Humanity has but three great enemies: Fever, famine, and war; of these by far the greatest, by far the most terrible, is fever.
Malaria is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes. The most important of the parasitic diseases of humans, it is transmitted in 106 countries containing 3 billion people and causes approximately 2000 deaths each day; mortality rates are decreasing as a result of highly effective control programs in several countries. Malaria has been eliminated from the United States, Canada, Europe, and Russia; in the late twentieth and early twenty-first centuries, however, its prevalence rose in many parts of the tropics. Increases in the drug resistance of the parasite, the insecticide resistance of its vectors, and human travel and migration have contributed to this resurgence. Occasional local transmission after importation of malaria has occurred in several southern and eastern areas of the United States and in Europe, indicating the continual danger to nonmalarious countries. Although there are many successful new control initiatives as well as promising research initiatives, malaria remains today, as it has been for centuries, a heavy burden on tropical communities, a threat to nonendemic countries, and a danger to travelers.
ETIOLOGY AND PATHOGENESIS
Six species of the genus Plasmodium cause nearly all malarial infections in humans. These are P. falciparum, P. vivax, two morphologically identical sympatric species of P. ovale (as suggested by recent evidence), P. malariae, and—in Southeast Asia—the monkey malaria parasite P. knowlesi (Table 248-1). While almost all deaths are caused by falciparum malaria, P. knowlesi and occasionally P. vivax also can cause severe illness. Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal (Fig. 248-1). These microscopic motile forms of the malaria parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction. By this amplification process (known as intrahepatic or preerythrocytic schizogony or merogony), a single sporozoite eventually may produce from 10,000 to >30,000 daughter merozoites. The swollen infected liver cells eventually burst, discharging motile merozoites into the bloodstream. These merozoites then invade the red blood cells (RBCs) and multiply six- to twentyfold every 48 h (P. knowlesi, 24 h; P. malariae, 72 h). When the parasites reach densities of ~50/μL of blood (~100 million parasites in the blood of an adult), the symptomatic stage of the infection begins. In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain inert for a period ranging from 3 weeks to ≥1 year before reproduction begins. These dormant forms, or hypnozoites, are the cause of the relapses that characterize infection with these two species.
TABLE 248-1Characteristics of Plasmodium Species Infecting Humans ||Download (.pdf) TABLE 248-1Characteristics of Plasmodium Species Infecting Humans
| ||Finding for Indicated Speciesa |
|Characteristic ||P. falciparum ||P. vivax ||P. ovale ||P. malariae |
|Duration of intrahepatic phase (days) ||5.5 ||8 ||9 ||15 |
|Number of merozoites released per infected hepatocyte ||30,000 ||10,000 ||15,000 ||15,000 |
|Duration of erythrocytic cycle (hours) ||48 ||48 ||50 ||72 |
|Red cell preference ||Younger cells (but can invade cells of all ages) ||Reticulocytes and cells up to 2 weeks old ||Reticulocytes ||Older cells |
|Morphology ||Usually only ring formsb; banana-shaped gametocytes ||Irregularly shaped large rings and trophozoites; enlarged erythrocytes; Schüffner’s dots ||Infected erythrocytes, enlarged and oval with tufted ends; Schüffner’s dots ||Band or rectangular forms of trophozoites common |
|Pigment color ||Black ||Yellow-brown ||Dark brown ||Brown-black |
|Ability to cause relapses ||No ||Yes ||Yes ||No |
The malaria transmission cycle from mosquito to human and targets of immunity. RBC, red blood cell.
After entry into the bloodstream, merozoites rapidly invade erythrocytes and become trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. For P. falciparum, the reticulocyte-binding protein homologue 5 (PfRh5) is indispensable for erythrocyte invasion. Basigin (CD147, EMMPRIN) is the erythrocyte receptor of PfRh5. In the case of P. vivax, this receptor is related to the Duffy blood-group antigen Fya or Fyb. Most West Africans and people with origins in that region carry the Duffy-negative FyFy phenotype and are therefore resistant to P. vivax malaria. During the early stage of intraerythrocytic development, the small “ring forms” of the different parasitic species appear similar under light microscopy. As the trophozoites enlarge, species-specific characteristics become evident, pigment becomes visible, and the parasite assumes an irregular or ameboid shape. By the end of the intraerythrocytic life cycle, the parasite has consumed two-thirds of the RBC’s hemoglobin and has grown to occupy most of the cell. It is now called a schizont. Multiple nuclear divisions have taken place (schizogony or merogony). The RBC then ruptures to release 6–30 daughter merozoites, each potentially capable of invading a new RBC and repeating the cycle. The disease in human beings is caused by the direct effects of the asexual parasite—RBC invasion and destruction—and by the host’s reaction. After release from the liver (P. vivax, P. ovale, P. malariae, P. knowlesi), some of the blood-stage parasites develop into morphologically distinct, longer-lived sexual forms (gametocytes) that can transmit malaria. In falciparum malaria, a delay of several asexual cycles precedes this switch to gametocytogenesis.
After being ingested in the blood meal of a biting female anopheline mosquito, the male and female gametocytes form a zygote in the insect’s midgut. This zygote matures into an ookinete, which penetrates and encysts in the mosquito’s gut wall. The resulting oocyst expands by asexual division until it bursts to liberate myriad motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into another human at the next feeding.
Malaria occurs throughout most of the tropical regions of the world (Fig. 248-2). P. falciparum predominates in Africa, New Guinea, and Hispaniola (i.e., the Dominican Republic and Haiti); P. vivax is more common in Central America. The prevalence of these two species is approximately equal in South America, the Indian subcontinent, eastern Asia, and Oceania. P. malariae is found in most endemic areas, especially throughout sub-Saharan Africa, but is much less common. P. ovale is relatively unusual outside of Africa and, where it is found, comprises <1% of isolates. Patients infected with P. knowlesi have been identified on the island of Borneo and, to a lesser extent, elsewhere in Southeast Asia, where the main hosts, long-tailed and pig-tailed macaques, are found.
Malaria-endemic countries in the Americas (bottom) and in Africa, the Middle East, Asia, and the South Pacific (top), 2007. CAR, Central African Republic; DROC, Democratic Republic of the Congo; UAE, United Arab Emirates. Several countries in the Americas, the Middle East, and North Africa are close to eliminating malaria.
The epidemiology of malaria is complex and may vary considerably even within relatively small geographic areas. Endemicity traditionally has been defined in terms of parasitemia rates or palpable-spleen rates in children 2–9 years of age and classified as hypoendemic (<10%), mesoendemic (11–50%), hyperendemic (51–75%), and holoendemic (>75%). Until recently, it was uncommon to use these indices for planning control programs; however, many countries are now conducting national surveys to assess program progress. In holo- and hyperendemic areas (e.g., certain regions of tropical Africa or coastal New Guinea) where there is intense P. falciparum transmission, people may sustain more than one infectious mosquito bite per day and are infected repeatedly throughout their lives. In such settings, rates of morbidity and mortality due to malaria are considerable during early childhood. Immunity against disease is hard won in these areas, and the burden of disease in young children is high; by adulthood, however, most malarial infections are asymptomatic. As control measures progress and urbanization expands, environmental conditions become less conducive to transmission, and all age groups may lose protective immunity and become susceptible to illness. Constant, frequent, year-round infection is termed stable transmission. In areas where transmission is low, erratic, or focal, full protective immunity is not acquired, and symptomatic disease may occur at all ages. This situation usually exists in hypoendemic areas and is termed unstable transmission. Even in stable-transmission areas, there is often an increased incidence of symptomatic malaria coinciding with increased mosquito breeding and transmission during the rainy season. Malaria can behave like an epidemic disease in some areas, particularly those with unstable malaria, such as northern India (the Punjab region), the horn of Africa, Rwanda, Burundi, southern Africa, and Madagascar. An epidemic can develop when there are changes in environmental, economic, or social conditions, such as heavy rains following drought or migrations (usually of refugees or workers) from a nonmalarious region to an area of high transmission, along with failure to invest in national programs; a breakdown in malaria control and prevention services caused by war or civil disorder can intensify epidemic conditions. This situation usually results in considerable mortality among all age groups.
The principal determinants of the epidemiology of malaria are the number (density), the human-biting habits, and the longevity of the anopheline mosquito vectors. More than 100 of the >400 anopheline species can transmit malaria, but the ~40 species that do so commonly vary considerably in their efficiency as malaria vectors. More specifically, the transmission of malaria is directly proportional to the density of the vector, the square of the number of human bites per day per mosquito, and the tenth power of the probability of the mosquito’s surviving for 1 day. Mosquito longevity is particularly important because the portion of the parasite’s life cycle that takes place within the mosquito—from gametocyte ingestion to subsequent inoculation (sporogony)—lasts 8–30 days, depending on ambient temperature; thus, to transmit malaria, the mosquito must survive for >7 days. Sporogony is not completed at cooler temperatures—i.e., <16°C (60.8°F) for P. vivax and <21°C (69.8°F) for P. falciparum; thus transmission does not occur below these temperatures or at high altitudes, although malaria outbreaks and transmission have occurred in the highlands (>1500 m) of eastern Africa, which were previously free of vectors. The most effective mosquito vectors of malaria are those, such as Anopheles gambiae in Africa, that are long-lived, occur in high densities in tropical climates, breed readily, and bite humans in preference to other animals. The entomologic inoculation rate (i.e., the number of sporozoite-positive mosquito bites per person per year) is the most common measure of malaria transmission and varies from <1 in some parts of Latin America and Southeast Asia to >300 in parts of tropical Africa.
ERYTHROCYTE CHANGES IN MALARIA
After invading an erythrocyte, the growing malarial parasite progressively consumes and degrades intracellular proteins, principally hemoglobin. The potentially toxic heme is detoxified by lipid-mediated crystallization to biologically inert hemozoin (malaria pigment). The parasite also alters the RBC membrane by changing its transport properties, exposing cryptic surface antigens, and inserting new parasite-derived proteins. The RBC becomes more irregular in shape, more antigenic, and less deformable.
In P. falciparum infections, membrane protuberances appear on the erythrocyte’s surface 12–15 h after the cell’s invasion. These “knobs” extrude a high-molecular-weight, antigenically variant, strain-specific erythrocyte membrane adhesive protein (PfEMP1) that mediates attachment to receptors on venular and capillary endothelium—an event termed cytoadherence. Several vascular receptors have been identified, of which intercellular adhesion molecule 1 is probably the most important in the brain, chondroitin sulfate B in the placenta, and CD36 in most other organs. Thus, the infected erythrocytes stick inside and eventually block capillaries and venules. At the same stage, these P. falciparum–infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythrocytes (agglutination). The processes of cytoadherence, rosetting, and agglutination are central to the pathogenesis of falciparum malaria. They result in the sequestration of RBCs containing mature forms of the parasite in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the principal host defense mechanism: splenic processing and filtration. As a consequence, only the younger ring forms of the asexual parasites are seen circulating in the peripheral blood in falciparum malaria, and the level of peripheral parasitemia underestimates the true number of parasites within the body. Severe malaria is also associated with reduced deformability of the uninfected erythrocytes, which compromises their passage through the partially obstructed capillaries and venules and shortens RBC survival.
In the other human malarias, sequestration does not occur, and all stages of the parasite’s development are evident on peripheral-blood smears. Whereas P. vivax, P. ovale, and P. malariae show a marked predilection for either young RBCs (P. vivax, P. ovale) or old cells (P. malariae) and produce a level of parasitemia that is seldom >2%, P. falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.
Initially, the host responds to plasmodial infection by activating nonspecific defense mechanisms. Splenic immunologic and filtrative clearance functions are augmented in malaria, and the removal of both parasitized and uninfected erythrocytes is accelerated. The spleen is able to remove damaged ring-form parasites and return the once-infected erythrocytes to the circulation, where their survival period is shortened. The parasitized cells escaping splenic removal are destroyed when the schizont ruptures. The material released induces the activation of macrophages and the release of proinflammatory cytokines, which cause fever and exert other pathologic effects. Temperatures of ≥40°C (104°F) damage mature parasites; in untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally served to characterize the different malarias. These regular fever patterns (quotidian, daily; tertian, every 2 days; quartan, every 3 days) are seldom seen today in patients who receive prompt and effective antimalarial treatment.
The geographic distributions of sickle cell disease, hemoglobins C and E, hereditary ovalocytosis, the thalassemias, and glucose-6-phosphate dehydrogenase (G6PD) deficiency closely resemble that of falciparum malaria before the introduction of control measures. This similarity suggests that these genetic disorders confer protection against death from falciparum malaria. For example, HbA/S heterozygotes (sickle cell trait) have a sixfold reduction in the risk of dying from severe falciparum malaria. Hemoglobin S–containing RBCs impair parasite growth at low oxygen tensions, and P. falciparum–infected RBCs containing hemoglobins S and C exhibit reduced cytoadherence because of reduced surface presentation of the adhesin PfEMP1. Parasite multiplication in HbA/E heterozygotes is reduced at high parasite densities. In Melanesia, children with α-thalassemia appear to have more frequent malaria (both vivax and falciparum) in the early years of life, and this pattern of infection appears to protect them against severe disease. In Melanesian ovalocytosis, rigid erythrocytes resist merozoite invasion, and the intraerythrocytic milieu is hostile.
Nonspecific host defense mechanisms stop the infection’s expansion, and the subsequent strain-specific immune response then controls the infection. Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection. As a result of this state of infection without illness (premunition), asymptomatic parasitemia is common among adults and older children living in regions with stable and intense transmission (i.e., holo- or hyperendemic areas) and also in parts of low-transmission areas. Immunity is mainly specific for both the species and the strain of infecting malarial parasite. Both humoral immunity and cellular immunity are necessary for protection, but the mechanisms of each are incompletely understood (Fig. 248-1). Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA, although much of this antibody is unrelated to protection. Antibodies to a variety of parasitic antigens presumably act in concert to limit in vivo replication of the parasite. In the case of falciparum malaria, the most important of these antigens is the surface adhesin—the variant protein PfEMP1. Passively transferred IgG from immune adults has been shown to reduce levels of parasitemia in children. Passive transfer of maternal antibody contributes to the relative (but not complete) protection of infants from severe malaria in the first months of life. This complex immunity to disease declines when a person lives outside an endemic area for several months or longer.
Several factors retard the development of cellular immunity to malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T cell recognition; malaria antigen–specific immune unresponsiveness; and the enormous strain diversity of malarial parasites, along with the ability of the parasites to express variant immunodominant antigens on the erythrocyte surface that change during the course of infection. Parasites may persist in the blood for months or years (or, in the case of P. malariae, for decades) if treatment is not given. The complexity of the immune response in malaria, the sophistication of the parasites’ evasion mechanisms, and the lack of a good in vitro correlate with clinical immunity have all slowed progress toward an effective vaccine.
Malaria is a very common cause of fever in tropical countries. The first symptoms of malaria are nonspecific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, cough, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, the neck stiffness and photophobia seen in meningitis do not occur. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale. The fever is usually irregular at first (that of falciparum malaria may never become regular); the temperature of nonimmune individuals and children often rises above 40°C (104°F) in conjunction with tachycardia and sometimes delirium. Although childhood febrile convulsions may occur with any of the malarias, generalized seizures are specifically associated with falciparum malaria and may herald the development of encephalopathy (cerebral malaria). Many clinical abnormalities have been described in acute malaria, but most patients with uncomplicated infections have few abnormal physical findings other than fever, malaise, mild anemia, and (in some cases) a palpable spleen. Anemia is common among young children living in areas with stable transmission, particularly where resistance has compromised the efficacy of antimalarial drugs. In nonimmune individuals with acute malaria, the spleen takes several days to become palpable, but splenic enlargement is found in a high proportion of otherwise healthy individuals in malaria-endemic areas and reflects repeated infections. Slight enlargement of the liver is also common, particularly among young children. Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated malaria and usually resolves over 1–3 weeks. Malaria is not associated with a rash like those seen in meningococcal septicemia, typhus, enteric fever, viral exanthems, and drug reactions. Petechial hemorrhages in the skin or mucous membranes—features of viral hemorrhagic fevers and leptospirosis—develop only very rarely in severe falciparum malaria.
SEVERE FALCIPARUM MALARIA
Appropriately and promptly treated, uncomplicated falciparum malaria (i.e., the patient can swallow medicines and food) carries a mortality rate of <0.1%. However, once vital-organ dysfunction occurs or the total proportion of erythrocytes infected increases to >2% (a level corresponding to >1012 parasites in an adult), mortality risk rises steeply. The major manifestations of severe falciparum malaria are shown in Table 248-2, and features indicating a poor prognosis are listed in Table 248-3.
TABLE 248-2Manifestations of Severe Falciparum Malaria ||Download (.pdf) TABLE 248-2Manifestations of Severe Falciparum Malaria
|Signs ||Manifestations |
|Unarousable coma/cerebral malaria ||Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion |
|Acidemia/acidosis ||Arterial pH of <7.25 or plasma bicarbonate level of <15 mmol/L; venous lactate level of >5 mmol/L; manifests as labored deep breathing, often termed “respiratory distress” |
|Severe normochromic, normocytic anemia ||Hematocrit of <15% or hemoglobin level of <50 g/L (<5 g/dL) with parasitemia <10,000/μL |
|Renal failure ||Serum or plasma creatinine level of >265 μmol/L (>3 mg/dL); urine output (24 h) of <400 mL in adults or <12 mL/kg in children; no improvement with rehydration |
|Pulmonary edema/adult respiratory distress syndrome ||Noncardiogenic pulmonary edema, often aggravated by overhydration |
|Hypoglycemia ||Plasma glucose level of <2.2 mmol/L (<40 mg/dL) |
|Hypotension/shock ||Systolic blood pressure of <50 mmHg in children 1–5 years or <80 mmHg in adults; core/skin temperature difference of >10°C; capillary refill >2 s |
|Bleeding/disseminated intravascular coagulation ||Significant bleeding and hemorrhage from the gums, nose, and gastrointestinal tract and/or evidence of disseminated intravascular coagulation |
|Convulsions ||More than two generalized seizures in 24 h; signs of continued seizure activity, sometimes subtle (e.g., tonic-clonic eye movements without limb or face movement) |
|Hemoglobinuriaa ||Macroscopic black, brown, or red urine; not associated with effects of oxidant drugs and red blood cell enzyme defects (such as G6PD deficiency) |
|Extreme weakness ||Prostration; inability to sit unaidedb |
|Hyperparasitemia ||Parasitemia level of >5% in nonimmune patients (>10% in any patient) |
|Jaundice ||Serum bilirubin level of >50 mmol/L (>3 mg/dL) if combined with a parasite density of 100,000/μL or other evidence of vital-organ dysfunction |
TABLE 248-3Features Indicating a Poor Prognosis in Severe Falciparum Malaria ||Download (.pdf) TABLE 248-3Features Indicating a Poor Prognosis in Severe Falciparum Malaria
| Marked agitation |
| Hyperventilation (respiratory distress) |
| Hypothermia (<36.5°C; <97.7°F) |
| Bleeding |
| Deep coma |
| Repeated convulsions |
| Anuria |
| Shock |
| Biochemistry |
| Hypoglycemia (<2.2 mmol/L) |
| Hyperlactatemia (>5 mmol/L) |
| Acidosis (arterial pH <7.3, serum HCO3 <15 mmol/L) |
| Elevated serum creatinine (>265 μmol/L) |
| Elevated total bilirubin (>50 μmol/L) |
| Elevated liver enzymes (AST/ALT 3 times upper limit of normal) |
| Elevated muscle enzymes (CPK ↑, myoglobin ↑) |
| Elevated urate (>600 μmol/L) |
| Hematology |
| Leukocytosis (>12,000/μL) |
| Severe anemia (PCV <15%) |
| Coagulopathy |
| Decreased platelet count (<50,000/μL) |
| Prolonged prothrombin time (>3 s) |
| Prolonged partial thromboplastin time |
| Decreased fibrinogen (<200 mg/dL) |
| Parasitology |
| Hyperparasitemia |
| Increased mortality at >100,000/μL |
| High mortality at >500,000/μL |
| >20% of parasites identified as pigment-containing trophozoites and schizonts |
| >5% of neutrophils with visible pigment |
Coma is a characteristic and ominous feature of falciparum malaria and, despite treatment, is associated with death rates of ~20% among adults and 15% among children. Any obtundation, delirium, or abnormal behavior should be taken very seriously. The onset may be gradual or sudden following a convulsion.
Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual. Although some passive resistance to head flexion may be detected, signs of meningeal irritation are absent. The eyes may be divergent and a pout reflex is common, but other primitive reflexes are usually absent. The corneal reflexes are preserved, except in deep coma. Muscle tone may be either increased or decreased. The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor; the abdominal and cremasteric reflexes are absent. Flexor or extensor posturing may be seen. On routine funduscopy, ~15% of patients have retinal hemorrhages; with pupillary dilation and indirect ophthalmoscopy, this figure increases to 30–40%. Other funduscopic abnormalities (Fig. 248-3) include discrete spots of retinal opacification (30–60%), papilledema (8% among children, rare among adults), cotton wool spots (<5%), and decolorization of a retinal vessel or segment of vessel (occasional cases). Convulsions, usually generalized and often repeated, occur in ~10% of adults and up to 50% of children with cerebral malaria. More covert seizure activity also is common, particularly among children, and may manifest as repetitive tonic-clonic eye movements or even hypersalivation. Whereas adults rarely (i.e., in <3% of cases) suffer neurologic sequelae, ~10% of children surviving cerebral malaria—especially those with hypoglycemia, severe anemia, repeated seizures, and deep coma—have residual neurologic deficits when they regain consciousness; hemiplegia, cerebral palsy, cortical blindness, deafness, and impaired cognition have been reported. The majority of these deficits improve markedly or resolve completely within 6 months. However, the prevalence of some other deficits increases over time; ~10% of children surviving cerebral malaria have a persistent language deficit. There may also be deficits in learning, planning and executive functions, attention, memory, and nonverbal functioning. The incidence of epilepsy is increased and life expectancy decreased among these children.
The eye in cerebral malaria: perimacular whitening and pale-centered retinal hemorrhages. (Courtesy of N. Beare, T. Taylor, S. Harding, S. Lewallen, and M. Molyneux; with permission.)
Hypoglycemia, an important and common complication of severe malaria, is associated with a poor prognosis and is particularly problematic in children and pregnant women. Hypoglycemia in malaria results from a failure of hepatic gluconeogenesis and an increase in the consumption of glucose by both the host and, to a much lesser extent, the malaria parasites. To compound the situation, quinine, which is still widely used for the treatment of both severe and uncomplicated falciparum malaria, is a powerful stimulant of pancreatic insulin secretion. Hyperinsulinemic hypoglycemia is especially troublesome in pregnant women receiving quinine treatment. In severe disease, the clinical diagnosis of hypoglycemia is difficult: the usual physical signs (sweating, gooseflesh, tachycardia) are absent, and the neurologic impairment caused by hypoglycemia cannot be distinguished from that caused by malaria.
Acidosis, an important cause of death from severe malaria, results from accumulation of organic acids. Hyperlactatemia commonly coexists with hypoglycemia. In adults, coexisting renal impairment often compounds the acidosis; in children, ketoacidosis also may contribute. Other, still-unidentified organic acids are major contributors to acidosis. Acidotic breathing, sometimes called “respiratory distress,” is a sign of poor prognosis. It is followed often by circulatory failure refractory to volume expansion or inotropic drug treatment and ultimately by respiratory arrest. The plasma concentrations of bicarbonate or lactate are the best biochemical prognosticators in severe malaria. Hypovolemia is not a major contributor to acidosis. Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues where sequestered parasites interfere with microcirculatory flow, lactate production by the parasites, and a failure of hepatic and renal lactate clearance. The prognosis of severe acidosis is poor.
Noncardiogenic Pulmonary Edema
Adults with severe falciparum malaria may develop noncardiogenic pulmonary edema even after several days of antimalarial therapy. The pathogenesis of this variant of the adult respiratory distress syndrome is unclear. The mortality rate is >80%. This condition can be aggravated by overly vigorous administration of IV fluid. Noncardiogenic pulmonary edema can also develop in otherwise uncomplicated vivax malaria, where recovery is usual.
Acute kidney injury is common in severe falciparum malaria, but oliguric renal failure is rare among children. The pathogenesis of renal failure is unclear but may be related to erythrocyte sequestration and agglutination interfering with renal microcirculatory flow and metabolism. Clinically and pathologically, this syndrome manifests as acute tubular necrosis. Renal cortical necrosis never develops. Acute renal failure may occur simultaneously with other vital-organ dysfunction (in which case the mortality risk is high) or may progress as other disease manifestations resolve. In survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17 days (Chap. 334). Early dialysis or hemofiltration considerably enhances the likelihood of a patient’s survival, particularly in acute hypercatabolic renal failure.
Anemia results from accelerated RBC removal by the spleen, obligatory RBC destruction at parasite schizogony, and ineffective erythropoiesis. In severe malaria, both infected and uninfected RBCs show reduced deformability, which correlates with prognosis and development of anemia. Splenic clearance of all RBCs is increased. In nonimmune individuals and in areas with unstable transmission, anemia can develop rapidly and transfusion is often required. As a consequence of repeated malarial infections, children in many areas of Africa and on the island of New Guinea may develop severe anemia resulting from both shortened survival of uninfected RBCs and marked dyserythropoiesis. Anemia is a common consequence of antimalarial drug resistance, which results in repeated or continued infection.
Slight coagulation abnormalities are common in falciparum malaria, and mild thrombocytopenia is usual (a normal platelet count should raise questions about the diagnosis of malaria). Of patients with severe malaria, <5% have significant bleeding with evidence of disseminated intravascular coagulation. Hematemesis from stress ulceration or acute gastric erosions also may occur rarely.
Mild hemolytic jaundice is common in malaria. Severe jaundice is associated with P. falciparum infections; is more common among adults than among children; and results from hemolysis, hepatocyte injury, and cholestasis. When accompanied by other vital-organ dysfunction (often renal impairment), liver dysfunction carries a poor prognosis. Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism. Occasional patients with falciparum malaria may develop deep jaundice (with hemolytic, hepatic, and cholestatic components) without evidence of other vital-organ dysfunction, in which case the prognosis is good.
HIV/AIDS and malnutrition predispose to more severe malaria in nonimmune individuals; malaria anemia is worsened by concurrent infections with intestinal helminths, hookworm in particular. Septicemia may complicate severe malaria, particularly in children. Differentiating severe malaria from sepsis with incidental parasitemia in childhood is very difficult. In endemic areas, Salmonella bacteremia has been associated specifically with P. falciparum infections. Chest infections and catheter-induced urinary tract infections are common among patients who are unconscious for >3 days. Aspiration pneumonia may follow generalized convulsions. The frequencies of complications of severe falciparum malaria are summarized in Table 248-4.
TABLE 248-4Relative Incidence of Severe Complications of Falciparum Malaria ||Download (.pdf) TABLE 248-4Relative Incidence of Severe Complications of Falciparum Malaria
|Complication ||Nonpregnant Adults ||Pregnant Women ||Children |
|Anemia ||+ ||++ ||+++ |
|Convulsions ||+ ||+ ||+++ |
|Hypoglycemia ||+ ||+++ ||+++ |
|Jaundice ||+++ ||+++ ||+ |
|Renal failure ||+++ ||+++ ||– |
|Pulmonary edema ||++ ||+++ ||+ |
Malaria in early pregnancy causes abortion. In areas of high malaria transmission, falciparum malaria in primi- and secundigravid women is associated with low birth weight (average reduction, ~170 g) and consequently increased infant mortality rates. In general, infected mothers in areas of stable transmission remain asymptomatic despite intense accumulation of parasitized erythrocytes in the placental microcirculation. Maternal HIV infection predisposes pregnant women to more frequent and higher-density malaria infections, predisposes their newborns to congenital malarial infection, and exacerbates the reduction in birth weight associated with malaria.
In areas with unstable transmission of malaria, pregnant women are prone to severe infections and are particularly vulnerable to high parasitemias with anemia, hypoglycemia, and acute pulmonary edema. Fetal distress, premature labor, and stillbirth or low birth weight are common results. Fetal death is usual in severe malaria. Congenital malaria occurs in <5% of newborns whose mothers are infected; its frequency and the level of parasitemia are related directly to the parasite density in maternal blood and in the placenta. P. vivax malaria in pregnancy is also associated with a reduction in birth weight (average, 110 g), but, in contrast to the situation in falciparum malaria, this effect is more pronounced in multigravid than in primigravid women. About 350,000 women die in childbirth yearly, with most deaths occurring in low-income countries; maternal death from hemorrhage at childbirth is correlated with malaria-induced anemia.
Most of the 660,000 persons who die of falciparum malaria each year are young African children. Convulsions, coma, hypoglycemia, metabolic acidosis, and severe anemia are relatively common among children with severe malaria, whereas deep jaundice, oliguric acute kidney injury, and acute pulmonary edema are unusual. Severely anemic children may present with labored deep breathing, which in the past has been attributed incorrectly to “anemic congestive cardiac failure” but in fact is usually caused by metabolic acidosis, often compounded by hypovolemia. In general, children tolerate antimalarial drugs well and respond rapidly to treatment.
Malaria can be transmitted by blood transfusion, needle-stick injury, sharing of needles by infected injection drug users, or organ transplantation. The incubation period in these settings is often short because there is no preerythrocytic stage of development. The clinical features and management of these cases are the same as for naturally acquired infections. Radical chemotherapy with primaquine is unnecessary for transfusion-transmitted P. vivax and P. ovale infections.
CHRONIC COMPLICATIONS OF MALARIA
TROPICAL SPLENOMEGALY (HYPERREACTIVE MALARIAL SPLENOMEGALY)
Chronic or repeated malarial infections produce hypergammaglobulinemia; normochromic, normocytic anemia; and, in certain situations, splenomegaly. Some residents of malaria-endemic areas in tropical Africa and Asia exhibit an abnormal immunologic response to repeated infections that is characterized by massive splenomegaly, hepatomegaly, marked elevations in serum titers of IgM and malarial antibody, hepatic sinusoidal lymphocytosis, and (in Africa) peripheral B cell lymphocytosis. This syndrome has been associated with the production of cytotoxic IgM antibodies to CD8+ T lymphocytes, antibodies to CD5+ T lymphocytes, and an increase in the ratio of CD4+ to CD8+ T cells. These events may lead to uninhibited B cell production of IgM and the formation of cryoglobulins (IgM aggregates and immune complexes). This immunologic process stimulates reticuloendothelial hyperplasia and clearance activity and eventually produces splenomegaly. Patients with hyperreactive malarial splenomegaly present with an abdominal mass or a dragging sensation in the abdomen and occasional sharp abdominal pains suggesting perisplenitis. Anemia and some degree of pancytopenia are usually evident, and in some cases malarial parasites cannot be found in peripheral-blood smears. Vulnerability to respiratory and skin infections is increased; many patients die of overwhelming sepsis. Persons with hyperreactive malarial splenomegaly who are living in endemic areas should receive antimalarial chemoprophylaxis; the results are usually good. In nonendemic areas, antimalarial treatment is advised. In some cases refractory to therapy, clonal lymphoproliferation may develop and can then evolve into a malignant lymphoproliferative disorder.
QUARTAN MALARIAL NEPHROPATHY
Chronic or repeated infections with P. malariae (and possibly with other malarial species) may cause soluble immune complex injury to the renal glomeruli, resulting in the nephrotic syndrome. Other unidentified factors must contribute to this process since only a very small proportion of infected patients develop renal disease. The histologic appearance is that of focal or segmental glomerulonephritis with splitting of the capillary basement membrane. Subendothelial dense deposits are seen on electron microscopy, and immunofluorescence reveals deposits of complement and immunoglobulins; in samples of renal tissue from children, P. malariae antigens are often visible. A coarse-granular pattern of basement membrane immunofluorescent deposits (predominantly IgG3) with selective proteinuria carries a better prognosis than a fine-granular, predominantly IgG2 pattern with nonselective proteinuria. Quartan nephropathy usually responds poorly to treatment with either antimalarial agents or glucocorticoids and cytotoxic drugs.
BURKITT’S LYMPHOMA AND EPSTEIN-BARR VIRUS INFECTION
It is possible that malaria-related immune dysregulation provokes infection with lymphoma viruses. Burkitt’s lymphoma is strongly associated with Epstein-Barr virus. The prevalence of this childhood tumor is high in malarious areas of Africa.
DEMONSTRATION OF THE PARASITE
The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained peripheral-blood smears. After a negative blood smear, repeat smears should be made if there is a high degree of suspicion. Of the Romanowsky stains, Giemsa at pH 7.2 is preferred; Field’s, Wright’s, or Leishman’s stain can also be used. Both thin (Figs. 248-4 and 248-5; see also Figs. 250e-3 and 250e-4) and thick (Figs. 248-6, 248-7, 248-8, and 248-9) blood smears should be examined. The thin blood smear should be rapidly air-dried, fixed in anhydrous methanol, and stained; the RBCs in the tail of the film should then be examined under oil immersion (×1000 magnification). The level of parasitemia is expressed as the number of parasitized erythrocytes per 1000 RBCs. The thick blood film should be of uneven thickness. The smear should be dried thoroughly and stained without fixing. As many layers of erythrocytes overlie one another and are lysed during the staining procedure, the thick film has the advantage of concentrating the parasites (by 40- to 100-fold compared with a thin blood film) and thus increasing diagnostic sensitivity. Both parasites and white blood cells (WBCs) are counted, and the number of parasites per unit volume is calculated from the total leukocyte count. Alternatively, a WBC count of 8000/μL is assumed. This figure is converted to the number of parasitized erythrocytes per microliter. A minimum of 200 WBCs should be counted under oil immersion. Interpretation of blood smear films requires some experience because artifacts are common. Before a thick smear is judged to be negative, 100–200 fields should be examined under oil immersion. In high-transmission areas, the presence of up to 10,000 parasites/μL of blood may be tolerated without symptoms or signs in partially immune individuals. Thus in these areas the detection of malaria parasites is sensitive but has low specificity in identifying malaria as the cause of illness. Low-density parasitemia is common in other conditions causing fever.
Thin blood films of Plasmodium falciparum. A. Young trophozoites. B. Old trophozoites. C. Pigment in polymorphonuclear cells and trophozoites. D. Mature schizonts. E. Female gametocytes. F. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Thin blood films of Plasmodium vivax. A. Young trophozoites. B. Old trophozoites. C. Mature schizonts. D. Female gametocytes. E. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)
Rapid, simple, sensitive, and specific antibody-based diagnostic stick or card tests that detect P. falciparum–specific, histidine-rich protein 2 (PfHRP2), lactate dehydrogenase, or aldolase antigens in finger-prick blood samples are now being used widely in control programs (Table 248-5). Some of these rapid diagnostic tests carry a second antibody, which allows falciparum malaria to be distinguished from the less dangerous malarias. PfHRP2-based tests may remain positive for several weeks after acute infection. This feature is a disadvantage in high-transmission areas where infections are frequent, but it is of value in the diagnosis of severe malaria in patients who have taken antimalarial drugs and cleared peripheral parasitemia (but in whom the PfHRP2 test remains strongly positive). Rapid diagnostic tests are replacing microscopy in many areas because of their simplicity and speed. Their disadvantage is that they do not quantify parasitemia.
TABLE 248-5Standard Methods for the Diagnosis of Malariaa ||Download (.pdf) TABLE 248-5Standard Methods for the Diagnosis of Malariaa
|Method ||Procedure ||Advantages ||Disadvantages |
|Thick blood filmb ||Blood should be uneven in thickness but thin enough that the hands of a watch can be read through part of the spot. Stain dried, unfixed blood spot with Giemsa, Field’s, or another Romanowsky stain. Count number of asexual parasites per 200 WBCs (or per 500 at low densities). Count gametocytes separately.c ||Sensitive (0.001% parasitemia); species specific; inexpensive ||Requires experience (artifacts may be misinterpreted as low-level parasitemia); underestimates true count |
|Thin blood filmd ||Stain fixed smear with Giemsa, Field’s, or another Romanowsky stain. Count number of RBCs containing asexual parasites per 1000 RBCs. In severe malaria, assess stage of parasite development and count neutrophils containing malaria pigment.e Count gametocytes separately.c ||Rapid; species specific; inexpensive; in severe malaria, provides prognostic informatione ||Insensitive (<0.05% parasitemia); uneven distribution of P. vivax, as enlarged infected red cells concentrate at leading edge |
|PfHRP2 dipstick or card test ||A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibody capture of parasitic antigens reads out as a colored band. ||Robust and relatively inexpensive; rapid; sensitivity similar to or slightly lower than that of thick films (~0.001% parasitemia) ||Detects only Plasmodium falciparum; remains positive for weeks after infectionf; does not quantitate P. falciparum parasitemia |
|Plasmodium LDH dipstick or card test ||A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibody capture of parasitic antigens reads out as two colored bands. One band is genus specific (all malarias), and the other is specific for P. falciparum. ||Rapid; sensitivity similar to or slightly lower than that of thick films for P. falciparum (~0.001% parasitemia) ||Slightly more difficult preparation than PfHRP2 tests; may miss low-level parasitemia with P. vivax, P. ovale, and P. malariae and may not speciate these organisms; does not quantitate P. falciparum parasitemia |
|Microtube concentration methods with acridine orange staining ||Blood is collected in a specialized tube containing acridine orange, anticoagulant, and a float. After centrifugation, which concentrates the parasitized cells around the float, fluorescence microscopy is performed. ||Sensitivity similar or superior to that of thick films (~0.001% parasitemia); ideal for processing large numbers of samples rapidly ||Does not speciate or quantitate; requires fluorescence microscopy |
The relationship between parasitemia and prognosis is complex; in general, patients with >105 parasites/μL are at increased risk of dying, but nonimmune patients may die with much lower counts, and partially immune persons may tolerate parasitemia levels many times higher with only minor symptoms. In severe malaria, a poor prognosis is indicated by a predominance of more mature P. falciparum parasites (i.e., >20% of parasites with visible pigment) in the peripheral-blood film or by the presence of phagocytosed malarial pigment in >5% of neutrophils. In P. falciparum infections, gametocytemia peaks 1 week after the peak of asexual parasites. Because the mature gametocytes of P. falciparum (unlike those of other plasmodia) are not affected by most antimalarial drugs, their persistence does not constitute evidence of drug resistance. Phagocytosed malarial pigment is sometimes seen inside peripheral-blood monocytes or polymorphonuclear leukocytes and may provide a clue to recent infection if malaria parasites are not detectable. After the clearance of the parasites, this intraphagocytic malarial pigment is often evident for several days in the peripheral blood films or for longer in bone marrow aspirates or smears of fluid expressed after intradermal puncture. Staining of parasites with the fluorescent dye acridine orange allows more rapid diagnosis of malaria (but not speciation of the infection) in patients with low-level parasitemia.
Molecular diagnosis by polymerase chain reaction (PCR) amplification of parasite nucleic acid is more sensitive than microscopy or rapid diagnostic tests for detecting malaria parasites and defining malarial species. While currently impractical in the standard clinical setting, PCR is used in reference centers in endemic areas. In epidemiologic surveys, sensitive PCR detection may prove very useful in identifying asymptomatic infections as control and eradication programs drive parasite prevalence down to very low levels. Serologic diagnosis with either indirect fluorescent antibody or enzyme-linked immunosorbent assays may prove useful as measures of transmission intensity in future epidemiologic studies. Serology has no place in the diagnosis of acute illness.
Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high. The platelet count is usually reduced to ~105/μL. Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia. Levels of antithrombin III are reduced even in mild infection. In uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal. Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin. Hypergammaglobulinemia is usual in immune and semi-immune subjects. Urinalysis generally gives normal results. In adults and children with cerebral malaria, the mean cerebrospinal fluid (CSF) opening pressure at lumbar puncture is ~160 mm; usually the CSF content is normal or there is a slight elevation of total protein level (<1.0 g/L [<100 mg/dL]) and cell count (<20/μL).
(Table 248-6) When a patient in or from a malarious area presents with fever, thick and thin blood smears should be prepared and examined immediately to confirm the diagnosis and identify the species of infecting parasite (Figs. 248-4,248-5,248-6,248-7,248-8, and 248-9). Repeat blood smears should be performed at least every 12–24 h for 2 days if the first smears are negative and malaria is strongly suspected. Alternatively, a rapid antigen detection card or stick test should be performed. Patients with severe malaria or those unable to take oral drugs should receive parenteral antimalarial therapy. If there is any doubt about the resistance status of the infecting organism, it should be considered resistant. Antimalarial drug susceptibility testing can be performed but is rarely available, has poor predictive value in an individual case, and yields results too slowly to influence the choice of treatment. Several drugs are available for oral treatment. The choice of drug depends on the likely sensitivity of the infecting parasites. Despite increasing evidence of chloroquine resistance in P. vivax (from parts of Indonesia, Oceania, eastern and southern Asia, and Central and South America), chloroquine remains a first-line treatment for the non-falciparum malarias (P. vivax, P. ovale, P. malariae, P. knowlesi) except in Indonesia and Papua New Guinea, where high levels of resistance in P. vivax are prevalent.
The treatment of falciparum malaria has changed radically in recent years. In all endemic areas, the World Health Organization (WHO) now recommends artemisinin-based combinations (ACTs) as first-line treatment for uncomplicated falciparum malaria. These combinations are also highly effective for the other malarias. These rapidly and reliably effective drugs are sometimes unavailable in temperate countries, where treatment recommendations are limited by the registered available drugs. Fake or substandard antimalarials are commonly sold in many Asian and African countries. Thus, careful attention is required at the time of purchase and later, especially if the patient fails to respond as expected. Characteristics of antimalarial drugs are shown in Table 248-7. SEVERE MALARIA
In large studies, parenteral artesunate, a water-soluble artemisinin derivative, has reduced mortality rates in severe falciparum malaria among Asian adults and children by 35% and among African children by 22.5% compared with mortality rates with quinine treatment. Artesunate has therefore become the drug of choice for all patients with severe malaria everywhere. Artesunate is given by IV injection but can also be given by IM injection. Artemether and the closely related drug artemotil (arteether) are oil-based formulations given by IM injection; they are erratically absorbed and do not confer the same survival benefit as artesunate. A rectal formulation of artesunate has been developed as a community-based pre-referral treatment for patients in the rural tropics who cannot take oral medications. Pre-referral administration of rectal artesunate has been shown to decrease mortality risk among severely ill children in communities without access to immediate parenteral treatment. Although the artemisinin compounds are safer than quinine and considerably safer than quinidine, only one formulation is available in the United States. IV artesunate has been approved by the U.S. Food and Drug Administration for emergency use against severe malaria and can be obtained through the Centers for Disease Control and Prevention (CDC) Drug Service (see end of chapter for contact information). The antiarrhythmic quinidine gluconate is as effective as quinine and, as it was more readily available, replaced quinine for the treatment of malaria in the United States. The administration of quinidine must be closely monitored if dysrhythmias and hypotension are to be avoided. If total plasma levels exceed 8 μg/mL or the QTc interval exceeds 0.6 s or the QRS complex widens by more than 25% of baseline, then infusion rates should be slowed or infusion stopped temporarily. If arrhythmia or saline-unresponsive hypotension develops, treatment with this drug should be discontinued. Quinine is safer than quinidine; cardiovascular monitoring is not required except when the recipient has cardiac disease.
Severe falciparum malaria constitutes a medical emergency requiring intensive nursing care and careful management. The patient should be weighed and, if comatose, placed on his or her side. Frequent evaluation of the patient’s condition is essential. Adjunctive treatments such as high-dose glucocorticoids, urea, heparin, dextran, desferrioxamine, antibody to tumor necrosis factor α, high-dose phenobarbital (20 mg/kg), mannitol, or large-volume fluid or albumin boluses have proved either ineffective or harmful in clinical trials and should not be used. In acute renal failure or severe metabolic acidosis, hemofiltration or hemodialysis should be started as early as possible.
In severe malaria, parenteral antimalarial treatment should be started immediately. Artesunate, given by either IV or IM injection, is the agent of choice; it is simple to administer, safe, and rapidly effective. It does not require dose adjustments in liver dysfunction or renal failure, and it should be used in pregnant women with severe malaria. If artesunate is unavailable and artemether, quinine, or quinidine is used, an initial loading dose must be given so that therapeutic concentrations are reached as soon as possible. Both quinine and quinidine will cause dangerous hypotension if injected rapidly; when given IV, they must be administered carefully by rate-controlled infusion only. If this approach is not possible, quinine may be given by deep IM injections into the anterior thigh. The optimal therapeutic range for quinine and quinidine in severe malaria is not known with certainty, but total plasma concentrations of 8–15 mg/L for quinine and 3.5–8.0 mg/L for quinidine are effective and do not cause serious toxicity. The systemic clearance and apparent volume of distribution of these alkaloids are markedly reduced and plasma protein binding is increased in severe malaria, so that the blood concentrations attained with a given dose are higher. If the patient remains seriously ill or in acute renal failure for >2 days, maintenance doses of quinine or quinidine should be reduced by 30–50% to prevent toxic accumulation of the drug. The initial doses should never be reduced. If safe and feasible, exchange transfusion may be considered for patients with severe malaria, although the precise indications for this procedure have not been agreed upon and there is no clear evidence that this measure is beneficial, particularly with artesunate treatment. Convulsions should be treated promptly with IV (or rectal) benzodiazepines. The role of prophylactic anticonvulsants in children is uncertain. If respiratory support is not available, then a full loading dose of phenobarbital (20 mg/kg) to prevent convulsions should not be given as it may cause respiratory arrest.
When the patient is unconscious, the blood glucose level should be measured every 4–6 h. All patients should receive a continuous infusion of dextrose, and blood concentrations ideally should be maintained above 4 mmol/L. Hypoglycemia (<2.2 mmol/L or 40 mg/dL) should be treated immediately with bolus glucose. The parasite count and hematocrit level should be measured every 6–12 h. Anemia develops rapidly; if the hematocrit falls to <20%, then whole blood (preferably fresh) or packed cells should be transfused slowly, with careful attention to circulatory status. Renal function should be checked daily. Children presenting with severe anemia and acidotic breathing require immediate blood transfusion. Accurate assessment is vital. Management of fluid balance is difficult in severe malaria, particularly in adults, because of the thin dividing line between overhydration (leading to pulmonary edema) and underhydration (contributing to renal impairment). As soon as the patient can take fluids, oral therapy should be substituted for parenteral treatment. UNCOMPLICATED MALARIA
Infections due to sensitive strains of P. vivax, P. knowlesi, P. malariae, and P. ovale should be treated with oral chloroquine (total dose, 25 mg of base/kg) or with an ATC known to be efficacious. In much of the tropics, drug-resistant P. falciparum has been increasing in distribution, frequency, and intensity. It is now accepted that, to prevent resistance, falciparum malaria should be treated with drug combinations and not with single drugs in endemic areas; the same rationale has been applied successfully to the treatment of tuberculosis, HIV/AIDS, and cancers. This combination strategy is based on simultaneous use of two or more drugs with different modes of action. ACT regimens are now recommended as first-line treatment for falciparum malaria throughout the malaria-affected world. These regimens are safe and effective in adults, children, and after the first trimester of pregnancy (uncertainty regarding safety currently precludes their use in the first trimester). The rapidly eliminated artemisinin component is usually an artemisinin derivative (artesunate, artemether, or dihydroartemisinin) given for 3 days, and the partner drug is usually a more slowly eliminated antimalarial to which P. falciparum is sensitive. Five ACT regimens are currently recommended by the WHO. In areas with multidrug-resistant falciparum malaria (parts of Asia and South America, including those with mefloquine-resistant parasites; Fig. 248-10), artemether-lumefantrine, artesunate-mefloquine, or dihydroartemisinin-piperaquine should be used; these regimens provide cure rates of >90%. In areas with sensitive parasites, the aforementioned combinations, artesunate-sulfadoxine-pyrimethamine, or artesunate-amodiaquine also may be used. Pyronaridine-artesunate is still under evaluation. Atovaquone-proguanil is highly effective everywhere, although it is seldom used in endemic areas because of its high cost and the propensity for rapid emergence of resistance. Of great concern is the emergence of artemisinin-resistant P. falciparum in western Cambodia and eastern Myanmar. Infections with these parasites are cleared slowly from the blood, with clearance times typically exceeding 3 days, and cure rates with ACTs are reduced.
The 3-day ACT regimens are all well tolerated, although mefloquine is associated with increased rates of vomiting and dizziness. As second-line treatments for recrudescence following first-line therapy, a different ACT regimen may be given; another alternative is a 7-day course of either artesunate or quinine plus tetracycline, doxycycline, or clindamycin. Tetracycline and doxycycline cannot be given to pregnant women or to children <8 years of age. Oral quinine is extremely bitter and regularly produces cinchonism comprising tinnitus, high-tone deafness, nausea, vomiting, and dysphoria. Adherence is poor with the required 7-day regimens of quinine.
Patients should be monitored for vomiting for 1 h after the administration of any oral antimalarial drug. If there is vomiting, the dose should be repeated. Symptom-based treatment, with tepid sponging and acetaminophen administration, lowers fever and thereby reduces the patient’s propensity to vomit these drugs. Minor central nervous system reactions (nausea, dizziness, sleep disturbances) are common. The incidence of serious adverse neuropsychiatric reactions to mefloquine treatment is ~1 in 1000 in Asia but may be as high as 1 in 200 among Africans and Caucasians. All the antimalarial quinolines (chloroquine, mefloquine, and quinine) exacerbate the orthostatic hypotension associated with malaria, and all are tolerated better by children than by adults. Pregnant women, young children, patients unable to tolerate oral therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evaluated carefully and hospitalization considered. If there is any doubt as to the identity of the infecting malarial species, treatment for falciparum malaria should be given. A negative blood smear makes malaria unlikely but does not rule it out completely; thick blood films should be checked again 1 and 2 days later to exclude the diagnosis. Nonimmune patients receiving treatment for malaria should have daily parasite counts performed until the thick films are negative. If the level of parasitemia does not fall below 25% of the admission value in 48 h or if parasitemia has not cleared by 7 days (and adherence is assured), drug resistance is likely and the regimen should be changed.
To eradicate persistent liver stages and prevent relapse (radical treatment), primaquine (0.5 mg of base/kg or, in infections acquired in temperate areas, 0.25 mg/kg) should be given daily for 14 days to patients with P. vivax or P. ovale infections after laboratory tests for G6PD deficiency have proved negative. If the patient has a mild variant of G6PD deficiency, primaquine can be given in a dose of 0.75 mg of base/kg (45 mg maximum) once weekly for 8 weeks. Pregnant women with vivax or ovale malaria should not be given primaquine but should receive suppressive prophylaxis with chloroquine (5 mg of base/kg per week) until delivery, after which radical treatment can be given. COMPLICATIONS Acute Renal Failure
If the plasma level of BUN or creatinine rises despite adequate rehydration, fluid administration should be restricted to prevent volume overload. As in other forms of hypercatabolic acute renal failure, renal replacement therapy is best performed early (Chap. 334). Hemofiltration and hemodialysis are more effective than peritoneal dialysis and are associated with lower mortality risk. Some patients with renal impairment pass small volumes of urine sufficient to allow control of fluid balance; these cases can be managed conservatively if other indications for dialysis do not arise. Renal function usually improves within days, but full recovery may take weeks. Acute Pulmonary Edema (Acute Respiratory Distress Syndrome)
Patients should be positioned with the head of the bed at a 45° elevation and given oxygen and IV diuretics. Pulmonary artery occlusion pressures may be normal, indicating increased pulmonary capillary permeability. Positive-pressure ventilation should be started early if the immediate measures fail (Chap. 326). Hypoglycemia
An initial slow injection of 50% dextrose (0.5 g/kg) should be followed by an infusion of 10% dextrose (0.10 g/kg per hour). The blood glucose level should be checked regularly thereafter as recurrent hypoglycemia is common, particularly among patients receiving quinine or quinidine. In severely ill patients, hypoglycemia commonly occurs together with metabolic (lactic) acidosis and carries a poor prognosis. Other Complications
Patients who develop spontaneous bleeding should be given fresh blood and IV vitamin K. Convulsions should be treated with IV or rectal benzodiazepines and, if necessary, respiratory support. Aspiration pneumonia should be suspected in any unconscious patient with convulsions, particularly with persistent hyperventilation; IV antimicrobial agents and oxygen should be administered, and pulmonary toilet should be undertaken. Hypoglycemia or gram-negative septicemia should be suspected when the condition of any patient suddenly deteriorates for no obvious reason during antimalarial treatment. In malaria-endemic areas where a high proportion of children are parasitemic, it is usually impossible to distinguish severe malaria from bacterial sepsis with confidence. These children should be treated with both antimalarials and broad-spectrum antibiotics from the outset. Because nontyphoidal Salmonella infections are particularly common, empirical antibiotics should be selected to cover these organisms. Antibiotics should be considered for severely ill patients of any age who are not responding to antimalarial treatment.
Mefloquine and artemisinin resistance in Plasmodium falciparum in Southeast Asia: high-level mefloquine resistance (dark red), low-level mefloquine resistance (pink), and mefloquine sensitivity (failure rate, <20%; green). There is insufficient information for other areas. Artemisinin resistance is now prevalent in areas where mefloquine resistance has been reported (pink areas).
TABLE 248-6Regimens for the Treatment of Malariaa ||Download (.pdf) TABLE 248-6Regimens for the Treatment of Malariaa
|Type of Disease or Treatment ||Regimen(s) |
|Uncomplicated Malaria |
|Known chloroquine-sensitive strains of Plasmodium vivax, P. malariae, P. ovale, P. knowlesi, P. falciparumb || |
Chloroquine (10 mg of base/kg stat followed by 5 mg/kg at 12, 24, and 36 h or by 10 mg/kg at 24 h and 5 mg/kg at 48 h)
Amodiaquine (10–12 mg of base/kg qd for 3 days)
|Radical treatment for P. vivax or P. ovale infection ||In addition to chloroquine or amodiaquine as detailed above, primaquine (0.5 mg of base/kg qd in tropical regions and 0.25 mg/kg for temperate-origin P. vivax) should be given for 14 days to prevent relapse. In mild G6PD deficiency, 0.75 mg of base/kg should be given once weekly for 8 weeks. Primaquine should not be given in severe G6PD deficiency. |
|Sensitive P. falciparum malariac || |
Artesunated (4 mg/kg qd for 3 days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single dose
Artesunated (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)e
|Multidrug-resistant P. falciparum malaria || |
Either artemether-lumefantrined (1.5/9 mg/kg bid for 3 days with food)
Artesunated (4 mg/kg qd for 3 days) plus mefloquine (24–25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3)e
Dihydroartemisinin-piperaquined (2.5/20 mg/kg qd for 3 days)
|Second-line treatment/treatment of imported malaria || |
Either artesunated (2 mg/kg qd for 7 days) or quinine (10 mg of salt/kg tid for 7 days) plus 1 of the following 3:
1. Tetracyclinef (4 mg/kg qid for 7 days)
2. Doxycyclinef (3 mg/kg qd for 7 days)
3. Clindamycin (10 mg/kg bid for 7 days)
Atovaquone-proguanil (20/8 mg/kg qd for 3 days with food)
|Severe Falciparum Malariag |
| ||Artesunated (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary)h |
| ||or, if unavailable, |
| ||Artemetherd (3.2 mg/kg stat IM followed by 1.6 mg/kg qd) |
| ||or, if unavailable, |
| ||Quinine dihydrochloride (20 mg of salt/kgi infused over 4 h, followed by 10 mg of salt/kg infused over 2–8 h q8hj) |
| ||or, if unavailable, |
| ||Quinidine (10 mg of base/kgi infused over 1–2 h, followed by 1.2 mg of base/kg per hourj with electrocardiographic monitoring) |
TABLE 248-7Properties of Antimalarial Drugs ||Download (.pdf) TABLE 248-7Properties of Antimalarial Drugs
|Drug(s) ||Pharmacokinetic Properties ||Antimalarial Activity ||Minor Toxicity ||Major Toxicity |
|Quinine, quinidine ||Good oral and IM absorption (quinine); Cl and Vd reduced, but plasma protein binding (principally to ∝1 acid glycoprotein) increased (90%) in malaria; quinine t1/2: 16 h in malaria, 11 h in healthy persons; quinidine t1/2: 13 h in malaria, 8 h in healthy persons ||Acts mainly on trophozoite blood stage; kills gametocytes of P. vivax, P. ovale, and P. malariae (but not P. falciparum); no action on liver stages || |
“Cinchonism”: tinnitus, high-tone hearing loss, nausea, vomiting, dysphoria, postural hypotension; ECG QTc interval prolongation (quinine usually by <10% but quinidine by up to 25%)
Diarrhea, visual disturbance, rashes
Very bitter taste
|Hypotension, blindness, deafness, cardiac arrhythmias, thrombocytopenia, hemolysis, hemolytic-uremic syndrome, vasculitis, cholestatic hepatitis, neuromuscular paralysis |
|Quinidine more cardiotoxic |
|Chloroquine ||Good oral absorption, very rapid IM and SC absorption; complex pharmacokinetics; enormous Cl and Vd (unaffected by malaria); blood concentration profile determined by distribution processes in malaria; t1/2: 1–2 months ||As for quinine but acts slightly earlier in asexual cycle ||Common: ||Acute: |
|Nausea, dysphoria, pruritus in dark-skinned patients, postural hypotension, slight ECG QTC prolongation ||Hypotensive shock (parenteral), cardiac arrhythmias, neuropsychiatric reactions |
|Rare: ||Chronic: |
Accommodation difficulties, keratopathy, rash
|Retinopathy (cumulative dose, >100 g), skeletal and cardiac myopathy |
|Bitter taste, well tolerated |
|Piperaquine ||Adequate oral absorption, may be enhanced by fats; similar pharmacokinetics to chloroquine; t1/2: 21–28 days ||As for chloroquine, but retains activity against multidrug-resistant P. falciparum ||Epigastric pain, diarrhea, slight ECG QTc prolongation ||None identified |
|Amodiaquine ||Good oral absorption; largely converted to active metabolite desethylamodiaquine ||As for chloroquine ||Nausea (tastes better than chloroquine) ||Agranulocytosis; hepatitis, mainly with prophylactic use; should not be used with efavirenz |
|Primaquine ||Complete oral absorption; active metabolite not known; t1/2: 5–7 h ||Radical cure; eradicates hepatic forms of P. vivax and P. ovale; kills all stages of gametocyte development of P. falciparum ||Nausea, vomiting, diarrhea, abdominal pain, hemolysis, methemoglobinemia ||Massive hemolysis in subjects with severe G6PD deficiency |
|Mefloquine ||Adequate oral absorption; no parenteral preparation; t1/2: 14–20 days (shorter in malaria) ||As for quinine ||Nausea, giddiness, dysphoria, fuzzy thinking, sleeplessness, nightmares, sense of dissociation ||Neuropsychiatric reactions, convulsions, encephalopathy |
|Halofantrinea ||Highly variable absorption related to fat intake; t1/2: 1–3 days (active desbutyl metabolite t1/2: 3–7 days) ||As for quinine ||Diarrhea ||Cardiac conduction disturbances; atrioventricular block; marked ECG QTc interval prolongation; potentially lethal ventricular tachyarrhythmias |
|Lumefantrine ||Highly variable absorption related to fat intake; t1/2: 3–4 days ||As for quinine ||None identified ||None identified |
|Artemisinin and derivatives (artemether, artesunate) ||Good oral absorption, slow and variable absorption of IM artemether; artesunate and artemether biotransformed to active metabolite dihydroartemisinin; all drugs eliminated very rapidly; t1/2: <1 h ||Broader stage specificity and more rapid than other drugs; no action on liver stages; kills all but fully mature gametocytes of P. falciparum ||Reduction in reticulocyte count (but not anemia); neutropenia at high doses; in some cases, delayed anemia after treatment of severe malaria with hyperparasitemia ||Anaphylaxis, urticaria, fever |
|Pyrimethamine ||Good oral absorption, variable IM absorption; t1/2: 4 days ||For blood stages, acts mainly on mature forms; causal prophylactic ||Well tolerated ||Megaloblastic anemia, pancytopenia, pulmonary infiltration |
|Proguanil (chloroguanide) ||Good oral absorption; biotransformed to active metabolite cycloguanil; t1/2: 16 h; biotransformation reduced by oral contraceptive use and in pregnancy ||Causal prophylactic; not used alone for treatment ||Well tolerated; mouth ulcers and rare alopecia ||Megaloblastic anemia in renal failure |
|Atovaquone ||Highly variable absorption related to fat intake; t1/2: 30–70 h ||Acts mainly on trophozoite blood stage ||None identified ||None identified |
|Tetracycline, doxycyclineb ||Excellent absorption; t1/2: 8 h for tetracycline, 18 h for doxycycline ||Weak antimalarial activity; should not be used alone for treatment ||Gastrointestinal intolerance, deposition in growing bones and teeth, photosensitivity, moniliasis, benign intracranial hypertension ||Renal failure in patients with impaired renal function (tetracycline) |
In recent years, considerable progress has been made in malaria prevention, control, and research. Distribution of insecticide-treated bed-nets (ITNs) has been shown to reduce all-cause mortality in African children by 20%. New drugs have been discovered and developed, and one vaccine candidate (the RTS,S vaccine) will soon be considered for registration. Highly effective drugs, long-lasting ITNs, and insecticides for spraying dwellings are being purchased for endemic countries by the Global Fund to Fight AIDS, Tuberculosis, and Malaria; the President’s Malaria Initiative (funded by the U.S. Agency for International Development and managed by the CDC in partnership with endemic countries); UNICEF; and other organizations. Malaria research and control are being strongly supported by the National Institute of Allergy and Infectious Diseases, the CDC, the Wellcome Trust, the Bill & Melinda Gates Foundation, the Multilateral Initiative on Malaria, the Roll Back Malaria Partnership, and the WHO among others. While a laudable goal, the global eradication of malaria is not feasible in the immediate future because of the widespread distribution of Anopheles breeding sites; the great number of infected persons; the continued use of ineffective antimalarial drugs; and inadequacies in human and material resources, infrastructure, and control programs. The call for and commitment to ultimate eradication of malaria by the Gates Foundation in 2007—seconded by Margaret Chan, Director General of the WHO—added great impetus to all malaria initiatives, especially those aimed at discovery and implementation of new interventions. Malaria may be contained by judicious use of insecticides to kill the mosquito vector, rapid diagnosis, patient management, and—where effective and feasible—administration of intermittent preventive treatment, seasonal malaria chemoprevention, or chemoprophylaxis to high-risk groups such as pregnant women, young children, and travelers from nonendemic regions. Malaria researchers are intensifying their efforts to gain a better understanding of parasite-human-mosquito interactions and to develop more effective control and prevention interventions. Despite the enormous investment in efforts to develop a malaria vaccine and the 30–60% efficacy in African children of a recombinant protein sporozoite-targeted adjuvanted vaccine (RTS,S) in field trials, no safe, highly effective, long-lasting vaccine is likely to be available for general use in the near future (Chap. 148). Indeed, protection from RTS,S in the very youngest recipients dropped to 16% only 4 years after vaccination. While there is great promise for one or several malaria vaccines on the more distant horizon, prevention and control measures continue to rely on antivector and drug-use strategies. Furthermore, recent gains are threatened by increasing insecticide resistance and behavioral changes (to avoid ITN contact) in anopheline mosquito vectors and by spreading artemisinin resistance in P. falciparum.
PERSONAL PROTECTION AGAINST MALARIA
Simple measures to reduce the frequency of infected-mosquito bites in malarious areas are very important. These measures include the avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn) and the use of insect repellents containing 10–35% DEET (or, if DEET is unacceptable, 7% picaridin), suitable clothing, and ITNs or other insecticide-impregnated materials. Widespread use of bed nets treated with residual pyrethroids reduces the incidence of malaria in areas where vectors bite indoors at night.
(Table 248-8; wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/malaria) Recommendations for prophylaxis depend on knowledge of local patterns of Plasmodium species drug sensitivity and the likelihood of acquiring malarial infection. When there is uncertainty, drugs effective against resistant P. falciparum should be used (atovaquone-proguanil [Malarone], doxycycline, or mefloquine). Chemoprophylaxis is never entirely reliable, and malaria should always be considered in the differential diagnosis of fever in patients who have traveled to endemic areas, even if they are taking prophylactic antimalarial drugs.
TABLE 248-8Drugs Used in the Prophylaxis of Malaria ||Download (.pdf) TABLE 248-8Drugs Used in the Prophylaxis of Malaria
|Drug ||Usage ||Adult Dose ||Pediatric Dose ||Comments |
|Atovaquone-proguanil (Malarone) ||Prophylaxis in areas with chloroquine- or mefloquine-resistant Plasmodium falciparum ||1 adult tablet POa ||5–8 kg: ½ pediatric tabletb daily ||Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. Atovaquone-proguanil is contraindicated in persons with severe renal impairment (creatinine clearance rate <30 mL/min). In the absence of data, it is not recommended for children weighing <5 kg, pregnant women, or women breast-feeding infants weighing <5 kg. Atovaquone-proguanil should be taken with food or a milky drink. |
|≥8–10 kg: ¾ pediatric tablet daily |
|≥10–20 kg: 1 pediatric tablet daily |
|≥20–30 kg: 2 pediatric tablets daily |
|≥30–40 kg: 3 pediatric tablets daily |
|≥40 kg: 1 adult tablet daily |
|Chloroquine phosphate (Aralen and generic) ||Prophylaxis only in areas with chloroquine-sensitive P. falciparumc or areas with P. vivax only ||300 mg of base (500 mg of salt) PO once weekly ||5 mg/kg of base (8.3 mg of salt/kg) PO once weekly, up to maximum adult dose of 300 mg of base ||Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Chloroquine phosphate may exacerbate psoriasis. |
|Doxycycline (many brand names and generic) ||Prophylaxis in areas with chloroquine- or mefloquine-resistant P. falciparumc ||100 mg PO qd (except in pregnant women; see Comments) ||≥8 years of age: 2 mg/kg, up to adult dose ||Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 4 weeks after leaving such areas. Doxycycline is contraindicated in children <8 years of age and in pregnant women. |
|Hydroxychloroquine sulfate (Plaquenil) ||An alternative to chloroquine for primary prophylaxis only in areas with chloroquine-sensitive P. falciparumc or areas with P. vivax only ||310 mg of base (400 mg of salt) PO once weekly ||5 mg of base/kg (6.5 mg of salt/kg) PO once weekly, up to maximum adult dose of 310 mg of base ||Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Hydroxychloroquine may exacerbate psoriasis. |
|Mefloquine (Lariam and generic) ||Prophylaxis in areas with chloroquine-resistant P. falciparumc ||228 mg of base (250 mg of salt) PO once weekly ||≤9 kg: 4.6 mg of base/kg (5 mg of salt/kg) PO once weekly ||Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Mefloquine is contraindicated in persons allergic to this drug or related compounds (e.g., quinine and quinidine) and in persons with active or recent depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances or a history of depression. Mefloquine is not recommended for persons with cardiac conduction abnormalities. |
|10–19 kg: ¼ tablet once weekly |
|20–30 kg: ½ tablet once weekly |
|31–45 kg: ¾ tablet once weekly |
|≥46 kg: 1 tablet once weekly |
|Primaquine ||For prevention of malaria in areas with mainly P. vivax ||30 mg of base (52.6 mg of salt) PO qd ||0.5 mg of base/kg (0.8 mg of salt/kg) PO qd, up to adult dose; should be taken with food ||Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. Primaquine is contraindicated in persons with G6PD deficiency. It is also contraindicated during pregnancy and in lactation unless the infant being breast-fed has a documented normal G6PD level. |
|Primaquine ||Used for presumptive antirelapse therapy (terminal prophylaxis) to decrease risk of relapses of P. vivax and P. ovale ||30 mg of base (52.6 mg of salt) PO qd for 14 days after departure from the malarious area ||0.5 mg of base/kg (0.8 mg of salt/kg), up to adult dose, PO qd for 14 days after departure from the malarious area ||This therapy is indicated for persons who have had prolonged exposure to P. vivax and/or P. ovale. It is contraindicated in persons with G6PD deficiency as well as during pregnancy and in lactation unless the infant being breast-fed has a documented normal G6PD level. |
Pregnant women traveling to malarious areas should be warned about the potential risks. All pregnant women at risk in endemic areas should be encouraged to attend regular antenatal clinics. Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria; this drug is generally considered safe in the second and third trimesters of pregnancy, and the data on first-trimester exposure, although limited, are reassuring. Chloroquine and proguanil are regarded as safe. The safety of other prophylactic antimalarial agents in pregnancy has not been established. Antimalarial prophylaxis has been shown to reduce mortality rates among children between the ages of 3 months and 4 years in malaria-endemic areas; however, it is not a logistically or economically feasible option in many countries. The alternative—to give intermittent preventive treatment or seasonal malaria chemoprevention—shows promise for more widespread use in infants, young children, and pregnant women. Children born to nonimmune mothers in endemic areas (usually expatriates moving to malaria-endemic areas) should receive prophylaxis from birth.
Travelers should start taking antimalarial drugs 2 days to 2 weeks before departure so that any untoward reactions can be detected and so that therapeutic antimalarial blood concentrations will be present when needed (Table 248-8). Antimalarial prophylaxis should continue for 4 weeks after the traveler has left the endemic area, except if atovaquone-proguanil or primaquine has been taken; these drugs have significant activities against the liver stage of the infection (causal prophylaxis) and can be discontinued 1 week after departure from the endemic area. If suspected malaria develops while a traveler is abroad, obtaining a reliable diagnosis and antimalarial treatment locally is a top priority. Presumptive self-treatment for malaria with atovaquone-proguanil (for 3 consecutive days) or another drug can be considered under special circumstances; medical advice on self-treatment should be sought before departure for malarious areas and as soon as possible after illness begins. Every effort should be made to confirm the diagnosis by parasitologic studies.
Atovaquone-proguanil (Malarone; 3.75/1.5 mg/kg or 250/100 mg, daily adult dose) is a fixed-combination, once-daily prophylactic agent that is very well tolerated by adults and children, with fewer adverse gastrointestinal effects than chloroquine-proguanil and fewer adverse central nervous system effects than mefloquine. It is proguanil itself, rather than the antifolate metabolite cycloguanil, that acts synergistically with atovaquone. This combination is effective against all types of malaria, including multidrug-resistant falciparum malaria. Atovaquone-proguanil is best taken with food or a milky drink to optimize absorption. There are insufficient data on the safety of this regimen in pregnancy.
Mefloquine (250 mg of salt weekly, adult dose) has been widely used for malarial prophylaxis because it is usually effective against multidrug-resistant falciparum malaria and is reasonably well tolerated. The drug has been associated with rare episodes of psychosis and seizures at prophylactic doses; these reactions are more frequent at the higher doses used for treatment. More common side effects with prophylactic doses of mefloquine include mild nausea, dizziness, fuzzy thinking, disturbed sleep patterns, vivid dreams, and malaise. The drug is contraindicated for use by travelers with known hypersensitivity to mefloquine or related compounds (e.g., quinine, quinidine) and by persons with active or recent depression, anxiety disorder, psychosis, schizophrenia, another major psychiatric disorder, or seizures; mefloquine is not recommended for persons with cardiac conduction abnormalities although the evidence that it is cardiotoxic is very weak. Confidence is increasing with regard to the safety of mefloquine prophylaxis during pregnancy; in studies in Africa, mefloquine prophylaxis was found to be effective and safe during pregnancy. However, in one study from Thailand, treatment of malaria with mefloquine was associated with an increased risk of stillbirth; this effect was not seen subsequently.
Daily administration of doxycycline (100 mg daily, adult dose) is an effective alternative to atovaquone-proguanil or mefloquine. Doxycycline is generally well tolerated but may cause vulvovaginal thrush, diarrhea, and photosensitivity and cannot be used by children <8 years old or by pregnant women.
Chloroquine can no longer be relied upon to prevent P. falciparum infections in most areas but is used to prevent and treat malaria due to the other human Plasmodium species and for P. falciparum malaria in Central American countries west and north of the Panama Canal, Caribbean countries, and some countries in the Middle East. Chloroquine-resistant P. vivax has been reported from parts of eastern Asia, Oceania, and Central and South America. This drug is generally well tolerated, although some patients cannot take it because of malaise, headache, visual symptoms (due to reversible keratopathy), gastrointestinal intolerance, or pruritus. Chloroquine is considered safe in pregnancy. With chronic administration for >5 years, a characteristic dose-related retinopathy may develop, but this condition is rare at the doses used for antimalarial prophylaxis. Idiosyncratic or allergic reactions are also rare. Skeletal and/or cardiac myopathy is a potential problem with protracted prophylactic use; such myopathy is more likely to occur at the high doses used in the treatment of rheumatoid arthritis. Neuropsychiatric reactions and skin rashes are unusual. When used continuously, amodiaquine, a related aminoquinoline, is associated with a high risk of agranulocytosis (~1 person in 2000) and hepatotoxicity (~1 person in 16,000); thus this agent should not be used for prophylaxis.
Primaquine (daily adult dose, 0.5 mg of base/kg or 30 mg taken with food), an 8-aminoquinoline compound, has proved safe and effective in the prevention of drug-resistant falciparum and vivax malaria in adults. This drug can be considered for persons who are traveling to areas with or without drug-resistant P. falciparum and who are intolerant to other recommended drugs. Abdominal pain and oxidant hemolysis—the principal adverse effects—are not common as long as the drug is taken with food and is not given to G6PD-deficient persons, in whom it can cause serious hemolysis. Travelers must be tested for G6PD deficiency and be shown to have a level in the normal range before receiving primaquine. Primaquine should not be given to pregnant women or neonates. Primaquine, given in a single dose of 0.25 mg/kg as a gametocytocide, together with an ACT is recommended in falciparum malaria treatment regimens in malaria elimination programs.
In the past, the dihydrofolate reductase inhibitors pyrimethamine and proguanil (chloroguanide) were administered widely, but the rapid selection of resistance in both P. falciparum and P. vivax has limited their use. Whereas antimalarial quinolines such as chloroquine (a 4-aminoquinoline) act on the erythrocyte stage of parasitic development, the dihydrofolate reductase inhibitors also inhibit preerythrocytic growth in the liver (causal prophylaxis) and development in the mosquito (sporontocidal activity). Proguanil is safe and well tolerated, although mouth ulceration occurs in ~8% of persons using this drug; it is considered safe for antimalarial prophylaxis in pregnancy. The prophylactic use of the combination of pyrimethamine and sulfadoxine is not recommended because of an unacceptable incidence of severe toxicity, principally exfoliative dermatitis and other skin rashes, agranulocytosis, hepatitis, and pulmonary eosinophilia (incidence, 1:7000; fatal reactions, 1:18,000). The combination of pyrimethamine with dapsone (0.2/1.5 mg/kg weekly; 12.5/100 mg, adult dose) has been used in some countries. Dapsone may cause methemoglobinemia and allergic reactions and (at higher doses) may pose a significant risk of agranulocytosis. Proguanil and the pyrimethamine-dapsone combination are not available in the United States.
Because of the increasing spread and intensity of antimalarial drug resistance (Figs. 248-2 and 248-10), the CDC recommends that travelers and their providers consider their destination, type of travel, and current medications and health risks when choosing antimalarial chemoprophylaxis. There is an increasingly appreciated problem of counterfeit and substandard antimalarial drugs (and other medicines) on the shelves of pharmacies in Southeast Asia and sub-Saharan Africa; hence, travelers should purchase their preventive drugs from a reputable source before going to a malarious country. Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and local health departments and the CDC Malaria Hotline (770-488-7788) or the CDC Emergency Operations Center (770-488-7100).