Clinic Consult: Pediatrics (Malaria) Ritabrata Kundu, Jaydeep Choudhury
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_FM1CLINIC CONSULT PEDIATRICS Malaria_FM2
_FM3CLINIC CONSULT PEDIATRICS Malaria
Authors Ritabrata Kundu MBBS MD (Ped) FIAP Professor Department of Pediatrics Institute of Child Health Kolkata, West Bengal, India Jaydeep Choudhury MBBS DNB (Ped) MNAMS FIAP Associate Professor Department of Pediatrics Institute of Child Health Kolkata, West Bengal, India
_FM4
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Clinic Consult Pediatrics: Malaria
First Edition: 2016
9789351527732
Printed at
_FM5Dedicated to
Institute of Child Health, Kolkata
It has nurtured us over the years_FM6
_FM7Preface
The World Malaria Report 2014 published by World Health Organization declares that malaria target under Millennium Development Goal 6 (MDG 6) has been met. It also states that 55 countries are on track to reduce their malaria burden by 75% which is in line with the World Health Assembly's target for 2015. Despite impressive increase in malaria intervention coverage, millions of people still do not receive the services they need. Poverty and low education are significant predictors of coverage gaps for fever care, diagnostic testing, and treatment in pregnancy, availability of insecticide-treated mosquito nets, and receipt of artemisinin-based combination therapy.
Malaria is still a major public health problem in India, accounting for sizeable morbidity, mortality, and economic loss. Epidemiologically, India is primarily a low-transmission area, 67% of the population belongs to this category and another 22% of the population belongs to high-transmission area. Around 1.5 million confirmed cases of malaria are reported in India annually by the National Vector Borne Disease Control Program (NVBDCP). Among the major Plasmodium species, 53% are Plasmodium falciparum and 47% are Plasmodium vivax. Thus, there are more cases of P. falciparum than P. vivax in India. Chloroquine-resistant P. falciparum malaria has been observed with increasing frequency in many parts of the _FM8country for a long time. Continued treatment of such cases with chloroquine is probably one of the important factors responsible for increased proportion of P. falciparum relative to P. vivax in India. Parasitological diagnosis is of utmost importance towards proper management of malaria, followed by therapy with appropriate medicines. Progress in reducing the human suffering due to malaria in many parts of the world has shown that, with adequate initiative, and right strategies, malaria can be controlled to a great extent.
The chapters compiled in this book cover the various aspects of malaria in a concise, easy-to-read presentation. Focus has been given to the changing epidemiology of malaria, clinical features, investigations, management, including overview of the antimalarial drugs, treatment of special situations, severe malaria, chemoprophylaxis, and prevention of malaria.
This book is meant for all the medical practitioners who treat patients suffering from malaria and also for undergraduate and postgraduate medical students. The subject is presented in a brief, to-the-point, and easy-to-read format for handy reference.
Ritabrata Kundu
Jaydeep Choudhury
1 January, 2016
_FM9Acknowledgments
We are deeply indebted to the innumerable patients suffering from malaria who attend our hospital. They have taught us the most. The ever-cooperative staff of the Department of Pathology at the Institute of Child Health, Kolkata, especially Mr Probal Chakraborty, and Mr Amrita Naskar deserve special mention.
We would like to express our gratitude to Professor Apurba Ghosh and Professor Maya Mukhopadhyay for always being kind and supportive to us for all our endeavors. Whenever we undertake any academic project, we remember Late Dr Tapan Kumar Ghosh who inspired us in all our publishing efforts.
Sincere gratitude to our family members for being supportive to us.
We appreciate the support and cooperation that we have always received from Shri Jitendar P Vij (Chairman and Managing Director), Mr Ankit Vij, Mr Tarun Duneja, Dr Neeraj Choudhary, Ms Shweta Tiwari, Mrs Samina Khan (PA to Director) and the team of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi and Mr Sandeep Gupta, Mr Sabyasachi Hazra and the team from Kolkata branch for their whole-hearted effort and cooperation._FM10

Malaria—An OverviewCHAPTER 1

 
INTRODUCTION
Malaria is one of the major public health problems in many parts of the world, especially in tropical countries. It contributes considerably to under five mortality in children. It is heartening to note that the total number of malaria cases in India has come down from near 2 million cases, in the beginning of this millennium to about 1.5 million cases in the past few years. At the same time, it is disturbing to find that Plasmodium falciparum malaria, which contributed only 38.8% in 1995, has increased to nearly 50% in 2008–2011 (Figures 1.1 and 1.2). The problem of increasing P. falciparum cases is further enhanced by development of resistance to first-line antimalarial drugs like chloroquine. The most important factor contributing to resistance is drug pressure and haphazard use of antimalarials without a proper parasitological diagnosis. Considerable decrease in antimalarial drug use could be achieved through improving the diagnosis of malaria. Moreover, uniform prescribing practices will limit the spread and intensification of drug resistance.
Chloroquine-resistant Plasmodium falciparum malaria was initially identified in the northeastern states of India. Thereafter, it has spread relentlessly throughout the country that 80 districts of 21 states of India report chloroquine resistance (Figures 1.3 and 1.4).2
Figure 1.1: Malaria trend in India from 2001 to 2012. National Vector Borne Disease Control Program.
Figure 1.2: Plasmodium falciparum cases in India from 1995 to 2010. National Vector Borne Disease Control Program.
3
Figure 1.3: Chloroquine resistant areas in India from 1978 to August 2008.Source: National Vector Borne Disease Control Program.
The previous notion, that malaria is restricted to low-income rural areas of eastern and northeastern states of India, does not hold true. It has been found in central as well as more arid western parts of the country. Initially, villages were thought to be the major hub of malaria in India, but this trend is reversing since early seventies. Urban malaria was thought to be restricted only in large towns, but small cities and towns are showing a rising trend.4
Figure 1.4: Districts reporting chloroquine resistant malaria in India.
About 10% of all malaria cases are reported from urban areas. The increasing problem of urban malaria is due to “rural push”, i.e., population migration from village to earn livelihood and “urban pull”, i.e., better facility in the city. Unplanned boom in urban growth has created “urban slum” with poor sewerage and housing condition that facilitate mosquito breeding. Poor water supply in these unplanned expansions has led to water storing practices favoring mosquito breeding. Moreover, due to large population pressure, parallel cities were formed with same prevailing epidemic situations like Navi Mumbai, Gurgaon, etc.5
The clinical manifestation of malaria greatly depends on the background level of acquired protective immunity. This factor is the outcome of the pattern and intensity of malaria transmission in a particular area. The transmission dynamics is of the following types.
  • Stable transmission: It occurs when the population is continuously exposed to a constant, high rate of malarial inoculations. The entomological inoculation rate is more than 10 per year. There is partial immunity to malaria and its severe manifestations, which is acquired early in childhood. This type of transmission is seen in sub-Saharan Africa and parts of Oceania. Here, the acute clinical disease is mostly seen in young children. They may progress rapidly to severe malaria. Adolescents and adults are partially immune and seldom suffer. Immunity is modified in pregnancy and when individuals move out of the endemic areas.
  • Unstable malaria: The rate of malaria inoculation fluctuates greatly during various seasons and over the years. The entomological inoculation rate is less than five per year and often less than one per year. Unstable malaria is prevalent in Asia, Latin America, and other malaria endemic areas. Immunity is low in these areas due to unstable transmission. People of all ages are prone to suffer from acute malaria. Epidemics may occur due to sudden increase in inoculation rate following increase in mosquito vector density. Severe malaria is common. Nonimmune travelers to a malaria endemic area are at great risk of acquiring malaria.
Malaria has an unstable transmission characteristic in India. Most of the areas have low transmission with clear seasonal 6variation. The incidence increases with or following monsoon rains. With this unstable transmission dynamics, most of the population have little or no immunity against malaria. All age groups including children and infants are at risk of developing serious malaria. Intense malaria transmission is seen in northeastern states, large areas of Odisha, Jharkhand, Rajasthan, Chhattisgarh, and Madhya Pradesh. Peculiarities of these areas with forests, rivulets, and hilly tracts provide perfect opportunity and ecological support for malaria transmission throughout the year. Here, only young children, who are not mature enough to develop immunity of their own and has lost the immunity availed from their mother, are prone to develop severe malaria. Also the visitors, particularly army personnel, and migratory labor in these areas, are prone to severe malaria.
Transmission of malaria largely depends upon conditions favoring vector abundance. Anopheles culicifacies is the main vector in rural and peri-urban areas, which breeds in natural and manmade breeding sites. It is highly zoophilic, hence, high cattle density may give some protection to man. Anopheles stephensi is responsible for malaria in urban and industrial areas. It breeds in stagnant water. Anopheles fluviatilis is the main vector in hilly areas, forests, and forest fringe areas, especially in the eastern parts of India. Most of the vectors, including A. culicifacies, start biting soon after dark and continue till dawn. Resistance to dichlorodiphenyltrichloroethane (DDT) and malathion, the common insecticides, are seen in both the important species.
The two most important species of malaria parasite in India are Plasmodium falciparum and Plasmodium vivax. They occur together in many states with P. falciparum as more dominant in some northern states of India, Odisha, Jharkhand, Andhra Pradesh, and Telangana (Figure 1.5).7
Figure 1.5: Plasmodium falciparum distribution in India.
Mortality from malaria is highest in these states of India (Figure 1.6). Hence, malaria in India is dual species infection with different treatment in each species. Thus, correct diagnosis of the type of malaria is extremely important not only to cure the patient but also to restrain the spread of drug resistance.8
Figure 1.6: Malaria mortality in India. National Vector Borne Disease Control Program.

Magnitude of ProblemCHAPTER 2

 
MAGNITUDE OF PROBLEM
Despite remarkable progress in the treatment of malaria, it is still a leading cause of morbidity and mortality in many parts of the world, including India. Approximately 2 billion people, roughly a third of the world's population, live in malaria-endemic areas. It imposes a substantial economic and social burden on these societies. Recent estimates indicate that there are approximately 300–500 million clinical cases and 1.5–2.7 million deaths every year due to malaria worldwide. The indirect costs of malaria to society include poor educational performance in children, exacerbation of malnutrition and anemia, which have a negative impact on the cognitive and physical capacity of both children and adults. It is estimated that malaria is responsible for up to 45 million disability-adjusted life years (DALY) annually across Africa.
Malaria is endemic in whole of India except at elevations above 1800 meters and in some coastal areas (Figure 2.1). In India, approximately 1.1 million malaria cases were reported in 2000. Plasmodium vivax is the commonest (60–70%), followed by Plasmodium falciparum (30–45%), Plasmodium malariae species is rarely found, and Plasmodium ovale is not found in India.10
Figure 2.1: Malaria endemicity in India.
11However, in subsequent years, P. falciparum malaria is on the rise and at present it contributes half of the total malaria cases in India. P. falciparum is a malignant variety of malaria as 0.5–2% may develop complicated malaria, of which up to 50% are fatal, if timely treatment is not commenced. Almost all malaria mortality is due to P. falciparum. Urban and peri-urban malaria are on the increase in South Asia and in many parts of Africa (Figure 2.2). Another disquieting factor is the re-emergence of malaria in areas where it had been eradicated or its increase in countries where it was nearly eradicated.
There are many obstacles to the effective implementation of the highly efficacious treatment options. Resistance of P. falciparum to chloroquine is now common in practically all malaria endemic countries. Resistance to sulfadoxine-pyrimethamine is widespread in Southeast Asia and South America.
Figure 2.2: Urban malaria in India.
12Mefloquine resistance is now common in the border areas of Thailand with Cambodia and Myanmar. Resistance of P. vivax to chloroquine has now been reported from Indonesia, Myanmar, Papua New Guinea, and Vanuatu.
Although the total number of cases of malaria in India has remained relatively constant for the last 5 years, outbreaks have increased the number of malaria deaths. Plasmodium falciparum cases have also consistently increased from 9.73% of malaria cases in 1977 to 34.5% of cases in 1995, with a peak of nearly 50% in 2010–11.
Figure 2.3 shows confirmed malaria cases per 1000 population/parasite prevalence (PP) in India (2011). Figure 2.4 shows proportion of cases of P. falciparum in India (2011 report).
Figure 2.3: Confirmed malaria cases per 1000 population/parasite prevalence (PP) in India (2011 report).
13
Figure 2.4: Proportion of cases of Plasmodium falciparum in India (2011 report).
Table 2.1   Epidemiological profile of malaria in India
Population
2013
%
High transmission (>1 case per 1000 population)
275,500000
22
Low transmission (0–1 cases per 1000 population)
8,38,900000
67
Malaria-free (0 cases)
1,37,700000
11
Total
1,252,100000
Table 2.1 shows the epidemiological profile of malaria in India.14

Life Cycle of MalariaCHAPTER 3

 
INTRODUCTION
The cycle starts with the bite of a female anopheline mosquito with introduction of sporozoite at the site of the bite (Figure 3.1). Sporozoites enter the circulation either directly or through the lymphatic channels. They enter the hepatocytes to multiply and produce thousands of merozoites. This phase is known as pre-erythrocytic or hepatic schizogony. However, some sporozoites, in case of Plasmodium vivax inside the hepatocytes, instead of multiplying to merozoites, assume an inert or resting stage known as hypnozoites. These hypnozoites may become active after weeks or months to cause relapse in case of P. vivax malaria. In case of Plasmodium falciparum malaria, the hypnozoites are not produced, hence, there is no relapse. In the liver cycle as only a few liver cells are involved, they never produce any symptoms.
Following rupture of the liver cells, numerous merozoites are liberated in the bloodstream. They rapidly invade the red blood cells (RBCs). P. vivax shows a tendency to invade young red cells whereas P. falciparum does not show any preference. This results in P. vivax malaria involving about 13% red cell population. In contrast, P. falciparum in uncomplicated malaria involves 40% of red blood cells.16
Figure 3.1: Life cycle of malaria.Source: Center for Disease Control and Prevention.**The malaria parasite life cycle involves two hosts. During a blood meal, a malaria infected female Anopheles mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and release merozoites (4). (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exoerythrocytic schizogony (A)), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony (B)). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal (8). The parasites’ multiplication in the mosquito is known as the sporogonic cycle (C). While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes (9). The zygotes in turn become motile and elongated (ookinetes) (10) which invade the midgut wall of the mosquito where they develop into oocysts (11). The oocysts grow, rupture, and release sporozoites (1), which make their way to the mosquito's salivary glands. Inoculation of the sporozoites (12) into a new human host perpetuates the malaria life cycle.
1718During the phase of erythrocytic cycle also known as erythrocytic schizogony, malaria parasite passes through the stages of early ring form, trophozoites, schizonts, and merozoites. Ultimately, the parasite occupies the entire red blood cell which becomes rigid and deformed with full of merozoites. The swollen red blood cells rupture with release of multiple merozoites, which again invade other red cells to start a new asexual cycle.
In P. vivax malaria, the cycle of erythrocytic schizogony is completed in the peripheral circulation. Schizogony in P. falciparum malaria occurs in the capillaries of the internal organs, like spleen, liver, brain, etc., with only the early ring forms normally seen in the peripheral blood. Red blood cell containing the mature form of P. falciparum parasite, i.e., beyond early ring form, renders the red cells sticky. This causes two important problems in P. falciparum malaria, namely parasitized RBCs adhere to microvascular endothelium (cytoadherence) and also they adhere to noninfected erythrocytes (rosetting). The net result is impedance in forward flow of blood in venules and capillaries of vital organs leading to microcirculatory obstruction.
After a series of asexual cycles, some merozoites, instead of developing into trophozoites and schizonts, give rise to forms which are capable of sexual functions outside the human host. They are called gametocytes, both male and female. Gametocytes do not cause any fever in human host but are produced for propagation of the species. Female Anopheles mosquito during its blood meal from an infected person ingests both male and female gametocytes. These gametocytes undergo series of developmental process in the mosquito with ultimate release of sporozoites which concentrate in the salivary glands of the mosquito. Following the bite of an 19infected anopheline mosquito, the sporozoites are introduced in the human to continue the cycle.
 
RELAPSE OF MALARIA
In Plasmodium vivax infection, there may be renewed clinical manifestation with parasitemia after resolution of the primary infection. This is due to reactivation of the hypnozoites in the liver cells which starts a new cycle. Relapse may occur weeks, months or years after the primary infection. As P. falciparum does not produce hypnozoites, so, there is no relapse in P. falciparum malaria.
 
RECRUDESCENCE OF MALARIA
Often due to incomplete treatment, some erythrocytic form of parasite survives in human host, only with time it multiplies, and produces symptoms of malaria. This is specially seen in case of P. falciparum malaria and is known as recrudescence. It can be seen as long as 10 weeks following treatment.

Clinical DiseaseCHAPTER 4

 
INTRODUCTION
Malaria in India, unlike high transmission areas of Africa, fluctuates greatly over seasons and years. This seasonal variation hinders the population from acquiring lasting immunity against malaria. Hence, all age groups suffer from acute malaria with chances of progression to severe malaria particularly in cases of Plasmodium falciparum infection.
It is very important to distinguish uncomplicated and complicated or severe malaria as the latter needs highest level of patient care for favorable outcome. If treatment is delayed or ineffective in early uncomplicated stage of P. falciparum malaria, the parasite mass will rapidly increase to produce organ dysfunction resulting in severe malaria.
Initial symptoms of malaria are nonspecific and resemble viral fevers like influenza. Both the species cause muscle ache, headache, lethargy, and vague abdominal pain. Plasmodium vivax malaria may cause well-defined fever paroxysm with chills and rigor. P. falciparum malaria, on the other hand, may cause erratic fever and it may not regularize to any definitive paroxysm. The classical cold stage with chills followed by hot 21stage and sweating stage may not be seen. Children may be extremely lethargic, anorectic and, at times irritable. As the disease continues, spleen and liver enlarge with developing anemia. Mild abdominal discomfort is common in malaria with occasional constipation or diarrhea. Respiratory rate may increase due to dehydration, acidosis, and anemia.
These symptoms and signs are nonspecific resembling many common infections in children. Thus, symptomatic diagnosis of malaria invariably leads to overdiagnosis.
Complicated or severe malaria is defined as symptomatic malaria with signs of severity or evidence of vital organ dysfunction.
Severe malaria due to P. vivax is rare. Occasional severe manifestation in P. vivax malaria may be due to splenic rupture, either traumatic or spontaneous. Most of the complicated malaria is due to P. falciparum infection. Here, early recognition is of utmost importance. Any of the following clinical or laboratory features is suggestive of complicated or severe malaria.
 
Cerebral Malaria
The diagnostic clue is unarousable coma not attributable to any other cause in a patient with P. falciparum malaria. Unlike febrile seizures, coma in cerebral malaria persists for 30 minutes to 1 hour following seizure. Convulsion, at times may be subtle to start with, like twitching in the corner of the mouth or intermittent nystagmus. Features are usually of symmetrical encephalopathy with no focal signs. There may be mild resistance to neck flexion, but signs of meningeal irritation are usually absent. Confusion, delirium, and disorientation 22are absent and extreme agitation suggests poor prognosis. Motor abnormalities like decorticate and decerebrate rigidity may occur. Opisthotonus posturing with unarousable coma suggests poor prognosis. Abdominal reflexes are usually lost, which helps to distinguish from hysterical patients.
Papilledema and retinal edema are rare. Retinal hemorrhages are often seen resembling Roth's spots. Retinal vessels show segmental whitening, which is sequestrated red cells with scanty hemoglobin and mature parasites.
Cerebrospinal fluid (CSF) in cerebral malaria is clear with fewer than 10 cells per micro liter of fluid, predominantly lymphocytes. CSF protein is slightly raised with normal glucose. Electroencephalograph abnormalities are nonspecific and computerized axial tomography (CT) scan of brain is normal.
 
Neurological Sequelae of Cerebral Malaria
About 10% of children and 3% adults have neurological deficit following cerebral malaria. Hemiparesis with or without hemianopia, cortical blindness, behavioral abnormality, generalized spasticity, and speech disorders may develop. Psychosis, rigidity, tremor, and cerebellar dysfunction are also seen as post-malarial neurological syndrome. These neurological abnormalities are rarely seen following uncomplicated malaria. These sequelae are more common in patients treated with mefloquine, hence, it is not advocated for treatment of cerebral malaria. Many of these abnormalities recover with time. Poor prognostic indicators are deep coma, absent corneal reflexes, and abnormal posturing (decerebrate or decorticate rigidity and opisthotonus).23
 
Severe Anemia
Anemia is a common finding in severe malaria, particularly in children, and pregnant women. Hemoglobin is often below 5 g/dL and hematocrit below 15%. Usually, it is microcytic hypochromic anemia due to concurrent iron deficiency. Children with hyperparasitemia may develop anemia rapidly due to widespread destruction of parasitized red blood cells. Patients with repeated untreated episodes of malaria may develop normocytic anemia. Sometimes, patients with severe anemia have absent or low parasitemia, where useful indicator of malaria is the presence of malaria pigments in neutrophilic leukocytes.
Children with severe anemia present with tachycardia and respiratory distress. This is due to acidosis contributed by hypovolemic tissue hypoxia and rarely due to congestive heart failure. Anemia may lead to cerebral signs like confusion and restlessness and cardiopulmonary signs like gallop rhythm, hepatomegaly, pulmonary edema, and heart failure. Anemia in pregnancy results in increased perinatal morbidity and postpartum hemorrhage.
 
Hypoglycemia
Hypoglycemia is defined as whole blood glucose concentration less than 40 mg/dL (2.2 mmol/L). It is particularly seen in young children and pregnant women. Patients treated with quinine may develop hypoglycemia due to quinine-induced hyperinsulinemia. It is also commonly seen in patients with hyperparasitemia, convulsions, or profound coma. It may present with classic symptoms like anxiety, sweating, and fainting but, at times presents with altered consciousness and 24convulsion. Later features are often confused with cerebral malaria. In pregnant women, it is associated with signs of fetal distress and fetal bradycardia.
 
Respiratory Distress (Acidosis)
Acidosis is defined as arterial or capillary pH below 7.35 or plasma bicarbonate concentration below 15 mmol/L. Usual presentation is labored hyperventilation with retraction of the chest wall but without any localizing chest signs. This is usually due to lactic acidosis particularly in children with cerebral malaria or severe anemia, who are dehydrated and hypovolemic. Persistent respiratory distress has poor prognosis. Raised venous lactic acid above 5 mmol/L also has poor outcome.
 
Circulatory Collapse or Shock (Algid Malaria)
It is defined as systolic blood pressure less than 50 mmHg in children (1–5 years) or less than 80 mmHg in adults. Patients present with listlessness accompanied by cold, clammy skin, and feeble pulse. Recurrent vomiting with loose stool may lead to dehydration and hypovolemia. Following gastrointestinal bleeding or ruptured spleen, the patient may pass into shock stage. Shock is often associated with Gram-negative septicemia, and in every case the source of infection (meningitis, urinary tract infection, indwelling catheters) must be sought.
 
Pulmonary Edema
Pulmonary edema is one of the grave complications of severe malaria but fortunately less common in children. It may develop several days after initiation of treatment even, when 25the parasite level is diminishing. The earliest sign is increase in respiratory rate followed by ominous labored breathing. It is usually due to increased pulmonary capillary permeability but, at times may be due to fluid overload. Radiological sign of “bat wing edema”, may develop. It is particularly dangerous in pregnant women with malaria who may develop suddenly and at time soon after delivery.
 
Abnormal Bleeding and Disseminated Intravascular Coagulation
Fortunately, this complication is rare among immune patients in malaria-endemic areas. Bleeding may be either due to thrombocytopenia or due to disseminated intravascular coagulation (DIC). Thrombocytopenia is common in cerebral malaria and may also occur as a complication of quinine therapy. It may result in petechiae and subconjunctival hemorrhage. The thrombocytopenia is self-limiting and usually improves with successful treatment of malaria.
Disseminated intravascular coagulation causes spontaneous bleeding from various sites, usually seen in patients with cerebral malaria, secondary infection, and malaria in pregnancy. There may be bleeding from gums, epistaxis, or severe gastrointestinal bleeding.
 
Renal Failure
It is defined as serum creatinine more than 3.0 mg/dL or urine volume less than 0.5 mL/kg/hour in children or less than 400 mL in 24 hours in adults, despite normal hydration. This complication is almost exclusively seen in adults and rare in children.26
Acute tubular necrosis is usually the cause of renal failure leading to oliguria and eventually anuria. The presentation may be acute with metabolic acidosis, jaundice, and pulmonary edema. Subacute presentation has better prognosis with gradually rising serum creatinine, oliguria, and never anuria. Patients with subacute presentation are often referred to hospital following clearing of parasitemia. Renal failure is also seen in patients with massive hemolysis with hemoglobinuria.
 
Hemoglobinuria
This is due to acute intravascular hemolysis accompanied by hemoglobinuria. Usually seen in nonimmune people, visiting malaria endemic regions. At times, it is seen in persons taking antimalarial therapy particularly quinine, though the exact reason is not known. Renal failure and hepatic dysfunctions are common in patients with blackwater fever. Hemoglobinuria is also seen in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, treated with primaquine, and other oxidant drugs.
 
Jaundice
Jaundice in malaria is defined as serum bilirubin more than 3 mg/dL or presence of clinical icterus. If present with other signs of severe malaria, then it is of greater significance.
 
Hyperparasitemia
There is no standard agreed definition of hyperparasitemia. In high transmission area, if the proportion of parasitized red cells is 10% or more and in low transmission area the proportion is 5% or more, then it is considered hyperparasitemia.27
Though, hyperparasitemic patients are considered to be at high risk but there is a subgroup of patients, who can tolerate high parasite density. These patients have signs and symptoms of uncomplicated malaria even with high parasite load. Hyperparasitemic patients have two important dangers—firstly, the risk of progression to severe malaria, and secondly, the chances of treatment failure. It has been seen in low transmission areas of Thailand, where mortality rate in uncomplicated malaria is only 0.1% but increases to 3% when parasite density is above 4%.
Treatment failure is more likely in patients with high parasite load with little or low immunity in low transmission areas.
 
MALARIA IN SPECIAL SITUATIONS
 
Malaria in Infants and Children
Severe malaria in infants and young children are not very common as they have some immunity from their mother. In the later part of infancy or early childhood, the acquired immunity declines and at that time, they are not mature enough to develop immunity of their own. If severe malaria occurs in this age group, it is usually fatal. Unlike adults, progression to severe malaria is rapid within a day or two but resolution of coma is also rapid. Common manifestations of severe malaria in children are cerebral malaria, severe anemia, respiratory distress with acidosis, and hypoglycemia. Mortality is high in children in deep coma with acidotic breathing. Jaundice and pulmonary edema are uncommon in children and renal failure is a rare entity. Neurological sequelae following cerebral 28malaria are more frequent in this age group as compared to adults.
Children tolerate antimalarials better than adults but chances of vomiting are high if antimalarials are given during fever. Dose of drugs in malaria should always be on the basis of body weight rather than on age or eye estimates.
Plasmodium vivax, at times results in severe life-threatening malaria in children. Severe P. vivax malaria usually presents with cerebral malaria, severe anemia, splenic rupture, severe thrombocytopenia, and pancytopenia.
 
Malaria in Pregnancy
The manifestations of malaria depend upon the immune status of the pregnant woman. In low transmission area, complications, like pulmonary edema and hypoglycemia, particularly those receiving quinine, are also higher. In high transmission areas, malaria is usually asymptomatic with development of anemia.
The parasites in pregnant women are sequestered in the placenta, thereby interfering with transfer of nutrients to the fetus. The ultimate result is intrauterine growth retardation. They have also increased risk of abortion, stillbirth, and premature delivery. The risk of low birth weight and abortion is more common in primigravida. P. falciparum malaria, particularly at height of fever, induces uterine contraction which may lead to premature labor.
At times, severe malaria may present following delivery, and postpartum bacterial infections in these cases are also common.
Anemia due to malaria may be further aggravated by concurrent iron and folic acid deficiency. Severe anemia during pregnancy not only increases maternal and perinatal 29morbidity and mortality but may lead to severe postpartum hemorrhage.
Pulmonary edema, another common complication in pregnancy associated malaria, may develop suddenly, and soon after separation of placenta.
Hypoglycemia, another common complication, may be associated with signs of fetal distress.
During pregnancy in endemic areas, acquired antimalarial immunity decreases due to alteration in the balance of T helper cells 1 and 2 immune factors. The risk of gestational malaria is more in the first pregnancy as compared to the subsequent pregnancies.
 
Congenital Malaria
In the past, congenital malaria was thought to be a rare event, even though malaria was common in pregnant women in endemic areas. However, recent studies in sub-Saharan Africa revealed that it is not that uncommon as previously presumed. Number of studies done during 2005–2010 shows prevalence ranging from roughly 10% to as high as above 50%. Incidence of congenital malaria in our country is not available, though a number of case reports are there. This wide variation in incidence may be due to the fact that there is no accepted definition of congenital malaria.
The relative rarity of congenital malaria as compared to malaria in pregnancy is due to various reasons as follows.
  • Physical barrier posed by intact placenta to infected RBC
  • Passive transfer of maternal antibodies
  • Hostile environment of fetal RBC for P. falciparum replication.30
 
Definition
Congenital malaria is defined as malaria acquired by the fetus or newborn directly from mother either in utero or during delivery.
Some experts opine that if malaria parasite is detected within 24 hours of birth in a newborn, it should be regarded as congenital malaria. While others extend this period till 7 days after birth. However, many a times the newborn is able to clear the parasite in time without developing overt malaria. Thus, the parasitemia may be cleared without any disease manifestation.
 
Risk Factors for Congenital Malaria
It has been seen that nonimmune mothers in endemic areas (visitors) are more prone to congenital malaria. Similarly, primigravida as compared to multigravida is more at risk. The risk is also increased with the presence of antepartum malaria in mother and placental parasitemia.
 
Mechanism of Transmission
The mechanism and timing of transfer of malaria parasite from mother to the fetus are still obscure. That some in utero transmission occurs, is supported by the fact that, at times newborn develops symptomatic malaria within hours of birth, parasites may be demonstrated in the cord blood and parasites are found in fetal autopsy. The possible mechanism of transmission may be direct penetration through chorionic villi, premature separation of placenta, and physiological transfer of maternal RBC to fetal circulation in utero or at the time of delivery.31
 
Features of Congenital Malaria
Though, cases have been reported soon after birth, typical symptoms develop 10–30 days after birth. Incidentally, half-life of maternal IgG is also the same. Most common presentation is similar to septicemia with fever, anemia, and splenomegaly. Jaundice, particularly conjugated hyperbilirubinemia with hepatomegaly, is another presentation. Other features include poor feeding, drowsiness or restlessness. At times, they can present with recurrent vomiting and loose stool. Point to note is that clinical presentation is nonspecific and may resemble many neonatal diseases. At times, delay in disease presentation, may be attributed to placental transfer of maternal antibodies and hostile environment provided by fetal hemoglobin and low oxygen tension for P. falciparum multiplication.
Most of the cases of congenital malaria in endemic areas are due to P. falciparum, though P. vivax may also be responsible to a lesser extent.
 
Treatment of Congenital Malaria
There is no established recommendation by competent authorities to treat congenital or even neonatal malaria. However, disease in nonimmune setting is a life-threatening emergency needing prompt intervention.
Severe cases of congenital malaria should be managed with either intravenous (IV) quinine or IV artesunate, which has been approved for investigational use by Center for Disease Control and Prevention (CDC). These drugs have been used effectively in older children, hence, adapted for neonates to treat congenital malaria. A study in China comparing the efficacy of artesunate and quinine found that the former is more efficacious than the latter.32
 
COEXISTING MORBIDITIES
 
Human Immunodeficiency Virus Infection
Malaria and human immunodeficiency virus (HIV) share considerable geographic overlap. Thus, there is chance of individuals with HIV and malaria coinfection. HIV-related immunosuppression may lead to manifestations of more severe malaria. There is a chance of treatment failure also.
 
Severe Malnutrition
Severe malnourished patients suffering from malaria may have poor drug absorption due to vomiting, diarrhea, rapid gut transit, and atrophy of bowel mucosa. Even absorption of intramuscular drugs is slower due to poor muscle mass. Various metabolic derangements may lead to altered pharmacokinetic properties of the antimalarial drugs.

Diagnosis of MalariaCHAPTER 5

 
INTRODUCTION
Clinical diagnosis of malaria based on signs and symptoms should be discouraged as it invariably leads to overdiagnosis.
All suspected cases of malaria need a parasitological diagnosis. The rapid diagnostic tests (RDTs) do not need expertise and they are available even in the periphery. However, in complicated malaria or malaria with danger signs, presumptive treatment may be started after collecting blood for examination for confirmation of malaria.
 
MICROSCOPIC DIAGNOSIS
Light microscopy of well stained thick and thin films by a skilled microscopist still remains the “gold standard”, for malaria diagnosis. Thick films are nearly 10 times more sensitive for diagnosis of malaria as larger amount of blood are there in a given area as compared to thin films. Species identification is better with thin films as morphology of the parasites and red blood cells (RBCs) are well preserved.34
 
Collection of Blood Sample
Timing of sample collection should be as soon as malaria is suspected. It can be collected any time irrespective of fever and not necessarily only at the height of fever. Collection should be before administration of antimalarials, as it causes morphologic alteration of parasites which makes diagnosis difficult.
 
Examination of Blood Film
Smears should be prepared as soon as after collection of sample as it enables better adherence of films to the slide and cause minimal distortion of parasites and red cells. In blood collected with anticoagulants, films should be prepared within 2 hours for best results. Thin blood films are made by placing a drop of blood on one end of a slide, and using another slide to draw the blood over the slide's length. The aim is to get a monolayer, where the cells are spaced to be counted and differentiated. The monolayer is found near the edge. An ideal thin film is shown in Figure 5.1. Thick blood films are made by placing a drop of blood on one end of a slide, and using the corner of another slide to spread the drop and make a smear. An ideal thick smear is shown in Figure 5.2. A few poor thick blood smears are shown in Figure 5.3. The ideal technique for blood collection and preparation of thin and thick films are shown in Figure 5.4.
Figure 5.1: Ideal thin blood film.
35
Figure 5.3: Poor thick blood smears.
Figure 5.2: Ideal thick blood smear.
Smear should be examined with 100x oil immersion objective with minimum 100 fields examined before concluding the slide to be negative. Once negative, samples may be examined for at least three consecutive days when clinical suspicion of malaria persists.
Figure 5.5 shows schizont of Plasmodium vivax. Figures 5.6 and 5.7 show early trophozoites of P. vivax and Figure 5.8 shows mature trophozoites of P. vivax. Figure 5.9 shows gametocytes and schizont of P. vivax. Figure 5.10 shows gametocytes of P. vivax. Figure 5.11 shows banana-shaped gametocytes of P. falciparum.3637
Figure 5.4: Technique for blood collection and preparation of thin and thick films.
38
Figure 5.5: Schizont of Plasmodium vivax.
Figure 5.6: Early trophozoites of Plasmodium vivax.
39
Figure 5.7: Early trophozoites of Plasmodium vivax.
Figure 5.8: Mature trophozoites of Plasmodium vivax.
40
Figure 5.9: Gametocytes and schizont of Plasmodium vivax.
Figure 5.10: Gametocytes of Plasmodium vivax.
41
Figure 5.11: Banana-shaped gametocytes of Plasmodium falciparum.
If more than half of the parasites are in tiny ring stage where diameter of the nucleus is less than 50% of the diameter of the rim of the cytoplasm, then it carries a good prognosis. Whereas, if more than 20% of parasites contain visible pigment (mature trophozoites or schizonts) or more than 5% leukocytes and monocytes contain malaria pigment, then it indicates bad prognosis.
 
Advantages of Microscopy
  • A skilled microscopist with proper infrastructure can pick up parasite as low as 5–10 parasites per µL of blood. However, in actual field conditions with limited resources, detection capability reduces to 100 parasites per µL of blood
  • Species identification along with characterization of the stage of parasite is possible by microscopy; it helps in adequate treatment and prognostication42
  • Microscopy has the advantage of determining the parasite density. The parasite load is considered to determine the severity of malaria along with prognosis and assessing the response to treatment
  • In profound anemia, parasites in peripheral blood are often absent but presence of malaria pigment in polymorphonuclear leukocytes (PMNs) and monocytes points out the diagnosis and if more than 5% of PMNs contain visible pigment, then it denotes poor prognosis.
 
Disadvantages of Microscopy
  • Microscopy is time consuming, usually requiring at least 60 minutes from specimen collection to result interpretation. In certain situations, the slides have to be sent to distant central laboratory, and it may lead to delay in starting definitive treatment
  • It needs skilled technicians, good microscope, proper reagents with proper infrastructure which is often unavailable at the peripheral centers. The facility should ideally be available at all times, during weekends, holidays, and at odd hours
  • Microscopy cannot detect parasite sequestered deep in the vascular compartment. In order to avoid misdiagnosis, repeated blood smear examination is needed.
 
RAPID DIAGNOSTIC TESTS
Rapid diagnostic tests are immunochromatographic tests to detect malaria antigens by monoclonal antibodies with the hope that they would offer cheap, rapid, and accurate diagnosis as compared to traditional microscopy. These tests 43have shown limitations in terms of their poor sensitivity with low parasite density, inability to distinguish between different species accurately, and poor robustness in hot and humid tropical countries where malaria is rife. However, they are simple to perform, interpret, and do not require much time and sophisticated devices.
The kit contains antibody labeled with a visually detectable marker. If the targeted antigen is present in the sample then antigen-antibody complex is formed. The labeled complex is immobilized at the predisposed line of antibody capture and is visually detectable. Irrespective of the presence of targeted antigen, the control line will be visible as labeled antibody is captured by the predeposited line of antibody directed against it.
 
Targeted Antigens in Currently Available Rapid Diagnostic Tests
  • Histidine-rich protein II (HRP2) is actively secreted by asexual stages and young gametocytes of Plasmodium falciparum but not by mature gametocytes
  • A metabolic enzyme Parasite lactate dehydrogenase (pLDH) is produced by all four species of plasmodia, both asexual and sexual (gametocytes) stages provided they are viable. Monoclonal antibodies produced against this antigen are of three groups. One specific for P. falciparum and the second specific for Plasmodium vivax. The third is pan-specific antibody which reacts with all the four species of plasmodia, i.e., P. vivax, P. falciparum, P. ovale, and P. malariae, but unable to separate them individually. Commercially available kit can detect P. falciparum, P. vivax, and other 44malaria, but cannot differentiate P. ovale and P. malariae malaria. Point to note that P. ovale and P. malariae are particularly nonexistent in our country
  • Certain new antigens, like Plasmodium aldolase, an enzyme of the glycolytic pathway, produced by all four species has been recently developed.
Currently, commercially available rapid diagnostic tests target the following antigens as shown in Table 5.1.
Different rapid diagnostic tests are available in India as shown in Table 5.2.
In our country, where P. falciparum and P. vivax malaria parasites co-circulate, typically occurring as a single species infection, an RDT which can detect both P. falciparum and P. vivax malaria and distinguish between them is warranted. There are some commercially available kits, which detect P. falciparum specific lactate dehydrogenase (LDH) and pan-specific LDH. So, they can distinguish between falciparum from non-falciparum malaria. Problem with these kits are twofold, firstly they cannot distinguish P. falciparum malaria from mixed infection and secondly as P. vivax malaria is almost the only non-P. falciparum malaria in our country so often they equate non-falciparum malaria with vivax malaria. Also, treatment of P. falciparum and P. vivax malaria is different in our country.
Table 5.1   Rapid diagnostic tests detecting malaria antigens
Species
Antigen
HRP2
pLDH
Aldolase
Plasmodium falciparum-specific
Plasmodium vivax-specific
All species (pan-specific)
HRP2, histidine-rich protein II; pLDH, parasite lactate dehydrogenase.
45
Table 5.2   Currently available rapid diagnostic tests in India
Trade name
Antigens detected
Detection of Plasmodium falciparum
Detection of Plasmodium vivax
Detection of non-falciparum
OptiMAL-IT®
  • pLDH (falciparum-specific)
  • pLDH (pan-specific)
Yes
No
Yes
ParaHIT f®
HRP2
Yes
No
No
SD Malaria
  • HRP2
  • pLDH (pan-specific)
Yes
No
Yes
Falcivax®
  • HRP2
  • pLDH (pan-specific)
Yes
Yes
No
Paramax-3®
  • HRP2
  • pLDH (vivax- specific)
  • pLDH (pan-specific)
Yes
Yes
Yes
Diagnose MALARIA CARD®
  • HRP2
  • pLDH (vivax-specific)
Yes
Yes
No
pLDH, parasite lactate dehydrogenase; HRP2, histidine-rich protein II.
So, RDT which can detect both the species will be helpful.
The World Health Organization has recommended a minimum standard of 95% sensitivity for P. falciparum densities of 100 parasite/mL of blood and a specificity of 95%.46
Rapid diagnostic tests using HRP2 are generally more sensitive than RDTs detecting P. falciparum specific pLDH. P. vivax specific monoclonal antibodies have undergone limited evaluation. Unfortunately, independent peer reviewed evaluation for most commercially available RDTs are not available. In general, with high parasite density these tests are fairly sensitive but with low parasite load, sensitivity decreases often yielding false negative results. False positive result may also develop when gametocytes are present but asexual stage parasites are eradicated by therapy.
Histidine-rich protein II antigens persist at detectable levels for more than 28 days even after successful therapy.
Aldolase and pLDH rapidly fall to undetectable levels after initiation of effective therapy but these antigens are expressed in gametocytes which may appear after clinical infection is cleared. So, none of the RDTs is useful for monitoring the response to treatment for which microcopy is the investigation of choice.
Tests are usually simple without much training requirement, easy to interpret, does not need electricity, and results are available rapidly. The stability of the kit in high environmental temperature and humidity of tropics should be taken into account. Figure 5.12 shows the general procedural steps in RDTs.
 
Role of RDTs in the Diagnosis of Malaria in Our Country
In comparison to high transmission area, malaria in our country occurs less frequently, occurs in all age groups, and is almost always symptomatic. Resistance including multidrug-resistance has started emerging in our country and therefore, laboratory confirmation of malaria is an essential component of disease management.47
Figure 5.12: General procedural steps in rapid diagnostic tests.
48
Also, P. falciparum and P. vivax malaria occurs commonly as a single species infection in nearly equal numbers. The treatment differs in these two types of malaria, hence, confirmation of the species is essential.
Microscopic diagnosis needs expertise and is unavailable in remote parts with poor health infrastructure. So, RDTs will be useful in following situations in our country:
  • In remote areas with poor health infrastructure where microscopic diagnosis is not available. Also, in areas where laboratory service is inadequate, of an unacceptable standard, or not available at odd hours
  • In places where both RDT and microscopy are available, they can complement each other. RDTs will provide screening diagnosis in suspected cases whereas microscopy reserved for resolution of doubtful cases, confirmation of negative results in RDTs with high clinical suspicion of malaria
  • Microscopy may fail to demonstrate parasite due to sequestration in capillaries of the organ whereas RDT can pick up antigen in these cases.
  • According to the National Drug Policy on Malaria (2013), all fever cases clinically suspected of malaria should be investigated for confirmation of malaria by microscopy or RDT.
 
Disadvantages of RDTs in Comparison to Microscopy
  • Rapid diagnostic tests, that target HRP2 of P. falciparum, show antigenemia to persist longer than parasitemia. This 49test is also unsuitable for assessment of treatment failure and monitoring of drug resistance. A newer test that target pLDH, which is elaborated only by live parasite, has the advantage of monitoring treatment. As studies with this test are few they are not recommended at present for monitoring treatment
  • It cannot distinguish new infection from a recent and effectively treated infection
  • As they do not quantify the parasite load so neither they have prognostic value nor they can detect therapeutic efficacy of antimalarial drugs
  • Under optimal conditions, an expert microscopist can detect even 5–10 parasites per µL of blood. Whereas, for all practical purpose detection threshold of RDTs is 40–60 parasites per µL of blood
  • Gametocytes of P. falciparum can persist even after successful chemotherapy which are nonpathogenic. RDTs in such situation will give rise to false positive result with chances of unnecessary treatment.
  • Currently available RDT kits have to be stored at under 30°C. In remote areas without electricity, the temperature often reaches 40°C or more.
So, in conclusion, RDTs permit on the spot confirmation of malaria even at the peripheral health care system by unskilled health worker with minimal training. This will reduce unnecessary treatment based on symptomatic diagnosis, hence in turn, decrease drug pressure.
Other diagnostic methods, namely microscopy using fluorochromes, molecular probes, polymerase chain reaction (PCR), and serology are also available.50
 
OTHER MICROSCOPIC METHODS OF DIAGNOSIS
 
Acridine Orange Staining
Microscopy using acridine orange on blood smear shows differential staining of nuclear material of malaria parasite when viewed under ultraviolet light. This technique is easier and less time consuming as compared to conventional microscopy. However, it requires costly equipments, thus limiting its widespread use in field conditions.
 
Quantitative Buffy Coat Technique
In this method, 55 µL blood sample is taken into a specialized capillary tube containing acridine orange stain and a float. Following centrifugation, the parasitized RBCs get concentrated around the float. The capillary tubes are examined under fluorescent microscope. As more amount of blood is examined, the chance of detecting the parasite is high as compared to conventional microscopy. The advantage of this technique is that it requires less training to operate and is quicker in contrast to conventional microscopy. The disadvantages are that parasite count is not possible, species identification is not accurate, it is expensive, and not possible to do in fields. It can be used for mass screening of large number of samples rapidly.
 
MOLECULAR METHODS OF DIAGNOSIS
 
Molecular Probes
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) probes are used for diagnosis of malaria. Its use in field conditions is impractical.51
 
Polymerase Chain Reaction
This test can also be used for diagnosis of malaria particularly in cases of low parasitemia and mixed infection. This technique is expensive, needs expertise, and time consuming. It is better suited for epidemiological monitoring.
 
SEROLOGY
Antibody detection by this method cannot differentiate between present and past infection and has no utility in routine practice.
Microscopy and RDTs are the mainstay for diagnosis of malaria. The other tests are not suitable for routine disease management and their use is currently for only research and epidemiological purpose.

Antimalarial DrugsCHAPTER 6

 
CHLOROQUINE
Chloroquine is active against all stages of schizonts of the chloroquine-sensitive strains of Plasmodium. It is also gametocytocidal against Plasmodium vivax, P. malariae and P. ovale as well as immature gametocytes of P. falciparum. Chloroquine is inactive against hypnozoites, thus chloroquine alone cannot achieve radical cure of malaria. Due to widespread resistance, chloroquine is not recommended for treatment of P. falciparum infection.
Malaria parasites utilize hemoglobin for production of its amino acids, which in the process releases heme. Free heme is toxic to malarial parasites. Chloroquine acts by interfering with malaria parasite heme detoxification.
Chloroquine is rapidly and almost completely absorbed from gastrointestinal tract following oral administration. The peak concentration is reached within 30 minutes. It is extensively distributed in all body tissues including placenta and breast milk. Chloroquine is metabolized in liver and slowly eliminated from the body through kidneys. The elimination half-life is 1–2 months.53
 
Dose
The total dose for treatment of malaria is 25 mg/kg as base. Initial dose is 10 mg/kg, followed by 5 mg/kg, 6–8 hours later and 5 mg/kg each on the following 2 days. Alternatively, 10 mg/kg of base on the first and second days and 5 mg/kg on the third day. Increasing the dose beyond 25 mg/kg of base does not have any advantage, nor does it benefit in overcoming resistance.
 
Toxicity
Unpleasant taste is a disturbing adverse effect. Pruritus may develop especially in dark-skinned people. Headache, skin eruptions, nausea, vomiting, and diarrhea are less common side effects. Rarely, central nervous system (CNS) toxicity including convulsion, myopathy, reduced hearing, keratopathy, and retinopathy may occur. Aplastic anemia is very rare.
Chloroquine has very low safety margin and is dangerous in overdose. Large doses are used for the treatment of rheumatoid arthritis. Acute overdose, as little as twice the therapeutic dose is very dangerous and death may precipitate within a few hours due to convulsion, hypokalemia, hypotension, and cardiac arrhythmias.
 
Drug Interaction
Antacids reduce the absorption of chloroquine. Its metabolism and clearance are reduced with cimetidine, there is increased risk of acute dystonic reactions with metronidazole, reduced bioavailability of ampicillin and reduced therapeutic effect of thyroxine. There is possible antagonistic effect on antiepileptic drugs like carbamazepine and sodium valproate. There is 54chance of precipitation of cardiac arrhythmia when given along with other drugs that cause prolonged QT interval.
Chloroquine is safe in pregnancy.
 
QUININE
Quinine has potent schizontocidal activity against all malaria species. It is active against gametocytes of all species except P. falciparum. It does not have hypnozoitocidal activity.
Quinine opposes polymerization of hemin into hemozoin, thus interferes with heme detoxification.
Quinine has good oral bioavailability. The peak plasma concentration is reached within 1–3 hours. It is widely distributed throughout the body, crosses the placental barrier and is found in cerebrospinal fluid (CSF). Quinine is metabolized in the liver, mean elimination half-life about 11 hours and excreted in urine.
 
Dose
 
Oral
Quinine as 10 mg/kg salt three times daily for 7 days. It should be combined with a single dose of sulfadoxine-pyrimethamine or tetracycline or doxycycline or clindamycin.
 
Parenteral
In severe malaria, quinine should be given as 10 mg/kg salt by slow intravenous infusion in 5% dextrose slowly over 4 hours and repeated every 8 hourly, till the person is able to take oral quinine and continued as mentioned above. A loading dose of 20 mg/kg is recommended for severe and complicated malaria, 55but should be avoided if there is history of intake of quinine or mefloquine or halofantrine in the past 24 hours.
 
Toxicity
Hypoglycemia is common; hence, blood sugar should be frequently monitored. Repeated quinine administration causes cinchonism characterized by tinnitus, headache, nausea, and visual impairment.
Even a single high dose of quinine of more than 3 g is capable of causing potentially fatal intoxication like CNS depression, seizure, dysrrhythmia, hypotension, cardiac arrest, and blindness.
 
Drug Interaction
Quinine increases plasma concentration of digoxin. Cimetidine inhibits quinine metabolism, rifampicin increases clearance and decreases plasma concentration of quinine. There is risk of precipitation of cardiac arrhythmia when given along with other drugs that cause prolonged QT interval. Quinine is safe in pregnancy.
 
ARTEMISININ AND ITS DERIVATIVES
Artemisinin derivatives are potent and rapidly acting blood schizontocidal drug. They act on all stages of parasites including gametocytes, trophozoites, and schizonts. It is devoid of hypnozoitocidal action.
All the derivatives are metabolized to the bioactive metabolite dihydroartemisinin. Hemozoin of Plasmodium catalyzes decomposition of the labile peroxide bridge in 56artemisinin compounds. Free oxygen radicals released from the reaction are toxic to the parasite membrane.
Various derivatives are well absorbed following oral or parenteral administration. Peak plasma concentration occurs around 3 hours after administration and the elimination half-life is around 1 hour.
 
Dose
As mentioned in the chapter on Treatment of Severe and Complicated Malaria.
 
Toxicity
All the artemisinin derivatives are safe and well tolerated. Gastrointestinal disturbances, dizziness, tinnitus, neutropenia, and elevated liver enzymes are occasional adverse effects. Type 1 hypersensitivity, though rarely seen is the only potential serious side effect.
 
Drug Interaction
No drug interactions are known.
 
PRIMAQUINE
Primaquine is active against gametocytes of all malaria species and against hypnozoites of P. vivax and P. ovale. It is used for prevention of relapse.
It acts by damaging the parasite mitochondria.
Primaquine is given orally; it is well absorbed and metabolized in liver. Peak plasma concentration occurs within 1–3 hours.57
 
Dose
Primaquine may be given concurrently with antimalarials from the first day. Dose is 0.3 mg/kg body weight for 14 days in P. vivax malaria. Ideally glucose-6-phosphate dehydrogenase (G6PD) deficiency should be excluded before starting primaquine as anti-relapse therapy. In case of borderline G6PD deficiency, once weekly dose of primaquine 0.6–0.8 mg/kg is given for 6 weeks. In P. falciparum malaria a single dose of 0.75 mg/kg is given to eliminate residual gametocytes.
 
Toxicity
Hemolytic anemia in patients with G6PD deficiency is the most important adverse effect, it is usually self-limiting. Overdosage may cause leukopenia, agranulocytosis, hemolytic anemia, and methemoglobinemia. Minor side effects include gastrointestinal disturbances.
 
Drug Interaction
It should not be administered with other drugs that induce hematological disorders like sulfadoxine-pyrimethamine and chloramphenicol.
 
SULFADOXINE-PYRIMETHAMINE
Sulfadoxine-pyrimethamine is used in fixed-dose combination of 20 parts sulfadoxine to 1 part pyrimethamine. It is schizontocidal for P. falciparum and weakly schizontocidal against P. vivax. It does not have any hypnozoitocidal or gametocytocidal activity.58
Sulfadoxine-pyrimethamine targets folate metabolism by the parasites. This synergistic combination acts against the parasite-specific enzyme dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR).
Both the drugs are readily absorbed from gastrointestinal tract. They are highly bound to plasma protein and have long plasma elimination half-life of about 100 hours. The drugs cross the placental barrier and are also detected in breast milk.
 
Dose
The sulfadoxine-pyrimethamine combination is recommended as a single dose therapy calculated as 1.25 mg/kg of pyrimethamine and 25 mg/kg of sulfadoxine.
 
Toxicity
Single dose sulfadoxine-pyrimethamine is generally well tolerated. Serious hypersensitivity may occur in persons allergic to sulfa drugs. Stevens-Johnson syndrome and toxic epidermal necrolysis are rarely seen.
 
Drug Interactions
Coadministration of sulfadoxine-pyrimethamine with other folate antagonists like phenytoin, cotrimoxazole, and methotrexate may cause bone marrow depression.
 
MEFLOQUINE
Mefloquine is active against blood schizonts of all plasmodia and particularly against drug-resistant P. falciparum. It does not have any gametocytocidal activity and is ineffective against the hepatic phases of malaria parasite.59
It binds with hemin and interferes with heme detoxification.
Mefloquine is well absorbed orally but there is marked individual variation in achieving peak plasma concentration. Mefloquine reaches higher serum levels in acute falciparum malaria, probably due to contraction of apparent volume of distribution. It is metabolized in liver and it has long elimination half-life of about 21 days.
 
Dose
Dose consists of 15-25 mg/kg of mefloquine base. Bioavailability is better with 25 mg/kg, but tolerance is poor. Bioavailability is also increased, if taken with food, and drinking water before drug administration.
For chemoprophylaxis, 5 mg/kg of mefloquine base weekly.
 
Toxicity
Minor side effects like nausea, vomiting, abdominal pain, diarrhea, headache, loss of balance, and sleep disorders like insomnia and abnormal dreams are common. CNS disturbances like seizure, encephalopathy, and psychosis are rare adverse effects. Other rare side effects are skin rashes, pruritus, liver function abnormalities, and cardiovascular effects like postural hypotension, bradycardia, and palpitation.
 
Drug Interaction
Mefloquine should not be administered within 12 hours of the last dose of quinine. Concomitant administration of mefloquine with quinine, quinidine, or chloroquine may cause electrocardiogram (ECG) abnormalities and increased risk of convulsion.60
There is increased chance of arrhythmia if mefloquine is given together with beta blockers, calcium channel blockers, digoxin or antidepressants.
 
LUMEFANTRINE
Lumefantrine is co-formulated along with artemether and is a component of artemisinin-based combination therapy (ACT) which is highly effective against multidrug-resistant P. falciparum. Tablets contain 20 mg artemether and 1,120 mg lumefantrine.
Lumefantrine has similar mechanism of action as quinine and mefloquine.
It is available only in oral form. Absorption increases after a meal. Peak plasma level occurs 10 hours after administration and elimination half-life is about 3 days.
Lumefantrine is well tolerated. It does not prolong QT interval significantly.
 
TETRACYCLINE
Tetracycline is potent against asexual blood stages of all plasmodia species. It also acts against primary intrahepatic stages of P. falciparum.
Absorption of tetracycline from the gut is poor. It is further decreased if milk, milk products or calcium, iron, aluminum, and magnesium salts are taken along with.
 
Dose
Tetracycline is given along with quinine. A dose of 250 mg or 4 mg/kg/dose tetracycline is given four times daily for 7 days. It should not be given in children less than 8 years and pregnant women.61
 
Toxicity
The most common are gastrointestinal side effects like abdominal discomfort, nausea, vomiting, and diarrhea. Dry mouth, glossitis, dysphagia, and esophageal ulceration may occur. Tetracyclines accumulate in patients with renal impairment and it may lead to renal failure. Pre-existing systemic lupus erythematosus may get worsened with the use of tetracycline. Hypersensitivity, fixed drug eruption, drug fever, hemolytic anemia, and photosensitivity may develop.
Tetracycline should not be given to pregnant women, lactating mothers, and children up to 8 years of age.
 
Drug Interaction
Tetracycline absorption is reduced if given with aluminum, zinc, iron, magnesium, calcium, and bismuth. Thus, antacids, calcium compounds, iron preparations, and dairy products should be avoided. Tetracycline increases plasma concentration of digoxin and theophylline. It antagonizes the action of penicillins.
 
DOXYCYCLINE
Doxycycline is an oxytetracycline derivative and has identical spectrum of activity. It is often preferred to tetracycline due to its longer half-life, better absorption, and better safety profile. The peak plasma concentration is achieved 2 hours after administration and half-life is 10–24 hours.
 
Dose
Along with quinine, doxycycline is given 3.5 mg/kg body weight once daily for 7 days. It should not be given to children 62below 8 years age. The dose for prophylaxis is 100 mg/day for adults and 1.5 mg/kg/day for children to be started 1 week before departure and continued for 4 weeks after return.
 
Toxicity
Compared to tetracycline, the safety profile of doxycycline is better. Doxycycline should not be given to pregnant women, lactating mothers, and children up to 8 years age.
 
Drug Interactions
Antacids and iron affect absorption. Metabolism is accelerated by phenytoin, phenobarbitone, rifampicin, and carbamazepine.
 
CLINDAMYCIN
Clindamycin is a slow-acting but effective blood schizontocide. It has got good oral bioavailability.
It can be used as an add-on drug and it can be used in pregnant women and children.
 
Dose
Along with quinine, clindamycin is given 20 mg/kg body weight in two divided doses for 7 days. It should be taken along with food and copious amount of water.
 
Toxicity
Pseudomembranous colitis caused by Clostridium difficile is the most serious adverse effect. Minor gastrointestinal effects may occur.63
 
Drug Interaction
Clindamycin may enhance the effects of drugs with neuromuscular blocking activity.
 
RESISTANCE TO ANTIMALARIAL DRUGS
Antimalarial drug resistance is defined as the ability of a parasite strain to survive and/or multiply despite proper administration and absorption of an antimalarial drug in the dose normally recommended.
The greatest problem with drug resistance occurs with Plasmodium falciparum (P. falciparum) infection. Drug resistant P. falciparum infection is of great concern because of the following:
  • Potential of P. falciparum to cause severe infection
  • Potential to cause epidemics
  • Increasing disease burden of P. falciparum
  • The cost of replacement drugs.
There are no tests available for detection of susceptibility of malaria parasites to antimalarial drugs. Monitoring the disease is the key to determine geographical trends in susceptibility and also emergence and spread of drug resistance.
Antimalarial drug resistance and treatment failure are not synonymous. Drug resistance may lead to treatment failure, but not all treatment failures are caused by drug resistance. Treatment failure on the other hand may be due to incorrect dosing, improper adherence and drug compliance, poor absorption of the drug, interaction with other drugs, poor quality of the drug, and misdiagnosis. All these factors may aid in spreading drug resistance.64
 
Spread of Drug Resistance
The initial part of development of resistance is the genetic event which produces the resistance strain. Subsequently, the selection process leads to preferential transmission of resistant mutant strains and thus, spread of resistance.
Factors determining the propensity of resistance of antimalarial drugs are as follows:
  • The frequency of genetic change that is intrinsic to the drug
  • The degree of genetic change as a result of the genetic change
  • Pharmacokinetic and pharmacodynamic properties of the antimalarial drug
  • Number of parasites exposed to the drug and the concentration of the drug to which the parasites are exposed
  • The selection-proportion pressure of all transmissible infections that are exposed to the drug
  • Dosing, duration, and adherence of the individual pattern of drug use
  • Quality, availability, and distribution of the drug in the community
  • The immunity profile of the community and the individual
  • The cost of resistance mechanism
  • Simultaneous presence of other antimalarial drugs or substances in the blood to which the parasite is not resistant.
 
Transmission Intensity and Spread of Resistance
Resistance is propagated following recrudescence and subsequent transmission of an infection that has generated a de novo resistant malaria parasite. Gametocytes carrying resistance gene will not reach transmissible densities until the resistant biomass has expanded to numbers close to producing illness. Thus, to prevent resistance spreading from an infection that has generated 65a de novo resistance, gametocyte production from the recrudescent resistant infection must be prevented.
In low transmission areas, the majority of malaria infections are symptomatic. Relatively large number of parasites in an individual encounter antimalarials at concentrations that are maximally effective. But, in a proportion of patients, the blood concentrations are low and may select for resistance.
In high transmission areas, the majority of infections are asymptomatic. Symptomatic and sometimes fatal malaria occurs in the first year of life; thereafter, it is likely to be asymptomatic. This reflects a state of imperfect immunity. Immunity considerably reduces emergence of resistance.
The genetic vents that produce antimalarial drug resistance are spontaneous and rare. They are independent of the drug use.
 
Prevention of Resistance
Various diseases, like tuberculosis, leprosy, and human immunodeficiency virus, are treated by combination therapy and the same theory has been applied to malaria as well. When two drugs with different mechanism of action are used in combination, then the probability of developing resistance is much less than when a single drug is used.66

Treatment of Uncomplicated MalariaCHAPTER 7

 
INTRODUCTION
Malaria parasite develops resistance to drugs randomly due to de novo genetic mutations. As nonimmune patients of our country are infected with large number of parasites, if they receive inadequate treatment, they are a potent source of de novo resistance. Here lies the importance of prescribing highly effective treatment regimen in high parasitemic patients and ensuring good adherence to prescribed drugs.
It has been noted that monotherapy in case of falciparum malaria invariably results in failure. Sulfadoxine-pyrimethamine introduced following chloroquine resistance quickly developed resistance in the early 1980s. Whereas, mefloquine introduced as monotherapy for falciparum malaria took only 4–5 years to report resistance.
So, to counter the threat of resistance of falciparum to monotherapies, World Health Organization (WHO) recommends combinations of antimalarials for the treatment of falciparum malaria.68
 
STATUS OF DRUG RESISTANCE IN INDIA
In India, first reports of resistance of Plasmodium falciparum to chloroquine came from Diphu of Karbi Anglong district in Assam state. Thereafter, it started spreading throughout the country.
Reports of resistance to sulfadoxine-pyrimethamine at various levels in district of seven northeastern states of our country are there.
Though, a few reports of emergence of chloroquine-resistant P. vivax are there but the drug still retains its effectivity against vivax malaria in our country.
 
ANTIMALARIAL COMBINATION THERAPY
To improve treatment outcome and halt the threat of resistance to monotherapy, WHO recommends combination therapy for the treatment of falciparum malaria. Antimalarial 69combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent mode of action and thus different biochemical target in the parasite.
If two drugs, with different mode of action, and hence different resistance mechanism, are used in combination then the probability of developing resistance to both drugs is the product of their individual per parasite probabilities. If a mutant parasite develops de novo resistance during the course of infection to one drug, it will be killed by the other drug. However, to reap the benefit of combination therapy, the partners in the combination should be individually effective. This mutual protection will prevent or at least delay emergence of resistance to individual drugs. The only disadvantage of combination therapy is increased risk of adverse effect and increased cost of therapy.
According to WHO, one of the partners in combination therapy will be artemisinin, and its derivatives, hence known as artemisinin-based combination therapy (ACT). The reason for choosing artemisinin is its rapid clearance of parasitemia and resolution of symptoms. They reduce the parasite number by approximately 10,000 fold (104) in each asexual cycle. The second important reason is its rapid elimination from the body so that the residual concentration of the drug does not provide a selective filter for resistant parasites. The other reasons being its lack of serious adverse effects, absence of significant resistance till date, and reducing gametocyte carriage due to its gametocytocidal action.
Artemisinin if combined with other rapidly eliminated antimalarials like tetracycline or clindamycin, a 7 days course of treatment is required. This long course invariably results in poor adherence. But when combined with slowly eliminated antimalarials like sulfadoxine-pyrimethamine, mefloquine or lumefantrine, shorter courses of treatment (3 days) will be effective, and also ensure adherence.
In three days ACT regimen, artemisinin is present in the body during the two asexual parasite life cycles, each lasting for 2 days. This treatment reduces the number of parasites in the body by a factor of approximately one hundred million (104 × 104 = 108). The complete clearance of the parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentration until all the infecting parasites have been killed. Thus, the partner compound is to be relatively slowly eliminated.70
As a result of combination therapy, the artemisinin component is protected from resistance by the partner medicine, provided it is efficacious and partner medicine is in turn protected by the artemisinin derivative.
The following artemisinin-based combination therapies are currently available in our country:
  • Artesunate plus sulfadoxine-pyrimethamine
  • Artesunate plus mefloquine
  • Artemether-lumefantrine.
Of these artemether-lumefantrine is available as co-formulated tablets and liquid preparation and lumefantrine is not available as monotherapy. So, it has been never used alone for the treatment of malaria. Other combinations are available separately.
 
TREATMENT REGIME OF UNCOMPLICATED MALARIA
The ultimate goal of treating uncomplicated malaria is to cure the infection, so that, it does not progress to severe disease or to avoid the morbidity of treatment failure. At the same time, care should be taken that the infection does not transmit to others, and emergence or spread of resistance to antimalarial drugs is to be prevented.
Antimalarial drugs are to be used following parasitological confirmation otherwise indiscriminate use or use with clinical diagnosis alone will increase the drug pressure and favor resistance. Plasmodium falciparum malaria particularly in children can be rapidly progressive, hence, they need constant monitoring. However, their symptoms resolve more quickly following successful treatment and they can tolerate antimalarial drugs better as compared to adults.71
Treatment regimens are to be tailored specifically according to the resistance pattern of the region under consideration. However, in view of gradually increasing resistance, it has been decided that all falciparum cases should be treated with ACT both in public or private health care system to win the war against ongoing drug resistance. All cases of mixed infection, i.e., P. vivax and P. falciparum, are to be treated as falciparum malaria along with primaquine for 14 days.
Treatment regimens are to be tailored specifically according to the resistance pattern of the region under consideration (Tables 7.1 to 7.3).
Table 7.1   Recommended treatment of uncomplicated Plasmodium vivax malaria
Recommended treatment
  • Chloroquine 10 mg base/kg stat orally followed by 5 mg/kg at 6, 24, and 48 hours (total dose 25 mg/kg)
or
  • Chloroquine 10 mg base/kg stat orally followed by 10 mg/kg at 24 hours and 5 mg/kg at 48 hours. (total dose 25 mg base/kg)
  • Primaquine should be given in a dose of 0.25 mg/kg once daily for 14 days to prevent relapse
Chloroquine should not be given empty stomach and in high fever. Temperature should be brought down first. If vomiting occurs within 45 minutes of a dose of chloroquine that particular dose is to be repeated after taking care of vomiting by using antiemetic (domperidone/ondansetron).
As primaquine can cause hemolytic anemia in children with glucose-6-phosphate dehydrogenase (G6PD) deficiency, they should be preferably screened for the same prior to starting treatment. As infants are relatively G6PD-deficient, it is not recommended in this age group and children with 14 days regimen should be under close supervision to detect any complication. In cases of borderline G6PD deficiency, once weekly dose of primaquine 0.6–0.8 mg/kg is given for 6 weeks.
72
Table 7.2   Recommended treatment of uncomplicated Plasmodium falciparum malaria in all states other than north-eastern states of India
Recommended treatment
  • Artesunate 4 mg/kg of body weight orally once daily for 3 days and a single administration of sulfadoxine-pyrimethamine as 25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine on day 1
or
  • Artesunate as above and mefloquine 8.3 mg/kg of body weight once daily for 3 days
or
  • Co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine can be used as a 6 dose regimen orally twice a day for 3 days. For 5–14 kg body weight, one tablet at diagnosis, again after 8–12 hours and then twice daily on day 2 and day 3. For 15–24 kg body weight, same schedule with two tablets. For 25–35 kg body weight and above, same schedule with three and four tablets respectively
  • A single dose of primaquine (0.75 mg/kg) is given for gametocytocidal action
  • However according to WHO in low transmission areas a single dose of primaquine 0.25 mg/kg of body weight will suffice. It should not be given in pregnant women, infants below 6 months and women breastfeeding infants below 6 months
Mefloquine shares cross-resistance with quinine which is still an effective drug in our country. Health planners of our country do not advocate use of mefloquine
Advantage of artemether-lumefantrine combination is that lumefantrine is not available as monotherapy and has never been used alone for the treatment of malaria. Lumefantrine absorption is enhanced by coadministration with fatty food like milk
Artemether-lumefantrine has not been studied extensively in patients above 65 years or children weighing less than 5 kg, so these patients should be monitored closely.
 
Treatment of Plasmodium vivax Malaria
Though, there are some stray reports of chloroquine (CQ)-resistant P. vivax infection but CQ is still, the drug of choice for P. vivax malaria.73
Table 7.3   Recommended treatment of uncomplicated Plasmodium falciparum malaria in north-eastern states of India
Recommended treatment
  • Co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine can be used as a six dose regimen orally twice a day for 3 days. For 5–14 kg body weight, one tablet at diagnosis, again after 8–12 hours and then twice daily on day 2 and day 3. For 15–24 kg body weight, same schedule with two tablets. For 25–35 kg body weight and above, same schedule with three and four tablets respectively
or
  • Artesunate 4 mg/kg of body weight orally once daily for 3 days and mefloquine 8.3 mg/kg of body weight in two divided doses (15 mg/kg and 10 mg/kg) on day 2 and day 3
  • A single dose of primaquine (0.75 mg/kg) is given for gametocytocidal action
  • However according to WHO in low transmission areas a single dose of primaquine 0.25 mg/kg of body weight will suffice. It should not be given in pregnant women, infants below 6 months and women breastfeeding infants below 6 months
Mefloquine shares cross-resistance with quinine which is still an effective drug in our country. Health planners of our country do not advocate use of mefloquine
Advantage of artemether-lumefantrine combination is that lumefantrine is not available as monotherapy and has never been used alone for the treatment of malaria. Lumefantrine absorption is enhanced by coadministration with fatty food like milk
Artemether-lumefantrine has not been studied extensively in patients above 65 years or children weighing less than 5 kg, so these patients should be monitored closely.
According to National Vector Borne Disease Control Programme and National Institute of Malaria Research, CQ should be used in full therapeutic dose of 25 mg/kg divided over 3 days.74
 
Treatment of Uncomplicated Plasmodium falciparum Malaria
One of the major problems in the successful treatment of malaria is the development of resistance of P. falciparum to the first-line drug CQ in most of the areas of our country. The first incidence of CQ resistance, the cheapest, and the most used drug, was reported from Diphu of Karbi Anglong district of Assam in the year 1973. Thereafter, there is relentless spread of resistance throughout the country. The directorate of National Vector Borne Disease Control Programme under the Ministry of Health and Family Welfare, Government of India, has been monitoring the response of antimalarial drug in P. falciparum malaria in the country since 1978. Chloroquine resistance has been reported from 80 districts of 21 states of India which includes 113 primary health centers.
Plasmodium falciparum has developed resistance to almost all antimalarials currently used (CQ, SP, mefloquine, quinine, and amodiaquine), except artemisinin and its derivatives. Widespread and indiscriminate use of antimalarials places a strong selective pressure on the parasite favoring development of resistance. According to World Health Organization, resistance can be prevented or at least its onset delayed by combining different antimalarials with different mode of action and ensuring high cure rates through full adherence to correct dose regimens.
 
MONITORING OF UNCOMPLICATED MALARIA
As per WHO guideline to detect different grades of resistance, patients should be followed up for 28 days, which is difficult and at times practically not possible.75
Subsequently, WHO developed a new system of monitoring with follow-up for 14 days, where both clinical and parasitological assessment was done. Parasitological assessment should include detection of malaria parasite, species determination, and parasite density measurement. Patient should also be assessed clinically with examination of body temperature.
Reappearance of parasite in the blood indicates reduced parasite sensitivity to the treatment drug. Considerable number of treatment failures, that appear after day 14, so shorter period of observation will lead to significant overestimation of the efficacy of the tested antimalarial. This is particularly seen in areas with low failure rate and low level of resistance like India. So, the current recommendation to assess the in vivo therapeutic efficacy of antimalarials is to follow-up the cases for 28 days.
Microscopy should be done at day 0, before initiation of treatment, day 2, day 3, day 7, day 14, day 21 and day 28, if not indicated more frequently. Parasite count of day 0 is taken as 100% for that particular patient.
The following are the categories of treatment failure.
 
Early Treatment Failure
The patient is classified as early treatment failure under the following situations:
  • Development of danger sign or severe malaria on day 1, day 2, or day 3 in presence of parasitemia
  • Axillary temperature more than or equal to 37.5°C on day 2 with parasite count greater than on day 0
  • Axillary temperature more than or equal to 37.5°C on day 3 in presence of parasitemia76
  • On day 3 irrespective of axillary temperature, parasite count is greater than or equal to 25% of that of day 0.
 
Late Treatment Failure
Patient will be classified as late treatment failure under following situations:
  • Development of danger sign or severe malaria on any day between day 4 and day 28 in the presence of parasitemia
  • Axillary temperature more than or equal to 37.5°C in presence of parasitemia on any day from day 4 to 28.
Danger signs of malaria:
  • Not able to drink or breast-feed
  • Vomiting everything
  • Recent history of convulsion
  • Lethargic or unconscious state
  • Unable to sit or stand up.
The parent/guardian should be instructed to bring the child to the doctor, if the patient develops any of the danger signs during the follow-up.
So, from practical point of view the therapeutic response is taken as adequate if the patient shows clinical improvement without parasitemia from day 3 onward. In day-to-day practice, where repeated blood examination is not possible, resistance should be suspected in spite of full treatment and no history of vomiting or diarrhea, if patient does not respond parasitologically within 72 hours. If the patient shows therapeutic failure, then he/she should be given alternative therapy as guided in the treatment failure section.
If follow-up smear is not possible, in clinical follow-up by day 5 after the initial treatment, if there is no clinical 77improvement, a blood smear is to be repeated. In case, it is positive, then start alternative therapy. Development of danger signs on any day is also an indication to revise treatment.

Management of Treatment FailureCHAPTER 8

 
INTRODUCTION
Recurrence of Plasmodium falciparum malaria is due to either a reinfection or a recrudescence that is treatment failure. In a patient it may not be possible to distinguish either. If fever and parasitemia fail to resolve or recur within 2 weeks of treatment then it is considered treatment failure.
 
CAUSES OF TREATMENT FAILURE
  • Poor adherence
  • Inadequate drug: Underdosing, vomiting, interaction with other drugs
  • Drug resistance
  • Substandard medicine.
The first two conditions may be elicited from proper history of the patient.
Ideally, treatment failure must be confirmed parasitologically preferably by microscopic or LDH based RDTs examination. Rapid diagnostic tests (RDTs) such as Plasmodium falciparum histidine-rich protein 2 (PfHRP2) may remain 79positive for weeks after the initial infection, hence, they should be monitored.
 
FAILURE WITHIN 28 DAYS
Recommended second line ACT treatment effective in the region may be used.
The choice of second-line drugs depends on the initial therapy.
  • If artesunate was given initially—quinine plus tetracycline or doxycycline or clindamycin (given for total 7 days)
  • This treatment should be directly observed otherwise it may result in poor adherence
  • An alternate artemisinin-based combination therapy known to be effective in the region may be given.
 
FAILURE AFTER 28 DAYS
Reappearance of fever and parasitemia more than 4 weeks after successful treatment is either due to recrudescence or from a new infection. The distinction between the two could be made through parasite genotyping by polymerase chain reaction. But for practical purposes all treatment failures after 28 days of initial treatment should be considered as new infection, and should be treated with first-line ACT. It has to be remembered that reuse of mefloquine within 60 days of first treatment may be associated with an increased risk of neuropsychiatric problems. In patients where mefloquine was used initially, the second-line treatment should not contain mefloquine.80

Treatment of Severe and Complicated MalariaCHAPTER 9

 
INTRODUCTION
Severe life-threatening malaria is nearly always due to Plasmodium falciparum. All cases with severe manifestations are to be treated in the same line of complicated malaria with injectable antimalarials irrespective of the species.
High degree of suspicion of severe malaria is of utmost importance and any delay in initiation of treatment can be fatal. It should be treated as a medical emergency at highest level of medical facility available preferably in an intensive care setting. Confirmation of the diagnosis is preferable but one should not delay the treatment, if it needs more than 1 hour. Further in cases of strong clinical suspicion prompt antimalarial therapy is needed even if parasites are not found in the initial blood examination.
Effective therapy in children with severe malaria includes antimalarial chemotherapy, supportive management, and management of complications. All these three interventions are equally important and to be taken care of simultaneously.82
 
ANTIMALARIAL CHEMOTHERAPY OF SEVERE AND COMPLICATED MALARIA (Table 9.1)
Ideally, antimalarial drug should be given initially by intravenous (IV) infusion, which should be replaced by oral administration as soon as condition permits.
Antimalarials should be given according to the body weight of the patient. If parenteral injection is not possible, referral is likely to be delayed, and artemisinin is not available as suppository form, crushed antimalarial may be given by nasogastric tube.
Table 9.1   Recommended treatment of complicated and severe malaria
Drug
Dosage
Quinine salt
20 mg salt/kg (loading dose) diluted in 10 mL of isotonic fluid/kg by infusion over 4 hours. Then give a maintenance dose of 10 mg salt/kg every 8 hours, calculated from beginning of previous infusion, until the patient can swallow, then quinine tablets, 10 mg salt/kg 8 hourly to complete a 7-day course of treatment (including both parenteral and oral). Tetracycline or doxycycline or clindamycin is added to quinine as soon as the patient is able to swallow and should be continued for 7 days. Tetracycline (above 8 years) or doxycycline (above 8 years) to be given for 7 days 4 mg/kg/dose four times daily or 3.5 mg/kg once a day respectively. Clindamycin to be given 20 mg/kg/day in two divided doses for 7 days. If controlled intravenous (IV) infusion cannot be administered then quinine salt can be given in the same dosages by intramuscular (IM) injection in the anterior thigh (not in buttock). The dose of quinine should be divided between two sites, half the dose in each anterior thigh. If possible IM quinine should be diluted in normal saline to a concentration of 60–100 mg salt/mL (Quinine is usually available as 300 mg salt/mL). Tetracycline or doxycycline or clindamycin should be added as above
or83
Artesunate (2.4 mg/kg) IV stat then at 12 and 24 hours, then once a day. Once the patient is able to swallow oral medication, complete the treatment by giving a course of:
  • Artemether plus lumefantrine in northeastern states as shown in Table 7.3
  • Artesunate plus sulfadoxine-pyrimethamine in all states other than northeastern states of India as shown in Table 7.2
or
Artemether (3.2 mg/kg) (loading dose) IM, followed by 1.6 mg/kg daily. Once the patient is able to swallow oral medication, complete the treatment by giving a course of:
  • Artemether plus lumefantrine in northeastern states as shown in Table 7.3
  • Artesunate plus sulfadoxine-pyrimethamine in all states other than northeastern states of India as shown in Table 7.2
  • According to WHO children weighing less than 20 kg should receive higher dose of artesunate (3 mg/kg/dose) whereas, children above 20 kgs and adults should receive 2.4 mg/kg/dose
  • Parenteral therapy with artesunate should be continued for at least 24 hours and this may be followed by oral therapy if the patient is able to tolerate it
Parenteral treatment in severe malaria should be continued at least for 24 hours irrespective of patient's ability to tolerate oral medication earlier than 24 hours
Loading dose of quinine should not be used if the patient has received quinine, quinidine, or mefloquine within the preceding 12 hours. Alternatively, loading dose can be administered as 7 mg salt/kg by IV infusion pump over 30 minutes, followed immediately by 10 mg salt/kg diluted in 10 mL isotonic fluid/kg by IV infusion over 4 hours
Quinine should not be given by bolus or push injection. Infusion rate should not exceed 5 mg salt/kg/hour
If there is no clinical improvement after 48 hours of parenteral therapy, the maintenance dose of quinine should be reduced by one-third to one-half, i.e., 5–7 mg salt/kg.
Quinine should not be given subcutaneously as this may cause skin necrosis
Artesunate (60 mg/ampoule) is dissolved in 0.6 mL of 5% sodium bicarbonate diluted to 3–5 mL with 5% dextrose and given immediately by IV bolus (push injection)
Artemether is dispensed in 1 mL ampoule containing 80 mg of artemether in peanut oil
Mefloquine should be avoided in cerebral malaria due to neuropsychiatric complications associated with it.
84It has the risk of causing vomiting and may produce inadequate drug levels in the blood.
According to the National Anti-Malaria Programme (NAMP), in all cases of severe malaria, either IV quinine or parenteral artemisinin derivatives are to be given irrespective of chloroquine resistance status.
 
CHOICE OF THERAPY
Artemisinin are the most rapidly acting of all known antimalarial drugs, they often produce a 10,000 fold reduction of parasites per asexual cycle. They have the broadest time window of antimalarial effects from ring forms to early schizonts. Thus, they can stop parasite maturation, particularly from the less pathogenic circulating ring stages to the more pathogenic cytoadherent stages.
Artemisinin also have an excellent safety profile and the cost of therapy as compared to quinine is almost similar. There are no reports of resistance to artemisinin at present but declining sensitivity to quinine has been reported from some Southeast Asian countries like Thailand.
Randomized trials comparing artesunate and quinine from Southeast Asia show clear evidence of benefit with artesunate.
However, artemisinin should definitely be used when rate controlled IV infusion of quinine is not possible, patients have contraindications to quinine use, and evidence of inadequate response or resistance to quinine noted. Simultaneous use of quinine and artemisinin is not indicated as it may be harmful and there is no added advantage. In limited studies available, artesunate has been found to be better than artemether.85
 
SUPPORTIVE MANAGEMENT
  • Rapid clinical assessment with respect to level of consciousness, blood pressure, respiratory rate and depth, anemia, hydration, and temperature
  • Thick and thin blood films should be examined. Minimal investigation should include packed-cell volume (PCV) (hematocrit), blood glucose, and lumbar puncture especially in cerebral malaria. If lumbar puncture is delayed proper antibiotic cover for meningitis must be given. Antibiotics may also be considered if any secondary infection is suspected, which is common in severe malaria. Start IV antimalarial after drawing blood sample
  • Good nursing care with proper positioning, meticulous attention to airways, eyes, mucosa, and skin should be done. Appropriate fluid therapy is to be maintained
  • For unconscious child nasogastric tube is to be inserted to reduce the risk of aspiration
  • Oxygen therapy and respiratory support should be given if necessary
  • Resuscitation with normal saline or Ringer's lactate by bolus infusion in patients with shock. Underhydration or overhydration should be avoided
  • Convulsion should be treated with appropriate anticonvulsants
  • Hyperpyrexia should be treated with tepid sponging, fanning and paracetamol
  • Close monitoring of the vital signs preferably every 4 hours to be done till the patient is out of danger. Also, maintain intake output chart, and watch for hemoglobinuria86
  • Monitoring of the response to treatment is essential. Detail clinical examination with particular emphasis on hydration status, temperature, pulse, respiratory rate, blood pressure, and level of consciousness is to be done regularly. Blood smear examination every 6–12 hours for parasitemia during first 48 hours is needed
  • In case of quinine, parasite count may remain unchanged or even rise in first 18–24 hours which should not be taken as an indicator of quinine resistance. However, parasite count should fall after 24 hours of quinine therapy and should disappear within 5 days
  • In case of artemisinin derivatives, parasite count usually comes down within 5–6 hours of starting therapy. Asexual parasitemia generally disappears after 72 hours of therapy
  • Poor prognosis is suggested by high parasite densities [above 5% red blood cell (RBC) infected or parasite density >250,000/µL]. Prognosis worsens if there is predominance of more mature parasite stages irrespective of the amount of parasitemia. If more than 20% of the parasites contain visible pigment (mature trophozoites and schizonts), the prognosis worsens. Poor prognosis is also indicated if more than 5% of the peripheral blood polymorphonuclear leukocytes contain visible malaria pigment
  • In follow-up cases iron and folic acid should be added.
 
MANAGEMENT OF COMPLICATED AND SEVERE MALARIA
Of the various complications of falciparum malaria the common and important ones in children are as follows:
  • Cerebral malaria87
  • Severe anemia
  • Respiratory distress (acidosis)
  • Hypoglycemia
  • Hyperparasitemia
  • Circulatory collapse (algid malaria)
  • Spontaneous bleeding and coagulopathy (disseminated intravascular coagulation).
 
Cerebral Malaria
Cerebral malaria may present like any other infection with fever followed by inability to eat or drink. The progression to coma or convulsion is very rapid within 1 or 2 days. Convulsions may be very subtle with nystagmus, salivation or twitching of an isolated part of the body. Other treatable causes of coma (e.g., bacterial meningitis, hypoglycemia) should be excluded. Good nursing care, management of convulsions with diazepam or midazolam and avoidance of harmful ancillary treatment, like corticosteroids, mannitol, adrenalin, and phenobarbitone, are needed.
 
Severe Anemia
Children with hyperparasitemia due to acute destruction of red cells or malaria in children with already existing nutritional anemia may develop severe anemia. Packed-red cell transfusion should be given slowly and cautiously when PCV is 12% or less, or hemoglobin is below 4 g/dL. Transfusion should also be considered in patients with less severe anemia in the presence of respiratory distress (acidosis), impaired consciousness, or hyperparasitemia.88
 
Lactic Acidosis
Deep breathing with indrawing of lower chest wall without any localizing chest signs suggest lactic acidosis. Commonly seen in patients with cerebral malaria, anemia or dehydration. Judicious fluid therapy to correct hypovolemia, treatment of anemia, and prevention of seizures are needed. Monitoring acid base status, blood glucose, and urea and electrolyte level are also important.
 
Hypoglycemia
Common in children below 3 years, especially with hyperparasitemia or with convulsion, and particularly in patients treated with quinine. As manifestations are similar to those of cerebral malaria, so it can be easily overlooked unless looked for carefully. Hence, monitor blood sugar every 4–6 hourly. If facilities to monitor blood glucose are not available, assume hypoglycemia in symptomatic patient, and treat accordingly. Correct hypoglycemia with IV dextrose and it should be followed by slow infusion of 5% dextrose containing fluid to prevent recurrence.
 
Hyperpyrexia
High fever is common in children and may lead to convulsion and altered consciousness. Tepid sponging, fanning, and paracetamol (15 mg/kg) should be given.
 
Hyperparasitemia
Hyperparasitemia is especially seen in nonimmune children associated with severe disease. Exchange transfusion or 89cytapheresis to be considered if greater than 20% of RBCs are parasitized.
 
Circulatory Collapse (Algid Malaria)
In case of circulatory collapse, Gram-negative septicemia should be suspected. Blood sample for culture should be drawn before starting antibiotics. Resuscitation to be done with judicious use of fluids.
 
Spontaneous Bleeding and Coagulopathy (Disseminated Intravascular Coagulation)
It is usually seen is nonimmune children, who should be treated with vitamin K, blood or blood products as required.
 
ADJUNCTIVE TREATMENT
These are the various treatments of complications of malaria, usually P. falciparum.
  • Hyperpyrexia: Paracetamol, tepid sponging
  • Coma: Airway, breathing, and circulation. Management of any other treatable cause of coma like hypoglycemia, meningitis
  • Shock: Treatment of septicemia, correction of hemodynamic balance
  • Hypoglycemia: Monitoring of blood glucose and glucose infusion as required
  • Convulsion: Stabilization and management
  • Severe anemia: Blood transfusion
  • Bleeding: Transfusion, vitamin K injection90
  • Acute renal failure: Other treatable causes to be excluded and dialysis to be done if required
  • Pulmonary edema: Propped up position, oxygen inhalation, diuretics, and intubation if required
  • Metabolic acidosis: Hypoglycemia, hypovolemia, and septicemia to be treated.

Chemoprophylaxis of MalariaCHAPTER 10

 
INTRODUCTION
The aim of chemoprophylaxis is to prevent the development of malaria in an individual. Initially, quinine in different forms was used to prevent malaria but the drug itself has poor prophylactic properties.
Prophylactic drugs are classified into the following two types—causal prophylaxis and suppressive prophylaxis.
 
CAUSAL PROPHYLACTICS
The aim is to prevent establishment of malaria in the liver cells—the first stage in malaria cycle, in other words they prevent pre-erythrocytic activity. Pyrimethamine, proguanil, and atovaquone belong to this group. As these drugs act on liver stage, they can be stopped immediately once the person moves out of the malaria-endemic area.
 
SUPPRESSIVE PROPHYLACTICS
The parasites liberated from the liver are unable to establish in red blood cells, in other words these drugs inhibit development of asexual blood stage infection. Mefloquine is a suppressive 92prophylactic drug. It should be taken regularly up to 4 weeks after leaving the malaria-endemic area. This is to prevent the growth of parasite acquired shortly before departure from the endemic area.
Prophylactics are better taken 1 week before arrival in a malarious area in order to assess the tolerance of the drug and to establish a steady therapeutic blood level. Choice of prophylaxis will depend up on the transmission dynamics, risk, and degree of drug resistance in the area.
Prophylaxis for people living in malarious area is not well-established though there is some consensus about pregnant women living in these areas. The National Drug Policy on Malaria 2013 advocates that pregnant women should take personal protective measures along with insecticide treated bed nets. The policy does not advocate any chemoprophylaxis with antimalarials for pregnant women. The military and paramilitary forces especially on night duty in falciparum-endemic areas in India need prophylaxis. Antimalarial drugs are to be used as per the national policy.
 
SHORT-TERM PROPHYLAXIS FOR 6 WEEKS
Doxycycline (1.5 mg/kg) once daily for children above 8 years and 100 mg once daily for adults. The drug should be started 2 days before entry and continued 4 weeks after leaving the malarious area.
 
LONG-TERM PROPHYLAXIS FOR MORE THAN 6 WEEKS
Mefloquine (250 mg) once in a week for adults to be started 4 weeks before entry and continued 4 weeks after leaving the 93malarious area. Mefloquine should be avoided in persons with neuropsychiatric disorders, convulsion, or cardiac problems.

Prevention of MalariaCHAPTER 11

 
INTRODUCTION
The main pillar of prevention of malaria is vector control which can be by chemical control or biological control and along with it personal protective measures taken up by the individual or community.
 
CHEMICAL CONTROL
Indoor residual spraying has been there for a long time but mosquitoes develop resistance to it with the passage of time. Aerosol spray at day time and fogging with malathion are other methods of chemical control.
Dichlorodiphenyltrichloroethane (DDT) should be the insecticide of choice for residual spray. If resistance is found to DDT, then malathion is the alternative choice. In case of resistance to both DDT and malathion, synthetic pyrethroids are the choice. Resistance to pesticides was first noted in India in 1959. As resistance to DDT increased, so did the use of alternative insecticides, which resulted in emergence of vectors resistant to those insecticides as well. Currently, 70% of all insecticides in India are DDT and benzene hexachloride 95(BHC), and their use is increasing at a rate of 6% a year in India. The use of some of these pesticides in agriculture could have increased the speed with which malaria-transmitting mosquitoes became resistant. Pesticides are also toxic to humans and the environment. Both the pesticides are persistent and accumulate in soil, water, and biological organisms.
Larvicides like temephos confer long-lasting effect with low toxicity. It is relatively safe to warm-blooded animals and fish but has the drawback of repeated use at frequent intervals.
 
BIOLOGICAL CONTROL
Use of mosquito larvivorous fish in tanks and other water bodies where they breed are ways of biological control.
 
PERSONAL PROTECTION
Most anopheline mosquitoes remain within 2 km of their breeding sites as they cannot fly more than 4 km. Many vectors bite inside houses. The chances of being bitten by a malaria-infected female anopheline mosquito can be reduced by simple measures. Screenings of house with wire mesh are ways of personal protection. As mosquitoes bite from dusk to dawn, the biting time may be divided into two parts, from dusk till retiring to bed and during sleep to dawn. Use of repellent creams, coils, mats, and liquids, wearing long sleeve clothes are effective in the first part. Mosquito repellent creams offer protection for about 2 hours and coils, mats, and liquids offer protection for the time they burn. Sleeping under bed nets treated with insecticides is very effective. Pyrethroid insecticide (permethrin, deltamethrin)-impregnated nylon nets are the best, a single impregnation of cotton or nylon mosquito 96net will provide protection for 1 year. They can be washed and can tolerate small tears or holes without reducing the protective effects. If treated bed nets are not available, proper measure should be taken to avoid parts of the body coming in contact with the bed net.
 
ENVIRONMENTAL MANAGEMENT
Environmental management by reduction of breeding places, proper storage of water and reduction of unplanned construction will go a long way to prevent mosquito breeding.
 
Water Level Management
Though, this is an old method but drainage remains the most cost effective mode of vector control. Water level management to flush out mosquito breeding areas and to provide a hostile aquatic environment for mosquito egg and larval development is an alternative to drainage. Changing water salinity or allowing organic matter pollution may also reduce vector population. Major alterations to the environment should not be undertaken without proper planning.
 
Remote Sensing
Remote sensing (RS) technology is a tool for the surveillance of habitat, densities of vector species, and even prediction of the incidence of disease that is a new invention in the epidemiology of malaria and vector-borne diseases. Such data is generated in National Remote Sensing Agency, Hyderabad, India. A feasibility study using satellite data in collaboration with the Indian Space Research Organization in and around Delhi was carried out and correlation of changes in water 97bodies and vegetation with mosquito density was found significant in some sites.
Finally, it is an administrative initiative and community participation in these activities which is essential for effective malaria prevention.
 
MALARIA VACCINE APPROACH
Malaria parasite is complex and adaptable, and it has survived for millennia. A safe, effective, and affordable malaria vaccine would close the gap left by other interventions.
 
Malaria Vaccine Roadmap
The leading international health organizations have developed a global strategy for accelerating the development and licensing of a highly effective malaria vaccine. The plan is known as the Malaria Vaccine Technology Roadmap.
The most significant challenge that malaria vaccine scientists face is the lack of understanding of the specific immune responses associated with protection against the parasitic disease. As the malaria parasite is complex, scientists pursue a diversity of vaccine development approaches. Many believe that a malaria vaccine will need to encompass more than a single approach to reach a high degree of efficacy.
 
Types of Malaria Vaccines
 
Pre-erythrocytic Vaccine Candidates
The pre-erythrocytic vaccine candidates target the early stage of malaria infection, the stage at which the parasite enters or matures in an infected person's liver cells. The 98circumsporozoite (CS) protein is the major surface protein of the sporozoites. In the infective stage, the parasite is covered by an acidic peptide—CS protein. Immunization with irradiated sporozoites has produced protection associated with the development of high levels of polyclonal CS antibodies, which have been shown to inhibit sporozoite invasion of human hepatic cells. A successful pre-erythrocytic vaccine will either kill the sporozoites before they invade hepatocyte or destroy it once they are inside the hepatocyte. This vaccine will be a disease preventing vaccine. Actually, these are the ideal vaccine candidates, which will result in sterile immunity.
 
Blood-stage Vaccine Candidates
Blood-stage malaria vaccine will either destroy merozoite in the short time before they invade red cells or target malarial antigens expressed on red cell surface by invading parasites. Protection offered by these vaccines will be both antibody-dependent and cell-mediated immunity.
Blood-stage vaccine candidates target the malaria parasite at its most destructive stage, the rapid replication of the organism in human red blood cells. These vaccines do not aim to block all infection. These vaccines will suppress the exponential growth of dividing merozoites thereby reducing the disease manifestation. This is disease reducing vaccine. They will simulate the natural immunity that is found in highly endemic zones.
 
Transmission-blocking Vaccine Candidates
Transmission-blocking vaccine candidates seek to interrupt the life cycle of the parasite by inducing antibodies that prevent the parasite from maturing in the mosquito after it takes a 99blood meal from a vaccinated person. These vaccines would not prevent a person from getting malaria, nor would they lessen the symptoms of disease. They would, however, limit the spread of infection by preventing mosquitoes that fed on an infected person from spreading malaria to new hosts.

Glossary

Artemisinin-based combination therapy:
it refers to the combination of artemisinin or one of its derivatives with an antimalarial of a different class.
Asexual cycle:
the life cycle of malaria parasite in host starting from merozoite invasion of red blood cells to rupture of schizont. The sequence being merozoite → ring stage → trophozoite → schizont → merozoites. The duration is about 48 hours in P. falcipaurm, P. vivax, and P. ovale, whereas 72 hours in Plasmodium malariae.
Cerebral malaria:
severe malaria with cerebral manifestations usually caused by Plasmodium falciparum (P. falciparum). Malaria with coma persisting for more than 30 minutes after a seizure is considered to be cerebral malaria.
Combination therapy:
a combination of two or more different classes of antimalarial drugs with unrelated mechanism of action.
Cure:
elimination of the symptoms of malaria and disappearance of asexual blood stages of the malaria parasite that caused the person to seek treatment.
Drug resistance:
ability of a parasite strain to survive and/or multiply despite administration and absorption of a medicine given in doses equal to or higher than that usually recommended but within the tolerance of the subject, provided the drug exposure at the site of action is adequate.
Gametocyte:
sexual stage of malaria parasites present in the host red blood cells.
Hypnozoites:
it is the source of relapses. The persistent liver stages of P. vivax and P. ovale malaria that remains dormant in the host hepatocytes for an interval, usually 3–45 weeks before maturing to hepatic schizonts. 102The schizonts burst and release merozoites which infect the red blood cells.
Malaria pigment (hemozoin):
it is formed by malaria parasites as a by-product of hemoglobin catabolism. The pigment is dark brown in color. It is evident in mature trophozoites and schizonts and sometimes, in white blood cells and placenta.
Merozoites:
parasites released into the bloodstream following rupture of hepatic or erythrocytic schizont.
Pre-erythrocytic cycle:
when an infected female Anopheles mosquito bites a human, the parasite enters the host. The sporozoites invade parenchymal cells in the host liver and multiply within the hepatocytes for 5–12 days, thus forming hepatic schizonts. It then bursts liberating merozoites in the blood stream, which subsequently invade the red blood cells.
Radical cure:
it comprises of cure as defined above plus prevention of relapses by killing hypnozoites. This is feasible only for Plasmodium vivax (P. vivax) and Plasmodium ovale (P. ovale) infections.
Rapid diagnostic tests:
it is an antigen-based test where a colored line indicates the presence of plasmodial antigens. It may be stick, cassette, or card test.
Recrudescence:
it refers to the recurrence of asexual parasitemia after treatment of the same infection that caused the original disease. It is due to incomplete clearance of parasitemia due to inadequate or ineffective treatment.
Recurrence:
the recurrence of asexual parasitemia following treatment. This may be due to recrudescence, relapse, or a new infection.
Relapse:
it is the condition of recurrence of asexual parasitemia in P. vivax and P. ovale malaria derived from persisting liver stages. Relapse occurs when the blood stage infection has been eliminated, but hypnozoites persist in the liver and mature.
Ring stage:
intra-erythrocytic young malaria parasite which is ring-shaped.
Schizont:
mature malaria parasites in the host liver cells, known as hepatic schizonts or in the red blood cells, known as erythrocytic schizonts that are undergoing nuclear division. The process is called schizogony.103
Severe anemia:
hemoglobin concentration less than 5 g/100 mL of blood.
Severe falciparum malaria:
falciparum malaria with signs of severity with or without evidence of vital organ dysfunction.
Trophozoites:
stage of development of malaria parasites within host red blood cells from the ring stage and before nuclear division. Mature trophozoites contain visible malaria pigment.
Uncomplicated malaria:
symptomatic infection with malaria parasitemia without signs of severity and evidence of vital organ dysfunction.

Further Reading

  1. Achieving the malaria MDG target. Reversing the incidence of malaria 2000–2015. UNICEF and WHO. Geneva: World Health Organization; 2015.
  1. Alonso Pl, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, et al. Duration of protection with RTS, S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005;366(9502):2012–8.
  1. Alonso Pl, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, et al. Efficacy of the RTS, S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet. 2004;364(9443):1411–20.
  1. Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis. 2004;39(9):1336–45.
  1. Epstein JE, Giersing B, Mullen G, Moorthy V, Richie TL. Malaria vaccines: are we getting closer? Curr Opin Mol Ther. 2007;9(1):12–24.
  1. Global technical strategy for malaria 2016–2030. Geneva: World Health Organization;  2015.
  1. Guerin PJ, Olliaro P, Nosten F, Druilhe P, Laxminarayan R, Binka F, et al. Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infect Dis. 2002;2:564–73.
  1. Guidelines for diagnosis and treatment of malaria in India. Government of India. New Delhi: National Institute of Malaria Research;  2011.
  1. Guidelines for the treatment of malaria, 3rd edition. Geneva: World Health Organization;  2015.
  1. Malaria rapid diagnostic test performance. Result of WHO product testing of malaria RDTs: round 5 (2013). Geneva: World Health Organization; 2014.
  1. Malkin E, Dubovsky F, Moree M. Progress towards the development of malaria vaccines. Trends Parasitol. 2006;22(7):292–5.106
  1. National Anti-malaria Program. [online] Available from: www.mohfw.nic.in/reports. [Accessed March, 2015].
  1. National drug policy on malaria. Directorate of National Vector Borne Disease Control Program. Directorate General of Health Services. New Delhi: Ministry of Health and Family Welfare,  Government of India; 2013.
  1. National Vector Borne Disease Control Program. Annual Report 2014-15. Directorate of National Vector Borne Disease Control Program. Directorate General of Health Services. New Delhi: Ministry of Health and Family Welfare, Government of India;  2015.
  1. Park K. Health programmes in India. In: Park K (Ed). Park’s Textbook of Preventive and Social Medicine, 19th edition. Jabalpur: Banarasidas Bhanot Publishers;  2007. pp. 346–78.
  1. Program for Appropriate Technology in Health (PATH), Accelerating Progress Towards Malaria Vaccines. Bethesda, MD: PATH; 2007.
  1. Singh N, Nagpal AC, Saxena A, Singh MP. Changing scenario of malaria in central India, the replacement of Plasmodium vivax by Plasmodium falciparum (1986-2000). Trop Med Int Health. 2004;9(3):364–71.
  1. White NJ. Malaria. In: Cook GC, Zumla AI (Eds). Manson’s Tropical Diseases, 21st edition. London: WB Saunders;  2003. pp 1205–95.
  1. WHO. South East Asia progress health for all, 1997-2000. New Delhi: Regional Office of SEARO; 2000.
  1. World Malaria Report, 2008. Geneva: World Health Organization;  2008. [online] Available from: www.mohfw.nic.in/reports. [Accessed March, 2014].