient. Patient concerns or beliefs about asthma need to be addressed. Ideally the primary clinician should introduce the key educational messages. This message needs to be reinforced by nurses, pharmacists and other health care professionals. If a team approach is used it is important that each member gives a consistent message.
• 4. Behavioural Strategies
Behavioral strategies include use of techniques like reminders, reinforcement, monitoring, changing health beliefs and contracting to influence nonadherent behavior. These strategies should be followed in day-to-day practice for maximal patient adherence.18
- Reminders have a well-substantiated role in behavior therapy. They have been documented to be useful in maintaining adherence in asthmatic followed as outpatients after rehabilitation. An occasional phone call by the physician can have a rejuvenating influence on patients adherence and motivation.
- Tailoring refers to molding the desired regimen to meet patient demands. Tailoring entails modifying treatment plans to suite every patient.
- Reinforcement refers to any consequences that increase the possibility of a behavior being repeated. Positive reinforcement is giving the patient some incentive like praise, a small reward for a successful performance. It is a useful strategy and is a component of almost all behavioural programmes.
- Self-monitoring is a process of observing and recording ones own behavior. Asthma diaries, checklists or charts kept by patients are an important component of self-management programmes. The patient records his behavior, evaluates it and then regulates it.
- Providing feedback to the patients regarding medication adherence is another useful clinical strategy.
• Maintaining Adherence
Self-management plans that encompass both behavioral and educational aspects have been developed. The most recent set of guidelines have the following points.20
- Education of the patient beginning at the time of diagnosis and integrated into every aspect of asthma care.
- Patient education provided by all members of the team
- Teaching skills for the self-management of asthma by tailoring information and treatment to fit the needs of each patient
- Joint development of treatment plans by team members and patients
- Encouragement of active partnership by providing written self-management and individualized asthma action plans to patients
- Encouraging adherence to the treatment plan jointly developed by the interdisciplinary team and the patients.
- Encourage adherence by promoting open communication, individualizing, reviewing and adjusting plans as needed, emphasizing goals and outcomes and encouraging family Self-management plans have demonstrated their effectiveness in decreasing symptoms; school absence and emergency care as well as improving education about asthma.21
The daily self management plans list all prescribed medication as well as dose and frequency and methods of administration, recommended monitoring techniques and treatment goals. The goals listed in the action plan should be reasonable, attainable, individualized and specific. Both short term and long-term goals need to be established. The role of various treatment measures in achievement of goals should be discussed. The management plan should be continuously revised and reviewed as necessary.
- ParameshH. Epidemiology of asthma in India. Indian J Pediatr 2002;69(4):309–12.
- Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjuctivitis, and atopic eczema: ISSAC. The International Study of asthma and allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351(9111):1225–32.
- Asthma. In SabateE. eds Adherence to long term therapies: Evidence for action. ISBN 92 G 154599WHO Geneva, 2003;47–58.
- WeinsteinAG. Clinical management strategies to maintain drug compliance in asthmatic Children Ann Allergy, Asthma and Immunol 1995;74:304–08.
- CouttsJAP, GibsonNA, PatonJY. Measuring compliance with inhaled medication in asthma. Arch Dis Child 1992;67:332–33.
- GibsonNA, FergusonAE, AitchisonTC, PatonJY. Compliance with inhaled asthma medication in preschool children. Thorax 1995;50:1274–75.
- WeinsteinAG, BenderB, ApterA, MilgromH, KobrynskiL, et al. Achieving Adherence To Asthma Therapy. AAAAI Quality of Care for Asthma Committee Paper.
- MatsuiDM. Drug Compliance in Pediatrics; clinical research issues. Pediatr Clin of North America 1997;44:1–14
- BaumanLJ, WrightE, LeicklyFE, CrainE, Kruszon-MoranD, WadeSL, Visness CM Relationship of adherence to pediatric asthma morbidity among inner city children. Pediatrics 2002;110:e6.
- EshelG, RavivR, Ben-AbrahamR, BarrJ, BerkovitchM, et al. Inadequate asthma treatment practices and non-compliance in Israel. Pediatr Pulmonol. 2002;33:85–89.
- MilgromH, et al. Non compliance and treatment failure in children with asthma. J Allergy Clin Immunol 1996;98:1051–57.
- BouletLP. Perception of the role and potential side effects of inhaled corticosteroids among Asthmatic patents. Chest 1993;113:587–92.
- BrownR. Behavioral issues in asthma management. Pediatr Pulmonol Suppl 2001;21:26–30.
- GeppertEF, CollazoS. Establishing a partnership with the patient with asthma. J Allergy Clin Immunol 1998;101:s 405–08.
- LuskinAT. Relationship: The forgotten component. Ann Allergy, Asthma and Immunol 1998;81:519–21.
- WatsonJP, LewisRA. Is asthma treatment affordable in developing countries Thorax 1997;52:605–07.
- British Thoracic society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax Feb 2003;58 (Suppl 1): i1–94.
- McPhersonA, GlazebrookC, SmythA. Double click for health: the role of multimedia in asthma education. Arch Dis Child 2001;85:447–49.
- National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. J Allergy Clin Immunol. Nov 2002;110(5 Suppl):S141–219.
- WolfFM, GueveraJP, GrumCM, ClarkNM, CatesCJ. Educational interventions for asthma in children (Cochrane review). In: The Cochrane Library Issue 2, 2004. John Willey and Sons, Ltd. Chichester, UK:
• What is Wheezing?
Wheezing is typically described as a `whistling´ sound audible during respiration. While it is a frequent symptom during infancy and early childhood, it can extend into older childhood and even adulthood. 1 It is a sound most parents and caregivers are familiar with. However, it often has different connotations and many parents use the term loosely to describe noisy breathing that has better nomenclature. A survey of parents, who described `wheezing´ in their infants, showed that many reclassified the sound when they were shown a video film that depicted different lung sounds in infants. Only a minority of parents continued to describe the sounds as `wheezing´.2,3 This error in labelling a sound is not restricted to lay persons, but also occurs among physicians caring for children.
• What Causes Wheezing?
For all practical purposes, wheezing reflects narrowing of small airways. This may occur due to actual narrowing of airway calibre through contraction of airway smooth muscle, accumulation of mucus and secretions in the airways and narrowing of airway lumen by extrinsic compression. Whatever be the aetiology, the narrowed airway usually permits airflow into the lungs, but restricts movement outwards. This results in the typical whistling sound described as wheezing. Thus wheezing can occur in infants in a variety of clinical conditions besides bronchiolitis and asthma. These include lower respiratory tract infection including pneumonia, cystic fibrosis, gastro-esophgeal reflux, micro-aspirations and congenital anomalies such as tracheo bronchomalacia and compression of the airway by vascular rings. Aspiration of a foreign body into the airway also results in narrowing of the lumen and wheezing. One other condition that must be remembered in wheezing infants is congestive cardiac failure, particularly against a backdrop of congenital cardiac defects. The two most common clinical diagnoses entertained in wheezing infants are bronchiolitis and infantile asthma. Both these terms are often used interchangeably and even managed without making a distinction between them. However the treatment, clinical course and long term prognosis of these conditions vary widely and necessitate an accurate understanding of the pathophysiological process. Bronchiolitis is a frequent acute respiratory tract affection among infants characterized by fever, coryza, cough, expiratory wheezing, and respiratory distress.4 It is usually viral in origin with respiratory syncytial virus (RSV) being the major causative organism.5 However, other viruses including adenovirus, rhinovirus, influenza virus and parainfluenza virus can result in identical disease, as also Mycoplasma pneumoniae.6 Recently the human metapneumovirus (HMPV) has been identified as an agent that induces a similar illness.7 Conservative estimates suggest that one of every ten infants suffers from bronchiolitis and about 20% of them have to undergo hospitalization for this.8
On the other hand, bronchial asthma is a chronic inflammatory disease of the lower airways that is associated with airway hyper-reactivity, mucus secretion and reversible bronchoconstriction. This condition can start in infancy and present as recurrent wheezing episodes. The first episode is often indistinguishable from bronchiolitis, which is usually an acute condition that does not recur. However, it must be remembered that a viral bronchiolitis episode in infancy can induce a specific IgE antigen and eosinophilia, and be associated with recurrent wheezing in infancy and later childhood.9 Therefore there is now a line of view that chronicity must be demonstrated in wheezing infants at the time of diagnosing them as bronchial asthma. In the absence of this, there should be a reasonable degree of certainty that the infant is not likely to wheeze in later life as well. Therefore, infantile asthma can be redefined as recurrent wheezing that is likely to recur.10
• Predictors of Recurrent Wheezing in Infants
Broadly, infantile wheezing has been categorized as viral-induced wheezing and wheezing associated with allergy/atopy. The two types have a rough proportion of 2:1 among wheezing infants. Majority of these infants have a single episode of acute wheezing, normal pulmonary functions, require minimal medical attention and are unlikely to wheeze in the future. The clinical diagnosis of bronchiolitis would be appropriate in most of these infants and there is no need for further investigations. The other cohort of babies with wheezing has associated allergy/atopy either in themselves or a close family member. These are likely to develop wheezing in later life as well and have deterioration in pulmonary function. Atopy has been identified as the major risk factor associated with recurrence of wheezing in later life.11 There is a lot of ongoing research to identify specific allergens that can induce this phenomenon. House dust, pollen and dust mite have been identified as definite triggers. There is also evidence that early exposure to household pets particularly dogs may be associated with an atopic tendency. Atopy may manifest with recurrent wheezing, allergic rhinitis or non-respiratory tract conditions such as conjunctivitis and eczema. A family history of asthma and presence of atopic state are probably the strongest pointers towards an asthmatic tendency. Based on the presence or absence of these characteristics, an “allergy index” has been proposed that has a significant negative predictive value, in that greater than 95% infants with a negative index will not develop asthma in later childhood.12 There are possibly prenatal and perinatal risk factors that increase the risk of wheezing in infancy. One of the proposed factors is maternal smoking, whereas breast feeding seems to have a protective effect. The presence of siblings in the family and attendance at day care centres increased the risk of wheezing. There is some evidence that boys are more likely to wheeze than girls. The onset of some types of food allergy in early childhood is also associated with later wheezing episodes. Besides, these, the exact role of several other factors such as cognitive skills of the caregiver, parental anxiety, nature of housing, family income and ethnicity have not been delineated so far. Nevertheless, the mere presence or absence of one or more of the proposed risk factors does not man that an infant will wheeze in later childhood or develop asthma. Therefore some investigative modalities have been incorporated that include measurement of serum levels of IgE in response to a variety of antigens, eosinophil cationic protein (ECP) and nasal smear eosinophilia. These have varying degrees of sensitivity, specificity and predictive value. It is now increasingly believed that there is an immunologically mediated mechanism in childhood asthma. Activated T-cells produce interleukins and other cytokines that result in bronchconstriction. The relative proportion of T helper 1 (Th1) and T helper 2 (Th2) cells determines the type of response that a particular infant will exhibit in response to an antigenic stimulus. It is believed that early in neonatal life, the body´s immune system `chooses´ a Th1 or Th 2 type of response. Those with a Th 2 type of response are more likely in later life to have allergic disorders whereas those with a Th1 type of response are protected from such diseases.
• Management Issues
There is a tendency to treat every wheezing episode as bronchiolitis and when the response is inadequate, to resort to a trial with bronchodilators or corticosteroids as in the therapy for asthma. This may work in some patients, but is an unscientific method of management. The mainstay of management in bronchiolitis is good supportive care with the inhalation of cool humidified oxygen. Several pharmacological modalities have been tried in bronchiolitis, but only the use of nebulized epinephrine (racemic or otherwise) has been proven to be of benefit on improvement of symptoms,13 although the evidence on this is not unequivocal.14 Use of inhaled bronchodilators,15 corticosteroids,16 specific therapy such as ribavarin,17 RSV immunoglobulin18 and modifications in supportive care such as nebulisation with a helium-oxygen mixture etc. have not been clearly shown to be of benefit in the short or long term. There is some evidence that some of these treatment measures may reduce the risk of wheezing in later life, but there is as yet no treatment guideline on the management of bronchiolitis. It must be emphasized that the value of clinical trials of various therapeutic modalities in bronchiolitis is often limited by poor methodological quality including imprecise definitions, inadequate recruitment criteria and low power. Likewise, the beneficial effects of some modalities such as surfactant or immunoglobulin may be restricted to a subset of infants with bronchiolitis. International guidelines for the treatment of asthma in children do not describe the management of wheezing in infants. However, those who are diagnosed as bronchial asthma after careful consideration of the clinical profile, family history and some basic tests such as nasal smear for eosinophils, will receive treatment as per the standard guidelines and evidence-based medicine.19 In addition, efforts have to be made to identify trigger factors and ensure avoidance of the same. Ongoing research is required to study the long term effects of management of infantile asthma, on clinical profile, growth and prognosis. Other conditions resulting in wheezing need management based on the underlying cause. Thus congenital anomalies of the respiratory or cardiovascular system need surgical correction wherever feasible. Similarly, pharmacological and non-pharamacological interventions for the management of gastroesophageal reflux will be ameliorative in that condition. A detailed discussion on the treatment of these conditions is beyond the scope of this article.
Most infants who have an episode of wheezing will not undergo the experience again. They are likely to have normal respiratory function and no impairment in later life. Two-thirds of infants with recurrent wheezing are likely to outgrow their symptoms during the subsequent five years or so.20 On the other hand, children who have a severe episode, require intensive care or undergo mechanical ventilation during the acute episode are more likely in later life to manifest with hyper-reactive airway disease.
- DoullIJM, LampeFC, SmithS, SchreiberJ, FreezerNJ, HolgateST. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomized double blind placebo controlled trial. BMJ 1997 315: 858–62.
- ElphickHE, SherlockP, FoxallGH, SimpsonEJ, ShiellNA, et al. Survey of respiratory sounds in infants. Arch Dis Child 2001 84: 35–39.
- CaneRS, RanganathanSC, Mc Kenzie.SA. What do parents of wheezy children understand by `wheeze´? Arch Dis Child 2000 82: 327–32.
- KlassenTP. Recent advances in the treatment of bronchiolitis and laryngitis. Pediatr Clin North Am 1997 44: 249–61.
- EverardML. Bronchiol itis: Origins and optimal management. Drugs 1995; 49(6): 885–96.
- KurthCD, GoodwinSR. In: Beck KoffP, EitzmanD, NeuJ, editor(s). Neonatal and Pediatric Respiratory Care. Mosby-Year St. Louis: 2nd Edition. Book Inc, 1993;121–25.
- WilliamsJV, HarrisPA, TollefsonSJ, Halburnt-RushLL, PingsterhausJM, EdwardsKM, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. New Engl J Med 2004;350:443.
- FloresG, HorwitzRI. Efficacy of beta 2-agonists in bronchiolitis: A reappraisal and meta-analysis. Pediatrics 1997;100(2):233–39.
- BeverHV. Wheezing during the first year of life: is it asthma? Indian Pediatr 2004 41: 1101–04.
- LauS, NickelR, NiggemannB, GruberC, SoimmerfieldC, IlliS, et al. MAS Group. The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS). Paedtr Resp Rev 2002 3: 265–67.
- Castro-RodriguezJA, HolbergCJ, WrightAL, MartinezFD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000 162: 1403–06.
- BertrandP, AranibarH, CastroE, SanchezI. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonoll 2001 31: 284–88.
- Abul-AinineA, LuytD. Short term effects of adrenaline in bronchiolitis: A randomised controlled trial. Arch Dis Child 2002 86: 276–79.
- KellnerJD, OhlssonA, GadomskiAM, WangEEL. Efficacy of bronchodilator therapy in bronchiolitis: A meta-analysis. Arch Pediatr Adolesc Med 1996 150: 1166–72.
- GarrisonMM. ChristakisDA. HarveyE. CummingsP. DavisRL. Systemic corticosteroids. in infant. bronchiolitis: A meta-analysis. Pediatrics 2000;105:E44.
- RandolphAG, WangEEL. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software.
- WangEEL, TangNK. Immunoglobulin for preventing respiratory syncytial virus infection (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software.
- MartinezFD, WrightAL, TaussigL, HolbergCJ, HalonenM, MorganW. Asthma and wheezing in the first six years of life. New England Journal of Medicine 1995;332(3):133–38.
Food allergy is defined as an adverse immunological response to food that is reproducible under blinded conditions. As a result of changing environmental conditions, westernized life style, air pollution, and the consumption of lots of additives and preservatives with foods, food allergy and asthma are increasing worldwide. Allergic Rhinitis (hay fever or “indoor/outdoor,” “seasonal,” “perennial” or “nasal” allergies): characterized by nasal stuffiness, sneezing, nasal itching, clear nasal discharge, and itching of the roof of the mouth and/or ears.1,2,3
Allergic Asthma (asthma symptoms triggered by an allergic reaction): Characterized by airway obstruction that is at least partially reversible with medication and is always associated with allergy. Symptoms include coughing, wheezing, shortness of breath or rapid breathing, chest tightness, and occasional fatigue and slight chest pain. Asthma is one of the 3 manifestations of a pattern of allergy, called atopy. The associated disorders are eczema and hay fever. Food allergy can cause both immediate and delayed patterns of asthma. Immediate food reactions can cause sudden, dramatic and life-threatening asthma as one of the consequences of anaphylactic reactions to food. Delayed patterns of food allergy can cause chronic asthma and/or bronchitis and are among the most neglected causes of chronic or “intrinsic” asthma. Diet revision can resolve chronic asthma.
Type 1 Allergy patients often have positive skin tests to inhalant allergens which cause skin reactions to foods which prove to be a problem. Foods that produce significant positive skin tests should be avoided in the diet; however, other foods that do not show skin reactions may contribute to the disease. If all the attention is directed toward the more obvious skin-positive inhalant allergies, an opportunity to benefit from comprehensive diet revision is lost. Patients with delayed pattern food allergy have the most persistent inflammatory form of chronic asthma. Skin tests do not show delayed patterns of food allergy and diet revision must be complete and comprehensive to resolve this common form or allergic asthma.
Here are the basic ideas about asthma causes and treatment:
- Asthma is allergy until proven otherwise.
- Allergy comes from airborne and food sources.
- Solve asthma by improving air quality and doing diet revision.
The three basic treatment choices are:
- Remove the cause of Asthma
- Treat the symptoms
- Alter the host to be more tolerant of the causes
Many studies of food allergy involve patients with food-induced asthma; the asthma is easily recognized if symptoms begin within a few hours of eating food and the asthma is associated with other symptoms of food allergy. Eczema and asthma are often associated in atopic patients with food allergy. It is reported that in a group of 320 children with atopic dermatitis 55% had asthma.5 Food challenges triggered respiratory symptoms in 59% of including rhinitis, laryngeal edema, wheezing and dyspnea. Gastrointestinal symptoms occurred in 41% of positive challenges. Often, asthma is treated only as an airborne allergy problem or as a problem unrelated to allergic processes and the possible role of food allergy is neglected.
“Food allergy is a very important cause of asthma but is often overlooked. It is important because it may cause severe symptoms of asthma and still has a high mortality despite improvements in drug therapy. It is overlooked because the usual skin tests are often negative and the history is often not helpful as symptoms appear gradually hours or days after ingestion of the food.” IgE and Non-IgE mechanisms can cause asthma. Patients with no positive skin tests were shown to react to foods. In our studies, Milk, Wheat, Egg, Banana, Mango, Rice, Groundnut, Fish, were the main foods implicated. Other manifestations of food allergy are typical in 65% of the asthmatic patients. Diet revision with elimination of foods or a “low allergen” diet was used to induce remission of symptoms then foods were re-introduced to determine reactivity. The role of food allergy in patients with bronchial complaints is still underestimated by clinicians because: (1) of the death of information in this area (2) The involvement of foods in patients with allergic disorders is complex and has various forms. (3) The diagnostic procedures and confirmation of adverse reactions to foods is difficult. In a study of mechanisms increasing circulating immune complexes (IgE and IgG) were demonstrated following challenges with allergenic foods (egg) and correlated with symptoms. Complexes peaked at 24 hours after food ingestion and the appearance of symptoms was followed only later. Twelve of the 14 subjects studied had asthma; associated problems were eczema, rhinitis, arthralgia, urticaria, and diarrhoea. In a review of 320 children and young adults with atopic dermatitis 55% had asthma. With food challenges respiratory symptoms occurred in 236 (42%) including nasal symptoms, dyspnea, wheezing, and laryngeal edema. Chronic coughs may mean allergic bronchitis with or without asthma. Food allergy patients are often given antibiotics repeatedly, since allergic symptoms and infection symptoms are similar. Antibiotics may offer no benefits and may increase the risk of further allergic reactions. Many patients report long-term deterioration after repeated or prolonged antibiotic use. This apparent adverse effect of antibiotics has been blamed on yeast overgrowth in GIT, but the real reason is probably more complex. Food allergens travel from the digestive tract to the lungs. Food allergens may be found in the blood stream in circulating immune complexes that trigger the release of immune mediators in the bloodstream. These chemicals cause a variety of symptoms, including constriction of the bronchial smooth muscle in the lungs; this is the first event of an asthmatic attack. Airflow is reduced in the narrowed tubes. Air has a harder time leaving the lungs than entering-the result is prolonged noisy expiration. If you listen with a stethoscope, you will hear scattered whistles from the narrowed bronchi on breathing out. Later, the small tubes in the lung swell and plug with increased mucus secretion, making the obstruction to airflow worse. This inflammatory, obstructive phase is the most important mechanism of chronic asthmatic bronchitis. Our patients usually have asthma with associated symptoms that suggest a whole-body food allergy problem.
Food Allergen: Most prevalent in very young children and frequently outgrown, food allergies are characterized by a broad range of allergic reactions. Symptoms may include itching or swelling of lips or tongue; tightness of the throat with hoarseness; nausea and vomiting; diarrhoea; occasionally chest tightness and wheezing; itching of the eyes; decreased blood pressure or loss of consciousness and anaphylaxis. Although some researchers would argue that an allergic component contributes to more than 80% of young asthmatics and approximately 40% of adult asthmatics who experience the association between diet and non-food allergies are widely ignored. It is reported in the United States that about 6-8% of infants and about 1.5% of adults are allergic to food. Food is very important cause of asthma but is often overlooked, as usual skin tests are often negative and history is often not helpful. In most of the patients, symptoms appear gradually hours or days after ingestion of the food. It has been estimated that less than 10% of asthmatics may notice that their symptoms are provoked by certain foods or drinks.7,9–11 The majority of these deaths are due to severe allergy to peanut and nuts, and asthma appears to be an important risk factor for this form of allergy. Sensitivity can occur by ingestion of minute quantities of food allergens and even by inhalation of food allergens carried in air or in cooking fumes. A food allergic reaction is presumed to be the result of abnormal immunological responses, consisting both of IgE mediated and non-Ig-E-mediated response after ingestion of a relevant food. Sensitization occurs as a result of pinocytosis of antigenic protein molecules by intestine mucosal cells (perhaps in the Peyer's Patches) and induction of an IgE antibody response. Subsequent entry of antigen into the blood-stream provokes an IgE-mediated reaction. The representative symptoms of food allergy are “Oral allergy syndrome” with oral and perioral itching and rash, gastrointestinal symptoms such as nausea, vomiting and diarrhoea, and dermatological manifestations such as urticaria and eczema.12 We have seen infants develop rashes after a traditional bath with milk or curd. Food allergy can cause both immediate and delayed patterns of asthma. Effect of foods on asthma can be mediated through increase in synthesis of prostaglandin-E2 (PG-E2). This can in turn promote the formation of IgE and consequently allergic sensitization. Immediate food reaction (Type-I allergy mediated by IgE), can cause sudden, dramatic and life threatening asthma, is one consequence of anaphylactic reaction to food. Delayed patterns of food allergy (Non-IgE-mediated) can cause more persistent inflammatory form of chronic asthma. This is among the most neglected causes of intrinsic asthma. Skin tests do not show delayed pattern of food allergy.
Common foods causing asthma are milk, eggs, fish, peanuts, soy, yeast, cheese, wheat, rice and chocolates.4,6,8 Food preservatives can also trigger an asthma attack. Additives such as sodium bisulfite, potassium bisulfite, sodium metabisulfite, potassium metabisulfite and sodium sulfite are commonly used in food processing or preparation and can be found in foods such as: Dried fruits or vegetables, Potatoes (packaged and some prepared), wine and beer, bottled lime or lemon juice, shrimp (fresh, frozen or prepared) pickled foods.
• Doctors Diagnose Allergies in Three Steps (Patient Education Points)
- Personal and medical history. Your doctor will ask you questions to get a complete understanding of your symptoms and their possible causes. Bring your notes to help for your memory. Be ready to answer questions about your family history the kinds of medicines you take and your lifestyle at home, school and work.
- Physical examination: If your doctor suspects an allergy, he/she will pay special attention to your ears, eyes, nose, throat, chest and skin during the physical examination. This exam may include a pulmonary function test to detect how well you exhale air from your lungs. You may also need an X-ray of your lungs or sinuses.
- Tests to determine your allergens. Your doctor may do a skin test, patch test or blood test.
Skin test - For most people, skin tests are the most accurate and least expensive way to confirm suspected allergens. There are two types of allergen skin tests. In prick/scratch testing, a small drop of the possible allergen is placed on the skin, followed by lightly pricking or scratching with a needle through the drop. In intra-dermal (under the skin) testing, a very small amount of allergen is injected into the outer layer of skin. With either test, if you are allergic to the substance, you will develop redness, swelling and itching at the test site within 20 minutes. You may also see a “wheal” or raised round area that looks like a hive. Usually, the larger the wheal, the more sensitive you are to the allergen.
Patch test - This test determines if you have contact dermatitis. Your doctor will place a small amount of a possible allergen on your skin, cover it with a bandage and check your reaction after 48 hours. If you are allergic to the substance, you should develop a rash.
Blood tests - Allergen blood tests (also called Radioallergosorbent tests [RAST], Enzyme-Linked Immunosorbent Assays [ELISA], Fluorescent Allergosorbent tests [FAST], Multiple Radioallergosorbent tests [MAST] or Radioimmunosorbent tests [RIST] are sometimes used when people have a skin condition or are taking medicines which interfere with skin testing. The lab adds the allergen to the blood sample, and then measures the amount of antibodies the blood produces to attack the allergens. However, it is important to establish a clinical correlation with the positive tects.
- MullinsRJ. Paediatric food allergy trends in a community-based specialist allergy practice, 1995–2006. Med J Aust 2007; 186:618–21.
- WallaceDV, DykewiczMS BernsteinDI Blessing-MooreJ CoxL KhanDA et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol Aug 2008; 122(2).
- JenA BaroodyF de TineoM HaneyL BlairC et al. As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol Apr 2000; 105(4): 732–38.
- SampsonHA. Update on food allergy. J Allergy Clin Immunol 2004; 113:805–19.
- JamesJM CrespoJF. Allergic reactions to foods by inhalation. Curr Allergy Asthma Rep.
- WainsteinBK YeeA JelleyD et al. Combining skin prick immediate skin application and specific-IgE testing in the diagnosis of peanut allergy in children Pediatr Allergy Immunol 2007; 18:231–39.
- SampsonHA. Adverse reactions to foods. in Allergy: Principles and Practice, Middleton Jr,E ReedCE EllisEF. Eds. 4th ed. Mosby St. Louis, 1993;1661.
- BabaM Food allergy. in Clinical Allergy, MiyamotoT MakinoS BabaM. Eds. Nankodo, Tokyo, 1992; 364.
- AgarkhedkarSR BapatHB BapatBN. Avoidance of food allergens in childhood asthma. Indian Paediatrics 2005; 42:362–6.46.
- NakougawaT. Food allergens as the possible cause of asthma and anaphylaxis. Intern Med 1998; 37(1):
- SampsonHA. McCaskillCC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985; 107:669-75. 38. Steinman HA. “Hidden”allergens in foods. J Allergy Clin Immunol 1996; 98:241–50.
Allergen immunotherapy (also called allergy vaccine therapy) involves subcutaneous injections of gradually increasing quantities of specific allergens to an allergic patient until a dose is reached that will raise the patient's tolerance to the allergen over time, thereby minimizing symptomatic expression of the disease. Because the proteins and glycoproteins used in allergen immunotherapy are extracted from materials such as pollens, molds, pelt, and insect venoms, they were originally called allergen extracts. In 1998, the World Health Organization (WHO) proposed the term “allergen vaccine” to replace “allergen extract,” because allergen immunotherapy is an immune modifier just as vaccines are.1 The efficacy of allergen immunotherapy has been known since 1911, when Noon injected an extract of grass pollen into a person in England whose allergic symptoms coincided with the pollination of grass.2 Since then, controlled studies have shown that allergen immunotherapy is effective in patients with allergic rhinitis, allergic conjunctivitis, allergic asthma, and allergic reactions to Hymenoptera venom.3–6 Patients with one or more of these diagnoses are considered for immunotherapy if they have well-defined, clinically relevant allergic triggers that markedly affect their quality of life or daily function, and if they do not attain adequate symptom relief with avoidance measures and pharmacotherapy.
• Mechanism of Action
Allergen-specific immunotherapy (SIT) has been used for almost a century as a desensitizing therapy for allergic diseases and represents the only curative and specific method of treatment. Administration of appropriate ions of allergen extracts has been shown to be reproducibly effective when patients are carefully selected. The mechanisms by which allergen-SIT has its effects include the modulation of T-cell and B-cell responses and related antibody isotypes as well as effector cells of allergic inflammation. The balance between allergen-specific T-regulatory (Treg) and TH2 cells appears to be decisive in the development of allergic and healthy immune responses against allergens.7–9 Treg cells consistently represent the dominant subset specific for common environmental allergens in sensitized healthy individuals. In contrast, there is a high frequency of allergen-specific TH2 cells in patients with allergy. The induction of a tolerant state in peripheral T cells represents an essential step in allergen-SIT. Peripheral T-cell tolerance is characterized mainly by generation of allergen-specific Treg cells leading to suppressed T-cell proliferation and TH1 and TH2 cytokine responses against the allergen. This is accompanied by a significant increase in allergen-specific IgG, Ig A and a decrease in IgE in the late stage of the disease. In addition, decreased tissue infiltration of mast cells and eosinophils and their mediator release including circulating basophils takes place. There is increasing evidence to support IL-10 and/or TGF-β secreting Treg cells8–10 and immunosuppressive cytokines as key players in mediating successful allergen-SIT and a healthy immune response to allergens. In sensitized individuals, peripheral T-cell tolerance represents the key mechanism in healthy immune responses to allergens. Peripheral tolerance to allergens induced by allergen-SIT involves control of the allergen-specific immune response in multiple phases including specific T-cell suppression, generation of non-inflammatory antibody isotypes such as IgG4 and IgA, suppression of IgE and type 1 hypersensitivity responses and suppression of late phase reaction and mast cells, eosinophils, and basophils.11 Taking the recent advances in knowledge of peripheral tolerance mechanisms into account, developments of safer approaches and more efficient methods of allergen-SIT await.
- Allergic rhinitis, conjunctivitis, or allergic asthma.
- Patient wishes to avoid the long-term use or potential adverse effects of medications.
- Symptoms are not adequately controlled by avoidance measures or medications.
- Cost of immunotherapy will be less than cost of long-term medications.
- Asthma triggered by exposure to airborne allergens, PLUS: Poor response to asthma medicines or environmental controls, avoiding your triggers is unrealistic or impossible, having problematic side effects from asthma medicine.
The allergens for which immunotherapy is known to be effective are pollens,5, 6 cat dander,12 dust mites,13 cockroaches,14 and fungi.15 Allergy immunotherapy cannot be used for food allergies because the risk of anaphylaxis is too great. For immunotherapy to be effective, an optimal dose of each allergen must be determined. When a patient has multiple sensitivities caused by related and unrelated allergens, vaccines containing mixtures of these allergens may be prescribed. As multiple vaccines are mixed, not only will the concentration of each allergen be decreased, but certain allergens will interact. For example, fungi, dust mites, insect venoms, and cockroach have high proteolytic enzyme activity and may be combined with each other but should not be mixed with other allergens.
Durham and colleagues16 conducted a randomized, double-blind, placebocontrolled trial to look at effects in patients who had received three to four years of immunotherapy. They were able to demonstrate a marked reduction in allergy symptom scores and antiallergic medication usage, as well as an alteration in the natural course of allergic disease. Preliminary reports suggest that immunotherapy for allergic rhinitis may reduce the risk for later development of asthma in children.17,18 In addition, early treatment with allergen immunotherapy in children who were sensitive only to house dust mites reduced development of sensitivity to other allergens.19 In contrast to the use of antiallergic medication, allergen immunotherapy has the potential to alter the natural course of allergic disease and prevent progression or development of multiple allergies. Consequently, many allergists have suggested its use earlier in the course of allergic disease. In 2000, the Immunotherapy Committee of the American Academy of Allergy, Asthma, and Immunology (AAAAI) provided a five-year cost comparison of medication usage and single-injection allergen immunotherapy for allergic rhinitis. The cost of medications is much greater than that of single injection immunotherapy. Long term costs deriving from the morbidity and complications of allergic diseases are not established, but allergies usually begin early in life and persist if not treated with allergen immunotherapy. A reasonable assumption is that allergen immunotherapy dramatically lowers the cost of treating allergic diseases.
• Evidence from Meta-analysis
Sub-cutaneous Immunotherapy (SCIT): Currently subcutaneous immunotherapy is established as effective treatment for patients with allergic rhinitis20 and allergic bronchial asthma.21 In their updated meta-analysis using 75 trials including 3506 participants (36 trials of immunotherapy for house mite allergy; 20 pollen allergy trials; ten animal dander allergy trials; two cladosporium mould allergy, one latex and six trials looking at multiple allergens), Abramson et al21 confirmed that allergen specific immunotherapy can significantly reduce asthma symptoms and medication requirements. Whilst inhaled corticosteroid therapy remains the mainstay of asthma management, any reduction in this type of treatment while maintaining good asthma control would be welcome. There was no consistent effect of immunotherapy upon lung function and there was significant heterogeneity in the trials that reported PEFR measurements Patients randomised to immunotherapy were significantly less likely to develop increased nonspecific bronchial hyperresponsiveness (BHR), and there were modest improvements in indices of nonspecific BHR. Allergen immunotherapy significantly reduced allergen specific BHR. Not surprisingly it would appear that allergen immunotherapy has a greater effect upon allergen specific BHR than upon nonspecific BHR. The finding that allergen immunotherapy significantly and homogeneously improves allergen specific bronchial BHR is clinically important. Patients with brittle extrinsic (allergic) asthma are at risk of sudden deterioration when exposed to increased levels of an aeroallergen to which they are sensitive. An intervention that reduces the risk of an acute episode of asthma under these circumstances may be clinically useful. Currently, the measurement of allergen specific BHR is the only accurate method of assessing such a risk. There is some evidence that house dust mite extracts may reduce asthma symptoms and allergen specific BHR compared to house dust extracts. One study even suggested that house dust extracts alone could reduce allergen specific BHR, challenging the view that such extracts are antigenically inactive. However taken together, these results are consistent with the greater efficacy of house dust mite extracts compared with placebo. Although not consistently reported in the randomised controlled trials, there are well recognised adverse effects of immunotherapy. Three recent studies22–24 reported the incidence of non-fatal systemic reactions to inhalant allergen immunotherapy. The total number of participants was 4768 and the studies recorded events over 7 to 12 years. The incidence of systemic reactions was one per 1250 to one per 2206 injections. Most reactions were mild. Deaths due to allergen immunotherapy were extremely rare, with estimates ranging from one per one million to one per two million injections.
Sub-lingual Immunotherapy (SLIT): Meta-analyses have confirmed that SLIT is effective therapy for allergic rhinitis,25 including in pediatric patients,26 and for allergic asthma.27 A meta-analysis of 21 trials involving 959 subjects with allergic rhinitis found a significant reduction in symptoms and medication use, but no clear relationship between results and the dose or duration of therapy could be established.25 The pediatric rhinitis study, which included trials with 484 subjects, found significant improvement in symptoms with pollen, but not house dust mite extracts, and with treatment for more than 18 months, but not with briefer treatment.25 Twenty-five studies with 1706 participants were included in the asthma metaanalysis.27 Although the evidence found in the meta-analysis was not very strong, the results from assessing all parameters suggested SLIT reduced asthma expression.
The major advantage offered by SLIT over SCIT is safety; no fatal or near fatal reactions have been reported.28 This reputation for safety has allowed home administration of SLIT, thus avoiding the other shortcoming of SCIT, the inconvenience of frequent visits to a physician's office to receive the injections. The absence of fatal or life-threatening reactions with SLIT does not, however, mean that this form of treatment is without adverse reactions. The predominant reaction is oral pruritus or swelling. In a double-blind study, 634 subjects with grass allergy received an oral tablet of timothy extract containing 15 μg Phl p 5 without a build-up phase. Oral itching or swelling was reported by 46% receiving active and 4% receiving placebo therapy.29 A review of all published studies of SLIT from 1986 to 2004 included 25 studies, approximately half in which the dose was 1 to 50 times the customary SCIT dose and half in which the dose was 50 to 500 times the SCIT dose.30 The rate of systemic reactions including ocular, cutaneous, and respiratory was similar in the low-dose and high-dose studies, about 0.5 per 100 doses. In another review of the literature on SLIT, information on the occurrence of serious adverse reactions was available from studies including 1,019,826 doses administered to 3984 patients.28 There were 14 probable SLIT-related serious adverse events, the majority being respiratory, with single episodes of uvula edema, urticaria, abdominal pain, and vomiting that resulted in hospitalization. One cutaneous-respiratory reaction to a multiple allergen mix has been reported.31 Symptoms suggested hypotension, but a fall in blood pressure was not documented.
• Safety Issues
Allergen immunotherapy is safe, but the potential for an adverse reaction isalways present. Although these reactions are rare, they can be life-threatening. In 1924, Lamson reported the first case of death following immunotherapy.32 A statistical review of the literature about systemic reactions following allergen immunotherapy by Lockey and colleagues33 found that severe systemic reactions occurred in less than 1 percent of the patients receiving conventional immunotherapy in the United States. From 1985 to 1993 in the United States, 52.3 million administrations of immunotherapy resulted in 35 deaths. These numbers equate to a mortality incidence of less than one per 1 million.34 Patients with medical conditions that reduce their ability to survive systemic allergic reactions are not candidates for allergen immunotherapy. Examples of such conditions include chronic lung disease with a forced expiratory volume in one second (FEV1) of less than 50 percent, beta-blocker or angiotensin-converting enzyme (ACE) inhibitor therapy, uncontrolled hypertension and major organ failure. Allergen immunotherapy also cannot be used in patients who would have difficulty reporting signs and symptoms of a systemic reaction, such as children younger than three or four years. Patients who have not been compliant with other forms of therapy are not likely to be compliant with immunotherapy, thus necessitating frequent alteration in dosage schedules and increasing the chance for errors. Patients should be assessed with each injection for newly acquired risks that may not have been present at the beginning of allergen immunotherapy. Patients with severe, poorly controlled asthma are at higher risk for systemic reactions to immunotherapy injections than patients with stable, well-controlled asthma.33 Some physicians measure peak expiratory flow readings in all patients with asthma before administering allergen immunotherapy and with hold injections if the reading is less than 70 percent of predicted.
Anaphylaxis is the most serious risk related to allergen immunotherapy. The vaccines must be administered in a setting with trained professionals who are equipped to recognize and treat anaphylaxis.35 A retrospective study found that most systemic reactions occurred within 30 minutes of injection.36 Hence, the current recommendation is to allow at least 20 to 30 minutes of observation following an injection. Patients who have had a systemic reaction after more than 30 minutes following an injection require longer observation; in addition, they should be given injectable epinephrine to carry and instructions about how to use it. Nonetheless, reactions may occur without warning signs or symptoms, and documentation of informed consent must be obtained from the patient.
• Persistence of Effect After Discontinuation
Given the persistence of the protective effect after discontinuing immunotherapy on the development of new sensitizations and progression to asthma, it is not surprising that there is also persistence of reduction of clinical symptoms.37–39 This has been shown most convincingly by a double-blind study in which subjects who had received 3 or 4 years of timothy grass immunotherapy were randomized to continue receiving monthly maintenance injections of grass extract or to receive placebo injections.39 After 3 more years, there was no difference in control of symptoms or medication use between the 2 groups.
Immunotherapy remains the only truly disease-modifying treatment for asthma and allergic rhinitis. It restores the normal immune response to common allergens. It can prevent new sensitizations in monosensitized individuals and prevent the development of clinical asthma in those with only rhinitis. Furthermore, its salutary effects continue for years after completion of the course of treatment. The factors limiting the greater use of immunotherapy are concerns of safety and the inconvenience of prolonged build-up and maintenance treatment schedules. Numerous approaches to improve the safety and increase the convenience of immunotherapy are being studied. The only one currently in clinical use is sublingual administration of the allergen extracts. Evidence for the effectiveness of this approach is quite convincing. There remain questions to be resolved including optimal dosing, frequency, and duration of treatment. There is also the question of the effectiveness of administration of mixes of multiple allergen extracts sublingually. Finally, SLIT appears to be, at least in the short term, less effective than SCIT. It is likely there is a place for both approaches to immunotherapy in the treatment armamentarium. Other new approaches to immunotherapy are under study. These include modified recombinant allergens, peptides, immunostimulatory DNA sequences covalently bound to allergenic proteins, and fusion proteins designed to give an inhibitory signal to mast cells and basophils. Whether any of these approaches will replace current immunotherapy practices depends on the demonstration of increased safety and convenience, cost effectiveness, and retention of the efficacy of current injection immunotherapy.
- Allergen immunotherapy: therapeutic vaccines for allergic diseases. Geneva: January 27–29,1997. Allergy 1998; 53 (44 suppl): 1–42.
- NoonL CantabBC. Prophylactic inoculation against hay fever. Lancet 1911; 1:1572–74.
- PichlerCE HelblingA PichlerWJ. Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity. Allergy 2001; 56:301–06.
- Adkinson JrNF EgglestonPA EneyD GoldsteinEO SchuberthKC et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997; 336:324 –31.
- RossRN NelsonHS FinegoldI. Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, single or doubleblind, placebo-controlled studies. Clin Ther 2000; 22:329–41.
- AkdisCA AkdisM BleskenT WymannD AlkanSS MullerU et al. Epitope specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J Clin Invest 1996; 98:1676–83.
- AkdisCA BleskenT AkdisM WuthrichB, BlaserK. Role of IL-10 in specific immunotherapy. J Clin Invest 1998; 102:98–106.
- JutelM AkdisM BudakF Aebischer-CasaultaC WrzyszczM BlaserK et al. IL-10 and TGF-b cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003; 33:1205–14.
- FrancisJN TillSJ DurhamSR. Induction of IL-101CD41CD251 T cells by grass pollen immunotherapy. J Allergy Clin Immunol 2003; 111:1255–61.
- AkdisM BlaserK AkdisCA. T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J Allergy Clin Immunol 2005; 116:961–8;quiz 9.
- VarneyVA EdwardsJ TabbahK BrewsterH MavroleonG FrewAJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind, placebo-controlled trial. Clin Exp Allergy 1997; 27:860–67.
- OlsenOT LarsenKR JacobsanL SvendsenUG. A one year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults. Allergy 1997; 52:853–59.
- KangBC JohnsonJ MorganC ChangJL. The role of immunotherapy in cockroach asthma. J Asthma 1988; 25:205–18.
- DreborgS AgrellB FoucardT KjellmanNI KoivikkoA NilssonS. A doubleblind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. I. Clinical results. Allergy 1986; 41:131–40.
- MollerC DreborgS FerdousiHA HalkenS HostA JacobsenL et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109:251–56.
- GrembialeRD CamporotaL NatyS TranfaCM DjukanovicR, MarsicoSA. Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000; 162:2048–52.
- Des RochesA ParadisL MenardoJL BougesS DauresJP BousquetJ. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450–53.
- RossRN NelsonHS FinegoldI. Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized prospective, single- or double-blind, placebo-controlled studies. Clin Ther 2000; 22:342–50.
- AbramsonMJ PuyRM WeinerJM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003; 4:CD001186.
- BusincoL ZanninoL CantaniA CorriasA FiocchiA LaLa. Systemic reactions to specific immunotherapy in children with respiratory allergy: a prospective study. Pediatric Allergy and Immunology 1995; 6:44–7.
- KaraayvaM, ErelF CaliskerZ, OzanquaN. Systemic reactions due to allergen imunotherapy. Journal of Investigational Allergology and Clinical Immunology 1999; 9:39–44.
- WilsonDR Torres-LimaM DurhamSR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005; 60:4–12.
- PenagosM CompalatiE TarantiniF Baena-CagnaniR HuertaJ PassalacquaG et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized placebo- controlled, double-blind trials. Ann Allergy Asthma Immunol 2006; 97:141–48.
- CalamitaZ SaconatoH PelaAB AtallahAN. Efficacy of sublingual immunotherapy in asthmatics: systematic review of randomized clinical trials using the Cochrane Collaboration method. Allergy 2006; 61:1162–72.
- CoxLS LinnemannDL NolteH WeldonD FinegoldI NelsonHS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 2006; 117:1021–35.
- DahlR KappA ColomboG de MonchyJGR RakS EmmingerW et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 118:434–40.
- GidaroGB MarcucciF SensiL IncorvaiaC FratiF CiprandiG. The safety of sublingual-swallow immune therapy: an analysis of published studies. Clin Exp Allergy 2005; 35:565–71.
- DunskyEH GoldsteinMF DvorinDJ BelecanachGA. Anaphylaxis to sublingual immunotherapy. Allergy 2006; 61:1235.
- LamsonRW. Sudden death associated with injection of foreign substances. JAMA 1924; 82:1090.
- TurkeltaubP. Deaths associated with allergenic extracts. FDA Medical Bulletin 24, May 1994.
- PumphreyRS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30:1144–50.
- GreenbergMA KaufmanCR GonzalezGE RosenblattCD SmithLJ SummersRJ. Late and immediate systemic- allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol 1986; 77:865–70.
- EbnerC KraftD EbnerH. Booster immunotherapy (IT). Allergy 1994; 49:38–42.
- Des RochesA ParadisL KnaniJ HejjaouiA DhivertH ChanezP et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract, V: duration of the efficacy of immunotherapy after its cessation. Allergy 1996; 51:430–33.
- DurhamSR WalkerSM VargaE-M, JacobsonMR O’BrienF NobleW et al. Long-term clinical efficacy of grass pollen immunotherapy. N Engl J Med 1999; 344:468–75.
Asthma has a genetic predisposition but it needs environmental factors to initiate the events leading to clinical development of allergy. Asthma affects children in many ways and can result in a significantly decreased quality of life, with reduced exercise tolerance and increased school absences.1 Furthermore the symptoms of asthma diagnosed in childhood persist into adulthood. For example, 50% of children with asthma referred to one hospital clinic had on going symptoms in adulthood some 30 years later.2 Current asthma treatment palliates but does not cure symptoms. Better understanding of asthma pathogenesis in children is essential for future advances in asthma management. In many developing countries, increasing Westernization is associated with a rapid rise in the prevalence of previously uncommon atopic disorders. Not with standing the importance of genetic factors, the time frame over which these increases have occurred makes it implausible that they could be the result of genetic changes, highlighting the importance of environmental factors in the pathogenesis of allergic sensitization and the expression of atopic diseases. Both observational and interventional studies continue to shed new light on the critical influence of early life events - such as events in pregnancy, exposure to allergens and endotoxin, pet ownership, infections, family size - and have highlighted important gene-environment interactions that modify the relationships between environmental exposures and atopic outcomes.
• Family Size and Hygiene Hypothesis
Early childhood respiratory infections were associated with an increased asthma risk, whereas early contact with older children was linked to permanent protection against asthma and increased the chances of remission of childhood asthma. These patterns of association were independent of the presence or absence of allergen-specific IgE, suggesting that exposure to microbial infections can partially interfere with an acquired predisposition to asthma. Similarly, otitis media and other infections in infancy may protect against allergic sensitization in older children and teenagers.3,4 Household endotoxin levels appear to be inversely associated with a subsequent diagnosis of eczema, even after adjusting for income, season of birth and gender.5
• Pets Exposure
The effect of family pets on the development of atopic disease remains controversial. While few would argue with the recommendation that sensitized patients should minimize exposure to cats and dogs, it is becoming increasingly clear that avoidance of such exposures is ineffective in preventing sensitization in young children and may indeed be counterproductive.6 Early exposure to cats appears to protect against cat allergy and subsequent asthma 7– 9 and may also reduce sensitization to other allergens,7 while other investigators report no relationship between cat allergen exposure and atopy or asthma outcomes.10 Dog ownership in early life also appears to be associated with reduced allergic sensitization and atopic dermatitis. 8,11 Dogs, rodents, birds and other furry or feathered animals in the home may contribute in varying degrees to the animal allergens within the home. Dogs may have breed-specific allergens and are less uniformly allergenic than cats.12 Rodent allergens can come from pets or pests in the home. Birds and feathers have been suggested as allergenic; however, it may be that the dust mites associated with feathers (including feathers in pillows and clothes) are the culprits 13 The type of microbial exposure during immune system maturation may influence the development of atopy and asthma. In children with the CD14 - 159C allele who had regular contact with household pets, serum IgE levels were higher than with the T allele.14 The opposite occurred in children with regular contact with stable animals where the C allele was associated with lower IgE levels.
• Farm Animals
Living on a farm with continuous exposure to the animals has been found to cut down the risk of many allergic diseases and asthma. It has been reported that the protection against these diseases starts building even before birth. Life in a farm means continuous exposure to the animal bacteria through direct animal exposure or through unpasteurized milk consumption. The researchers say that this exposure may suppress the development of specific immune cells that are related to asthma.
Exposure to moluds may lead to allergic sensitization and may exacerbate asthma or allergic rhinitis.15 At least 60 species of moulds have spores thought to be allergenic.16 Species of particular concern are Penicillium, Aspergillus, Cladosporium, Alternaria. On exposure to these species, nasal congestion, runny nose, sneezing, conjunctivitis, lacrimation, wheezing, chest tightness and shortness of breath may occur. Among patients studied, children are the most sensitive to molud allergens.17
• House Dust Mite
House dust mites are tiny (up to 0.3 mm) animals related to ticks and spiders and live in housedust. There is not a house without them, but some houses contain huge numbers and other houses contain almost none. This does not only depend on cleanliness, but depends very much on the amount of moisture in the house; dry houses in very cold climates or on high mountains have few mites, but houses in temperate climates and normal altitudes have more. House dust mites eat the dust which comes from our skin all the time. They leave droppings everywhere they go. Their droppings contain left-over enzymes which the mites use to digest the skin dust. It is these enzymes which are the most important part of mite dust in causing asthma and other allergic diseases. In fact, house dust mites and their droppings are the most important cause of asthma worldwide. There is ample proof that living in surroundings with little or no mite dust improves or cures asthma in those people whose asthma is caused by it. Previous investigators have reported that exposure to domestic levels of Der p 1 in excess of 10 mg/g of dust in infancy is a risk factor for asthma in older
Children,18 but only in those with a family history of allergic disease. Higher mite allergen exposure is associated with a greater risk of sensitization in children with a positive family history, but a lower risk of sensitization in children without a history of parental atopy.19 Cullinan and co-workers20 reported no overall relationship between early mite allergen exposure and IgE sensitization or atopic asthma at the age of 5 years. However, closer examination of the exposure- response relationships showed an increase in sensitization and wheeze at low levels of allergen exposure and a reduction in both outcomes at high levels of allergen exposure.20
• Other Factors
Prolonged delivery was associated with the development of atopy in a prospective birth cohort followed to the age of 20 years, whereas prenatal smoke exposure and childhood pets decreased the risk of atopy,21 suggesting that events in pregnancy or at birth may have an enduring effect on atopy many years later. Psychological stress in caregivers is reportedly associated with larger T-cell responses to allergens and higher total IgE levels in the first two years of life,22 while elevated body mass index and an early onset of puberty may be linked to persistence of asthma from childhood into adolescence.23 Use of skin creams containing peanut oil and intake of soymilk or soy-based formula, are associated with the development of peanut allergy.24 Despite asthma´s high prevalence and considerable quality of life implications, its pathogenesis in children is not completely understood. What has been established is that asthma is a complex condition, where both genetic and environmental factors are important.
• Environmental Tobacco Smoke
Exposure to environmental tobacco smoke (ETS) is a risk factor for asthma attacks in children.25 Children with asthma and whose parents smoke have more frequent asthma attacks and more severe symptoms.26–28 There is clear evidence of an association between exposure to environmental tobacco smoke and the development and exacerbations of asthma. Exposure to ETS also places children at increased risk for sinusitis, otitis media and bronchiolitis.13,29 Exposure to environmental tobacco smoke may increase the risk of asthma in susceptible individuals. In a study of Puerto Rican and Mexican families, people with asthma with the CD14 ρ1437GG or GC genotypes and exposure to environmental tobacco smoke had a mean forced expiratory volume in 1 st lower by 8.6% of that predicted, compared with nonexposed individuals.30
• Combustion Devices
Improperly used or malfunctioning heating devices are a major source of combustion pollutants indoors. Possible sources of contaminants include gas ranges, especially if used for home heating; improperly vented fireplaces; inefficient or malfunctioning furnaces; stoves burning wood, coal, or other biomass; and unvented or improperly vented kerosene or gas space heaters. The combustion products from these devices include carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter and sulfur dioxide (SO2). Although CO is a major health concern, it is not an irritating gas and is not likely by itself to exacerbate asthma. In combination, these combustion products will often exacerbate asthma symptoms.31
• Air Pollution
Ozone is a major air pollutant with adverse effects on the lungs. In mice, regions of genetic linkage with ozone-induced lung injury include the tumour necrosis factor-α (alpha) (TNF) gene.32 A role for TNF polymorphism in susceptibility to childhood asthma in response to environmental ozone exposure has now also been established.33 Air pollutants include diesel exhaust particles with particulate matters less than 10 mm or 2.5 mm. These diesel exhaust particles are thought to exert their detrimental effects through generation of reactive oxygen species. The glutathione- S-transferase genes protect from oxidant stress. Thus, carriers of the glutathione-S-transferase genes that result in loss of function may be at increased risk for respiratory morbidity when exposed to air pollution.
• Occupational Agents
There are well over 300 agents reported to cause occupational asthma,34 and an equal or greater number of agents and conditions at work can aggravate existing asthma. Numerous workplace biologic allergens can cause asthma, including natural rubber latex in medical care settings and animal allergens in research laboratories and veterinary offices. A wide range of airborne dusts, gases, fumes, and vapors can cause dose-related symptoms in individuals exposed to them in the workplace. Among the chemicals associated with occupational asthma, the acid anhydrides have been signal agents for study because of their inherent and complex biological activity and the wide range of associated occupational airway disease seen in exposed workers in various occupational settings.35 In addition to traditional “dirty” workplaces, offices and other non-industrial indoor work environments can pose a risk for asthma. Sufficient evidence exists for associating the presence of mould or other agents in damp buildings to nasal and throat symptoms, cough, wheeze, and asthma symptoms in sensitized asthmatics.36 There are other reports also that exposure to damp indoor environments and mold can lead to the development of asthma.37,38 In practice, asthma is likely to be caused by combinations of several genetic and environmental factors, all of which should be considered when studying asthma pathogenesis. Environmental and lifestyle factors which have undergone rapid changes have therefore been recognized as the cause of the steep rise in allergic diseases and thus require a better understanding.
- MerikallioVJ, MustalahtiK, RemesST, et al. Comparison of quality of life between asthmatic and healthy school children. Pediatr Allergy Immunol 2005;16(4):332–40.
- VonkJM, PostmaDS, BoezenHM, et al. Childhood factors associated with asthma remission after 30 year follow up. Thorax 2004;59(11):925–29.
- NjaF, NystadW, HetlevikO, et al. Airway infections in infancy and the presence of allergy and asthma in school age children. Arch Dis Child 2003;88:566–69
- McDadeTW, KuzawaCW, AdairLS, BeckMA. Prenatal and early postnatal environments are significant predictors of total immunoglobulin E concentration in Filipino adolescents. Clin Exp Allergy 2004;34:44–50
- PhipatanakulW, CeledonJC, RabyBA, et al. Endotoxin exposure and eczema in the first year of life. Pediatrics 2004;114:13–18
- OryszczynMP, Annesi-MaesanoI, CharpinD, KauffmannF. Allergy markers in adults in relation to the timing of pet exposure: the EGEA study. Allergy 2003;58:1136–43
- RonmarkE, PerzanowskiM, Platts-MillsT, LundbackB. Four-year incidence of allergic sensitization among schoolchildren in a community where allergy to cat and dog dominates sensitization: report from the Obstructive Lung Disease in Northern Sweden Study Group. J Allergy Clin Immunol 2003;112:747–54
- de MeerG, ToelleBG, NgK, et al. Presence and timing of cat ownership by age 18 and the effect on atopy and asthma at age 28 years. J Allergy Clin Immunol 2004;113:433–38
- BeckerA, WatsonW, FergusonA, et al. The Canadian asthma primary prevention study: outcomes at 2 years of age. J Allergy Clin Immunol 2004;113:650–56
- GernJE, ReardonCL, HoffjanS, et al. Effects of dog ownership and genotype on immune development and atopy in infancy. J Allergy Clin Immunol 2004;113:307–14
- LindgrenS, BelinL, DreborgS, EinarssonR, PahlmanI. Breed-specific dog-dandruff allergens. J Allergy Clin Immunol 1988;82:196–204
- [IOM] Institute of Medicine, Committee on the Assessment of Asthma and Indoor Air. 2000. Clearing the air: asthma and indoor air exposures. Washington, DC: National Academy Press.
- EderW, KlimeckiW, YuL, et al. Opposite effects of CD14/_260 on serum IgE levels in children raised in different environments. J Allergy Clin Immunol 2005;116:601–07
- PopeA.M. PattersonR. and BurgeH. (eds.). “Indoor Allergens: Assessing and Controlling Adverse Health Effects.” Committee on the Health Effects of Indoor Allergens. Division of Health Promotion and Disease Prevention. Institute of Medicine. National Academy Press. Washington, DC: Available online at http://books.nap.edu/catalog/2056.html 1993.
- BurgeHA. Airborne allergenic fungi. Classification, nomenclature, and distribution. Immunol Allergy Clin North Am. 1989;9:307–19
- EtzelRA. How Environmental Exposures Influence the Development and Exacerbation of Asthma. Pediatrics 2003;112:233–39
- SporikR, HolgateST, Platts-MillsTA, CogswellJJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323:502–07
- Cole JohnsonC, OwnbyDR, HavstadSL, PetersonEL. Family history, dust mite exposure in early childhood, and risk for pediatric atopy and asthma. J Allergy Clin Immunol 2004;114:105–10
- CullinanP, MacNeillSJ, HarrisJM, et al. Early allergen exposure, skin prick responses, and atopic wheeze at age 5 years in English children: a cohort study. Thorax 2004;59:855–61
- VonkJM, BoezenHM, PostmaDS, et al. Perinatal risk factors for bronchial hyperresponsiveness and atopy after a follow-up of 20 years. J Allergy Clin Immunol 2004;114:270–76
- WrightRJ, FinnP, ContrerasJP, et al. Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin Immunol 2004;113:1051–57
- GuerraS, WrightAL, MorganWJ, et al. Persistence of asthma symptoms during adolescence: role of obesity and age at the onset of puberty. Am J Respir Crit Care Med 2004;170:78–85.
- LackG, FoxD, NorthstoneK, GoldingJ. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977–85.
- WeitzmanM, GortmakerS, WalkerDK, SobolA. Maternal smoking and childhood asthma. Pediatrics. 1990;85:505–11
- MartinezFD, ClineM, BurrowsB. Increased incidence of asthma in children of smoking mothers. Pediatrics 1992;89:21–26
- MurrayAB, MorrisonBJ. The decrease in severity of asthma in children of parents who smoke since the parents have been exposing them to less cigarette smoke. J Allergy Clin Immunol 1993;91:102–10
- TagerIB, HanrahanJP, TostesonTD, CastileRG, BrownRW, WeissST, et al. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am Rev Respir Dis. 1993;147(4):811–17.
- ChoudhryS, AvilaPC, NazarioS, et al. CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. Am J Respir Crit Care Med 2005;172:173–82
- (AAPCEH) American Academy of Pediatrics Committee on Environmental Health. EtzelRA, editor. Pediatric environmental health. 2nd ed. Elk American Academy of Pediatrics; Grove Village, IL: 2003.
- KleebergerSR, LevittRC, ZhangLY, et al. Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice. Nat Genet 1997;17:475–78.
- LiYF, GaudermanWJ, AvolE, et al. Associations of tumor necrosis factor G- 308A with childhood asthma and wheezing. Am J Respir Crit Care Med 2006;173:970–76
- ZeissCR. Advances in acid anhydride induced occupational asthma. Curr Opin Allergy Clin Immunol. 2002;2(2):89–92.
- [IOM] Institute of Medicine of the National Academies. Damp Indoor Spaces and Health. The National Academies Press. Washington, DC. 2004.
- Cox-GanserJM, WhiteSK, JonesR, HilsbosK, StoreyE, EnrightPL, et al. Respiratory morbidity in office workers in a water-damaged building. Environ Health Perspect. 2005;113:485–90
- JaakkolaJJ, HwangBF, JaakkolaN. Home Dampness and Molds, Parental Atopy, and Asthma in Childhood: A Six-Year Population-Based Cohort Study. Environ Health Perspect. 2005;113(3):357–61.
Asthma is a condition, often chronic, characterized by respiratory symptoms, variable airflow limitation and/or airway hyper-reactivity with symptoms causally related to family history, environmental influences, exposure to viruses and allergens as examples. The high economic burden associated with asthma is associated primarily with health care costs, missed work or school days. Families with patients suffering from asthma are always in search of a wonder cure for this disease. There is a wealth of information in traditional knowledge on this aspect which needs to be used and researched in a scientific way.1 Drug therapy is normally used to control symptoms. However the use of complementary or alternative medicine (CAM) is widespread. In a UK survey of National Asthma Campaign members, only 41% said that they had not used CAM and of those 41%, 67% said that they would consider using CAM for their asthma in the future. The most popular forms of CAM in the study population were breathing techniques, homeopathy and herbs. A survey of CAM use in asthma or rhino sinusitis sufferers in the USA found that 42% of the study population had used some form of CAM for their condition in the 12 months prior to the study. Herbal treatments emerged as being the most commonly reported form of CAM being used. Another US survey of CAM use found that allergies and lung problems ranked as some of the most frequently reported medical conditions that CAM is used for. The most popular forms of CAM for these conditions were herbs, relaxation and spiritual healing. Why then, when there are effective treatments available for asthma do people turn to complementary or alternative medicine, especially given that evidence in support of treatments such as acupuncture and homeopathy are weak. The reasons for people turning to CAM can be divided into positive and negative motivations. Positive motivations include perceived effectiveness and safety; ‘spiritual’ or holistic nature of the therapy; personal control over treatment; good relationship with the therapist; and accessibility. Negative reasons include dissatisfaction with conventional methods; rejection of the ‘establishment’ and desperation. A study into the beliefs and motivations of CAM users in Canada supports this theory. It found that the two main reasons people used CAM were that it allows them to take a more active role in their health, and a feeling that conventional medicine was not effective for their health condition.
• Traditional Herbs
A systematic review has been conducted to determine the study quality of articles investigating ayurvedic/collateral herbs, the effectiveness/efficacy and safety profile, as reported in the studies. Literature searches were conducted using PubMed, EMBASE, Mantis, Ovid, Annotated Bibliography of Indian Medicine and Cochrane library to identify published trials on herbal medicines for asthma of which Ayruvedic herbals are a subset. Randomized Controlled Trials (RCTs) and Quasi-Experimental Designs (QEDs) were included in this systematic review. Herbs included in Traditional Chinese Medicine were excluded from this review. Forty-two articles were retrieved and 37 studies were ultimately reviewed utilizing 3 independent evaluators/1 arbitrator.
Articles reviewed indicated benefit from most of the herbs used either as a primary or adjunctive treatment for Asthma.1 Study quality was mixed and therefore caution in interpretation of findings of usefulness of these herbals must be suggested. Limited safety information was available and generally was related to GI symptoms, though one herb investigated reported more serious side effects. It was concluded that herbs may be useful in treatment of asthma but there is insufficient evidence to make recommendations for or against the use of these herbals. Established effectiveness must be balanced with study quality and safety profile for the herb. A recent Cochrane Review has also addressed this issue.2 Herbal therapy is a popular form of CAM in asthma. There is a long history of using herbs to treat asthma and a number of asthma drugs have their origins in herbal remedies. For example, ephedrine was developed from the traditional Chinese herbal remedy ‘ma huang’, and tea leaves are the herbal origin of theophylline. Caffeine, found in tea and coffee, is a member of the same family as theophylline, and has been used for centuries as a treatment for asthma. A recent Cochrane review found that it improved lung function for up to four hours after ingestion. There are many different herbs and herbal preparations that are used to treat asthma and each culture has its own approach. Table 13.1 shows examples of herbs used for the treatment of asthma by culture. Western cultures use products from local plants but also borrow from Eastern cultures. Herbal interventions for asthma are often used in addition to conventional medicine rather than as a sole agent.
One of the positive motivations for using CAM is perceived safety. However there are risks with the use of herbal remedies including drug interactions, inconsistent dosing, contamination and natural toxicity. Drug interactions could be a particular concern as a survey of herbal therapy users found that 81% also used conventional medicines. It was also found that herbal remedy users would be less likely to consult their GPs for suspected adverse events to a herbal remedy than they would for a conventional over-the-counter medicine. In fact, herbal therapy users tend to self-medicate or take the advice of a friend or relative so are unlikely to consult any practitioner at all on the use of herbal products. Whether herbal products are actually effective in the treatment of asthma is uncertain. A systematic review of herbs for asthma conducted in 2000 found 17 randomised controlled trials: six assessing traditional Chinese herbs; eight assessing traditional Indian remedies; one assessing a Japanese herbal preparation; one assessing dried ivy-leaf extract, and one assessing use of marijuana. They found the methodological quality of the trials was poor and concluded that herbal products are of “uncertain value in the treatment of asthma”. However, they also concluded that were some “promising data”.
• Role of Yoga
Yogic exercises are practised throughout the world for health and disease. These practices comprise of Meditation, Praanayam (breathing exercises) and yogic postures or Asanas.3 Bronchial asthma is a chronic inflammatory disease in which these exercises have been shown to have some positive effect. Breathing techniques are used by a large proportion of asthma sufferers. A systematic review was conducted aimed at determining whether or not these interventions are effective. Four independent literature searches identified six randomized controlled trials. The results of these studies are not uniform. Collectively the data imply that physiotherapeutic breathing techniques may have some potential in benefiting patients with asthma. The safety issue has so far not been addressed satisfactorily. It is concluded that too few studies have been carried out to warrant firm judgements. It has been recommended that further rigorous trials should be carried out in order to redress this situation. Some studies have been conducted in our country testing some of the yogic practices in treatment of bronchial asthma.4 The effects of two pranayama yoga breathing exercises on airway reactivity, airway calibre, symptom scores, and medication use in patients with mild asthma were assessed in a randomised, double-blind, placebo-controlled, crossover-trial. After baseline assessment over 1 week, 18 patients with mild asthma practised slow deep breathing for 15 min twice a day for two consecutive 2-week periods. During the active period, subjects were asked to breathe through a Pink City lung (PCL) exerciser—a device which imposes slowing of breathing and a 1:2 inspiration:expiration duration ratio equivalent to pranayama breathing methods; during the control period, subjects breathed through a matched placebo device. Mean forced expiratory volume in 1 s (FEV1), peak expiratory flow rate, symptom score, and inhaler use over the last 3 days of each treatment period were assessed in comparison with the baseline assessment period; all improved more with the PCL exerciser than with the placebo device, but the differences were not significant. There was a statistically significant increase in the dose of histamine needed to provoke a 20% reduction in FEV1 (PD20) during pranayama breathing but not with the placebo device. The usefulness of controlled ventilation exercises in the control of asthma should be further investigated.
• Suggestions and Hypnosis
A prospective, randomised, single blind, and controlled trial of a hypnotic technique was undertaken in 39 adults with mild to moderate asthma graded for low and high susceptibility to hypnosis.5 After a six week course of hypnotherapy 12 patients with a high susceptibility score showed a 74.9% improvement (p less than 0.01) in the degree of bronchial hyper-responsiveness to a standardised methacholine challenge test. Daily home recordings of symptoms improved by 41% (p less than 0.01), peak expiratory flow rates improved by 5.5% (p less than 0.01), and use of bronchodilators decreased by 26.2% (p less than 0.05). The improvement in bronchial hyper-reactivity occurred without a change in subjective appreciation of the degree of bronchoconstriction. A control group 17 patients and 10 patients undergoing treatment with low susceptibility to hypnosis had no change in either bronchial hyper-responsiveness or any of the symptoms recorded at home. This study shows the efficacy of a hypnotic technique in adult asthmatics who are moderately to highly susceptible to hypnosis. In authors experience use of meditation besides its spiritual effects has a positive role in stress relief. Certain yogasans specially suryanamaskar are particularly helpful for children. Techniques like Neti and Ujjai Pranayam are specially useful for allergies.
• Surya Namaskar
One round of Sun Salutation consists of two sequences, the first leading with the right foot in positons 4 and 9, the second leading with the left. Keep your hands in one place from positons 3 to 10 and try to co-ordinate your movements with your breathing. Start by practicing four rounds and gradually build up to twelve rounds.
- Stand erect with feet together and hands in the prayer position in front of your chest. Make sure your weight is evenly distributed. Exhale.
- Inhaling, stretch your arms up and arch back from the waist, pushing the hips out, legs straight. Relax your neck.
- Exhaling, fold forward, and press your palms down, fingertips in linewith toes - bend your knees if necessary.
- Inhaling, bring the left (or right) leg back and place the knee on the floor. Arch back and look up, lifting your chin.
- Retaining the breath, bring the other leg back and support your weight on hands and toes.
- Exhaling, lower your knees, then your chest and then your forehead, keeping your hips up and your toes curled under.
- Inhaling, lower your hips, point your toes and bend back. Keep legs together and shoulders down. Look up and back.
- Inhaling, step forward and place the left (or right) foot between your hands. Rest the other knee on the floor and look up, as in position 4.
- Exhaling, bring the other leg forward and bend down from the waist, keeping your palms as in position 3.
- Inhaling, streach your arms forward, then up and back over your head and bend back slowly from the waist, as in position 1. Exhaling, gently come back to an upright position and bring your arms down by your sides.
- SinghBB, KhorsanR, VinjamurySP, Der-MartirosianC, KizhakkeveettilA, AndersonTM. Herbal treatments of asthma: a systematic review. J Asthma. Nov 2007;44(9):685–98.
- ArnoldE, ClarkCE, LassersonTJ, WuT. Herbal interventions for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD005989. DOI: 10.1002/14651858. CD005989. pub2.
- Lancet. 1990 Jun 9; 335(8702):1381–3. Comment in: Lancet. 1990 Nov 10;336(8724):1192. Effect of yoga breathing exercises (pranayama) on airway reactivity in subjects with asthma. SinghV, WisniewskiA, BrittonJ, TattersfieldA.
- Respiratory Medicine Unit, City Hospital, Nottingham, UK.: Eur Respir J. 2000 May; 15(5):969–72. Breathing techniques—adjunctive treatment modalities for asthma? A systematic review. Ernst E. Dept of Complementary Medicine, Postgraduate Medical School, University of Exeter, UK.
- ErnstE. Breathing techniques—adjunctive treatment modalities for asthma? A systematic review.. Eur Respir J. May 2000;15(5):969–72.
Asthma is a chronic inflammatory disorder of the airways. Chronically inflamed airways are hyper-responsive; they become obstructed and airflow is limited (by bronchoconstriction, mucus plugs, and increased inflammation) when airways are exposed to various risk factors.
• Control of Asthma
Asthma is one of the most common chronic diseases worldwide and unfortunately, the prevalence is increasing, especially among children. The prevalence of asthma symptoms in children varies from 0 to 30 percent in different population with the highest prevalence occurring in Australia, New Zealand and England.
Prevalence in India: International Study of Asthma and Allergies in children (ISAAC) has shown prevalence of atopic disorders raging from 3–17% in different areas in India. Asthma can be treated and controlled so that almost all children can:
- Avoid troublesome symptoms night and day.
- Avoid serious attacks.
- Use little or no reliever medications.
- Have productive, physically active lives.
- Have normal or near normal lung function.
Risk factors for asthma include host factors that predispose individuals to or protect them from developing asthma (genetic Predisposition, gender, and race) and environmental factors that influence the susceptibility to the development of asthma in predisposed individuals, precipitate asthma exacerbations and/or cause symptoms to persist. Exposure to allergies, viral and bacterial infections, diet, tobacco, smoke, socioeconomic status and family size are the main environmental factors that influence the susceptibility to the development of asthma in predisposed Individuals. Exposure to allergies and viral infections are the main environmental factors causing exacerbations of asthma and/or the persistence of symptoms in children. Asthma attacks (or exacerbations) are episodic, but airway inflammation is chronically present. For many patients, medications must be taken every day to control symptoms, improve lung functions, and prevent attacks. Medications may also be required to relieve acute symptoms, such as wheezing, chest tightness, and cough.
• Diagnosis of Asthma
Asthma can often be diagnosed on the basis of symptoms. However, measurements of lung function, and particularly the reversibility of lung function abnormalities, greatly enhance diagnostic confidence in children 5 years and older.
• Is It Asthma?
Consider asthma if any of the following are present:
- Wheezing-high-pitches whistling sounds when breathing out-especially in children. (A normal chest examination does not exclude asthma.)
- History of any of the following:
- Cough, worse particularly at night.
- Recurrent wheeze.
- Recurrent difficulty in breathing.
- Recurrent chest tightness.
(Note: Eczema, hay fever or a family history of asthma or atopic disease are often associated with asthma.)
- Symptoms occur or worsen at night, awakening the patient.
- Symptoms occur or worse in the presence of:
- Animals with fur
- Aerosol chemicals
- Changes in temperature
- Respiratory (viral) infections
- Domestic dust mites
- Drugs (aspirin, beta blockers)
- Strong emotional expression
- Reversibility of airflow limitation
When using a peak flow meter, consider asthma if:
- PEF increase more than 15 percent 15 to 20 minutes after inhalation of a rapid-acting β-2 agonist, or
Recording Patient Details Patients Record and Database
_____________________ Tel. No. _____________________________
Age ___________ Sex _____________ Date of birth _______________
Father's occupation __________________________________________
Mother's occupation _________________________________________
Age at onset of symptom_____________________________
Duration (in months) ________________________________________
No diurnal variation
Aggravating factors ____________________________ Relieving factor
Chest pain __________________________________________
Duration (in months) ________________________________________
No. of previous episodes _____________________________________
□No diurnal variation
Aggravating factors _________________________________________
Relieving factors ___________________________________________
History of Ger
Sym. precipitated by feeds
Frequent nose block
Frequent running nose
Sneezing with watery discharge
Itching in throat
Itching in ears
Excess mucus production
Cooking fuel smoke
Harvesting or wheat threshing
Eating egg/egg products
Use of cosmetics/shampoos
Use of paints/chemicals
Consumption of drugs
(Mention drugs causing exacerbation)
Exertion and exercise
Symptoms Relieved By
Is there seasonal variation of symptoms?
No. of family members _______________________________________
No. of siblings
Presence of overcrowding
Family h/o similar complaints
Family h/o atopic dermatitis
Family h/o food allergy
Family h/o hay fever/rhinitis
Family h/o urticaria
H/o cigarette smoking
No. of cigarette/beedi smoked ________________________________
Type of residence
Duration of stay ___________________________________________
Presence of dampness
Use of carpets
Use of thick curtains
Use of heavy upholstery
Use of soft toys
Presence of pets/household animals
Use of kerosene/wood/coal fuel
Presence of cockroaches
Presence of dusty bookshelves
H/o previous hospitalizations
No. of previous hospitralizations _______________________________
H/o previous hospitalizations
Use of nebulization
Use of IV fluids/durgs
Use of inhaler
Nature of inhaler
Was compliance to therapy adequate
Wt. _______________ (kg) Ht/L _____________ (kg)
OFC ______________ HR _________________
RR _______________ BP _________________
Skeletal + chest wall abnormalities
Signs of vitamin deficiency
Eye signs of allergic rhinitis
Classification of severity
Follow-up date _____________
- PEF varies more than 20 percent from morning measurement upon arising to measurement 12 hours later in patients taking a bronchodilator (more than 10 percent in patients who are not taking a bronchodilators), or
- PEF decreases more than 15 percent after 6 minute of sustained running or exercise.
• Management Programme for Control of Asthma
The management programme for control of asthma includes:
- Education of children and their families.
- Assessment and monitoring of disease severity.
- Avoidance of exposure to risk factors.
- Establishment of individual medication plans for long-term management.
- Establishment of individualized treatment plan for acute attacks
- Regular follow-up care.
• Goals of Management
The goals of management of asthma are to achieve:
- Minimal or no symptoms, including night time symptoms
- Minimal asthma episodes or attacks
- No emergency visits to physicians or hospitals
- Minimal need for reliever medications
- No limitations on physical activities and exercise
- Near normal lung function
- Minimal or no side effects from medication
- Good quality of life
• Education of Children and Their Families
The successful control, prevention and treatment of asthma is based on a partnership approach towards the child, his family members and the medical team. With the help of those on the health care team, children and their families can and should be participating actively in managing asthma.
Education is directed towards learning to:
- Avoid risk factors.
- Take medications correctly.
- Understand the difference between “controller” and “reliever” medications.
- Monitor status using symptoms and, if available PEFR in children over 5years of age.
- Recognize signs that asthma is worsening and take action.
- Seek medical help as appropriate.
- Accept the condition and live productive life free from fear and limitation of activity.
An asthma management education plan should cover:
- Prevention steps for long-term control
- Avoidance of risk factors
- Taking medication daily
- Action steps to stop attacks
- How to recognize worsening asthma? Indicators such as increasing cough, chest tightness, wheeze, difficult breathing sleep disturbance, increasing use of reliever medication or PEF below personal best despite increased use of medications suggest worsening asthma.
- How to treat worsening asthma? List the names and doses of reliever medications and glucocorticosteroid tablets and when to use them.
- How and when to seek medical attention? List Indicators such as an attack with sudden onset, shortness of breath while resting or speaking a few words, feeling panicky, PEF below a specified level, or a history of severe attacks.
- Where to seek medical attention: List the name, location, and telephone number of the physician's office or clinic or hospital.
- Ongoing education
- Updating children and their families about basic asthma facts, inhalation techniques and any advances that might have occurred in management modalities.
- Reviewing their concerns and queries to foster adherence to medication and dispel fear and misconceptions.
- An attempt should be made to reach an agreement with the child/parent about timing and frequency of medications matching the pharmacokinetics of the drugs used.
Control of asthma requires continual long-term care and monitoring. Monitoring includes review of symptoms and, as far as possible, measurement of lung function in children over 5 years of age.
- PEF monitoring at every physician visit, (Spirometry is preferred but not always available), along with review of symptoms, helps in evaluating the child's response to therapy and adjusting treatment accordingly. PEF consistently greater than 80 percent of the child's personal best suggests good control.
- Long-term monitoring at home can help children and their families recognize early signs of worsening asthma (PEF less than 80 percent of personal best) before symptoms occurs. Children and/or their parents can act promptly according to their personal asthma management plan to avoid serious attacks.
- Home PEF monitoring is not always practical, but for children who cannot perceive symptoms and for those who have ever been hospitalized, home PEF monitoring has a high priority.
- Regular visits (at 1-to 3-month intervals as appropriate) are essential, even after control of asthma is established. At each visit review the issues raised in the questionnaire (Table 15.1): long period without follow-up visits lead to attriction in adherence to management protocols. Follow-up visits must include hands on demonstration on inhalation devices.
- Compliance/adherence with asthma management plans is improved when children and their parents have the opportunity to talk about their concerns, fears, and expectations related to their asthma.
• Peak Flow Meters
A peak flow meter is a device that measures how well air moves out of your lungs. During an asthma attack the air tubes of the lungs begin to narrow slowly. The peak flow meter can be used to find out if there is narrowing in the airways hours, even days before you have any symptoms of asthma. By taking your medicine early (before symptoms) you may be able to stop the attack quickly and avoid a serious attack of asthma. Peak flow meters are as good to check your asthma as the blood pressure instrument used to check high blood pressure.
Uses: The peak flow meter can also be used to help you and your doctor.
- Decide if your medicine plan is working well.
- Decide when to add or stop medicine.
- Decide when to seek emergency care.
- Identify triggers that is, what causes your asthma symptoms to increase.
All children older than 5 years of age who have moderate to severe asthma should think about using a peak flow meter. Younger children can also be taught to use it. Ask your doctor to show you how to use a peak flow meter.
• Patient Education Points
• How to Use a Peak Flow Meter
- Place the indicator at the base of the number scale
- Stand up
- Take a deep breath
- Place the meter in your mouth and close your lips around the mouthpiece. Do not put your tongue inside the hole.
- Blow out as hard and fast as you can
- Write down the number you get
- Repeat steps 1 through 6 two more times
- Write down the best of three numbers achieved
Find your personal best peak flow number Your personal best peak flow numbers is the highest peak flow number you can achieve over a 2-week period when your asthma is under good control. Good control is when you feel good and do not have any asthma symptoms. Each patient's asthma is different and your best peak flow may be higher or lower than the average usual number for someone of your height, weight and sex. This means that it is important for you to find your own personal best peak flow number, your own medicine plan needs to be based on your own personal best peak flow number. To find out your personal best peak flow number, take peak flow readings:
- Every day for 2 weeks
- Mornings and evenings (when you wake up and about 10–12 hours later)
- Before and after taking inhaled bronchodilator (reliever), if you are taking this medicine.
- As instructed by your doctor.
- Write down these readings on worksheet: Weekly asthma symptom and peak flow diary. Ask your doctor for a copy.
The Peak Flow Zone System: Once you know personal best peak flow number, your doctor will give you the numbers that tell you what to do. The peak flow numbers are put into zones that are set up like a traffic light. This will help what to do when your peak flow number changes. For example: Green Zone (80 to 100 percent of your personal best number) signals all clear: No asthma symptoms are present, and you may take your medicines as usual or do without medicines. Yellow Zone (50 to 80 percent of your personal best number) signals caution. You may be having an attack of asthma that requires an increase in your medicines. Or your overall asthma may not be under control, and the doctor may need to change your medicine plan. Red Zone (below 50 percent of your personal best number) signals a medical alert. You must take an inhaled bronchodilator immediately and call on your doctor.
- Record your personal best peak flow number and peak flow zones on the upper left hand corner of worksheet: Weekly asthma symptoms and peak flow diary
- Use the diary to keep neard of your peak flow
- Write down your peak flow number on the diary every day, or as instructed by your doctor
- Discuss with your doctor what to do when peak flow number change
• Don't Forget
- A decrease in peak flow of 20 to 30 percent of your personal best may mean the start of an asthma attack.
- When this happens, follow your asthma control plan for treating an asthma attack.
Peak expiratory flow rate and peak flow meters Peak expiratory flow rate (PEFR) provides a simple, quantitative, reproducible measure of airway obstruction that can be obtained by using peak flow meters. PEFR measurements when done with a good effort correlate well with FEV I measured by Spirometry. PEFR is an objective measurements and it is as important as we measure blood pressure with a sphygmomanometer, or monitor blood glucose level of a diabetic.
PEFR measurement is a valuable clinical tool
- In the clinic or emergency department, wards of a hospital to assess degree of airflow obstruction and severity.
- For diagnosing exercise-induced asthma.
- For monitoring response to therapy.
- For detecting asymptomatic deterioration.
For routine monitoring at most outpatient visits, measurement of PEF with a peak flow meter is generally a sufficient assessment of pulmonary function, particularly in mild intermittent, mild persistent and moderate persistent asthma. Patients with moderate-to-severe persistent asthma should learn how to monitor their PEF with a peak flow meter at home. PEFR measurement, however, are not sufficient to make a diagnosis or to fully evaluate physiologic impairment associated with asthma because PEFR is effort dependent and measures only large airway function. When patients learn how to take PEFR measurement at home, the doctor's ability to provide effective treatment is improved. Daily monitoring of PEFR helps for examples, in detecting early stages of airway hyperresponsiveness), providing objective criteria in planning, initiating, or terminating treatment, facilitating communication between patient and the doctor, and investigating specific allergens in school or workplace/ occupational exposures that may exacerbate symptoms
• Monitoring Techniques related to PEFR Measurement
Several kinds of peak flow meters and spirometers are available, and the technique for use is similar for all. It is important to use a “low flow” peak flow meter for younger children. Appropriate ages for use are usually indicated by the manufacturer. To use a peak flow meter:
- Stand up and hold the peak flow meter without restricting movement of the marker. Make sure the marker is at the bottom of the scale.
- Take a deep breath, put the peak flow meter in your mouth, seal your lips around the mouthpiece, and the breathe out as hard and fast as possible. Do not put your tongue inside the mouthpiece
- Record the result. Return the marker to zero.
- Repeat twice more. Choose the highest of the three readings.
Daily PEF monitoring for 2 to 3 weeks is useful, when it is available, for establishing a diagnosis and treatment. If during 2 to 3 weeks a child cannot achieve 80 percent of predicted PEF (predicted values are provided with all peak flow meters), it is suggestive of bronchial asthma. As far as possible, one should try to use locally available norms. It may be necessary to determine the child's personal best value, e.g. following a course of oral glucocorticosteroid. Long-term PEF monitoring is useful, along with review of symptoms, for evaluating a child's response to therapy. PEF monitoring can also help detect early signs of worsening before symptoms occur.
Interpreting PEFR measurements: Most children's values are consistently higher or lower than average predicted norms. It is important for each child to establish a personal best PEFR value. This personal best value will be the standard against which subsequent measurements are evaluated by the patient and doctor. Personal best values can be established during a 2 to 3 week period in which the patient records PEFR measurement twice a day after period of maximum therapy. A course of oral steroids may be needed to establish this personal best, and if the personal best is below 80 percent of the predicted value, more aggressive therapy and continued daily monitoring are indicated. The personal best value should be revaluated at least every 6 months to establish changes in the child's personal best that occurs with growth. Periodic reassessed value can also be used to see progression of disease in children. Further, peak flow meter measurement should be correlated periodically with spirometry. The expected PEFR for boys and girls based on height are available locally. To differentiate asthma from chronic obstructive pulmonary disease, restrictive pulmonary disease or possible central airway obstruction, assessment of other pulmonary functions like lung volumes, inspiratory and expiratory flow volume loop may be required. Diffusing capacity test differentiates emphysema. Assessment of diurnal variation in peak expiratory flow over 1–2 weeks is recommended in asthma patients with normal spirometry findings. It is done on first awakening and between noon to 4 P.M. A difference of 20% between two measurements suggests asthma.
PEFR variability: Can be calculated by measuring morning (8:00 AM) PEFR and every PEFR (4:00 PM) and using the formula:
PATIENT ASTHMA DIARY
Expected PEFR Date
Limitation of activity
Daily medication taken
To improve the control of asthma and reduce medication needs, children should avoid exposure to risk factors (allergens and irritants that make asthma worse). Primary prevention of asthma is not yet possible, but is being actively investigated. Prolonged exclusive breast feeding, avoidance of smoking and known allergenic foods for nursing mothers and recommended.
• Principals of planning treatment
A stepwise approach is used to guide treatment (Table 17.1)
The number and frequency of medications increase (step up) as the need for asthma therapy increases, and decrease (step down) when asthma is under control.
Step down if control is not achieved and sustained. Generally, improvement should be achieved within one month. But first review the child's medication technique, adherence, and avoidance of risk factors.
Step down if control is sustained for at least 3 months; follow a gradual stepwise reduction in treatment. The goal is to decrease to the least medication necessary to maintain control.
Selection of Medications
Anti-inflammatory agents, particularly inhaled glucocorticosteroids, are currently the most effective long-term preventive medications and are effective in reducing asthma attacks.
Persistent asthma is more effectively controlled by long-term treatment to suppress and reverse the inflammation than by only treating acute bronchoconstriction and related symptoms.
There are two approaches to gaining control of asthma
- Establish control promptly with high level of therapy (for example, add short course of oral glucocorticosteroid and/ or a higher dose of inhaled glucocorticosteroids plus long-acting ²-2 agonist to the therapy that corresponds with the patient's level of asthma severity) and then step down.
- Start treatment at the step most appropriate to the level of asthma severity and step up if necessary.
Review treatment every 3–6 months once asthma is under control.
Consultation and Referral
Consult with an asthma specialist when other conditions complicate asthma (e.g., sinusitis), the child does not respond to therapy, or treatment at steps 3 or 4 is required.
Devices available to deliver inhaled medication include pressurized metered-dose inhalers (pMDIs), breath-actuated metered dose inhalers, dry powder inhalers (DPIs), and nebulizers. Spacer (or holding chamber) devices make inhaler easier to use. Spacers also reduce systemic absorption and side effects of inhaled glucocorticosteroids. Teach children and their parents how to use inhaler devices, Different devices need different inhalation techniques.
- Give demonstrations and illustrated instructions.
- Ask patients to show their technique at every visit.
- For each child, select the most appropriate device.
- Children younger than 4 years of age should use a pMDI plus a spacer with face mask, or a nebulizer with face mask.
- Children aged 4 to 6 years should use a pMDI plus a spacer with mouthpiece, a DP(I), or, if necessary, nebulizer with face mask.
- For children using spacers, the spacer must fit the inhaler.
- Children of any age over 6 years who have difficulty using pMDIs should use a pMDI with a spacer, a breath-actuated inhaler, a DPI, or a nebulizer. DPIs require an inspiratory effort that may be difficult to achieve during severe attacks.
- Children who are having severe attacks should usea pMDI with a spacer or a nebulizer. Multi Haler pMDI and Spacer Autohaler Turbohaler
• Use of Inhalation Devices (Patient Education Points)
Using a metered dose inhaler or an aerosol inhaler is a good way to take asthma medicines because the medicine goes right to the lungs and not to other parts of the body.
It takes only 5 to 10 minutes for the medicine to have an effect compared to medicines in liquid or tablet form which can take 1 to 3 hours. Inhalers can be used by all asthma patients above the age of 6 years. A spacer or holding chamber attached to the inhaler can be used even for younger children (around 3 years). These devices are helpful to people having difficulty in using an inhaler. The inhaler must be cleaned often to prevent clogging that reduces the medicine flow:
- The guidelines that follow will help patients use the inhaler correctly.
- Ask your doctor to show you how to use the inhaler.
• using the inhaler
Metered dose inhaler
- Remove the cap and hold the inhaler upright.
- Shake the inhaler.
- Tilt your head back slightly and breathe out.
- Put the inhaler in your mouth and close the mouth over it.
- Press down on the inhaler to release the medicine as you start to breathe in slowly.
- Breathe in slowly for 3 to 5 seconds.
- Hold your breath for about 10 seconds to allow the medicine to reach deeply into your lungs.
- Repeat puffs as prescribed. Waiting 1 minute between puffs is good.
- Rinse your mouth with water after the treatment.
Dry powder capsules (Rotacaps) are used differently. Put the capsule in the place indicated on the side of the Rotahaler, and rotate the Rotahaler to open it up.
To use a dry powder inhaler (Rotahaler). Close your mouth tightly around the mouth piece and inhaler ver fast.
- Clean the inhaler and cap by rinsing it in warm running water. Once a day and let it dry before you use it again.
- Wash the plastic mouthpiece with mild soap and warm water. Twice a week rinse and dry well before putting it back.
Checking how much medicine is left in the canister
- If the canister is new, it is full.
- An easy way to check the amount of medicine left in your metered dose inhaler is to place the canister in a container of water and observe position.
- In the water, if it sinks, it is full. If it floats half way it is half full and if floats on surface, it is empty.
Unless you use your inhaler correctly in a coordinated manner as described much of the medicine may end up on your tongue, on the back of your throat, or in the air. Use of a spacer or holding chamber can help solve this problem. A spacer or holding chamber is a device that attaches to a metered dose inhaler. It holds the medicine in its chamber long enough for you to inhale it in one or two slow deep breaths. The spacer makes it easy for you to use the medicines correctly (especially if your child is young or you have a hard time using just an inhaler). It helps you not to cough when using in inhaler. A spacer will also help prevent you from getting a yeast infection in your mouth (thrust) when taking inhaled steroid medicines.
• How to use a spacer
- Attach the inhaler to the spacer or holding chamber as explained by your doctor or by using the directions that come with project.
- Shake well.
- Press the button on the inhaler. This will put one puff of the medicine in the holding chamber.
- Place the mouthpiece of the spacer in your mouth immediately and inhale slowly (A face mask may be helpful for a young child).
- Hold your breath for a few seconds and then exhale. Repeat steps 4 and 5 two more times.
- If you have been prescribed two puffs, wait between puffs for the amount of times the doctor has directed and repeat steps 4 and 5.
Alternatively if the child cannot follow instructions for deep inhalation, let him breathe normally with the spacer mouthpiece in his mouth. In small babies spacers with valve can be kept vertical to open the valve by gravity.
• Use and care of a nebulizer
A nebulizer is a device driven by a compressed air machine. It allows you to take asthma medicine in the form of a mist. It consists of a cup, a mouthpiece attached to a T-shaped part or a mask, and thin, plastic tubing to connect to the compressed air machine. It is used mostly by three types of patients:
- Young children under the age of 5 years.
- Children who have problems using metered dose inhalers.
- Children with severe asthma.
A nebulizer helps make sure that they get the right amount of medicine Directions for using the compressed air machine may vary with different persons. Check it with your doctor.
• How to use a nebulizer
- Measures the correct amount of normal saline solution using a clean dropper and put it into the cup. If your medicine is premixed, go to step 3.
- Put the correct amount of medicine using a clean dropper into the cup with the saline solution.
- For a child over the age of 3, a mouthpiece can be used.
- Put the mouthpiece in your mouth. Seal your lips tightly around it or place the mask on your or baby's face.
- Turn on the air compressor machine.
- Encourage the child to take deep breaths in through the mouth.
- Hold each breath 1 to 2 seconds before breathing out, if possible.
- Continue until the medicine is finished from the cup (it takes 10–15 minutes).
- Store the medicine as directed after each use.
• Cleaning the nebulizer
Don't forget: Cleaning and getting rid of germs prevents infection. Cleaning keeps the nebulizer from clogging up and helps it last longer.
• After each use
- Remove the mask or the mouthpiece and T-shaped part from the cup. Remove the tubing and set it aside. The tubing should not be washed or rinsed.Rinse the mask or mouthpiece and T-shaped part as well as the dropper or syringe in warm running water for 30 seconds.
- Shake off excess water. Air dry on a clean cloth or paper towel.
- Put the mask or the mouthpiece and T-shaped part, cup, and tubing back together and connect the device to the compressed air machine. Run the machine for 10 to 20 seconds to dry the inside of the nebulizer.
- Disconnect the tubing from the compressed air machine.
- Place a cover over the compressed air machine.
Once every day
- Remove the mask or the mouthpiece and T-shaped part from the cup. Remove the tubing and set it aside. The tubing should not be washed or rinsed.
- Wash the mask or the mouthpiece and T-shaped part as well as the dropper or syringe with a mild soap and warm water.
- Rinse for 30 seconds under a strong steam of water. Use distilled (or sterile) water if possible.
- Shake off excess water. Air dry on a clean cloth or paper towel.
- Put the mask or the mouthpiece and T-shaped part, cup and tubing back together and connect the device to the compressed air machine. Run the machine for 10 to 20 seconds to dry the inside of the nebulizer.
- Disconnect the tubing from the compressed air machine. Store the nebulizer in zippered plastic bag.
- Place a cover over the compressed air machine.
• Once or twice a week
- Remove the mask or the mouthpiece and T-shaped part form the cup. Remove the tubing and set it aside. The tubing should not be washed or rinsed. Wash the mask or the mouthpiece and T-shaped part as well as the dropper or syringe with a mild soap and warm water.
- Rinse for 30 seconds under a strong stream of water.
- Soak for 30 minutes in a solution that is one part white vinegar and two parts distilled water. Throw out the vinegar water solution after use; do not reuse it.
- Rinse the nebulizer part and the dropper or syringe under warm running water for 1 minute. Use distilled or sterile water, if possible.
- Shake off excess water. Air dry on a clean cloth or paper towel.
- Put the mask or the mouthpiece and T-shaped part, cup and tubing back together and connect the device to the compressed air machine. Run the machine for 10 to 20 seconds to dry the inside of the nebulizer thoroughly.
- Disconnect the tubing from the compresses air machine.
- Clean the surface of the compressed air machine with a well-wrung soap cloth or sponge. You could also use an alcohol or disinfectant wipe. NEVER PUT THE COMPRESSED AIR MACHINE IN WATER.
- Place a cover over the compressed air machine.
• According to Global Initiative of Asthma
- Do not underestimate the severity of an attack, severe asthma attacks may be life threatening.
- Initial Treatment Inhaled rapid-acting β-2 agonist up to three in 1 hour. Families should contact the physician promptly after initial treatment, especially if the child has had a recent hospitalization for asthma (Table 18.1).
- Patients should immediately seek medical care if…The attack is severe if initial assessment shows that:The patient is breathless at rest, is hunched forward, talks in words rather than sentences (infant stops feeding), agitated, drowsy or confused, has bradycardia, or a respiratory rate greater than 30 per minute.Wheeze is loud, biphasic or absent.Pulse is greater than 120/min (greater than 160/min for infants)PEF is less than 60 percent of predicted or personal best even after initial treatment.
- The response to the initial bronchodilator treatment is not prompt and sustained for at least 3 hours.
- There is no improvement within 2 to 6 hours after oral glucocorticosteroid treatment is started. There is deterioration.
- Children/adolescents at high risk for asthma-related death include those with:
- History of near-fatal asthma.
- Hospitalization or emergency visit for asthma within the past year or prior intubation for asthma.
- Current use of or recent withdrawal from, oral glucocorticosteroids.
- Over-dependence on rapid-acting inhaled β-2 agonist.
- History of psychosocial problems or denial of asthma or its severity.
- History of noncompliance with asthma medication plan.
• Principal of Institutional Treatment
Classify severity of acute exacerbations (Table 18.2).
- Inhaled rapid-acting β-2 agonists in adequate doses are essential. If the child has extreme obstruction with silent chest or inhaled medications are not available, systemic bronchodilators may be considered.
- Oral glucocorticosteroids introduced early in the course of a moderate or severe attack help to reverse the inflammations and speed recovery.
- Oxygen is given at health centres or hospitals if the patient is hypoxemic.
- Methylxanthines are not recommended if used in addition to high doses of inhaled β-2-agonist.
However, theophylline can be used if inhaled β-2-agonist are not available. If the patient is already taking theophylline on a daily basis, serum concentration should be measured before adding short-acting theophylline.
- Epinephrine (adrenaline) may be indicated for acute treatment of anaphylaxis and angioedema.
- The following therapies are not recommended for treating attacks;
- Sedatives (strictly avoid).
- Mucolytic drugs (may worsen cough).
- Chest physical therapy/physiotherapy (may increase patient discomfort).
- Hydration with large volumes of fluid for adults and older children (may be necessary for young children and infants).
- Monitor response to treatment
Evaluate symptoms and, as much as possible, peak flow. In hospital, also assess oxygen saturation; consider arterial blood gas measurement in patients with suspected hypoventilation, exhaustion, severe distress, or peak flow 30–50 percent predicted, if at all recordable. Sometimes it is not possible to record PEF in seriously ill patients. One should never force a child to perform the manoeuvre if he/she expresses inability to do so (Table 18.3).
• Treatment Phase-I 1st hour
- Oxygen by mask to achieve saturation > 90% (minimum 5lt/min. of O2 through Simple face mask)
- In case of non availability of nebulizer or MDI and spacer or where the patient cannot move the needle of the peak flow meter-parenteral beta agonist (adrenalin/ternutalin) should be given in the dose of 0.01mg/ kg-upto 0.3 to 0.5 mg every 20 minutes for 3 doses in the first hour subcutaneously.
- All children presenting with acute exacerbation should receive systemic steroids. Prednisolone 2mg.kg, dose or Methyl Prednisolone 1–2mg.kg/dosse or hydrocortisone 10mg/kg/dose. At the end of 1 hour repeat assessment with more emphasis on symptoms and signs. PEFR done if possible. In interpreting PEFR value is compared with predicted value if
Indian children or personal best of the child if available. From the assessment 2 groups are identified.
- Good response: Physical examination normal (decrease in heart rate. Respiratory rate, pulse paradoxus<10mm/Hg, no usage of accessory muscles, alert sensorium) O2 saturation >90% PEFR>70%
- Incomplete response/poor response: Mild to moderately severe symptoms and signs (see appendix for mild, moderate and severe classification of symptoms/signs PEFR < 50 to <70%.
• Phase-II Management
- Good response group: Discharge, continue treatment with β2 agonist and course of oral systemic corticosteroid 1–2mg/kg/day max. 60mg/day in a single or 2 divided doses for 3–10 days.Patient educations. Review medicine use, initiate action plan, Recommend close medical follow up.
- Incomplete/ poor responders: Continue O2,β2 sympathomimetic inhalations every 20 min. Continuous nebulization can also be used under strict monitoring for heart rate and blood potassium levels.
- Continue systemic steroids
- Add ipratropium bromide nebulization 250 Micrograms every 20 mts. For three doses. May mix in same nebulizer with β2 Sympathomimetic
- If no response, aminophylline infusion, (0.9Mg/kg/hr) can be tried. IV 50% MgSO4 50mg/kg/dose IV infusion in 30 ml normal saline/30 min can be given before transfer to ICU
Continue to assess every one hour, continue same treatment for 4 hours.
- Improvement -at end of 6 hours since initiation of treatment decrease the frequency of β2 sympathomimetic inhalations every 1–4 hrs as needed, stop parenteral aminophylline. Continue systemic steroids 1–2mg/kg/day in 2 divided doses for 3–10 days
- If no deterioration continue same treatment
- If deterioration follow intensive care of child with asthma in PICU for possible intubation and Mechanical ventilation in presence of i) exhaustion, shallow respiration, confusion or drowsiness ii) coma/respiratory arrest iii) worsening or persisting hypoxia.
The drugs used can be broadly classified as ‘preventers’ and ‘relievers’.
These are the most potent anti-inflammatory medications currently available for the treatment of asthma. They have a broad anti-inflammatory action. Inhaled corticosteroids are the cornerstone of asthma therapy. Inhaled corticosteroid are the most effective long-term therapy available for persistent asthma. In general these are well tolerated and safe at recommended dosages. The potential but small risk of adverse effects form their use is well balanced by their efficacy. To reduce their adverse effects, the following measures are recommended:
- Administration with spacer/holding chambers.
- Advise patients to rinse their months (rinse and spit) following inhalation.
- Use of lowest possible dose of inhaled corticosteroid to maintain control
- For children, monitor growth.
- Complete opthalmological examination must be done every six months.
• Inhaled Long-acting β-2 Agonists
These are recommended as adjunctive therapy in patients taking regular anti-inflammatory medications who still require frequent use of bronchodilator. They should not be used alone for relief of symptoms or maintenance therapy. Long-acting β-2-agonist can be added to a regimen with inhaled corticosteroids instead of increasing the corticosteroids dose.
• Leukotriene Modifiers
These new classes of drugs either inhibit the production of leukotrienes or block the Leukotriene receptor. These are Zileuton, Zafirlukast and Montelukast. These agents block the inflammatory and bronchoconstricting actions of leukotrienes. Their role in asthma control is emerging, but they could be considered as an alternative to cromolyn and Nedocromil in children or as an adjunct to inhaled corticosteroids. They are uniquely effective in aspirin-sensitive asthma and have shown useful results in mild persistent asthma.
These have moderate bronchodilator activity with anti-inflammatory effects. Although used in the past for maintenance therapy, it is now considered an adjunctive drug for use with inhaled corticosteroids and not recommended in routine.
• Cromolyn and Nedocromil Sodium
Both have anti-inflammatory actions that differ somewhat from those of corticosteroids. Considered equivalent in potency to lower doses of inhaled corticosteroids, these drugs work best in patients with significant allergic triggers. They are unique among anti-inflammatory medications in their ability to suppress both the early and late phase reactions in asthma responses if given before allergen exposure or provocation. Cromolyn and Nedocromil sodium also effectively block exercise- induced asthma. Nedocromil also appears to be particularly effective in asthma patients whose predominant sign is cough. It is faster acting and more potent than cromolyn which may take up to 6 weeks to be effective. Both drugs are given at least three times a day, and neither has any significant systemic adverse effect.
This category includes bronchodilators and systemic corticosteroids. Bronchodilators relax airway smooth muscles and are the treatment of choice for the treatment of acute exacerbation of asthma to decrease airflow limitation.
• β-2 adrenergic Agonists
These cause an increase in intracellular cyclic adenosine monophosphate (cAMP), which antagonizes bonchoconstriction. Inhaled forms of short acting β-2-agonist are the treatment of choice for acute symptoms and for preventing exercise-induced asthma.
• Anticholinergic Drugs (Ipratropium Bromide)
These have moderate bronchodilator effects. They have not been recommended for routine use in asthma, but appear to provide an additive benefit with inhaled β-2-agonist in severe asthma exacerbations.
Systemic corticosteroids are used as quick relief medications during an acute exacerbation when appropriate response is not achieved with initial therapy with inhalation of short-acting β-2-agonists.
• Risk of Overuse of Short-acting Inhaled β-2 Agonists
Short-acting inhaled β-2 agonists (e.g. Salbutamol) are the medications of choice for treating exacerbations of asthma and for preventing exercise-induced bronchospasm (EIB). Increasing use for short-acting β-2-agonist or the use of more than one canister per month indicates inadequate control of asthma and the need for initiating or intensifying anti-inflammatory therapy. Regularly scheduled, daily use of short-acting β-2-agonist is generally not recommended. Before 1990, many clinicians prescribed short-acting β-2-agonist on a regular schedule in the belief that this treatment regimen improved overall asthma symptom control. Some recent reports, however, have modified these beliefs. In a study of moderate asthma, regular use of a potent inhaled β-2 agonist produced a significant diminution in asthma control and objective measurements of pulmonary function. In mild asthma, regularly scheduled use of Salbutamol compared to use on PRN basis showed no significant differences. Although regularly scheduled use of β-2-agonists in mild asthma produced no harmful effects in a 4-month period. It also produced no demonstrable benefits. Other authors have also reported similar observations and it is now recommended that daily or regularly scheduled use of short acting β-2 agonist be avoided. The frequency of β-2-agonists use can be a clinically useful tool in measuring the severity of disease, and increasing use of β-2-agonists has been associated with increased risk for death or near death in patients with asthma.
• Long Acting β-2 Agonists (LABA) Long Term Control
Recent studies suggest that for patients with inadequate symptom control who are receiving inhaled corticosteroids. it may be more beneficial to add LABA than to increae the dose of inhaled corticosteroids, long-acting β-2 agonists (Salmeterol, Formoterol and Bambuterol) can be beneficial to patients when added to inhaled corticosteroid therapy, especially to control night time symptoms. Long acting β-2- agonists have several beneficial clinical properties. They also improve nocturnal asthma symptoms. The potential for patients to incorrectly use LABA as a quick relief medication warrants special attention by the clinician and appropriate patient education based on current information long acting inhaled β-2 agonists should be used only in conjunctions with anti-inflammatory medication. Salmeterol is not effective in relieving acute symptoms or exacerbations. Patients should be instructed not to stop anti-inflammatory therapy while taking LABA even though their symptoms may significantly improve. Long-acting β-2- agonists have been shown to be effective only in the long term control of asthma. Other drugs that have a role to play in long term control, also reduce the need for inhaled corticosteroids. Cromolyn sodium and Nedocromil sodium may be useful for some patients but are less effective and need to be taken 3–4 times a day. Expert Panel recommends cromolyn to be used in children before inhaled steroids are started in mild persistent asthma. Conventional short acting β-2-agonist have no role controlling asthma as inhaled corticosteroids can do this effectively both in children and adults. Although theophylline alone does not control asthma as effectively as corticosteroids and has more frequent side effects, it may have useful additive effect.
• Role of Combining Two Types of Drugs
Combining two types of drugs (quick relief drugs with long term control drugs) i.e. short-acting β-2-agonist and inhaled steroids can create confusion. Since β-2-agonist are not capable of inhibiting inflammation, their use as primary chronic therapy is questionable. The role of these drugs and combinations appears currently to be limited in controlling symptoms on a PRN basis in acute asthma. Inhaled corticosteroids, the potent anti-inflammatory drugs are the best to achieve long term control, although they seem to be expensive, but can lead to saving in the direct costs of asthma treatment by reducing the number of visits to the doctor and hospital admissions. From this it only seems justified not to over-rely on short acting β-2-agonist or their combinations with corticosteroids for long term control. However, studies have appeared in literature about use of low dose Inhaled corticosteroids and LABA use in single inhaler in children with asthma where therapeutic benefit has been shown in comparison to increasing the dose of inhaled steroids.
• Practical Disadvantages and Harm of Over-reliance on Short Acting β-2-agonists
The frequency of need of short acting β-2-agonist has been used as a tool to measure asthma control. In patients who use these drugs inappropriately for long term control, classifying asthma on the basis on frequency of use may be difficult. Regular scheduled use of short acting β-2-agonist can reduce control in patients with moderate asthma and has been associated with loss of bronchoprotective effects against exercise and allergies.
• Possible Reasons for Over-reliance on Short-acting β-2-agonists
Possible reasons for doctors overusing β-2-agonists or their combinations include:
- The belief that β-2-agonists are the most effective drugs in relief of asthma; they might feel insecure when treating asthma with anti-inflammatory therapy and tend to use both or rely more on short acting b-2-agonists.
- Ignorance of recent advances and guidelines.
- General well-being of the patient on the combinations of short acting b-2- agonists and corticosteroids may prompt the doctor to continue its use.
- Commercial promotions of such drugs for better and easier control.
• Possible Solutions
- Improved information to the doctors on advances in asthma care and its management by professional bodies government. NGOs, WHO and other international agencies concerned with peoples health.
- Asthma action group for the country may be constituted with representation from all sectors of health care and a national consensus document may be produced which should be updated and revises periodically.
- Manufactures should consider and try to adhere to global guidelines and recommendations for asthma treatment while marketing their products.
- Senior faculty members and consultants should practice and teach recommended clinical guidelines of asthma management and serve as role models.
There are serious implications of the overuse of β-2-agonists and their combination with corticosteroids. The number of poorly controlled asthmatics is likely to increase. This could mean increased morbidity and mortality due to asthma at the national level, tremendously increased cost and lost man-days. Use of combinations short acting β-2-agonists and inhaled steroids does not lead to optimal asthma control. In fact it is disadvantageous in that it prevents its use as an indicator of severity. Current available data decries the use of fixed dose combination of corticosteroids and β-2-agonists. There has been tremendous change in recent years in the pharmacotherapy of asthma and the emphasis now is on continuous control of underlying inflammation as well as reversal of airway obstruction. Greater awareness of the disease and effective diagnosis and therapy would provide greater relief, economic and social benefits to individuals and the country and save millions of rupees as well.
• Management Guidelines According to Grade of Severity
• Step 1: Mild Intermittent Asthma
A child has intermittent asthma if he/she experiences symptoms (episodes of cough, wheezing or dyspnea) less than or equal to two times a week. The exacerbations are brief, generally lasting only a few hours to a few days. Nocturnal asthma symptoms do not occur more than two times a month. In between attacks the child is asymptomatic and has a completely normal lung function, i.e. a pretreatment baseline EFV1 or PEF greater than 80 percent of predicted or personal best and PEF variability of less than 20 percent. Intermittent asthma includes the child with allergy who is occasionally exposed to the allergen that is responsible for causing his or her asthma symptoms, but who is completely symptom free and has normal lung function when not exposed to the allergen. Seasonal asthma comes under this category. Intermittent asthma also includes the patient who has occasional exercise-induced asthma. Infants and children who occasionally wheeze during a period of viral upper respiratory tract infection also fall in this category. Intermittent asthma is nor trivial. The severity of the asthma exacerbations may vary from patient to patient and from time to time. Such an exacerbation might even be life threatening, although it is rare. The low frequency of the attacks and the fact that in between exacerbations the patient has a completely normal lung function support the recommendations that no long term treatment with a controller medication should be started. Further compliance with long term therapy when the patient only experiences occasional symptoms could be low. Rather the exacerbations should be treated as such, depending on the severity of exacerbations.
Treatment plan for Mild Intermittent Asthma
- It includes medications prior to exercise as needed (inhaled β-2-agonists or cromoglycate) or to allergen exposure, seasonal exacerbation to well recognized allergens (sodium cromoglycate or nedocromil).
- Treatment of the exacerbation includes inhaled short acting β-2-agonists taken as needed to relieve the asthma symptoms. This is usually sufficient.
- Acute exacerbations may require a short course of oral corticosteroids during mild intermittent asthma.
- If β-2-agonists are needed more than 2 times a week the child should be moved to the next step regardless of PEF measurements. The same applies if the lung function in between exacerbation becomes abnormal.
• Step-2: Mild Persistent Asthma
Mild persistent asthma is present if the child experiences symptoms two or more than two times a week but less than once a day, exacerbations affect sleep and activity levels; and nocturnal asthma symptoms more than two times a month. The child with mild persistent asthma has pretreatment baseline PEF of more than 80 percent of predicted or personal best and PEF variability of 20 to 30 percent. Cough variant asthma should be treated as mild persistent asthma.
Children with mild persistent asthma require long term controller medication every day to achieve and maintain control of their asthma. The primary therapy for mild persistent asthma is regular use of anti-inflammatory medication taken on a daily basis. Treatment can be started with either inhaled corticosteroids or sodium cromoglycate. Although cromoglycate is hardly used now a days, If parents prefer oral therapy then montelukast can be used for a short period of time.
• Step-3: Moderate Persistent Asthma
It is characterized by daily symptoms over a prolonged time or nocturnal asthma more than once a week, patient has to take reliever drug daily and exacerbations last days which may be>2 times/week. The child with moderate persistent asthma has a pretreatment baseline PEF of more than 60 percent but less than 80 percent of predicated or personal best and PEF variability of 20 to 30 percent.
Children with moderate persistent asthma require long term controller medication every day to achieve and maintain control of their asthma. Spacer device with the inhaler is recommended to reduce oropharyngeal side effects and systemic absorption. Long acting bronchodilators in addition to the inhaled corticosteroids may also be considered. Particularly to control nocturnal symptoms. Sustained release theophylline, an oral slow release β-2-agonists or a long acting inhaled β-2-agonists or Leukotriene antagonist like mouteleukast may have a complementary effect to inhaled corticosteroid. The role of anticholinergics (Ipratropium bromide) in long therapy is not well established, but an introduction of anticholinergics may be considered as an alternative for patients who experience such adverse effects as tachycardia or tremor from inhaled β-2-agonists. Inhaled short acting β-2-agonists should be available to take as needed to relieve symptoms, but should not be taken more than three to four times a day.
• Step-4: Severe Persistent Asthma
If the child experiences highly variable, continuous symptoms and frequent nocturnal; symptoms, has limited activities, and experiences severe exacerbations in spite of medications, the child has severe persistent asthma. The patient with severe persistent asthma has a pretreatment baseline PEF of less than 60 percent of predicted or personal best and PEF variability greater than 30 percent. In severe persistent asthma the goal of therapy becomes achieving best possible result the least symptoms the least need for short acting β-2-agonists, the best flow rates, the least circadian (night a to day) variation and the least side effects from medication.
Therapy needs multiple daily controller medications primary therapy includes inhaled corticosteroids at higher doses. A long acting bronchodilator is recommended such as long acting inhaled β-2-agonists or long acting oral β-2- agonists or oral sustained release theophylline. Children whose asthma is not controlled on high doses of inhaled corticosteroids and the addition of long acting bronchodilator may also need oral systemic corticosteroids which should be used in the lowest possible dose (alternate or single daily dose). Persistent trials of high dose of inhaled corticosteroids administered with a spacer device should be made in an attempt to reduce oral corticosteroids. When children are transferred from oral corticosteroids to high dose inhaled corticosteroids, they should be monitored closely for evidence of adrenal insufficiency. Access and adherence to moderate or high dose inhaled corticosteroid therapy are sometimes difficult for patients, and their health care professionals should consider the alternative of frequent bursts of lower dose oral corticosteroids There are not sufficient data to indicate whether this latter approach leads to similarly effective control of asthma. However, the data on side effects indicate that the therapeutic index (effect/side effect) of long term oral or parenteral corticosteroids therapy. The complexity of a multiple daily medication regimen is often a factor in patient non-adherence, and this in turn complicates control of the asthma. Patients with severe persistent asthma may require particularly intensive patient education.
Reduction of maintenance therapy is indicated after the child has achieved control and re-evaluation by the physician after 3–6 months has found that control of asthma is achieved. Therapy is then brought down to a step lower than startup to see how the children keep control of asthma. It is recommended that regular follow-up visits should be planned to asses for appropriate therapy.
- Persistent asthma is more effectively controlled by daily controller medication.
- A step-wise approach to drug therapy is recommended to establish control of asthma. The amount and frequency of drugs is dictated by severity of asthma.
- The amount and frequency of drugs is dictated by asthma severity.
- Aggressive approach to initiate at a higher step is useful in establishing control.
- Regular follow-up for assessment in 3–6 months is essential.
- The doctors should individualize specific medication plans.
• Administration of Medications
Medications for asthma can be administered via different ways, including inhaled, oral (ingested), and parenteral (subcutaneous, intramuscular, or intravenous) routes. The major advantages of delivering drugs directly into the airways via inhalation is that high concentrations can be delivered more effectively to the airways, and systemic side effects are avoided or minimized. Some of the drugs that are effective in asthma can only be used via inhalation because they are not absorbed when given orally. The onset of action of bronchodilators given via inhalation is subsequently shorter than when given orally.
Aerosolized medications that are used to treat asthma are available as pressurized metered-dose inhalers (pMDI), breath-actuated MDI, dry powder inhalers (Rotahalers, accuhalers and turbuhalers) and nebulizer solution for use through a nebulizer. Patient should be instructed in the use of a metered dose inhaler or other devices, and their techniques should be checked regularly.
• Different Inhalation Modes
• Pressurized metered dose inhaler (pMDI)
This is the most commonly used device for management of asthma. A pressurized aerosol is used in a canister which releases metered dose of medications upon actuation. The major disadvantages of pressurized metered dose inhaler therapy are that training and skill are required to coordinate actuation of the drug, through inhalation. For the patient who has difficulty using a metered dose inhaler, a spacer improves the drug delivery. This can be used by patients over 5 years of age. The technique needs an actuation during slow (30 L/min or 3–5 seconds) deep inhalation β-2-agonists, cromolyn sodium and nedocromil, anticholinergics and corticosteroids are available as MDIs.
Open mouth technique (holding MDI 2 inches away from open mouth) has clinically been found to be similar when compared to closes-mouth technique (closing lips around MDI mouthpiece). It may be difficult, particularly in young children. Patients may incorrectly stop inhalation at actuation.
The spacer device allows discharge of the drug into a chamber where particles of medications are held in suspension for 3 to 5 seconds. During this time the patient can inhaled the drug. Spacers also reduce deposition of the drug in the mouth and oropharynx, decreasing cough as well as the possibility of oral candidiasis when used to deliver inhaled corticosteroids. Further the use of spacers for the delivery of inhaled corticosteroids has been shown to decrease the systemic bioavailability of corticosteroids and the Short acting β-2-agonists administered from metered dose inhalers using spacer devices achieve bronchodilators equivalent to that effected by nebulization in treating acute exacerbations.
Spacer/holding chamber can be used for children around 4 years of age but in less than that it can be used with a mask if child does not use the mouthpiece. It requires a slow (30 L/min for 3–5 seconds) inhalation or tidal breathing immediately following actuation. Using 8–10 inhalations are sufficient to completely empty the drug in the spacer. Only one actuation into spacer/holding chamber at a time is preferred. If face mask is used again allow 8–10 inhalations per actuation. It takes about 15–20 seconds to do that in infants. The dose can be delivered to a sleeping baby. It is also preferred to use the spacers that have inspiratory and expiratory valves. The spacers are easier to use than MDI alone. With a face mask, it enables MDI to be used in small children. Simple tubes do not obviate coordinating actuation and inhalation. The larger volume spacers/holding chambers (>600 cc) may increase drug delivery over MDI alone in patients with poor MDI technique. The effect of a spacer/holding chamber on output from an MDI is dependent on both MDI and spacer type; thus data from one combination should not be extrapolated to all others. The innovative spacers of paper have also been shown to be effective in over 12 years children. All spacers that we use need good evaluation before choosing one, simply advising a spacer without knowing its true value and efficacy may only add to cost of therapy without additional benefits of drugs delivery.
After selection of appropriate inhalation devices, patients and their families should receive suitable training and education about correct inhalers use and about the need for compliance with treatment. For individual patients, such attention to detail will optimize drug delivery to the lungs and improve overall asthma control.
Basically, children (aged from 1month to 5 years) with asthma, wheezy bronchitis, and cystic fibrosis or bronchopulmonary dysplasia are unable to coordinate their inspiratory efforts with actuation of an MDI; small tidal volumes and low inspiratory airflow also means that most of these generally administered to young children via a nebulizer or MDI plus spacer. The latter route is more appropriate, since it obviates the need for prolonged period of drug administration, which are required for nebulizer therapy to be achieved. Large-volume (750 ml) spacers designed for use in adults are inappropriate for use in babies, whose small tidal volumes (8–10 ml/kg body weight) mean that too many breaths are required for full doses to be inhaled. Conversely, if the volume of a spacer is too small and if the device is too narrow, drug particles may not be produced in the optimal size range-they may be deposited on the sides of the inhalation chamber, rather than remaining as an aerosol cloud. Hence, the small volume (350 ml) spacer device, which is 230 mm long and contains a one-way, low-resistance valve, (opens at an air flow rate of 75 ml. the valve resistance is <0.02 kPa/Us) was designed to overcome some of these problems. This novel inhalation device has been successfully used to administer Salbutamol to wheezy infants, with significant improvements in lung function (indicated by thoracic gas volume and airway conductance measurements) having been noted.
Breath Actuate Devices
These are indicated for children who are unable to coordinate inhalation and actuation. Slow inhalation may be difficult in them and they may incorrectly stop inhalation at actuation, requires more rapid inspiration to activate than is optimal for deposition. Cannot be used with currently available spacer/ holding chamber devices. Breath actuated devices containing β-2-agonists are available
Dry Powder Inhalers
Dry powder inhalers do not utilize CFUs (chlorofluorocarbons) propellants. These devices have potency similar to standard metered dose inhalers, dry powder inhalers require an inhalation technique that is different from the MDI technique and are generally easier to use, thus it may be difficult for some children to use during an acute attack of asthma. Dose is lost if patient exhales through device. Drug delivery may be > more or less depending on device and technique. MDI can be used in children over 4 years old, but effects are more consistent with children >5 years. Most Rotahalers appear to have similar delivery efficiency as MDI either with or without spacer/holding chamber, but some may have delivery more than MDI. Mouth washing is effective in reducing systemic absorption. Other dry powder devices available in India are accuhalers and diskhaler. However, each delivers a particular drug combination.
Nebulized or “wet” aerosols generated by an air compressor are particularly useful for children under 5 years of age and in the treatment of acute severe asthma in which respiratory insufficiency could impair inhalation from a metered dose inhaler or dry powder inhaler. β-2-agonists, cromolyn, anticholinergics and corticosteroids are available as nebulizer solution. The nebulizers can be used for children under two years. Those who can not use MDI with or without spacers with mask during exacerbations would need nebulizers. Slow tidal breathing is all that a child has to do with nebulizers with occasional deep breaths. Tighty fitting face mask for those unable to use mouthpiece is useful. Less dependence on patient coordination or cooperation makes it a choice for delivery of cromolyn in children and for high dose β-2- agonists and anticholinergics in moderate to sever exacerbations in all patients. These are expensive; time consuming with inter nebulizer and intra nebulizer output variances.
Special Considerations for Children
Metered dose inhalers are often difficult for children to use correctly. The use of spacer devices with a valved septum allows children as young as 2 to 3 years of age to use the MDI after careful training. A device that combines a face mask with a spacer may also decrease the age at which MDIs can be used. A good inspiratory effort is required for the dry powder systems. The lower age limit for the devices will vary. In general, they are most suitable for children over 5 years old. During acute attacks young children may have difficulty in using the MDI, with or without a spacer device. Under such circumstances, nebulizer or spacers with low resistant valves are the best option. Nebulizer are of value to children under 2 years of age, older children who have difficulty with the MDI or dry powder techniques, and those prone to severe attacks.
Barriers to Optimal Efficacy of the Existing Drugs
Pharmacological therapy is only useful if the drugs are actually used by patients and are delivered to the lungs. There are a number of barriers that stand in the way of adherence to an asthma management plan and optimal use of drugs. These include:
- Inability to understand the management plan/drugs
- Inability to use the metered dose inhaler (MDI) or other devices
- Adverse effects
- Complexity of the regimen
- Cost and
1. Inability to understand the management plan/drugs: Children and their families often have great difficulty understanding the difference between bronchodilators and anti-inflammatory drugs and which inhaler has which drug. There is need for education as an integral part of the management plan.
2. Inability to use an MDI or other devices: Approximately 50% of patients are unable to use a MDI correctly. A recent study by Goodman at al reported (data from 59 patients with asthma or chronic obstructive pulmonary disease) that most patient use their MDIs incorrectly. Thus study highlights the importance of correct technique and of observing and recorrecting technique with every visit of patient to the doctor.
All anti asthma drugs have the potential for causing adverse effects. Attention to dose and mode of delivery can help to minimize these adverse effects.
Complexity of the Regimen
Generally, adherence to a particular drug regimen falls off if it is complex. It is important to keep this in mind when developing a management plan. For example, if an individual is expected to take two inhalers over a period of 20 minutes, twice or three rimes each day, it is unlikely that he or she will adhere to this plan. Likewise, as the number of puffs and frequency of prescribed medication increase, the adherence becomes poor.
5. Cost: The cost of asthma drugs is an important barrier for many. It is important for the doctor to be sensitive to this issue when prescribing because the patient may not feel comfortable saying anything, but may then just miss the important drugs.
6. Cost-effectiveness: The cost effectiveness of different asthma therapies is fortunately receiving greater attention now than it did in the past. It is very useful to convey to the patient/parents about asthma therapy and its cost effectiveness. This can ensure a better acceptance of long term prevention plan. It is estimated that a child would need Rs. 2 to 6 per day to use long term beclomethasone or Budesonide daily, cost for treatment for one acute episode may be as high as Rs. 500 and if hospitalization becomes necessary, another Rs. 500 to 100 per day are added to the cost of treatment. Since appropriate use of inhaled corticosteroids may reduce hospitalization, consequently medical costs are reduced appreciably.
IndexAAdherencein pediatric population to asthma treatment Air pollution Airwayepithelium remodeling , Allergenimmunotherapy specific immunotherapy Allergicasthma rhinitis , Allergy vaccine therapy Amino acids Animals dander Anti oxidants Anticholinergic drugs Anti-IgE antibody Asthma , , , symptom score trigger control plan for patients Avoidance ofasthma triggers exposure to risk factors BBacillus calmettle guerin Barriers to optimal efficacy of existing drugs Beclometasone dipropionate Blood tests Breast feeding Breath actuate devices Bronchialasthma submucosal glands Budesonide Burden of respiratory allergy CCarotene Causes wheezing Chemokines , Childhood asthma Chronic inflammatory disease Ciclesonide Cigarette smoke Cochroach allergen Cold and infections Combustion devices Complexity of regimen Control of asthma Corticosteroids , Cromolyn Cytokines , DDefinition of asthma Diagnosis of asthma Different inhalation modes Difficulties in treatment of respiratory allergy Disability adjusted life years Dry powder inhalers EEconomic costs Environment and asthma Environmental tobacco smoke Eosinophiland asthma cationic protein Extent of problem FFactors determining adherence Family size and hygiene hypothesis Farm animals Flavanoids Flavones Fluticasone propionate Foodallergen allergy in asthma Formeterol , , fumarate GGlobal initiative of asthma Goals of long terms management of asthma HHouse dust mites , Hypnosis IImmune responses in asthma Immunobiology of asthma Immunomodulatory cytokines Increasing prevalence of asthma Infection and allergy Inhalation devices Inhaled corticosteroids Interactions with corticosteroids Interleukin-5 antagonism Intestinal flora and probiotics Ipratropium bromide LLeukotrieneinhibitors modifiers Loteprednol etabonate MMagnesium Management of asthma Medications in asthma Methylxanthines Mildintermittent asthma persistent asthma Moderate persistent asthma Mycobacterium bovis NNational asthma education and prevention program Nebulizers , Nedocromil sodium Newer inhaled corticosteroids OOmalizumab PPatch test Peak flowmeters zone system Pets exposure Pharmacogenomics for asthma Pharmacotherapy of asthma Pressurized metered dose inhaler Probiotics for allergic respiratory diseases QQuality-of-life issues RRational use of drugs for bronchial asthma Relievers Respirable antisense oligonucleotides Reticular basement membrane Role ofcombining two types of drugs fatty acids immunity and allergy micronutrients in bronchial asthma yoga Rotahaler SSalmeterol , , Selenium Severe persistent asthma Skin test Smooth muscle Sodium Soft steroids Strong odours and sprays Sub-cutaneous immunotherapy Sub-lingual immunotherapy Surya namaskar TTobacco smoke Trace minerals Traditional herbs Treatment plan for mild intermittent asthma Type of non adherence observed UUse of inhalation devices VVitamin A and B C E WWheezing in infants Wood smoke
It is said that an attack of asthma must be preventied before it starts. Efforts start with avoiding factors that trigger asthma
Many things can start asthma attacks:
- Cigarette smoke
- Smoke from other sources
- Dust in beds and pillows
- Dust from sweeping
- Strong smells and sprays
- Pollen from trees and flowers
- The weather
- Running, sports, and working hard
- Animals with fur
Keep things that start asthma attacks out of home:
- Many people with asthma are allergic to animals with fur. Keep animals outside. Give away pets.
- No Smoking inside.
- Keep strong smells out of the home. No soap, shampoo, or lotion that smells like perfume. No incense and mosquito repellants.
Keep the bed simple:
- Dust collects in the mattress, blankets and pillows. This dust bothers most people with asthma.
- Put special dust-proof covers with zippers on the mattress and pillow.
- Do not use a pillow or a mattress made of straw.
- A simple sleeping mat may be better than a mattress.
- Wash sheets and blankets often in hot water. Put them in the sun to dry.
Use windows to keep the air fresh and clean:
- Open windows wide when it is hot or stuffy, when there is smoke from cooking, and when there are strong smells.
- If you heat with wood or kerosene, keep a window open and get rid of fumes.
- Close window when the air outside is full of exhaust from cars, pollution from factories, dust, or pollen from flowers and trees.
Plan to do the following chores when the child with asthma is not present:
- Sweep, vacuum, or dust
- Spray for cleaners
- Use strong cleaners
- Cook strong smelling foods
- Air out the house before the person with asthma returns
•Asthma Trigger Control Plan for Patients
Because you have asthma, your airways are very sensitive. They may react to things called triggers (stimuli that can cause asthma attack). Your airtubes may become swollen, tighten up, and produce excess mucus in the presence of one or more of the triggers below. These triggers may make asthma symptoms worse or keep you away from getting better. It is important to find out what your asthma triggers are. Learn ways to avoid them. If you cannot avoid triggers in your medicine plan then discuss allergy injection treatment (immunotherapy) along with medical treatment.
Ask your doctor to help you find out what the triggers are for your child.
Ask your doctor for help in deciding which actions will help the most to reduce the asthma symptoms.
Number each action item in order of importance. Carry out these actions first. Once you have completed these actions, move on to actions that are of lesser importance. Discuss the results of these efforts with your doctor.
Pollens and Moulds (Outdoor)
Ask the child to stay indoors during the midday and afternoon when the pollen count is high.
Use air conditioning, if possible.
Keep windows closed during seasons when pollen and mould are highest
Avoid sources of moulds (wet leaves, gardens debris).
House Dust Mites
- These are actions to control dust mites:
- Encase the child's mattress in an airtight cover.
- Either encase the pillow or wash it once a week every week.
- Avoid upholstered furniture in your house.
- Remove carpets that are laid on concrete.
- Wash the bed covers, cloths, and stuffed toys once a week in hot (130°F/72°C water.
- Reduce indoor humidity to les than 50 percent.
- Remove carpets from bedroom.
Animals Dander (or flakes from the skin, hair or feathers of all warm blooded pets including dogs, cats, birds and rodents). The length of a pet's hair does not matter. The allergen is in the saliva, urine and dander.
- Remove the animal from the house.
- If you must have a pet, keep the pet out of your child's bedroom at all times.
- Wash the pet weekly.
- The child should avoid visits to friends or relatives with pets.
- Give your child asthma medicine (cromolyn or beta-agonist; cromolyn is often preferred) before visiting homes or sites where animals are present.
- Avoid products made with feather, for example, pillow and comforters. Also avoid pillows, bedding and furniture stuffed with silky fibers.
Use insect sprays; but have someone else spray when you or your child are outside the home.
Air out the home for a few hours after spraying.
- Keep bathrooms, kitchens, and basements well aired.
- Clean bathrooms, kitchens, and basements regularly
- Do not use humidifiers, e.g. room or desert coolers.
- Do not smoke
- Do not allow smoking in the home.
- Have household members smoke outside, if they don't stop smoking.
- Do not allow any smoking in the child's bedroom. Encourage family members to quit smoking, their doctor can help them quit.
- Avoid using a wood burning heat stove to heat your home. The smoke increases asthma symptoms.
- Avoid using kerosene heaters in your house.
Strong Odours and Sprays
- Do not stay in your home when it is being painted. Allow enough time for the paint to dry.
- Avoid perfume and perfumed cosmetics such as talcum powder and hair spray.
- Do not use room deodourizers.
- Use nonperfumed household cleaning products whenever possible.
- Reduce strong cooking odours (especially frying) (by using a fan and opening windows.
- Avoid air pollution by asking the child to stay indoors on days when the air pollution is high such as heavy smog.
Cold and Infections
Your child with asthma should.
- Avoid people with colds or flu.
- Get rest, eat a balanced diet, and exercise regularly.
- Do not take cold and cough medicines, such as antihistamines and cough Syrup, unless you speak to your doctor first.
The child/parents should work out a medicine plan with doctor that allows them to exercise without symptoms.
- Take inhaled beta 2 agonist or cromolyn medicine before exercising.
- Warm up before doing exercise and cool down afterwards.
Ask the child to:
- Wear a scarf over his/her mouth and nose in very cold weather.
- Dress warmly in the winter or on windy days.
REMEMBER: making these changes will help keep asthma attacks from starting. An asthma triggers control plan is an important part of controlling asthma.
• Act Fast If An Asthma Attack Starts
- Know the signs that an asthma attack is starting. They may be one or more of:CoughCoughWheezeTight chestWake up at night
- Move away from the thing that started the attack.
- Take a quick-relief asthma medicine.
- Parents must stay calm as their anxiety reflects in the child's condition.
Get emergency help from a doctor if the child does not get better:
Get help if you see any of these asthma danger signs:
- Quick-relief medicine does not help for very long or it does not help at all breathing is still fast and hard.
- It is hard to talk.
- Lips or fingernails turn grey or blue.
- The nose opens wide when the child breathes.
- Skin is pulled in around the ribs and neck while breathing.
- The heartbeat or pulse is very fast.
- It is hard to walk.
Shift the patient to Emergency Care and follow the emergency management plan.