Malaria

Infection with any of four different species of Plasmodia, causing periodic paroxysms of chills, fever and sweating, anemia and splenomegaly.

Malaria is endemic in Africa, much of South and Southeast Asia, Central America, and northern South America. Malaria once was endemic in the USA but has been virtually eliminated from North America. However, anopheline mosquitoes capable of transmitting the disease are still found. Small epidemics caused by focal transmission of imported malaria have been reported in California, Florida, and New York City. Most cases in the USA occur in persons infected abroad (imported malaria); a small number result from blood transfusions.

The four important Plasmodium species are: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum, and more recently, P. vivax have become increasingly resistant to antimalarial drugs.

Most blacks in West Africa and the USA are resistant to P. vivax because their RBCs lack the Duffy blood group, which is required for the invasion of RBCs. The development of Plasmodium in RBCs is also retarded in patients with hemoglobin S, hemoglobin C, thalassemia, G6PD deficiency, or Melanesian elliptocytosis.

Etiology and Pathogenesis

The basic elements of the life cycle are the same for all four species. 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 develop into infective sporozoites. When the mosquito feeds on a human, it inoculates sporozoites, which quickly infect hepatocytes. This does not produce clinical illness. However, schizogony occurs within infected hepatocytes; 1 to 2 wk later they rupture and release merozoites that invade RBCs and there transform into trophozoites. Appearing as rings in stained RBCs, young trophozoites grow and develop into schizonts, which rupture the RBC. Merozoites released in plasma then rapidly invade new RBCs. Repeated cycles of schizogony (invasion to rupture of an RBC) are responsible for the clinical symptoms. Simultaneously, a separate cycle of development results in the formation of gametocytes in RBCs. These are clinically irrelevant but infect anopheline mosquitoes and thus maintain the parasite's life cycle.

Pre-erythrocytic schizonts in the liver may persist for 2 to 3 yr in infections with P. vivax and P. ovale, but not with P. falciparum or P. malariae. These long-lived hypnozoites serve as a seedbed for relapses and complicate chemotherapy because they are not killed by drugs used to treat clinical disease. The pre-erythrocytic part of the malarial life cycle is bypassed when infection is transmitted by blood transfusions, through sharing of contaminated needles, or congenitally.

Anemia and jaundice are caused by intravascular hemolysis of infected RBCs during release of merozoites, phagocytosis of infected and uninfected RBCs in the spleen, shortened survival of infected and uninfected RBCs, and ineffective hematopoiesis, especially with concomitant malnutrition.

Symptoms and Signs

The incubation period is usually 10 to 20 days for P. vivax, 12 to 14 days for P. falciparum, and about 1 mo for P. malariae. However, some strains of P. vivax in temperate climates may not cause clinical illness until a year after infection. Malaria is often atypical in a person who has been taking chemoprophylaxis. The incubation period may extend weeks after the drug is stopped. Instead of periodic chills and fever, the person may have headache, backache, and irregular fever; parasites may be difficult to find in blood samples.

Manifestations common to all forms of malaria include anemia, jaundice, splenomegaly, hepatomegaly, and the malarial paroxysm (rigor) that coincides with the release of merozoites from ruptured RBCs. A paroxysm starts with malaise, abrupt chills and fever rising to 39 to 41° C (102 to 106° F), rapid and thready pulse, polyuria, and increasing headache and nausea. Next, fever falls and profuse sweating occurs over a period of 2 to 3 h. Malarial paroxysms typically occur about every 48 h with P. vivax, P. falciparum, and P. ovale and about every 72 h with P. malariae. These intervals are not rigid: paroxysms may occur daily in mixed infections or early in the course of infection (especially with P. falciparum).

Anemia in malaria depends on the infecting species: usually severe in P. vivax and P. falciparum and usually mild in P. malariae. Splenomegaly usually becomes palpable by the end of the first wk of clinical disease but may not occur with P. falciparum. The enlarged spleen is soft and prone to traumatic rupture. Splenomegaly progressively decreases with recurrent attacks of malaria as functional immunity develops. After many bouts, the spleen becomes fibrotic and firm. Hepatomegaly usually accompanies splenomegaly.

P. falciparum causes the most severe disease and can be fatal if untreated. RBCs containing P. falciparum schizonts adhere to vascular endothelium, obstructing small blood vessels and causing tissue anoxia in various organs. Patients with cerebral malaria may develop symptoms ranging from irritability to coma; respiratory distress syndrome, diarrhea, icterus, epigastric tenderness, retinal hemorrhages, algid malaria (a shocklike syndrome), and severe thrombocytopenia also occur. Renal disease may result from volume depletion, the plugging of blood vessels, immune complex deposition, or blackwater fever (hemoglobinemia and hemoglobinuria resulting from intravascular hemolysis, either spontaneously or after treatment with quinine). Hypoglycemia and hyperinsulinemia are common and may be aggravated by quinine treatment. Placental involvement may lead to spontaneous abortions, stillbirths, or rarely congenital infection.

P. vivax and P. ovale rarely compromise the function of vital organs. Mortality is rare and is mostly due to splenic rupture or uncontrolled hyperparasitemia in asplenic persons. 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 to "big spleen disease." P. malariae is the most common cause of transfusion malaria.

Diagnosis

P. falciparum infection is a medical emergency. Recurrent attacks of chills and fever without apparent cause should always suggest malaria, particularly if the patient has been in an endemic area within 3 to 5 yr, has an enlarged spleen, or has been recently transfused. Finding Plasmodium in a blood smear is diagnostic. The infecting species must be identified, since this influences therapy and prognosis. Chances of finding parasites are greater between clinical episodes than just after a paroxysm.

Thin films for malaria are prepared in the same manner as thin films for hematologic studies. Thick films are prepared from a slightly larger drop of blood that is spread circularly over an area of the slide about 15 mm, so that blood cells are layered on top of each other. The thick film is allowed to dry thoroughly, preferably with the smear side facing down to protect it from dust, flies, and so on. Thick films are not fixed but are placed directly in the Giemsa solution. After staining, slides can be rinsed in tap or distilled water and then air-dried (not blotted). Glass slides must be free of lint and grease. Because Giemsa stain is aqueous, the RBCs are hemolyzed. The parasites therefore appear as extracellular organisms against a uniform background of red cell stroma. WBCs remain relatively unchanged.

Stained thin films provide good morphology but are less sensitive than thick films, which require more diagnostic expertise. Blood smears should be repeated every 6 h if the initial smear is negative. The quantitative buffy coat method of examining blood samples may increase sensitivity. Polymerase chain reaction and species-specific DNA probes are under evaluation, as is a dipstick method for detecting an antigen of P. falciparum during acute illness. Serology is only helpful in retrospect. IgM antibodies usually appear when parasites are first demonstrable in peripheral blood; later, the IgG response is marked.

Prevention

No measures are completely effective in preventing malaria; prompt medical evaluation should be sought for all febrile illnesses in those at risk. Malaria is particularly dangerous in children < 5 yr, pregnant women, and previously unexposed visitors to endemic areas. Experimental vaccines are being evaluated in controlled clinical trials.

Prophylaxis against mosquitoes includes using pyrethrum-containing residual insecticide sprays in homes and outbuildings, placing screens on doors and windows, using mosquito netting (preferably impregnated with pyrethrum) around beds, using mosquito repellents such as N,N-diethyl-metatoluamide (deet), and wearing protective clothing, especially between dusk and dawn.

Chemoprophylaxis should begin 1 to 2 wk before traveling to, and continue for 4 wk after returning from, an endemic area. Doxycycline, however, can be started 1 to 2 days before entering the endemic area. Once-weekly chloroquine is recommended for travelers to areas of risk where chloroquine-resistant P. falciparum has not been reported (eg, Haiti in 1996). Chloroquine is usually well tolerated. If not, hydroxychloroquine can be used.

Mefloquine is recommended for travel to areas where chloroquine-resistant P. falciparum exists. A fixed combination of mefloquine, pyrimethamine, and sulfadoxine is marketed under the name Fansimef in some countries. Fansimef should not be confused with mefloquine as it is not recommended for malaria prophylaxis.

Doxycycline taken daily is an alternative regimen for short-term travelers who cannot tolerate mefloquine or for persons in whom the drug is contraindicated (see below). For travelers who can use neither mefloquine nor doxycycline, pregnant women, and children <= 15 kg, a weekly dose of chloroquine is recommended. In case of a febrile illness during travel when professional medical care is not readily available, persons using chloroquine only should promptly take a dose of pyrimethamine plus sulfadoxine (except those with a history of sulfonamide intolerance) or of halofantrine. This so-called presumptive treatment is only a temporary measure, and prompt evaluation is imperative. Until the latter can be done, weekly chloroquine prophylaxis should be continued.

If exposure to P. vivax or P. ovale was intense or the traveler was splenectomized, a 14-day prophylactic course of primaquine phosphate on return may be indicated.

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 should be given. The safety of mefloquine during pregnancy is under study, but limited experience suggests that it may be safe after the 16th wk of gestation. The safety of pyrimethamine/sulfadoxine during pregnancy has not been established. Doxycycline and primaquine should not be used during pregnancy.

Once a person leaves an endemic area, functional resistance lasts only a few months and protects against only those parasite strains to which the person was exposed.

Treatment

Tables of "Recommended dosages of antimalarial drugs" exist. Common side effects and contraindications are described below. If CNS involvement with P. falciparum is suspected, therapy should be initiated immediately without waiting for a positive smear.

Several new antimalarial drugs are available outside the USA. Halofantrine can be used to treat chloroquine-resistant P. falciparum but should not to be used as a prophylactic. The drug may cause prolongation of the QT interval. Quinghaosu rapidly clears P. falciparum parasitemia, but recrudescences are common. Proguanil can be used for chemoprophylaxis in combination with weekly chloroquine but may cause megaloblastic anemia.

Treatment of the acute attack: Chloroquine is the drug of choice against P. malariae, P. ovale, and chloroquine-sensitive P. falciparum and P. vivax. The patient usually becomes afebrile in 48 to 72 h. In P. falciparum, slow IV administration of chloroquine is indicated if oral drug cannot be tolerated. In patients with rapidly rising parasitemia, exchange transfusions combined with parenteral antimalarials can rapidly remove infected RBCs and may be lifesaving. Corticosteroids are contraindicated in cerebral malaria.

Chloroquine-resistant P. falciparum is treated with oral quinine sulfate or, in severe illness, with IV quinidine or quinine dihydrochloride. Parenteral therapy should be continued until parasitemia is < 1% or oral medication is tolerated. Because of possible recrudescence, it is customary to supplement this regimen with pyrimethamine and sulfadoxine, tetracycline, or clindamycin. Other drugs include mefloquine, halofantrine, and artemisin derivatives.

Chloroquine-resistant P. vivax has occurred on New Guinea and the Solomon Islands. Treatment with quinine and tetracycline or with mefloquine is recommended.

Curative therapy: To prevent relapses of P. vivax or P. ovale malaria, hypnozoite stages must be eliminated with primaquine. Primaquine may be given simultaneously with chloroquine or afterward. Some strains are refractory and require repeated treatment. Curative therapy is not necessary for P. falciparum or P. malariae, as they do not have a persistent hepatic phase.

Adverse reactions and contraindications: Minor side effects of chloroquine and hydroxychloroquine, such as GI disturbances, headaches, dizziness, blurred vision, or pruritus, generally do not require discontinuing the drugs. Both drugs may exacerbate psoriasis. Periodic ophthalmologic examinations are recommended for persons using weekly chloroquine for > 6 yr because of rare occasions of retinopathy. Chloroquine is safe during pregnancy.

Although parenteral quinidine and quinine are generally well tolerated, the drugs should be used only in an intensive care unit where hemodynamic and ECG monitoring can be performed. Close attention to the patient's hydration and blood glucose level is mandatory. Plasma quinidine levels > 6 µg/mL (18 µmol/L), QT interval > 0.6 sec, or QRS widening beyond 25% of baseline indicate slowing infusion rates. Quinine may transiently cause tinnitus, nausea, and blurred vision.

Fatal cutaneous reactions occur in 1/11,000 to 1/25,000 U.S. travelers using pyrimethamine-sulfadoxine weekly for prophylaxis. Its use is also associated with erythema multiforme, Stevens-Johnson syndrome, toxic epidermal neurolysis, urticaria, exfoliative dermatitis, serum sickness, and hepatitis. The drug is contraindicated in persons with a history of intolerance to sulfonamides and in infants <= 2 mo.

Doxycycline is contraindicated in pregnancy and in children <= 8 yr. GI upset, photosensitivity and vaginal candidiasis are relatively common.

Mefloquine causes self-limited dizziness and GI disturbances. The drug also may cause sinus bradycardia and prolonged QT interval and should not be used by those receiving drugs that may prolong cardiac conduction (eg, beta-blockers, calcium channel blockers). Mefloquine may cause vertigo, confusion, psychosis, and convulsions and should not be used in patients with a history of epilepsy or psychiatric disorders or those whose occupation requires fine coordination and spatial discrimination. Mefloquine should not be used in children <= 15 kg or in pregnant women.

Because primaquine may cause severe intravascular hemolysis in persons with G6PD deficiency, patients should be screened for this defect before treatment. Abdominal cramps and methemoglobinuria may also occur, but the drug is otherwise generally well tolerated. Primaquine is contraindicated during pregnancy.

Several new antimalarial drugs are available overseas but not in the USA. Halofantrine can be used to treat chloroquine-resistant P. falciparum but should not be used as a prophylactic agent. The drug may cause prolongation of the QT interval. Quinghaosu (artemisin) is derived from a traditional Chinese herbal remedy. It rapidly clears P. falciparum parasitemia, but recrudescences are common. Several derivatives of the parent compound are being evaluated in some countries. Proguanil (Paludrine) is not available commercially in the USA but can be used for chemoprophylaxis in combination with weekly chloroquine. Proguanil is a dihydrofolate reductase inhibitor and thus may cause megaloblastic anemia.