Etiology

Malaria is caused by intracellular Plasmodium protozoa transmitted to humans by female Anopheles mosquitoes. Prior to 2004, only 4 species of Plasmodium were known to cause malaria in humans: P. falciparum, P. malariae, P. ovale, and P. vivax. In 2004 P. knowlesi (a primate malaria species) was also shown to cause human malaria, and cases of P. knowlesi infection have been documented in Malaysia, Indonesia, Singapore, and the Philippines. Malaria also can be transmitted through blood transfusion, use of contaminated needles, and from a pregnant woman to her fetus. The risk for blood transmission is small and decreasing in the USA but may occur by way of whole blood, packed red blood cells, platelets, leukocytes, and organ transplantation.

Epidemiology

Malaria is a major worldwide problem, occurring in more than 100 countries with a combined population of over 1.6 billion people (Fig. 280-1). The principal areas of transmission are Africa, Asia, and South America. P. falciparum and P. malariae are found in most malarious areas. P. falciparum is the predominant species in Africa, Haiti, and New Guinea. P. vivax predominates in Bangladesh, Central America, India, Pakistan, and Sri Lanka. P. vivax and P. falciparum predominate in Southeast Asia, South America, and Oceania. P. ovale is the least common species and is transmitted primarily in Africa. Transmission of malaria has been eliminated in most of North America (including the USA), Europe, and the Caribbean, as well as Australia, Chile, Israel, Japan, Korea, Lebanon, and Taiwan.

Figure 280-1 Global spatial distribution of Plasmodium falciparum malaria in 2007 and preliminary global distribution of Plasmodium vivax malaria.

(From Crawley J, Chu C, Mtove G, et al: Malaria in children, Lancet 375:1468–1478, 2010, Fig 1, p 1469.)

Most cases of malaria in the USA occur among previously infected visitors to the USA from endemic areas and among U.S. citizens who travel to endemic areas without appropriate chemoprophylaxis. The most common regions of acquisition of the 10,100 cases of malaria reported to the Centers for Disease Control and Prevention (CDC) among U.S. citizens between 1985 and 2001 were sub-Saharan Africa (58%), Asia (18%), and the Caribbean and Central or South America (16%). Most of the fatal cases were caused by P. falciparum (94% or 66 of the 70 cases), of which 47 (71%) were acquired in sub-Saharan Africa. Rare cases of apparent locally transmitted malaria have been reported since the 1950s. These cases are likely due to transmission from untreated and often asymptomatic infected individuals from malaria endemic countries who travel to the USA and infect local mosquitoes or to infected mosquitoes from malaria endemic areas that are transported to the USA on airplanes.

Pathogenesis

Plasmodium species exist in a variety of forms and have a complex life cycle that enables them to survive in different cellular environments in the human host (asexual phase) and the mosquito (sexual phase) (Fig. 280-2). A marked amplification of Plasmodium, from approximately 10² to as many as 10¹⁴ organisms, occurs during a 2-step process in humans, with the 1st phase in hepatic cells (exoerythrocytic phase) and the 2nd phase in the red cells (erythrocytic phase). The exoerythrocytic phase begins with inoculation of sporozoites into the bloodstream by a female Anopheles mosquito. Within minutes, the sporozoites enter the hepatocytes of the liver, where they develop and multiply asexually as a schizont. After 1-2 wk, the hepatocytes rupture and release thousands of merozoites into the circulation. The tissue schizonts of P. falciparum, P. malariae, and apparently P. knowlesi rupture once and do not persist in the liver. There are 2 types of tissue schizonts for P. ovale and P. vivax. The primary type ruptures in 6-9 days, and the secondary type remains dormant in the liver cell for weeks, months, or as long as 5 yr before releasing merozoites and causing relapse of infection. The erythrocytic phase of Plasmodium asexual development begins when the merozoites from the liver penetrate erythrocytes. Once inside the erythrocyte, the parasite transforms into the ring form, which then enlarges to become a trophozoite. These latter 2 forms can be identified with Giemsa stain on blood smear, the primary means of confirming the diagnosis of malaria (Fig. 280-3). The trophozoite multiplies asexually to produce a number of small erythrocytic merozoites that are released into the bloodstream when the erythrocyte membrane ruptures, which is associated with fever. Over time, some of the merozoites develop into male and female gametocytes that complete the Plasmodium life cycle when they are ingested during a blood meal by the female anopheline mosquito. The male and female gametocytes fuse to form a zygote in the stomach cavity of the mosquito. After a series of further transformations, sporozoites enter the salivary gland of the mosquito and are inoculated into a new host with the next blood meal.

Figure 280-2 Life cycle of Plasmodium spp.

(From Centers for Disease Control and Prevention: Laboratory diagnosis of malaria: Plasmodium spp. [pdf]. www.dpd.cdc.gov/dpdx/HTML/PDF_Files/Parasitemia_and_LifeCycle.pdf. Accessed September 20, 2010.)

Figure 280-3 Giemsa-stained thick (A) and thin (B-H) smears used for the diagnosis of malaria and the speciation of Plasmodium parasites. A, Multiple signet-ring Plasmodium falciparum trophozoites, which are visualized outside erythrocytes. B, A multiply infected erythrocyte containing signet-ring P. falciparum trophozoites, including an accolade form positioned up against the inner surface of the erythrocyte membrane. C, Banana-shaped gametocyte unique to P. falciparum. D, Ameboid trophozoite characteristic of Plasmodium vivax. Both P. vivax– and Plasmodium ovale–infected erythrocytes exhibit Schuffner dots and tend to be enlarged compared with uninfected erythrocytes. E, P. vivax schizont. Mature P. falciparum parasites, by contrast, are rarely seen on blood smears because they sequester in the systemic microvasculature. F, P. vivax spherical gametocyte. G, P. ovale trophozoite. Note Schuffner dots and ovoid shapes of the infected erythrocyte. H, Characteristic band form trophozoite of Plasmodium malariae, containing intracellular pigment hemozoin.

(A, B, and F from Centers for Disease Control and Prevention: DPDx: laboratory identification of parasites of public health concern. www.dpd.cdc.gov/dpdx/. C, D, E, G, and H courtesy of David Wyler, Newton Centre, MA.)

Four important pathologic processes have been identified in patients with malaria: fever, anemia, immunopathologic events, and tissue anoxia. Fever occurs when erythrocytes rupture and release merozoites into the circulation. Anemia is caused by hemolysis, sequestration of erythrocytes in the spleen and other organs, and bone marrow suppression. Immunopathologic events that have been documented in patients with malaria include excessive production of proinflammatory cytokines, such as tumor necrosis factor, that may be responsible for most of the pathology of the disease, including tissue anoxia; polyclonal activation resulting in both hypergammaglobulinemia and the formation of immune complexes; and immunosuppression. Cytoadherence of infected erythrocytes to vascular endothelium occurs in P. falciparum malaria and may lead to obstruction of blood flow and capillary damage, with resultant vascular leakage of blood, protein, and fluid and tissue anoxia. In addition, hypoglycemia and lactic acidemia are caused by anaerobic metabolism of glucose. The cumulative effects of these pathologic processes may lead to cerebral, cardiac, pulmonary, intestinal, renal, and hepatic failure.

Immunity after Plasmodium species infection is incomplete, preventing severe disease but still allowing future infection. In some cases, parasites circulate in small numbers for a long time but are prevented from rapidly multiplying and causing severe illness. Repeated episodes of infection occur because the parasite has developed a number of immune evasive strategies, such as intracellular replication, vascular cytoadherence that prevents infected erythrocytes from circulating through the spleen, rapid antigenic variation, and alteration of the host immune system resulting in partial immune suppression. The human host response to Plasmodium infection includes natural immune mechanisms that prevent infection by other Plasmodium species, such as those of birds or rodents, as well as several alterations in erythrocyte physiology that prevent or modify malarial infection. Erythrocytes containing hemoglobin S (sickle erythrocytes) resist malaria parasite growth, erythrocytes lacking Duffy blood group antigen are resistant to P. vivax, and erythrocytes containing hemoglobin F (fetal hemoglobin) and ovalocytes are resistant to P. falciparum. In hyperendemic areas, newborns rarely become ill with malaria, in part because of passive maternal antibody and high levels of fetal hemoglobin. Children 3 mo to 2-5 yr of age have little specific immunity to malaria species and therefore suffer yearly attacks of debilitating and potentially fatal disease. Immunity is subsequently acquired, and severe cases of malaria become less common. Severe disease may occur during pregnancy, particularly 1st pregnancies or after extended residence outside the endemic region. In general, extracellular Plasmodium organisms are targeted by antibody, whereas intracellular organisms are targeted by cellular defenses such as T lymphocytes, macrophages, polymorphonuclear leukocytes, and the spleen.

Clinical Manifestations

Children and adults are asymptomatic during the initial phase of infection, the incubation period of malaria infection. The usual incubation periods are 9-14 days for P. falciparum, 12-17 days for P. vivax, 16-18 days for P. ovale, and 18-40 days for P. malariae. The incubation period can be as long as 6-12 mo for P. vivax and can also be prolonged for patients with partial immunity or incomplete chemoprophylaxis. A prodrome lasting 2-3 days is noted in some patients before parasites are detected in the blood. Prodromal symptoms include headache, fatigue, anorexia, myalgia, slight fever, and pain in the chest, abdomen, and joints.

The classic presentation of malaria is seldom noted with other infectious diseases and consists of paroxysms of fever alternating with periods of fatigue but otherwise relative wellness. Febrile paroxysms are characterized by high fever, sweats, and headache, as well as myalgia, back pain, abdominal pain, nausea, vomiting, diarrhea, pallor, and jaundice. Paroxysms coincide with the rupture of schizonts that occurs every 48 hr with P. vivax and P. ovale, resulting in fever spikes every other day. Rupture of schizonts occurs every 72 hr with P. malariae, resulting in fever spikes every 3rd or 4th day. Periodicity is less apparent with P. falciparum and mixed infections and may not be apparent early on in infection, when parasite broods have not yet synchronized. Patients with primary infection, such as travelers from nonendemic regions, also may have irregular symptomatic episodes for 2-3 days before regular paroxysms begin. Children with malaria often lack typical paroxysms and have nonspecific symptoms, including fever (may be low-grade but is often greater than 104°F), headache, drowsiness, anorexia, nausea, vomiting, and diarrhea. Distinctive physical signs may include splenomegaly (common), hepatomegaly, and pallor due to anemia. Typical laboratory findings include anemia, thrombocytopenia, and a normal or low leukocyte count. The erythrocyte sedimentation rate (ESR) is often elevated.

P. falciparum is the most severe form of malaria and is associated with higher density parasitemia and a number of complications. The most common serious complication is severe anemia, which also is associated with other malaria species. Serious complications that appear unique to P. falciparum include cerebral malaria, acute renal failure, respiratory distress from metabolic acidosis, algid malaria and bleeding diatheses (see later section on complications, and Table 280-1). The diagnosis of P. falciparum malaria in a nonimmune individual constitutes a medical emergency. Severe complications and death can occur if appropriate therapy is not instituted promptly. In contrast to malaria caused by P. ovale, P. vivax, and P. malariae, which usually results in parasitemias of less than 2%, malaria caused by P. falciparum can be associated with parasitemia levels as high as 60%. The differences in parasitemia reflect the fact that P. falciparum infects both immature and mature erythrocytes, while P. ovale and P. vivax primarily infect immature erythrocytes and P. malariae infects only mature erythrocytes. Like P. falciparum, P. knowlesi has a 24 hr replication cycle and can also lead to very high density parasitemia.

P. vivax malaria has long been considered less severe than P. falciparum malaria, but recent reports suggest that in some areas of Indonesia it is as frequent a cause of severe disease and death as P. falciparum. Severe disease and death from P. vivax are usually due to severe anemia and sometimes to splenic rupture. P. ovale malaria is the least common type of malaria. It is similar to P. vivax malaria and commonly is found in conjunction with P. falciparum malaria. P. malariae is the mildest and most chronic of all malaria infections. Nephrotic syndrome is a rare complication of P. malariae infection that is not observed with any other human malaria species. Nephrotic syndrome associated with P. malariae infection is poorly responsive to steroids. Low-level, undetected P. malariae infection may be present for years and is sometimes unmasked by immunosuppression or physiological stress such as splenectomy or corticosteroid treatment.

Recrudescence after a primary attack may occur from the survival of erythrocyte forms in the bloodstream. Long-term relapse is caused by release of merozoites from an exoerythrocytic source in the liver, which occurs with P. vivax and P. ovale, or from persistence within the erythrocyte, which occurs with P. malariae and rarely with P. falciparum. A history of typical symptoms in a person more than 4 wk after return from an endemic area is therefore more likely to be P. vivax, P. ovale, or P. malariae infection than P. falciparum infection. In the most recent survey of malaria in the USA among individuals in whom a malaria species was identified, 48.6% of cases were due to P. falciparum, 22. 1% to P. vivax, 3.5% to P. malariae, and 2.5% to P. ovale. Ninety-four percent of P. falciparum infections were diagnosed within 30 days of arrival in the USA, and 99% within 90 days of arrival. In contrast, 50.7% of P. vivax cases occurred more than 30 days after arrival in the USA.

Congenital malaria is acquired from the mother prenatally or perinatally and is a serious problem in tropical areas but is rarely reported in the USA. In endemic areas, congenital malaria is an important cause of abortions, miscarriages, stillbirths, premature births, intrauterine growth retardation, and neonatal deaths. Congenital malaria usually occurs in the offspring of a nonimmune mother with P. vivax or P. malariae infection, although it can be observed with any of the human malaria species. The 1st sign or symptom most commonly occurs between 10 and 30 days of age (range 14 hr to several months of age). Signs and symptoms include fever, restlessness, drowsiness, pallor, jaundice, poor feeding, vomiting, diarrhea, cyanosis, and hepatosplenomegaly. Malaria is often severe during pregnancy and may have an adverse effect on the fetus or neonate, resulting in intrauterine growth retardation and low birthweight, even in the absence of transmission from mother to child.

Diagnosis

Any child who presents with fever or unexplained systemic illness and has traveled or resided in a malaria-endemic area within the previous year should be assumed to have life-threatening malaria until proven otherwise. Malaria should be considered regardless of the use of chemoprophylaxis. Important criteria that suggest P. falciparum malaria include symptoms occurring less than 1 mo after return from an endemic area, more than 2% parasitemia, ring forms with double chromatin dots, and erythrocytes infected with more than 1 parasite.

The diagnosis of malaria is established by identification of organisms on Giemsa-stained smears of peripheral blood (see Fig. 280-3) or by rapid immunochromatographic assay. Giemsa stain is superior to Wright stain or Leishman stain. Both thick and thin blood smears should be examined. The concentration of erythrocytes on a thick smear is 20-40 times that on a thin smear and is used to quickly scan large numbers of erythrocytes. The thin smear allows for positive identification of the malaria species and determination of the percentage of infected erythrocytes and is useful in following the response to therapy. Identification of the species is best made by an experienced microscopist and checked against color plates of the various Plasmodium species (see Fig. 280-3). Morphologically it is impossible to distinguish P. knowlesi from P. malariae, so polymerase chain reaction (PCR) detection by a reference lab or the CDC is required. Although P. falciparum is most likely to be identified from blood just after a febrile paroxysm, the timing of the smears is less important than their being obtained several times a day over a period of 3 successive days. A single negative blood smear does not exclude malaria. Most symptomatic patients with malaria will have detectable parasites on thick blood smears within 48 hr. For nonimmune persons, symptoms typically occur 1 to 2 days before parasites are detectable on blood smear.

The BinaxNOW Malaria test is approved by the U.S. Food and Drug Administration (FDA) 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. Aldolase is present in all 5 of the malaria species that infect humans. Thus, a positive result for P. vivax could be due to P. ovale or P. malariae infection. Sensitivity and specificity for P. falciparum (94-99% and 94-99%, respectively) and P. vivax (87-93% and 99%, respectively) are good, but sensitivity for P. ovale and P. malariae are lower. Sensitivity for P. falciparum decreases at lower levels of parasitemia, so microscopy is still advised in areas where expert microscopy is available. The test is simple to perform and can be done in the field or laboratory in 10 min. PCR is even more sensitive than microscopy but is technically more complex. It is available in some reference laboratories, but the time delay in availability of results generally precludes its use for acute diagnosis of malaria.

Differential Diagnosis

The differential diagnosis of malaria is broad and includes viral infections such as influenza and hepatitis, sepsis, pneumonia, meningitis, encephalitis, endocarditis, gastroenteritis, pyelonephritis, babesiosis, brucellosis, leptospirosis, tuberculosis, relapsing fever, typhoid fever, yellow fever, amebic liver abscess, Hodgkin disease, and collagen vascular disease.

Treatment

Physicians caring for patients with malaria or traveling to endemic areas need to be aware of current information regarding malaria because the problem of resistance to antimalarial drugs is changing and has greatly complicated therapy and prophylaxis. The best source for such information is the CDC Malaria Hotline, which is available to physicians 24 hr a day (770-488-7788 from 8:00 A.M. to 4:30 P.M. Eastern Standard Time (EST) and 770-488-7100 from 4:30 P.M. to 8:00 A.M. EST on weekends and holidays; ask the operator to page the person on call for the Malaria Epidemiology Branch). Fever without an obvious cause in any patient who has left a P. falciparum endemic area within 30 days and is nonimmune should be considered a medical emergency. Thick and thin blood smears should be obtained immediately, and all children with symptoms of severe disease should be hospitalized. If blood films are negative, they should be repeated every few hours. If the patient is severely ill, antimalarial therapy should be initiated immediately. Outpatient therapy generally is not given to nonimmune children but may be considered in immune or semi-immune children who have low-level parasitemia (less than 1%), no evidence of complications defined by the World Health Organization (WHO), no vomiting, and a lack of toxic appearance; who are able to contact the physician or emergency department at any time; and in whom follow-up within 24 hr is assured.

Complications of P. Falciparum Malaria

WHO has identified 10 complications of P. falciparum malaria that define severe malaria (see Table 280-1). The most common complications in children are severe anemia, impaired consciousness (including cerebral malaria), respiratory distress (due to metabolic acidosis), multiple seizures, prostration, and jaundice.

Severe malarial anemia (hemoglobin level less than 5 g/dL) is the most common severe complication of malaria in children and is the leading cause of anemia leading to hospital admission in African children. Anemia is associated with hemolysis, but removal of infected erythrocytes by the spleen and impairment of erythropoiesis likely play a greater role than hemolysis in the pathogenesis of severe malarial anemia. The primary treatment for severe malarial anemia is blood transfusion. With appropriate and timely treatment, severe malarial anemia usually has a relatively low mortality (~1%).

Cerebral malaria is defined as the presence of coma in a child with P. falciparum parasitemia and an absence of other reasons for coma. Children with altered mental status who are not in coma fall into the larger category of impaired consciousness. Cerebral malaria is most common in children in areas of midlevel transmission and in adolescents or adults in areas of very low transmission. It is less frequently seen in areas of very high transmission. Cerebral malaria often develops after the patient has been ill for several days but may develop precipitously. Cerebral malaria is associated with a fatality rate of 20-40% and is associated with long-term cognitive impairment in children. Repeated seizures are frequent in children with cerebral malaria. Hypoglycemia is common, but children with true cerebral malaria fail to arouse from coma even after receiving a dextrose infusion that normalizes their glucose level. Physical findings may be normal or may include high fever, seizures, muscular twitching, rhythmic movement of the head or extremities, contracted or unequal pupils, retinal hemorrhages, hemiplegia, absent or exaggerated deep tendon reflexes, and a positive Babinski sign. Lumbar puncture reveals increased pressure and cerebrospinal fluid protein with no pleocytosis and normal glucose and protein concentrations. Treatment of cerebral malaria other than antimalarial medications is largely supportive and includes evaluation of and treatment of seizures and hypoglycemia. Although increased intracranial pressure has been documented in some children with cerebral malaria, treatment with mannitol and corticosteroids has not improved outcomes in these children.

Respiratory distress is a poor prognostic indicator in severe malaria and appears to be due to metabolic acidosis rather than intrinsic pulmonary disease. To date, no successful interventions for treatment of metabolic acidosis in children with severe malaria have been described, but trials of dichloroacetate treatment and fluid expansion are ongoing.

Seizures are a common complication of severe malaria, particularly cerebral malaria. Benzodiazepines are first-line therapy for seizures, and intrarectal diazepam has been used successfully in children with malaria and seizures. Many seizures resolve with a single dose of diazepam. For persistent seizures, phenobarbital or phenytoin are the standard medications used. Phenytoin may be preferred for seizure treatment, particularly in hospitals or clinics where ventilatory support is not available. However, no comparative trials of the 2 drugs have been performed, and phenytoin is considerably more expensive than phenobarbital. There are currently no drugs recommended for seizure prophylaxis in children with severe malaria. Phenobarbital prophylaxis decreased seizure activity but increased mortality in 1 major study of children with severe malaria, probably because of the respiratory depression associated with phenobarbital that may have been exacerbated by benzodiazepine therapy.

Hypoglycemia is a complication of malaria that is more common in children, pregnant women, and patients receiving quinine therapy. Patients may have a decreased level of consciousness that can be confused with cerebral malaria. Any child with impaired consciousness and malaria should have a glucose level checked, and if glucometers are not available, an empirical bolus of dextrose should be given. Hypoglycemia is associated with increased mortality and neurologic sequelae.

Circulatory collapse (algid malaria) is a rare complication that manifests as hypotension, hypothermia, rapid weak pulse, shallow breathing, pallor, and vascular collapse. Death may occur within hours. Severe malaria is occasionally accompanied by bacteremia, which may have been the cause of some of the cases previously referred to as algid malaria. Any child with severe malaria and hypotension should have a blood culture obtained and be treated empirically for bacterial sepsis.

Long-term cognitive impairment occurs in 25% of children with cerebral malaria and also occurs in children with repeated episodes of uncomplicated disease. Prevention of attacks in these children significantly improves educational attainment.

Tropical splenomegaly syndrome is a chronic complication of P. falciparum malaria in which massive splenomegaly persists after treatment of acute infection. The syndrome is characterized by marked splenomegaly, hepatomegaly, anemia, and an elevated IgM level. Tropical splenomegaly syndrome is thought to be caused by an impaired immune response to P. falciparum antigens. Prolonged antimalarial prophylaxis (for at least several years) is required to treat this syndrome if the child remains in a malaria endemic area. Spleen size gradually regresses on antimalarial prophylaxis but often increases again if prophylaxis is stopped.

Other complications in children include jaundice, which is associated with a worse outcome, and prostration. Prostration is defined as the inability to sit, stand, or eat without support, in the absence of impaired consciousness. Prostration also has been associated with increased mortality in some studies, but the pathophysiology of this process is not well understood. Uncommon complications include hemoglobinuria, abnormal bleeding, pulmonary edema, and renal failure. These are uncommon complications in children with severe malaria and are more common in adults, particularly pulmonary edema and renal failure.

Prevention

Malaria prevention consists of reducing exposure to infected mosquitoes and chemoprophylaxis. The most accurate and current information on areas in the world where malaria risk and drug resistance exist can be obtained by contacting local and state health departments or the CDC or consulting Health Information for International Travel, which is published by the U.S. Public Health Service.

Travelers to endemic areas should remain in well-screened areas from dusk to dawn, when the risk for transmission is highest. They should sleep under permethrin-treated mosquito netting and spray insecticides indoors at sundown. During the day the travelers should wear clothing that covers the arms and legs, with trousers tucked into shoes or boots. Mosquito repellent should be applied to thin clothing and exposed areas of the skin, with applications repeated every 1-2 hr. A child should not be taken outside from dusk to dawn, but if at risk for exposure, a solution with 25-35% DEET (not greater than 40%) should be applied to exposed areas except for the eyes, mouth, or hands. Hands are excluded because they are often placed in the mouth. DEET should then be washed off as soon as the child comes back inside. The American Academy of Pediatrics recommends that DEET solutions be avoided in children less than 2 mo of age. Adverse reactions to DEET include rashes, toxic encephalopathy, and seizures, but these reactions occur almost exclusively with inappropriate application of high concentrations of DEET. Even with these precautions, a child should be taken to a physician immediately if he or she develops illness when traveling to a malarious area.

Chemoprophylaxis is necessary for all visitors to and residents of the tropics who have not lived there since infancy, including children of all ages (Table 280-3). Health care providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients. Chloroquine is given in the few remaining areas of the world free of chloroquine-resistant malaria strains. In areas where chloroquine-resistant P. falciparum exists, atovaquone-proguanil, mefloquine, or doxycycline may be given as chemoprophylaxis. Atovaquone-proguanil is generally recommended for shorter trips (up to 2 wk), since it must be taken daily. Pediatric tablets are available and are generally well tolerated, although the taste is sometimes unpleasant to very young children. For longer trips, mefloquine is preferred, as it is given only once a week. Mefloquine does not have a pediatric formulation and has an unpleasant taste that usually requires that the cut tablet be “disguised” in another food, such as chocolate syrup. Mefloquine should not be given to children if they have a known hypersensitivity to mefloquine, are receiving cardiotropic drugs, have a history of convulsive or certain psychiatric disorders, or travel to an area where mefloquine resistance exists (the borders of Thailand with Myanmar and Cambodia, the western provinces of Cambodia, and the eastern states of Myanmar). Atovaqoune-proguanil is started 1-2 days before travel, and mefloquine is started 2 wk before travel. It is important that these doses are given, both to allow therapeutic levels of the drugs to be achieved and also to be sure that the drugs are tolerated. Doxycycline is an alternative for children over 8 yr of age. It must be given daily and should be given with food. Side effects of doxycycline include photosensitivity and vaginal yeast infections. Provision of medication for self-treatment is controversial, but it can be considered in individuals who refuse to take prophylaxis or will be in very remote areas without accessible medical care. Provision of medication for self-treatment of malaria should be done in consultation with a travel medicine specialist, and the medication provided should be different than that used for prophylaxis.

Table 280-3 CHEMOPROPHYLAXIS OF MALARIA FOR CHILDREN

A number of other efforts are currently underway to prevent malaria in malaria endemic countries. Some have been highly successful, leading to a significant decrease in malaria incidence in many countries in Africa, Asia, and South America in the last 5 yr. These interventions include the use of insecticide-treated bed nets (which have decreased all-cause mortality in children under 5 yr of age in several highly malaria endemic areas by ~20%), indoor residual spraying with long-lasting insecticides, and the use of artemisinin-combination therapy for first-line malaria treatment. The 1st malaria vaccine to have any degree of efficacy is the RTS,S vaccine, which is based on the circumsporozoite protein of P. falciparum. In various clinical trials, this vaccine has shown an efficacy of 26-56% against uncomplicated malaria and 38-50% against severe malaria in young children in malaria endemic areas in periods as long as 45 mo after vaccination. The vaccine is now in large phase III trials. Given the relatively low efficacy of this vaccine, it will likely be used as part of a multipronged strategy in endemic areas that includes the already successful interventions mentioned. Numerous other vaccines are also in current clinical trials, and it is hoped that future vaccines will improve upon the efficacy of the RTS,S vaccine. There is currently no vaccine with sufficient efficacy to be considered for prevention of malaria in travelers.