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Malaria is infection with any of 4 species of Plasmodium. Symptoms are fever, which may be periodic, chills, sweating, hemolytic anemia, and splenomegaly. Diagnosis is by seeing Plasmodium in a peripheral blood smear. Treatment and prophylaxis depend on the species and drug sensitivity and include chloroquine, quinine, atovaquone and proguanil, mefloquine, doxycycline, and artemisinin derivatives. Patients infected with P. vivax and P. ovale also receive primaquine.

Malaria is endemic in Africa, much of South and Southeast Asia, Central America, and northern South America. There are between 300 and 500 million infected people worldwide, with between 1 and 2 million deaths yearly, most in children < 5 yr. Malaria once was endemic in the US but has been virtually eliminated from North America. About 1000 cases/yr occur in the US, nearly all acquired abroad; a small number result from blood transfusions or rare autochthonous transmission by local mosquitoes that feed on infected immigrants.

Etiology and Pathophysiology

The 4 Plasmodium species that infect humans are P. falciparum , P. vivax , P. ovale, and P. malariae. The basic elements of the life cycle are the same for all. Transmission begins when a female Anopheles mosquito feeds on a person with malaria and ingests blood containing gametocytes. During the following 1 to 2 wk, gametocytes inside the mosquito reproduce sexually and produce infective sporozoites. When the mosquito feeds again on a human, it transmits sporozoites, which quickly infect hepatocytes. The parasites mature into tissue schizonts within hepatocytes. Each schizont produces 10,000 to 30,000 merozoites, which are released into the bloodstream 1 to 3 wk later when the hepatocyte ruptures. Each merozoite can invade an RBC and there transform into a trophozoite. Trophozoites grow and develop into erythrocyte schizonts, which produce further merozoites, which 48 to 72 h later rupture the RBC and are released in plasma. These merozoites then rapidly invade new RBCs, repeating the cycle.

Tissue schizonts in the liver may persist as hypnozoites for up to 3 yr with P. vivax and P. ovale but not with P. falciparum or P. malariae. These dormant forms serve as “time- release capsules,” which cause relapses and complicate chemotherapy because they are not killed by most drugs.

The pre-erythrocytic (hepatic) stage of the malarial life cycle is bypassed when infection is transmitted by blood transfusions, sharing of contaminated needles, or congenitally. Therefore, these modes of transmission do not produce latent disease and delayed recurrences.

Rupture of RBCs during release of merozoites is responsible for the clinical symptoms. If severe, hemolysis produces anemia and jaundice, which are worsened by phagocytosis of infected RBCs in the spleen.

Unlike other forms of malaria, P. falciparum causes microvascular obstruction because infected RBCs adhere to vascular endothelial cells. Ischemia develops with resultant tissue hypoxia, particularly in the brain, kidneys, lungs, and GI tract; hypoglycemia; and lactic acidosis.

Resistance: Most West Africans have complete resistance to P. vivax because their RBCs lack the Duffy blood group, which is required for P. vivax invasion of RBCs; many African Americans are resistant. The development of Plasmodium in RBCs is also retarded in patients with hemoglobin S, hemoglobin C, thalassemia, G6PD deficiency, or Melanesian elliptocytosis.

Previous infections provide partial immunity. Once residents of hyperendemic areas leave, acquired immunity lasts only for a period of months, and symptomatic malaria may develop if they return home and become infected.

Symptoms and Signs

The incubation period is usually 12 to 17 days for P. vivax, 9 to 14 days for P. falciparum, 16 to 18 days or longer for P. ovale, and about 1 mo (18 to 40 days) or longer (years) for P. malariae. However, some strains of P. vivax in temperate climates may not cause clinical illness for months to more than a year after infection.

Manifestations common to all forms of malaria include fever, anemia, jaundice, splenomegaly, hepatomegaly, and the malarial paroxysm (rigor) that coincides with release of merozoites from ruptured RBCs. The classic paroxysm starts with malaise, abrupt chills and fever rising to 39 to 41° C, rapid and thready pulse, polyuria, and increasing headache and nausea. After 2 to 6 h, fever falls and profuse sweating occurs for 2 to 3 h, followed by extreme fatigue. Fever is often hectic at the start of infection. In established infections, malarial paroxysms typically occur about every 2 to 3 days depending on species; intervals are not rigid.

Anemia may be severe in P. falciparum infection or chronic P. vivax and tends to be mild in P. malariae. Splenomegaly usually becomes palpable by the end of the 1st week of clinical disease but may not occur with P. falciparum. The enlarged spleen is soft and prone to traumatic rupture. Splenomegaly may decrease with recurrent attacks of malaria as functional immunity develops. After many bouts, the spleen may become fibrotic and firm and occasionally becomes massively enlarged (tropical splenomegaly). Hepatomegaly usually accompanies splenomegaly.

P. falciparum causes the most severe disease because of its microvascular effects. It is the only species likely to cause fatal disease if untreated; nonimmune patients may die within days of their initial symptoms. Patients with cerebral malaria may develop symptoms ranging from irritability to seizures and coma. Respiratory distress syndrome, diarrhea, icterus, epigastric tenderness, retinal hemorrhages, algid malaria (a shocklike syndrome), and severe thrombocytopenia may also occur. Renal insufficiency may result from volume depletion, vascular obstruction by parasitized erythrocytes, or immune complex deposition. Hemoglobinemia and hemoglobinuria resulting from intravascular hemolysis may progress to blackwater fever (so named from the dark color of the urine), either spontaneously or after treatment with quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
. Hypoglycemia is common and may be aggravated by quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
treatment and associated hyperinsulinemia. Placental involvement may lead to spontaneous abortion, stillbirth, or, rarely, congenital infection.

P. vivax , P. ovale, and P. malariae typically do not compromise vital organs. Mortality is rare and is mostly due to splenic rupture or uncontrolled hyperparasitemia in asplenic patients. The clinical course with P. ovale is similar to that of P. vivax. In established infections, temperature spikes occur at 48-h intervals. P. malariae infections often cause no acute symptoms, but low-level parasitemia may persist for decades and lead to immune complex–mediated nephritis or nephrosis or tropical splenomegaly; when symptomatic, fever tends to occur at 72-h intervals.

In a person who has been taking chemoprophylaxis (see Extraintestinal Protozoa: Chemoprophylaxis), malaria may be atypical. The incubation period may extend weeks after the drug is stopped. Those infected may develop headache, backache, and irregular fever. Parasites may initially be difficult to find in blood samples.

Diagnosis

Fever and chills (particularly recurrent attacks) in a traveler returning from an endemic region should prompt immediate assessment for malaria, even as much as 1 to 2 yr after return. Malaria is typically diagnosed by finding parasites on microscopic examination of thick or thin blood smears. The infecting species is identified by characteristic features on smears (see Table 1: Extraintestinal Protozoa: Diagnostic Features of Plasmodium Species in Blood Films). The species determines therapy and prognosis. Blood smears should be repeated at 4- to 6-h intervals if the initial smear is negative.

Table 1
Diagnostic Features of Plasmodium Species in Blood Films Plasmodium Species* Characteristic Vivax Falciparum Malariae Infected RBCs enlarged Yes No No Schüffner's dots Yes† No No Maurer's dots or clefts No Yes† No Multiple infections in RBCs Rare Yes No Rings with 2 chromatin dots Rare Frequent No Crescentic gametocytes No Yes No Bayonet or band trophozoites No No Yes† Schizonts present in peripheral blood Yes Rare Yes Number of merozoites per schizont (mean [range]) 16 (12–24) 12 (8–24)‡ 8 (6–12) *RBCs infected with P. ovale are fimbriated, oval, and slightly enlarged; the parasites otherwise resemble P. malariae. †Not always visible. ‡Schizonts are trapped in viscera and usually are not present in peripheral blood.

Thick films are prepared by spreading a large drop of blood circularly over a 15-mm area of a glass slide so that blood cells are layered on top of each other. The slide is allowed to dry thoroughly. Thick films are stained with Giemsa or Wright's-Giemsa solutions. After staining, slides can be rinsed in buffered water and then air-dried (not blotted). Since RBCs are hemolyzed by water in unfixed thick smears, parasites appear as extracellular organisms against a uniform background of red cell stroma. Thin films, which are fixed in methanol before staining, are less sensitive than thick films but require less diagnostic expertise to interpret.

Bedside dipstick tests using monoclonal antibodies for histidine-rich protein-2 appear to be of comparable accuracy to blood smears in diagnosis of P. falciparum and require less training than microscopy. PCR and species-specific DNA probes may be used but are not widely available. Serologic tests may reflect prior exposure and are not appropriate to diagnose acute malaria.

Treatment

Malaria is particularly dangerous in children < 5 yr, pregnant women, and previously unexposed visitors to endemic areas. In case of a febrile illness during travel in an endemic region, prompt professional medical evaluation is essential; when this is not possible, self-medication with atovaquone-proguanil Some Trade Names

can be used pending evaluation.

If P. falciparum is suspected, therapy should be initiated immediately, even if the initial smear is negative. P. falciparum and, more recently, P. vivax have become increasingly resistant to antimalarial drugs. Recommended dosages of antimalarial drugs are listed in Table 2: Extraintestinal Protozoa: Treatment of Malaria  and Table 3: Extraintestinal Protozoa: Prevention of Malaria. Common adverse effects and contraindications are listed in Table 4: Extraintestinal Protozoa: Adverse Reactions and Contraindications of Antimalarial Drugs.

Table 2
Treatment of Malaria  This table is presented as a PDF and requires the free Adobe PDF reader. Get Adobe Reader

Table 3
Prevention of Malaria Infection Drug* Adult Dosage Pediatric Dosage Chloroquine-sensitive areas Drug of choice Chloroquine Some Trade Names ARALEN Click for Drug Monograph phosphate or 500 mg (300 mg base) once/wka 5 mg/kg base once/wk, up to adult dose of 300 mg basea   Atovaquone-proguanil Some Trade Names b 1 adult tablet/dayc 11–20 kg: 1 pediatric tablet/dayc 21–30 kg: 2 pediatric tablets/dayc 31–40 kg: 3 pediatric tablets/dayc > 40 kg: 1 adult tablet/dayc   Plus d       Primaquine Some Trade Names No US trade name Click for Drug Monograph 30 mg base once/day for last 2 wk of prophylaxis 0.6 mg/kg base once/day for last 2 wk of prophylaxis Chloroquine-resistant areas Drug of choice Atovaquone-proguanil Some Trade Names b 1 adult tablet/dayc 11–20 kg: 1 pediatric tablet/dayc 21–30 kg: 2 pediatric tablets/dayc 31–40 kg: 3 pediatric tablets/dayc > 40 kg: 1 adult tablet/dayc   Doxycycline Some Trade Names PERIOSTAT VIBRAMYCIN Click for Drug Monograph 100 mg once/daye 2 mg/kg once/day, up to 100 mg/daye   Mefloquine Some Trade Names LARIAM Click for Drug Monograph f 250 mg once/wka 5–10 kg: 1⁄8 tablet once/wka 11–20 kg: 1⁄4 tablet once/wka 21–30 kg: 1⁄2 tablet once/wka 31–45 kg: 3⁄4 tablet once/wka > 45 kg: 1 tablet once/wka   Plus d       Primaquine Some Trade Names No US trade name Click for Drug Monograph 30 mg base once/day for last 2 wk of prophylaxis 0.6 mg/kg base once/day for last 2 wk of prophylaxis Alternatives Primaquine Some Trade Names No US trade name Click for Drug Monograph or 30 mg base once/dayg 0.6 mg/kg base once/dayg   Chloroquine Some Trade Names ARALEN Click for Drug Monograph phosphate 500 mg (300 mg base) once/wka 5 mg/kg base once/wk, up to 300 mg basea   Plus       Proguanil 200 mg once/dayh < 2 yr: 50 mg once/dayh 2–6 yr: 100 mg once/dayh 7–10 yr: 150 mg once/dayh > 10 yr: 200 mg once/dayh *See Table 4: Extraintestinal Protozoa: Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications. a. Beginning 1 to 2 wk before travel and continuing weekly for the duration of stay and for 4 wk after leaving. b. Atovaquone Some Trade Names MEPRON Click for Drug Monograph plus proguanil is available as a fixed-dose combination tablet: adult tablets (250 mg atovaquone Some Trade Names MEPRON Click for Drug Monograph /100 mg proguanil) and pediatric tablets (62.5 mg atovaquone Some Trade Names MEPRON Click for Drug Monograph /25 mg proguanil). To enhance absorption, it should be taken with food or a milky drink. c. Beginning 1 to 2 days before travel and continuing for the duration of stay and for 1 wk after leaving. d. Recommended by some experts for prevention of attack after departure from areas where P. vivax and P. ovale are endemic, which includes almost all areas where malaria is found (except Haiti). Others prefer to avoid the toxicity of primaquine Some Trade Names No US trade name Click for Drug Monograph and rely on surveillance to detect cases when they occur, particularly when exposure was limited or doubtful. e. Beginning 1 to 2 days before travel and continuing for the duration of stay and for 4 wk after leaving. Use of tetracyclines is contraindicated in pregnancy and in children ≤ 8 yr. f. Resistance to mefloquine Some Trade Names LARIAM Click for Drug Monograph has been reported in some areas, such as the Thailand-Myanmar and Thailand-Cambodia borders; in these areas, atovaquone-proguanil Some Trade Names or doxycycline Some Trade Names PERIOSTAT VIBRAMYCIN Click for Drug Monograph should be used for prophylaxis. Many experts no longer recommend mefloquine Some Trade Names LARIAM Click for Drug Monograph because of its potential for serious neuropsychiatric effects. g. Beginning 1 day before travel and continued until 3 to 7 days after leaving may provide effective prophylaxis against chloroquine Some Trade Names ARALEN Click for Drug Monograph -resistant P. falciparum. Some studies have shown less efficacy against P. vivax. Nausea and abdominal pain can be diminished by taking with food. h. Prophylaxis is recommended during exposure and for 4 wk after. Adapted with permission from The Medical Letter on Drugs and Therapeutics. The Medical Letter, Inc., August 2004.

Table 4
Adverse Reactions and Contraindications of Antimalarial Drugs Drug Adverse Reactions Contraindications Atovaquone-proguanil Some Trade Names GI disturbances, headache, dizziness, pruritus Hypersensitivity, pregnancy, breastfeeding, severe renal impairment (creatinine clearance < 30 mL/min) Chloroquine Some Trade Names ARALEN Click for Drug Monograph phosphate Chloroquine Some Trade Names ARALEN Click for Drug Monograph HCl Hydroxychloroquine Some Trade Names PLAQUENIL Click for Drug Monograph sulfate GI disturbances, headaches, dizziness, blurred vision, rashes or pruritus, exacerbation of psoriasis, blood dyscrasias, alopecia, ECG changes, retinopathy, psychosis (rare) Hypersensitivity, retinal or visual field changes Clindamycin Some Trade Names CLEOCIN Click for Drug Monograph Hypotension, bone marrow toxicity, renal dysfunction, rashes, jaundice, tinnitus, pseudomembranous colitis Hypersensitivity Doxycycline Some Trade Names PERIOSTAT VIBRAMYCIN Click for Drug Monograph GI upset, photosensitivity, vaginal candidiasis, pseudomembranous colitis, erosive esophagitis Pregnancy, children ≤ 8 yr Halofantrine Some Trade Names HALFAN Prolongation of PR and QT intervals, cardiac arrhythmia, hypotension, GI disturbances, dizziness, mental changes, seizures, sudden death Cardiac conduction defects, familial QT prolongation, drugs that affect QT interval, hypersensitivity, pregnancy Mefloquine Some Trade Names LARIAM Click for Drug Monograph Bad dreams, neuropsychiatric symptoms, dizziness, vertigo, confusion, psychosis, seizures, sinus bradycardia, GI disturbances Hypersensitivity, history of seizures or psychiatric disorders, drugs that may prolong cardiac conduction (eg, β-blockers, Ca channel blockers, quinine Some Trade Names QUALAQUIN Click for Drug Monograph , quinidine Some Trade Names CARDIOQUIN QUINAGLUTE Click for Drug Monograph , halofantrine Some Trade Names HALFAN ) in patients with heart disease, occupations requiring fine coordination and spatial discrimination, pregnancy Quinine Some Trade Names QUALAQUIN Click for Drug Monograph sulfate Quinine Some Trade Names QUALAQUIN Click for Drug Monograph dihydrochloride GI disturbances, tinnitus, visual disturbances, allergic reactions, mental changes, arrhythmias, cardiotoxicity Hypersensitivity, G6PD deficiency, optic neuritis, tinnitus, pregnancy (relative contraindication), past adverse quinine Some Trade Names QUALAQUIN Click for Drug Monograph reaction (continuous ECG, BP [when given IV], and glucose monitoring recommended) Quinidine Some Trade Names CARDIOQUIN QUINAGLUTE Click for Drug Monograph gluconate Arrhythmias, prolonged Q-Tc interval, hypotension Hypersensitivity, thrombocytopenia (continuous ECG, BP, and glucose monitoring recommended) Primaquine Some Trade Names No US trade name Click for Drug Monograph phosphate Severe intravascular hemolysis in people with G6PD deficiency, GI disturbances, leukopenia, methemoglobinuria Concomitant quinacrine, potentially hemolytic or bone marrow suppressing agents, G6PD deficiency, pregnancy Pyrimethamine Some Trade Names DARAPRIM Click for Drug Monograph -sulfadoxine Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal neurolysis, urticaria, exfoliative dermatitis, serum sickness, hepatitis, seizures, mental changes, GI disturbances, stomatitis, pancreatitis, bone marrow toxicity, hemolysis, fever, nephrosis Hypersensitivity, folate deficiency anemia, infants ≤ 2 mo, pregnancy, breastfeeding

Treatment of the acute attack: Chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
is the drug of choice against P. malariae , P. ovale, and chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
-sensitive P. falciparum and P. vivax. Chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
resistance is common among P. falciparum strains throughout endemic areas, with the exception of Central America west of the Panama Canal, Haiti, and the Dominican Republic. Chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
resistance is not always complete, but chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
should be used only for malaria acquired in areas where Plasmodium sp are known to be sensitive.

Uncomplicated chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
-resistant P. falciparum can be treated with atovaquone-proguanil Some Trade Names

or quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
plus doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph
. If the patient is pregnant, quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
plus clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph
can be used. Mefloquine Some Trade Names
LARIAM
Click for Drug Monograph
at treatment doses is an option, but adverse effects are common. IV quinidine Some Trade Names
CARDIOQUIN
QUINAGLUTE
Click for Drug Monograph
or quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
dihydrochloride is used in patients unable to take oral drugs. These drugs should be used with hemodynamic and ECG monitoring; the infusion is slowed or temporarily suspended if the QT interval is > 0.6 sec or the QRS widens > 25% beyond baseline. Parenteral therapy should be continued until oral medication is tolerated. It is customary to supplement quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
and quinidine Some Trade Names
CARDIOQUIN
QUINAGLUTE
Click for Drug Monograph
with doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph
or clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph
to prevent late recrudescences. These antibiotics act too slowly to be used alone for the treatment of acute malaria. Halofantrine Some Trade Names
HALFAN

(not available in the US) may prolong the QT interval and has been associated with sudden death. Artesunate and several other artemisinin derivatives are available overseas but not in the US; they are usually combined with a 2nd drug (eg, lumefantrine) to prevent recrudescence.

The patient must be monitored closely for hypoglycemia and proper hydration. Exchange transfusions have been used in some patients with high parasitemia to remove infected RBCs, but there is not uniform agreement on this approach. After successful treatment, the patient usually shows improvement in 24 to 48 h, but symptoms can persist for 5 days with P. falciparum.

Chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
-resistant P. vivax is common in Papua New Guinea and Indonesia. It is treated with quinine Some Trade Names
QUALAQUIN
Click for Drug Monograph
plus doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph
or with mefloquine Some Trade Names
LARIAM
Click for Drug Monograph
.

Curative therapy for hypnozoites: To prevent relapses of P. vivax or P. ovale malaria, the hypnozoite stage must be eliminated from the liver with primaquine Some Trade Names
No US trade name
Click for Drug Monograph
. Primaquine Some Trade Names
No US trade name
Click for Drug Monograph
may be given simultaneously with chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
or afterward. Some P. vivax strains are less sensitive and require repeated treatment with higher doses. Primaquine Some Trade Names
No US trade name
Click for Drug Monograph
therapy is not necessary for P. falciparum or P. malariae , because these Plasmodium sp do not have a persistent hepatic phase.

Prevention

Prophylactic antimalarial drugs and insect repellants reduce but do not eliminate risk of malaria. No vaccine is currently available.

Prophylaxis against mosquitoes includes using permethrin Some Trade Names
ELIMITE
NIX
RID SPRAY
Click for Drug Monograph
- or pyrethrum-containing residual insecticide sprays on clothing or in homes and outbuildings, placing screens on doors and windows, using mosquito netting (preferably impregnated with permethrin Some Trade Names
ELIMITE
NIX
RID SPRAY
Click for Drug Monograph
or pyrethrum) around beds, using mosquito repellents such as DEET, and wearing protective clothing, especially between dusk and dawn, when Anopheles mosquitoes are active.

Chemoprophylaxis: Regimens and dosing vary by geographic location and patient characteristics (see Table 3: Extraintestinal Protozoa: Prevention of Malaria). If exposure to P. vivax or P. ovale was intense or prolonged or the traveler was splenectomized, a 14-day prophylactic course of primaquine Some Trade Names
No US trade name
Click for Drug Monograph
phosphate on return helps reduce the risk of recurrence. The major adverse effect is hemolysis in people with G6PD deficiency.

Malaria during pregnancy poses a serious threat to both the mother and fetus. If travel to an endemic area is unavoidable, chemoprophylaxis with at least chloroquine Some Trade Names
ARALEN
Click for Drug Monograph
should be given. The safety of mefloquine Some Trade Names
LARIAM
Click for Drug Monograph
during pregnancy has not been documented, but limited experience suggests that it may be used when the benefits are judged to outweigh the risks. Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph
, atovaquone-proguanil Some Trade Names

, and primaquine Some Trade Names
No US trade name
Click for Drug Monograph
should not be used during pregnancy.

Last full review/revision November 2005

Content last modified November 2005