Infectious Diseases Case of the Month Case #33

A forty year old white female was admitted to the hospital for high fever and chills three days after returning from a one month long stay in Uganda.

A native born U.S. citizen she had been regularly visiting Uganda for two to four week long stays as a Christian missionary for the last several years. Although on some prior visits she had taken antimalarial prophylaxis, on more recent visits, including this one, she had not taken prophylaxis in part because of the expense (Malarone). She did use a mosquito net at night and was unaware of any mosquito bites. She had no significant underlying medical illnesses.

She had become ill with fever, malaise, and abdominal cramping two days before departing Uganda and remained ill on her airplane flight back to the United States. In the three days prior to seeking care upon arrival in the U.S. she had had continued episodes of high fever with chills and had had nausea and vomiting.

At the time of her emergency room presentation laboratory evaluation included WBC 3.4 (L), Hgb 13.9, Plts 17 (L), AST 90 (H), Alt 118 (H), Bil 4.7 (H), Bicarb 26, Glu 111 (H), Creat 0.6, INR 1.1, PTT 30, fibrinogen 478, and D-Dimer >5250 (H). A blood smear for malaria was positive (see left) showing a high parasitemia (15%). CXR did not show significant abnormality.

She was begun on antimalarial therapy but within the first day of hospitalization became progressively obtunded. She was urgently transferred to a tertiary care facility for potential exchange transfusion and continued care.

What would be the most effective pharmaceutical therapy in this case of severe malaria?

       
Which therapy would be most effective?
   
     
Answer: Artesunate
   

This patient had severe (cerebral) malaria due to Plasmodium falciparum, and the most potent currently available therapy (circa 2011) is IV artesunate.

Patients with malaria can generally be categorized as having either uncomplicated or severe malaria (click here for criteria defining severe malaria). Infection with falciparum malaria is apt to cause severe disease due to this species' ability to parasitize all circulating red cells (regardless of maturity) and for red cells so parasitized to sequester in the microcirculation causing end organ damage. Those suffering from severe malaria should be treated with parenteral therapy.

For U.S. readers the question that introduced this discussion was something of a "trick" question as in the United States the only currently commercially available IV antimalarial is quinidine gluconate. However, this drug, formerly a commonly used cardiac anti-arrythmic, is no longer considered the preferred treatment for severe falciparum malaria. It is less potent as an antimalarial and has more significant side effects (cardiotoxicity, hypotension, hypoglycemia) than artesunate (click here for a larger version of the table at left describing artesunate's advantages).

Artesunate, an atemisinin, is derived from the Qinghao plant (Artemisia annua) known in the U.S. as sweet wormwood. The medicinal properties of this plant were known to the Chinese at least as far back as the 2nd century BC. The active ingredient of Qinghao, known as artemisinin, was isolated by Chinese scientists in 1971. Its higher efficacy in treatment may be due in part to its activity against more ring form stages than those affected by the quinoline antimalarials (quinine, quinidine, and mefloquine). Unfortunately, partial resistance has already developed to artemisinins in some regions of the world. The WHO recommends these compounds always be used in combination with other antimalarials to try to avoid the development of further resistance.

In the case described this patient with cerebral malaria and high parasitemia received IV quinidine locally and then artesunate when it was acquired at the tertiary care facility. She appeared to quickly benefit from the artesunate and has since recovered without severe neurologic sequelae. Interestingly, her strategy in Uganda had been for self testing and self treatment, a strategy thwarted by the appearance of illness as she was departing the country (she did not have access to the necessary testing and treatment drugs in that circumstance).

Artesunate is available for use in the United States through an investigational new drug (IND) protocol at the CDC. Its eventual commercial availability is being sought which to some degree is a financial issue as the costs of drug development and approval are very substantial particularly when it is considered that there are only about 1500 cases of malaria (all types) reported in the U.S. annually.

Malaria is a very complex illness that most U.S. practitioners don't encounter regularly. There are four species of Plasmodia that typically cause human disease. To see a schematic of the malarial life cycle click here. All the choices of therapy in the preceding vignette (see original format) have roles in treatment and/or prophylaxis of malaria depending on species and likely patterns of resistance.

Ref: WHO Guidelines for Treatment of Malaria, 2nd Ed, 2010

 

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