Chapter 352. Malaria

Malaria is among the leading infectious causes of morbidity and mortality in children worldwide. Each year, there are 300 to 500 million clinical cases, causing between 1.5 and 2.7 million deaths, most in sub-Saharan African children under the age of 5 years. Increasing drug resistance, climatic changes, population shifts, economic changes, abandonment of malaria control programs, and insecticide resistance all contributed to a resurgence of malaria in the developing world from the 1970s to the 2000s. Recent World Health Organization, governmental, and nonprofit foundation support for effective preventative measures—such as insecticide-treated bednets, indoor residual spraying, and the implementation of artemisinin combination therapy as first-line treatment for malaria in many sub-Saharan African countries—appears to have significantly reduced malaria incidence and deaths in some countries.1

More than 40% of the world’s population, or 2.5 billion people, are at risk for malaria in 90 countries in Africa, Asia, South and Central America, and Oceania (Fig. 352-1). For many years, it appeared that malaria in humans was caused by four species of Plasmodium: P falciparum, P vivax, P ovale, and P malariae. There is now evidence that P knowlesi, a Plasmodium species that usually infects monkeys, has crossed over to cause malaria in humans in Southeast Asia, notably in Malaysia4; it is now considered a fifth human malaria species. Plasmodium falciparum is found mainly in tropical areas, where warm weather ensures the relatively constant presence of the Anopheles vector. Plasmodium vivax has the widest geographic distribution of the four species and is found in both tropical and temperate areas. Plasmodium ovale is found primarily in sub-Saharan West Africa, where it appears to have almost completely replaced Plasmodium vivax. Plasmodium malariae can be seen in both tropical and temperate zones but is the least common of the malaria species.

Diagnostic and treatment approaches differ significantly in malaria endemic countries as compared to countries like the United States, where almost all malaria is imported. In the United States, all of the approximately 1500 cases of malaria that were reported to the Centers for Disease Control and Prevention (CDC) in 2005 occurred in travelers to or immigrants from malaria-endemic countries, with the exception of two cases of congenital malaria, in which the mothers were immigrants from malaria-endemic countries.2 Rare cases of local transmission have been reported in the United States.3

Malaria can be a life-threatening illness. Delay in seeking treatment, misdiagnosis, or both are often seen in individuals who die from malaria in the United States.2 Any febrile child who has been in a malaria-endemic area in the preceding year should be assessed for this illness.

Organisms and Life Cycle

Plasmodium species can infect many different animals but most are host-specific. P falciparum is the only Plasmodium species that infects all ages of red blood cells, so it generally causes a much higher level of parasitemia than the other Plasmodium species. P vivax and P ovale preferentially infect reticulocytes and tend to cause a lower level of parasitemia than does P falciparum. P malariae preferentially infects senescent red cells and causes the lowest level parasitemia of the human Plasmodium species, but this low-level parasitemia may persist for decades. It is not clear at this point if P knowlesi preferentially infects a subset of red cells, but it multiplies rapidly and can cause very high levels of parasitemia. Morphologically, it can be confused with P malariae on microscopic examination.

Understanding the malaria parasite life cycle is crucial to understanding malarial infection and disease. The malaria life cycle is summarized in Figure 352-2. Sporozoites are inoculated into the bloodstream by the Anopheles mosquito and migrate within minutes to the liver, where they invade hepatic parenchymal cells. Here, the sporozoites undergo asexual multiplication (hepatic schizogony), forming schizonts that rupture the hepatic cells and release merozoites into the bloodstream. Very few hepatic cells are invaded by sporozoites, but multiplication within the hepatic cell produces thousands of merozoites from each sporozoite-infected hepatic cell. The process of liver schizogony lasts from 7 to 10 days for P falciparum, P ovale, and P vivax and 10 to 14 days for P malariae. P vivax and P ovale can also produce dormant liver stages (hypnozoites) that can reactivate weeks or months after the initial infection and can cause clinical relapse.

Merozoites released by ruptured hepatic cells invade red blood cells, where they may asexually multiply or undergo sexual differentiation into male and female gametocytes. Parasites established in the red blood cell (trophozoites) that asexually multiply form red blood cell schizonts. These schizonts eventually rupture the red cells containing them and release more merozoites, which continue the cycle of red cell invasion and multiplication.

Male and female gametocytes are ingested by mosquitoes with their human blood meal. In the mosquito, the male gametocyte exflagellates, releasing a microgamete that fertilizes the female macrogamete, producing a zygote. The elongated zygote, or ookinete, penetrates the mosquito’s stomach wall and forms an oocyst behind it. The oocyst grows and eventually ruptures to release numerous sporozoites, which migrate throughout the mosquito. Those that enter the salivary glands can then infect humans the mosquito bites, thus renewing the cycle of infection.

Malaria can also be acquired by direct blood exposure through blood transfusions. With current blood-screening procedures, such cases are rare in the United States. Congenital malaria, with passage of infection from mother to newborn, can also occur, though it is relatively infrequent in endemic areas. It is seen more frequently in nonimmune women and in women who have an overt attack of clinical malaria during pregnancy. In areas where malaria is endemic, infection during pregnancy, even among semi-immune women, can lead to low birth weight and an increased risk of perinatal mortality.

Pathophysiology of Malaria Infection

Malarial disease is caused by the blood stages of the parasite. Rupture of red cells and release of merozoites into the blood leads to the fever, chills, and malaise seen in all forms of malaria. Plasmodium-infected erythrocytes, opsonized with antibodies or complement, are less deformable than uninfected erythrocytes and are consequently trapped in the spleen, leading to splenomegaly. Anemia and thrombocytopenia are due primarily to splenic consumption of erythrocytes and platelets, but autoimmune hemolysis plays a role in the continued destruction of erythrocytes that can occur for weeks after appropriate treatment. In addition, bone marrow suppression occurs in severe malarial anemia, so the anemia seen is due to both erythrocyte destruction (by autoimmune hemolysis and spleen removal of infected erythrocytes) and impaired erythropoiesis.

The pathogenesis of organ dysfunction in P falciparum malaria is complex, and precise mechanisms are still being worked out, but it clearly originates in the interactions between infected red blood cells (iRBCs) and the endothelial cells lining vascular organ beds. Cytoadherence of iRBCs in capillaries leads to sequestration of red cells and parasites in microvascular beds, and the resultant local tissue ischemia and hypoxia likely contributes to the renal, gastrointestinal, pulmonary, and central nervous system complications seen in falciparum malaria. However, several additional factors likely contribute to pathogenesis of P falciparum complications. Endothelial cell damage from activation by iRBCs may cause impairment of the blood-brain barrier (in cerebral malaria) or vascular damage in other organs and may lead to local release of cytokines and other inflammatory factors.5 In support of this hypothesis, several cytokines, notably TNF-α, are present in higher amounts in the cerebrospinal fluid of children with cerebral malaria than in control children.6 Animal models also strongly support the role of proinflammatory cytokines, particularly TNF-α and IFN-γ, in the pathogenesis of severe malaria.5 Regulatory polymorphisms of cytokine genes also appear to play a role in the development of disease.

The hypoglycemia seen in acute P falciparum infection is due to both a depletion of glycogen reserves and an increased demand for glucose because of increased anaerobic glycolysis in host tissues and in parasitized erythrocytes. Numerous factors contribute to lactic acidosis, including increased lactate production in parasitized erythrocytes, anaerobic glycolysis induced by seizures, increased metabolic rates caused by fever and anemia, and the decreased oxygen-carrying capacity of the blood in anemia.

Host Factors

Numerous host genetic factors can affect susceptibility to malarial infection and disease. Protective factors against disease with P falciparum include hemoglobinopathies (hemoglobin S [sickle cell trait], hemoglobin C and E, a and b thalassemia, blood group 0, and G6PD deficiency), and specific HLA class I and class II alleles; Duffy blood group antigens and hereditary ovalocytosis have been associated with protection against P vivax. The best described protective factors are the hemoglobinopathies. Heterozygous carriers of hemoglobin S (sickle cell trait) have an 80% to 95% protection from severe malarial disease, and the high prevalence of hemoglobin S in malaria-endemic areas of sub-Saharan Africa is thought to reflect this protection.7 Other hemoglobinopathies, including hemoglobin C and E and the α and β thalassemias, have also been associated with some degree of protection from severe malarial disease.8 Recently, a strong protective association of blood group O against severe malaria with P falciparum was demonstrated in children in Gambia.9 Alterations in erythrocyte structure or function can be protective against malarial infection and disease. The Duffy blood group antigens are required for the invasion of P vivax into erythrocytes, and the almost universal absence of these antigens in West African individuals convincingly correlates with their innate resistance to P vivax infection, in contrast to their susceptibility to the other three species of human malaria. Some protective effect has also been seen in individuals who carry the genes for hereditary ovalocytosis and G6PD deficiency. Finally, specific human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) can affect susceptibility to malarial disease. Studies have demonstrated that Gambian children without class I antigen HLAB53 and one form of class II antigen DR13 were more likely to have severe malaria than those with these HLA types.10

Development of Immunity

Individuals living in malaria-endemic areas never develop complete immunity to the illness. However, with repeated exposure to a variety of different malaria strains over several years, they become relatively tolerant to infection. These “semi-immune” individuals often have asymptomatic parasitemia, and when malarial disease does occur, it is generally much milder than that seen in nonimmune persons.

The major factors in acquiring immunity to malarial disease are repeated and frequent exposure to P falciparum, exposure to multiple strains of P falciparum, and age. Acquiring immunity to malarial disease occurs during childhood in malaria-endemic areas, but the pattern of acquisition differs in areas of differing endemicity. In areas of low- and midlevel endemicity, children acquire immunity more slowly than in areas of high-level endemicity. The primary manifestations of disease also tend to differ in areas of varying endemicity. In areas with high endemicity, children develop severe anemia, which is seen most commonly in those ages 6 months to 3 years. In areas with low- or midlevel endemicity, cerebral malaria is more common and occurs in a broader age range (6 months to 6 years). In malaria-endemic areas, children less than 6 months old, and especially those less than 3 months old, are protected from malarial infection and disease by fetal hemoglobin and passively transferred maternal antibodies.

Clinical Manifestations

The clinical presentation of malaria depends on the infected individual’s age and level of immunity and on the Plasmodium species causing the illness. In the United States, most children who present with malaria are nonimmune. More than 90% of those with P falciparum infection (the most common Plasmodium species in imported malaria) present within 3 months of travel to or immigration from a malaria-endemic area,2 while less than 50% of those with P vivax or P ovale infection present within 3 months; rarely, P vivax and P ovale may present more than a year after exposure.

Nonimmune individuals, whether children or adults, tend to present with more severe signs and symptoms than semi-immune individuals and may develop severe disease with relatively low-level parasitemia. Prodromal, flulike symptoms occur during the early cycles of erythrocytic infection and may include fever (with no specific pattern), headache, malaise, myalgias, arthralgias, abdominal pain, and diarrhea. Children, especially infants, may not exhibit the classic “febrile paroxysm” seen in adults. In infants, more nonspecific symptoms such as fever, lethargy, decreased appetite, and listlessness may continue to predominate. Vomiting, loose stools, and abdominal pain are very common complaints in both infants and children. Many infants and older children will also have intermittent fevers without a clear pattern, rather than the 48-hour (P vivax,P ovale,P falciparum) or 72-hour (P malariae) fever patterns classically described with these infections. Children with P falciparum in particular may exhibit very irregular fever patterns. Up to 10% of children with malarial disease may not have documented fever during the illness. Seizures are common in severe malaria. Nonimmune adults frequently exhibit the classic febrile paroxysm, which consists of three phases: a brief “cold” phase, with chills and sometimes rigors; a hot phase, with high fever, dry, flushed skin, tachypnea, and thirst; and a sweating stage, with defervescence accompanied by diaphoresis and a feeling of great relief but also great weakness. The paroxysms coincide with the rupture of infected erythrocytes and the release of merozoites, pigment, and cell debris into the circulation.

The physical signs most frequently seen in malaria are hepatomegaly and splenomegaly, which occur in about half of all children with acute malarial disease. In areas where malaria is highly endemic, a large percentage of children develop palpable splenomegaly over time, and the prevalence of splenomegaly in children ages 2 to 9 years has been used to define an area’s malaria-endemicity pattern. In areas of unstable transmission and in nonimmune individuals, it is less common.11 Although malaria often leads to some degree of anemia, particularly when not treated immediately, pallor is seen in only 25% of children with malaria in endemic areas and jaundice in only 10% to 15% of children. Scleral icterus may be seen in children. Jaundice is more common in nonimmune adults. Other physical exam findings relate to complications of malaria, such as coma or posturing in children with cerebral malaria or chest indrawing and respiratory distress in children with lactic acidosis.

Complications from P Falciparum Malaria

Nonimmune children with P falciparum malaria often develop complications from the disease. The World Health Organization (WHO) lists 10 defining criteria for severe malaria, as listed in Table 352-1.12 The most common of these complications in children are severe malarial anemia, respiratory distress, and impaired consciousness. Each of these complications can contribute to and exacerbate the others, and mortality increases as the number of malarial complications increases.

Cerebral Malaria

By WHO definition, cerebral malaria is present in a patient who (1) cannot localize a painful stimulus, (2) has peripheral asexual P falciparum parasitemia, and (3) has no other causes of an encephalopathy. The pathophysiology of impaired consciousness in a child with severe malaria is likely the same as that of coma. Recurrent convulsions are a frequent antecedent to subsequent impaired consciousness and coma: according to strict WHO criteria, 50% to 80% of African children with cerebral malaria have a prior history of convulsions.13

Cerebral malaria often develops rapidly. Parents typically give a history of 2 to 3 days of fever, followed by abrupt onset of convulsions or severely impaired consciousness. Children with cerebral malaria may progress from a normal sensorium to coma within hours. Focal seizures are occasionally seen, but focal neurological deficits are rare. Meningeal signs are usually absent. Abnormal posturing, pupillary changes, absent corneal reflexes, Cheyne-Stokes or Kussmaul respirations, and gaze abnormalities may be seen. “Malaria retinopathy” consists of four main components: retinal whitening, vessel changes, retinal hemorrhages, and papilledema. Retinal whitening and the vessel color changes are specific to malaria and are not seen in other ocular or systemic conditions.14 Retinal hemorrhages have been noted in 6% to 36% of African children on admission and papilledema in 2% to 12%. Retinal hemorrhages generally resolve without residual visual defects, but papilledema is an independent indicator of poor outcome. Malaria retinopathy appears to distinguish children with cerebral malaria from those with coma due to other causes15 but must be assessed with indirect ophthalmoscopy. Increased intracranial pressure (ICP), generally not seen in adults with cerebral malaria, is a feature of cerebral malaria in children; children with severely increased ICP (ICP > 40 mmHg) have a very high risk of death or severe neurological sequelae. It is unclear, however, whether severely increased intracranial pressure reflects a primary disease process due to P falciparum or to a terminal event.

The mortality rate for strictly defined cerebral malaria in African children is 16% to 20%. Concurrent respiratory distress, lactic acidosis, or severe malarial anemia increase the mortality rate. Given the severity of cerebral malaria, it is remarkable that only approximately 4% to 6% of children who survive cerebral malaria have long-term neurological deficits.13,16 Retrospective studies suggested that cerebral malaria is associated with cognitive impairment, and recent prospective studies have documented that approximately one in four children with cerebral malaria will have cognitive impairment 2 years after the illness.17

Nonimmune adults can develop neurological sequelae after severe malaria, even without cerebral malaria. Neurological sequelae seen in nonimmune adults may also be seen in nonimmune older children and may include cranial nerve defects, mononeuritis multiplex, polyneuropathy, and cerebellar dysfunction.

Severe Malarial Anemia

Malaria is the leading cause of anemia requiring hospital admission in the African child (eFig. 352.1). Severe anemia is seen most often in children less than 4 years old and is more frequent in areas of very high P falciparum transmission. Many children with malaria in endemic areas are already anemic from iron deficiency and hookworm infection, and the sudden worsening of anemia caused by P falciparum can lead to congestive heart failure, with subsequent respiratory distress and lactic acidosis.

Metabolic Dysfunction

Hypoglycemia (a blood glucose level of ⩽ 2.2 mmol/L) and lactic acidosis (a plasma lactate of ⩾ 5 mmol/L) are seen frequently in children with P falciparum malaria, often together, and are independent predictors of mortality.18 Children are more likely to be hypoglycemic on presentation with P falciparum malaria than are adults. Quinine induces hyperinsulinemia in patients with acute malaria, but peripheral insulin resistance increases in acute infection and counters the hypoglycemic effects of elevated insulin levels. Late-onset hypoglycemia may be seen when acute infection has resolved but quinine treatment continues. The signs of hypoglycemia (depressed consciousness, dilated pupils, seizures) may also be seen in cerebral malaria, so checking the blood glucose level is imperative in any severely ill child with malaria. Prolonged lactic acidosis is a strong predictor of mortality. Respiratory distress, another frequent complication of P falciparum malaria in children, is most often attributable to underlying metabolic acidosis rather than a primary pulmonary or cardiac process. The pulmonary edema seen in adults is rarely seen in children, and pneumonia is also uncommon in children with severe malaria.

Other Complications

Prostration (conscious but unable to sit, drink, or eat) is a common complication of malaria.11,19 The exact pathophysiology of this clinical phenomenon is not clear, but it can be associated with mortality as high as 8% even in the absence of other complications.19 Children with P falciparum malaria may have an elevated blood urea nitrogen and creatinine values on admission, but this is most often due to hypovolemia and corrects with fluid administration. Renal failure from glomerulonephritis or massive intravascular hemolysis (blackwater fever) is rarely seen in children in endemic areas, but it appears to be more common in adults. It may occasionally be seen in nonimmune children. Circulatory collapse may be due to concurrent bacterial meningitis or sepsis, which should be ruled out in children with severe malaria. Abnormal bleeding is also an infrequent clinical problem in children with severe malaria. Thrombocytopenia is frequently seen in children with P falciparum malaria, but bleeding problems are rare. Mild hyponatremia and hypokalemia are common in P falciparum malaria, but adverse outcomes due to either abnormality are rare.

Tropical splenomegaly syndrome is a chronic complication of P falciparum malaria in which splenomegaly persists after the acute infection is treated. Massive splenomegaly, hepatomegaly, anemia, and an elevated IgM level are the classic features of this disorder, which is thought to be due to an impaired immune response to P falciparum antigens. The only effective therapy for this disorder is lifelong antimalarial prophylaxis. With this treatment, spleen size gradually regresses but increases again if prophylaxis is stopped.

Complications from Non-Falciparum Malaria

In malaria due to P vivax and P ovale, complications other than anemia (which is seldom as severe as that caused by P falciparum) are uncommon. Nonetheless, nonimmune children with P vivax and P ovale malaria may be acutely ill and profoundly fatigued during recovery from their illness. Death can occur from P vivax or P ovale infection. Very rarely, splenic rupture may occur after trauma. Children and adults with chronic P malariae infection may develop nephrotic syndrome, caused by immune complex deposition on glomerular walls. The nephrotic syndrome caused by P malariae is poorly responsive to steroids. Because of its rapid life cycle, P knowlesi malaria can cause high-level parasitemia and severe seizures, and can rapidly lead to death.20 Since P knowlesi can be mistaken for P malariae on microscopy, it should be considered in any severely ill patient who acquires malaria in Southeast Asia, particularly in patients who are thought to have P malariae infection on microscopy but have high-level parasitemia, as high-level parasitemia with P malariae infection is unusual.

Diagnosis

Malaria is often misdiagnosed in the United States, and many of the deaths caused by malaria in this country are due to a delay in diagnosis. Every febrile child who has been in a malaria-endemic area within the year before presentation should be evaluated for malaria. Febrile newborns whose mothers were in malaria-endemic areas within 2 years of presentation should be assessed for congenital malaria.

In the nonimmune child returning from a malaria-endemic area, malaria is most likely to be confused with typhoid—which may also present with fever, abdominal pain, vomiting, diarrhea, and malaise—or dengue. The fevers of typhoid are unremitting and generally unaccompanied by chills, rigors, or diaphoresis, and the splenomegaly of typhoid is typically less marked than that of malaria. The classic typhoid “rose spot” exanthem is not seen in malaria, but it is often missing in cases of typhoid as well. In its prodromal phase, malaria can also be confused with viral or bacterial gastroenteritis, including hepatitis A, influenza, enteroviral infection, and other viral illnesses. Cerebral malaria may be confused with bacterial or viral meningitis or encephalitis. If blood smears are repeatedly negative for malaria parasites and if antimalarial treatment does not improve symptoms, the differential diagnosis should include tuberculosis, endocarditis, brucellosis, leptospirosis, trypanosomiasis, kala-azar, histoplasmosis, and noninfectious diseases such as rheumatologic or neoplastic disease.

Examination of Giemsa-stained thick and thin blood smears remains the primary method of diagnosing malaria. Thick smears are more sensitive in detecting parasites, but thin smears are necessary for identifying Plasmodium species and allow estimation of the degree of peripheral blood parasitemia. It is most important to distinguish P falciparum from the other three human malaria species. P falciparum malaria is suggested by parasitemia that exceeds 2% of red cells, red cells that contain multiple parasites, the almost exclusive presence of ring forms of the parasite, ring forms with a double chromatin dot, and the presence of parasites in all ages of red cells (eFig. 352.2a). The banana-shaped gametocyte is pathognomonic for P falciparum malaria (eFig. 352.2b). P malariae is characterized by low-level parasitemia and a characteristic band trophozoite (eFig. 352.2c; band trophozoite in center). Schuffner’s stippling is characteristic of P vivax (eFig. 352.2d) and P ovale, though it may be more subtle in P ovale infections. P ovale–infected cells often have an oval shape in addition to the stippling (eFig. 352.2e).

Asymptomatic parasitemia is common in highly endemic areas, so in these places, a positive blood smear for malaria does not necessarily implicate malaria as the cause of the patient’s disease. In these locations, it is sometimes difficult to distinguish acute malarial disease from other infectious diseases that cause similar symptoms.

In semi-immune individuals living in an area endemic for P falciparum malaria, the level of parasitemia often does not correlate with severity of disease, although there is a general correlation on a population level. In nonimmune individuals, the level of parasitemia generally does correlate with severity of disease, and high-level parasitemia (> 5%) in a nonimmune individual is frequently accompanied by complications of malaria. However, in nonimmune patients, even low-level parasitemia may be accompanied by severe illness. This may be in part because peripheral blood parasitemia is an imperfect indicator of sequestered parasite load, and persons with a high level of sequestered parasites in end-organ microvasculature may have low-level peripheral blood parasitemia. In a severely ill nonimmune child, malaria blood smears should be repeated every 8 to 12 hours, and at least three smears over a 48- to 72-hour period should be obtained before malaria is excluded as a diagnosis. Children have sometimes received treatment with antimalarial medication prior to seeing a physician, and this may lead to a negative blood smear for malaria parasites. If the clinical picture in these individuals is consistent with malaria, and no alternative diagnosis can be made, empirical treatment for malaria may be necessary. Testing with a rapid diagnostic test such as the Binax NOW (see below) is indicated in these children, because the test may remain positive up to 48 hours after treatment begins.

The Binax test is now FDA approved for rapid diagnosis of malaria. This immunochromatographic test for P falciparum histidine rich protein (HRP2) and aldolase is approved for testing for P falciparum and P vivax, and should also be able to detect P ovale and P malariae, though sensitivity and specificity for these organisms has not been assessed. Aldolase is present in all four of these species, and though the test would be read as positive for P vivax, the infection could be due to P ovale or P malariae. The test is simple to perform and can be done in the field or lab in 10 minutes. Other rapid tests for P falciparum also show high sensitivity and specificity but are not currently approved by the FDA. Parasite mRNA or DNA polymerase chain reaction (PCR) testing has been performed in research settings. It is much more sensitive than the traditional blood smear and allows parasite species and strain identification, but at present it remains a research tool. Of note, PCR testing at a reference lab is currently the only way to identify P knowlesi infection.

No other laboratory tests are diagnostic for malaria. Lab findings that support the diagnosis include a normocytic, normochromic anemia and thrombocytopenia. However, in children with concurrent hookworm infection or iron deficiency, microcytosis and hypochromia may be seen. Hypoglycemia and metabolic acidosis may occur with severe malaria. Elevation of indirect bilirubin and a mild elevation of transaminases may also be seen. The cerebrospinal fluid (CSF) in children with cerebral malaria is generally unremarkable, with less than five white blood cells per ml, no red blood cells, normal or mildly elevated protein, and a normal glucose relative to serum glucose. When elevated CSF lactate levels are seen, they are an independent predictor of mortality.

Treatment

Treatment of malaria can be complex. Physicians without experience in malaria treatment may call the CDC malaria hotline for expert advice (770-488-7788 Mon-Fri 8-4:30 Eastern US time; or 777-488-7100 at all other times). Four questions must be urgently answered in the evaluation of a child with malaria or suspected malaria: (1) Is the child semi-immune or nonimmune? (2) Does the child have P falciparum malaria? (3) Was the child exposed to malaria in an area with chloroquine-resistant or chloroquine-sensitive malaria parasites? (4) Does the child have any evidence of complications from malarial disease by history, exam, or lab findings?

All ill-appearing children should be considered nonimmune. Children less than 5 years old, children traveling to malaria-endemic areas but originally from a nonendemic area, and children who have been away from an endemic area for more than 6 months should be considered nonimmune. In many malaria-endemic countries, there are large cities where little or no malaria transmission occurs, and individuals from these cities are essentially nonimmune. A well-appearing child over 5 years of age who has arrived within 6 months from a malaria-endemic area but who has Plasmodium species infection on blood smear may be considered semi-immune. If there are no significant physical exam or laboratory findings of concern, and compliance with treatment and good follow-up are certain, such children may be considered for outpatient therapy.

P falciparum malaria can be a life-threatening emergency, especially in the nonimmune individual. Any child from a malaria-endemic area with signs and symptoms of severe malaria should be treated for P falciparum malaria while awaiting blood smear confirmation. Nonimmune children with documented P falciparum malaria should be hospitalized, because clinical decompensation can occur rapidly, even in children with a relatively benign initial presentation. Nonimmune children with P vivax,P ovale, or P malariae infection generally don’t develop severe complications, but they can appear quite ill with the initial paroxysm and also usually require hospitalization.

Decisions about antimalarial therapy are based on the chloroquine resistance pattern in the area malaria was acquired. The physician should search carefully for evidence of complications from malarial infection (as outlined in the “Diagnosis” section), because early treatment of these complications may ameliorate the disease process. In children, evidence of hypoglycemia, lactic acidosis, and severe anemia must be sought so that if present, they can be corrected appropriately.

Severe P Falciparum Malaria

In the United States, intravenous quinidine has been the drug of choice for all children with P falciparum malaria who require hospitalization. In malaria-endemic countries, intravenous or intramuscular quinine, artesunate, or artemether are the drugs of choice for severe chloroquine-resistant P falciparum malaria. Quinidine gluconate has become less available in United States hospitals with the advent of newer antiarrythmic drugs. Artensunate is recommended by the World Health Organization (WHO) in preference to quinidine for the treatment of severe malaria and has been used worldwide for many years and can now be obtained on a protocol through the CDC (see Table 352-2). Treating P falciparum infection with quinine, quinidine, artesunate, or artemether alone has been associated with significant recrudescence rates, which are decreased with the addition of doxycycline, sulfadoxine-pyrimethamine, or clindamycin (Table 352-2). High-level quinine resistance, though reported, remains uncommon.

The potential cardiac toxicity of quinidine necessitates that patients receive it as an intravenous infusion, never as a bolus, while on continuous electrocardiographic monitoring. Infusion rates should be reduced if the QT interval is prolonged by more than 25% of the baseline value. Both quinine and quinidine can induce hyperinsulinemic hypoglycemia, which may cause lethargy or unresponsiveness that is confused with cerebral malaria; therefore, glucose levels should be followed in severely ill patients who are on these medications. Long-term side effects from either medication are uncommon, and the cinchonism (nausea, dysphoria, tinnitus, and high-tone deafness) seen with quinine resolves with cessation of quinine therapy. When children are ready for oral therapy, they can complete treatment with the oral forms of quinine or artemsinin.

Several studies have investigated intrarectal administration of quinine and artesunate in children with severe P falciparum malaria with promising results,21,22 but standardized formulations and dosing for this route of administration have not yet been agreed upon.

Uncomplicated P Falciparum Malaria

Chloroquine-Resistant

In the United States, more than 90% of cases of clinical malaria reported to the CDC were acquired in Africa, Asia, or South America, all of which have high-level P falciparum chloroquine resistance.23

In the United States, a fixed combination of atovaquone and proguanil (marketed under the trade name Malarone by Glaxo Wellcome) is the preferred alternative to quinine treatment for uncomplicated chloroquine-resistant P falciparum malaria (Table 352-3). Atovaquone-proguanil has proven highly effective for treating chloroquine-resistant P falciparum malaria in both semi-immune and nonimmune individuals.25,26 Side effects (abdominal pain, vomiting, nausea, and headache) are infrequent and usually mild and self-limited. In some studies, an elevation of transaminases was seen with atovaquone-proguanil treatment, but transaminase elevations have not been associated with untoward clinical events.25 Atovaquone-proguanil should be taken with food or a milky drink. If vomiting occurs within 1 hour of dosing, a repeat dose should be given. All doses for treatment should be taken as a single daily dose.

Artemisinin derivatives are not available in the United States but are the primary alternative to quinine in many malaria-endemic countries. They have been used successfully for severe and uncomplicated malaria in Asia and Africa, and several large clinical trials have demonstrated that they are at least as effective as quinine and are well tolerated.27-29 Artemisinin-based therapies were superior to quinine for treating severe malaria in adolescents and adults in a large study in Southeast Asia, and artesunate is now considered standard treatment of severe malaria in Southeast Asia. In many countries in sub-Saharan Africa, the fixed combination of artemether/lumefantrine (Coartem) has now become the preferred treatment for uncomplicated malaria.

Oral quinine is the first-line medication in the United States for the child with chloroquine-resistant P falciparum infection who does not require hospitalization. Most authorities recommend concurrent treatment with doxycycline or sulfadoxine-pyrimethamine, because combined treatment permits a 3-day course of quinine and decreases the risk of recrudescence24 (Table 352-3). Children who acquire P falciparum infection in border areas of Thailand (where low-level quinine resistance is endemic), who have persistent parasitemia greater than 1%, or who receive clindamycin as their adjunctive therapy should receive a full 7-day course of quinine treatment.

Children frequently vomit after receiving quinine, especially if they are febrile when receiving the drug. Acetaminophen and sponge bathing prior to administration of oral quinine may decrease the likelihood of vomiting. If vomiting occurs within an hour, the full dose of quinine should be repeated. If vomiting occurs after 1 hour, no repeat quinine dosing is necessary. Other side effects of quinine are as noted above. In situations where urgent treatment is required and intravenous medications cannot be given, intrarectal or intramuscular quinine has been used successfully.

Mefloquine can be used to treat chloroquine-resistant malaria, but increasing mefloquine resistance (particularly in Southeast Asia) and significant central nervous system side effects with treatment dosages make it an inferior choice, to be used only when quinine or atovaquone/proguanil or an artemisinin-based therapy is not an option. Mefloquine should not be used if the child took mefloquine as prophylaxis, and it should not be used in conjunction with quinine or quinidine, as it may potentiate the cardiac side effects of these medications.

Increasing P falciparum sulfadoxine-pyrimethamine resistance in many malaria-endemic countries has led to extensive testing of drug combinations as potential new first-line therapies for P falciparum malaria. Combination therapies tested include sulfadoxine-pyrimethamine plus amodiaquine, chloroquine, or artesunate; artesunate plus mefloquine, lumefantrine, or amodiaquine; and dapsone plus proguanil. None of these combinations is currently available in the United States, but they may be viable alternatives for uncomplicated chloroquine-resistant P falciparum infection in malaria-endemic countries.

Chloroquine-Sensitive

At the time of publication, chloroquine-sensitive P falciparum still exists in the Middle East, eastern Europe, Central America north of the Panama Canal, Haiti, and the Dominican Republic, but this may change. The CDC Web site (www.cdc.gov) and the malaria hotline (770-488-7788) have up-to-date information on malaria drug resistance in every country. Chloroquine remains the drug of choice for chloroquine-sensitive P falciparum malaria. It is inexpensive, generally well tolerated, and easy to administer. Side effects include pruritus in dark-skinned patients (which is fairly common), and, in treatment doses, nausea, dysphoria, and rarely a transient neuropsychiatric syndrome or cerebellar dysfunction. If there is any doubt as to whether chloroquine resistance is present in the area malaria was acquired, quinine should be used. Quinine or quinidine is the preferred drug for parenteral treatment of chloroquine-sensitive malaria.

Malaria Due to P Vivax, P Ovale, P Malariae, or P Knowlesi

Severe illness or complications due to P vivax, P ovale, or P malariae are uncommon, though the high fevers, malaise, and anemia caused by P vivax may occasionally be severe enough to warrant hospitalization. Coinfection with P falciparum may be missed on blood smear if the slide reader is inexperienced or if the infection inoculum is low. Children hospitalized with non-falciparum malaria should be given the same drug treatment regimen as children hospitalized for falciparum malaria (Table 352-2).

Most guidelines still recommend chloroquine treatment for malaria due to P vivax,P ovale, and P malariae. High-grade P vivax resistance to chloroquine has been reported in Oceania and India and less commonly in other areas of Asia, Africa, and South America, but testing of drug alternatives to chloroquine for treating P vivax infection has been very limited. Quinine, artemisinin derivatives, and atovaquone-proguanil are effective in vitro and have shown efficacy in small clinical studies.30-32 In the absence of good data on drug alternatives to chloroquine for P vivax, and in light of the low risk of complications in P vivax malaria, chloroquine remains the initial drug of choice for P vivax infection. Indications for using alternative therapy are worsening or new symptoms, persistent P vivax parasitemia after 72 hours, and possibly acquisition of infection in Oceania or India.

Treatment with medications other than chloroquine should be done in consultation with the CDC or a clinician experienced in treating malaria. Although scattered reports of P ovale and P malariae chloroquine resistance exist, resistance is not widespread and chloroquine remains first-line therapy for these parasites. Patients with P vivax and P ovale malaria should also receive a 2-week course of primaquine to eradicate dormant liver stages of these parasites. Prior to treatment with primaquine, all patients should be screened for glucose-6-phosphatase-dehydrogenase (G6PD) deficiency. Individuals with the severe form of G6PD deficiency may experience an oxidant hemolysis and methemoglobinemia with primaquine administration and should not receive primaquine. There are currently no effective alternatives to primaquine for liver-stage parasite eradication. Based on limited evidence, chloroquine plus sulfadoxine-pyrimethamine should be used to treat P knowlesi infections4,20; quinine is an alternative in severely ill patients.

Prevention

For those traveling to endemic areas, avoiding mosquitoes and using barrier protection from mosquitoes are important ways to prevent malaria . The Anopheles mosquito feeds from dusk to dawn. During these hours, travelers should remain in well-screened areas, wear clothing that covers most of the body, stay in air-conditioned areas where possible, sleep under a bednet (ideally one impregnated with permethrin), and use insect repellants with N-N-diethyl-m-toluamide (DEET). Repellants with low DEET concentrations (< 20%) are effective for only a short period of time. Rare instances of toxic encephalopathy have been reported in young children exposured to high concentrations of DEET, but using repellent with no more than 40% DEET and avoiding repeated applications minimizes the risk of this complication. Concentrations of 25% to 35% DEET, to be applied every 6 to 8 hours as needed, are recommended for children.33 A newer insect repellant called picaridin (5–10%) is odorless and does not leave a sticky residue like DEET, but it last for only 1 to 2 hours.34 Spraying clothing with permethrin, a synthetic pyrethroid, is a safe and effective method of reducing insect bites in children. Permethrin-sprayed clothes remain effective for at least 2 weeks, even with laundering.

Chemoprophylaxis is the cornerstone of malaria prevention for nonimmune children and adults who travel to malaria-endemic areas (Table 352-4). Weekly mefloquine is the drug of choice for malaria chemoprophylaxis in children and adults traveling to areas with chloroquine-resistant P falciparum. The FDA does not approve mefloquine for children who weigh less than 15 kilograms, but since the risks of acquiring severe malaria outweigh the risks of potential mefloquine toxicity in these children, the CDC recommends that mefloquine prophylaxis be used for all children. The lack of a liquid or suspension formulation sometimes makes mefloquine administration difficult, and potential side effects include nausea and vomiting. Mefloquine is better tolerated by children if it is disguised in other foods. Adults have 10% to 25% incidence of sleep disturbances and dysphoria with mefloquine, but these side effects appear to be less common in children. A reasonable alternative to mefloquine is the fixed combination of atovaquone and proguanil (trade name Malarone), which was recently approved by the FDA for the treatment and prophylaxis of chloroquine-resistant P falciparum malaria in adults and children. Clinical trials in areas endemic for chloroquine-resistant P falciparum have shown atovaquone/proguanil prophylaxis effective against P falciparum infection in both adults and children, with minimal side effects (abdominal pain, vomiting, and headache) that rarely resulted in discontinuation of the medication.

Atovaquone/proguanil is approved for children weighing more than 11 kilograms. The major disadvantage of atovaquone/proguanil prophylaxis is that it must be taken every day, so it may be better suited for prophylaxis during short exposure periods. Doxycycline is another alternative for prophylaxis, but it cannot be used in children less than 8 years old, and it must be taken every day. Photosensitivity is a common side effect, and vaginal candidiasis may occur in women on doxycycline prophylaxis. Chloroquine, chloroquine-proguanil, and azithromycin do not provide adequate protection for children traveling to a chloroquine-resistant malaria-endemic area. Daily primaquine has been used successfully as malaria prophylaxis in adults and children in areas endemic for chloroquine-resistant P falciparum; however, it has not yet been studied extensively enough in nonimmune children to be recommended as routine chemoprophylaxis for these areas. In locations where malaria remains chloroquine-sensitive, chloroquine is the drug of choice for prophylaxis. The CDC Web site (www.cdc.gov) and hotline number (770-488-7788) are useful resources for determining the current malaria prophylaxis guidelines for specific countries. No prophylaxis is completely effective, and travelers may develop malaria despite taking the recommended malaria chemoprophylaxis.

On leaving an area endemic for P vivax or P ovale after a prolonged visit (> 3 months), children may require “terminal prophylaxis” with primaquine (0.6 mg/kg base or 1.0 mg/kg salt daily, up to a maximum dose of 30 mg base or 52.6 mg salt, for 14 days) to eliminate extraerythrocytic forms of P vivax and P ovale and to prevent relapses. Primaquine can cause severe hemolysis in G6PD-deficient individuals, so it is mandatory to rule out G6PD deficiency by lab testing before primaquine is prescribed.

Small amounts of antimalarial drugs are secreted into the breast milk of lactating women. The amounts of transferred drug are not considered harmful but do not provide adequate prophylaxis against malaria. Breast-feeding children should take standard doses of malaria chemoprophylaxis. Lactating women should avoid using doxycycline, as prolonged infant exposure to doxycycline via breast milk could be harmful.

In malaria-endemic areas of Africa, studies have demonstrated that insecticide-treated bednets (ITNs) can reduce all-cause mortality in children by 17% to 63%. Large-scale distribution of long-lasting ITNs has been supported by several funding agencies and the World Health Organization and is now occurring in many countries in sub-Saharan Africa. There is early evidence from several countries of a significant reduction in mortality and morbidity following large-scale ITN distribution.35 Questions remain as to whether these interventions are sustainable and whether the protection from infection caused by using bednets will decrease malarial immunity in the children protected and thereby shift malarial morbidity and mortality to an older age in these children, but the evidence to date has not shown a shift in morbidity or mortality.36 In areas of lower transmission, indoor residual spraying with long-lasting pyrethroid insecticides also appears to be an effective way to decrease malaria transmission.

The formulation of a malaria vaccine has been a complex problem because of the many antigens present in both pre-erythrocytic and erythrocytic phases of the parasite, polymorphisms in the parasite, polymorphisms in the human host, and the lack of sustained immunity from natural infection. Numerous malaria vaccine trials are in progress, using components of pre-erythrocytic and erythrocytic malarial antigens. The RTS.S vaccine, a vaccine based on the pre-erythrocytic antigen circumsporozoite protein (CSP), is the first vaccine to show significant efficacy in African children with a protective efficacy of 35% against clinical malaria in children ages 1 to 4 years.37 Several additional trials of different age groups and dosing regimens are currently under way.

Finally, artemisinin combination therapies as first-line treatment for malaria in areas of increasing drug resistance may also help limit transmission by reducing gametocytes, as gametocytes are the form of parasite required for transmission to and development in the Anopheles mosquito. A multistrategy approach using some combination of insecticide-treated bednets or indoor residual spraying, artemisinin combination therapy, and a partially effective vaccine may be the most effective way to reduce malaria transmission. Malaria eradication, first proposed in the 1950s but unsuccessful at that time, is now being proposed again. The likelihood of success in malaria eradication will depend on many factors, including the long-term commitment by funding agencies and national governments to this goal; the extent to which effective interventions can be successfully implemented, particularly in difficult-to-reach or politically troubled areas; the development of drug and insecticide resistance; and the continuation of careful malaria surveillance and follow-up after case numbers decrease.