Final Diagnosis -- Malaria (Intermittent fevers)


Malaria, probable Plasmodium falciparum.
Contributor's Note:

Malaria is caused by four Plasmodium species: falciparum, ovale, vivax, and malariae. It is estimated that over 100 million people worldwide are infected causing 1-2 million deaths per year. When diagnosed in the United States it is usually associated with travel to foreign countries or with recent immigration. In this case the patient was a foreign student recently arriving in the U.S. While not endemic to the U.S., occasional cases are encountered. Thus, it is important to understand the parasite life cycle, how to diagnose the infection, complications of the infection and treatment options.


The Plasmodium parasite undergoes two cycles of replication; sporogony (the sexual cycle) and schizogony (the asexual cycle). Sporogony occurs in the intestinal tract of the anopheline mosquito. Sporozoites, the product of sporogony, migrate to the salivary glands and are injected into the bloodstream when a mosquito bites a person. The sporozoites circulate briefly in the peripheral blood then enter hepatocytes. Inside hepatocytes (the exoerythrocytic stage) multiplication occurs. After approximately ten days, the merozoites enter the peripheral blood and infect erythrocytes (the intraerythrocytic stage). Inside the erythrocyte, the merozoite develops into the trophozoite or "ring form". The trophozoite develops into a schizont made up of multiple merozoites, a process called schizogony (the asexual replication cycle). The schizont matures causing rupture of the erythrocyte and releasing merozoites into the circulation which in turn infect other erythrocytes. The paroxysms or cyclical fevers classically associated with malaria occur shortly before or at the time of erythrocyte rupture. Infection with P. malaria causes paroxysms every 72 hours (quartan malaria). Infection with P. ovale or P. vivax cause tertian malaria with paroxysms every 48 hours. P. falciparum tends to produce irregular fever spikes superimposed upon a continuous fever or the tertian malaria paroxysms every 48 hours.

Merozoites will develop into gametocytes (female macrogametocytes and male microgametocytes) following several intraerythrocytic cycles. The gametocytes are infectious to the mosquito when ingested. In the intestine of the mosquito, the microgametocyte enters the macrogametocyte (sporogony) and zygotes are produced. The zygotes enter intestinal cells and develop into sporozoites. These sporozoites then migrate to the salivary glands continuing the Plasmodium life cycle.


Fever develops 7-10 days following infection, during the exoerythrocytic cycle of merozoite development in hepatocytes. It is during the intraerythrocytic cycle that the spiking fevers associated with erythrocyte lysis occur. Other symptoms include malaise, fatigue, anemia, headache and myalgias. Complications associated with P. falciparum infection include acute renal failure, pulmonary edema, and cerebral malaria (with seizures and coma). Hepatomegaly and splenomegaly have been documented with splenic rupture most commonly associated with P. vivax infection. P. malariae has been associated with an immune complex glomerulonephritis. Abnormal laboratory findings include decreased hemoglobin, hematocrit, platelet count and haptoglobin. Lactic dehydrogenase and reticulocyte count are generally increased. Increased bilirubin and increased serum enzymes may be noted and are not specifically associated with the exoerythrocytic stage.


Diagnosis is best made utilizing thick smears of peripheral blood but thin smears can also be used. In P. falciparum infection the parasite is identified as a tiny ring form within normal sized erythrocytes. These ring forms often show double nuclei and "applique" morphology against the cytoplasmic membrane. Multiple ring forms are commonly seen in P. falciparum. Merozoites when seen are usually >24 per cell. The gametocytes show a classic boomerang or banana shape. In P. vivax infection the parasite is identified as large ring forms (approximately 1/3 of cell width) in an enlarged erythrocyte. Shuffner's dots (pink granules) are commonly seen. Merozoites usually number between 12-24 per erythrocyte. Gametocytes are large and circular or ameoboid. P. malariae may demonstrate band like trophozoites. In P. malariae, the ring forms are rarely multiple and when multiple the possibility of a double infection with another Plasmodium species should be considered. Usually less than 12 merozoites per cell are seen. Indirect immunofluorescence may be used for serodiagnosis of malaria and a titer greater than 1:64 is considered diagnostic.

TREATMENT (Revised -- 12/07/95)

Decisions regarding treatment of malaria must take into account where the patient will be living while on therapy, the parasite load, the need for natural acquired immunity, patient symptoms, complications, and the problem of drug resistance. Pharmacologic treatment of malaria has become complicated by the emergence of drug resistant forms of parasites. Resistant forms of P. falciparum have been well documented for almost all antimalarial drugs, including chloroquine, other 4-aminoquinolines, and Fansidar. Cross resistance has quickly developed due to molecular similarities of drugs and limited modes of action on the parasite. When treating a patient as in this case, the World Health Organization provides useful epidemiologic information but it would be advisable to contact the Centers for Disease Control to obtain information concerning current knowledge of drug resistance in the specific region that the person was most likely infected, in this case Gambia, Africa [(404) 639-3311 days, (404)639-2888 nights and weekends]. The Centers for Disease Control also provide information on malaria prevention and prophylaxis for people traveling to endemic areas [(404) 639-3311].


Special thanks to Dr. Lory D. Wiviott, Department of Medicine, Division of Infectious Disease, California Pacific Medical Center and University of California, San Francisco, and Dr. Penny Williams, Department of Medicine, Division of Infectious Disease, University of Pittsburgh Medical Center for their help with the commentary concerning treatment of P. falciparum infections.


1. Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 4th ed.
Churchill Livingston, New York, 1995.

2. Campbell CC. Chalenges Facing Antimalarial Therapy in Africa. J Inf Dis 1991;163:1207-11.

3. Keystone JS, Malaria and the International Traveler. Travel Medicine Advisor.
American Health Consultants, Inc., Atlanta, 1992.

4. Longworth D, Drug-Resistant Malaria in Children and in Travelers. Ped Clin of N Am. 1995;42(3):649-64.

Contributed by Christine Dorvault, MD and Charles A. Richert, MD

DISCLAIMER: No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

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