Malaria and its prevention in the US

It is likely that readers of Infectious Diseases in Children have not treated a child or adult with malaria, as this otherwise globally common infectious disease has been eliminated endemically from the United States. Cases of malaria are reported here, however, occurring mostly in travelers who have returned from countries where malaria is endemic.

Approximately 50% of the world’s population is at significant risk for developing malaria, with an estimated 225 million clinical cases and 781,000 deaths reported in 2009 by WHO. Most of these deaths, approximately 85%, occurred in young children aged younger than 5 years. Most cases of malaria occur in sub-Saharan Africa, where approximately 20% of all childhood deaths are related to malaria. Malaria, pharmacotherapeutic agents used for its prevention and a newly developed vaccine are the focus of this month’s column, as I again recently traveled to Tanzania on a medical mission with a team of pediatric clinicians.

Plasmodium parasites cause malaria and are spread to humans by the bite of Anopheles mosquitoes. Four species of Plasmodium exist: P. falciparum; P. vivax; P. malariae; and P. ovale. Malaria from P. falciparum and P. vivax occur most commonly, and P. falciparum is more virulent. The presence of these species varies geographically. Fever is the most common clinical symptom of malaria, although gastrointestinal symptoms (nausea, diarrhea), malaise, cough and myalgia may also occur. Infected children can be jaundiced, anemic and exhibit splenomegaly and hepatomegaly. Clinical infection may recur months or years after initial infection, especially with P. vivax and P. ovale, as these species can persist in the liver as dormant stages (hypnozoites).

Malaria in the US

The CDC reports to the National Malaria Surveillance System on malaria infection and disease in the United States. In 2009, the CDC reported 1,484 US cases of malaria (four of which were fatal), a number similar to annual reported cases from 2000 to 2008. Of these cases, 99.6% resulted from travel to countries where malaria is endemic. In cases where the region of infection was determined, 74% were acquired in Africa.

The onset of symptoms occurred within 30 days in most cases. Most episodes of imported malaria in the United States do not occur in US travelers as tourists, but in immigrants visiting their native countries without use of appropriate chemoprophylaxis. They have the highest risk for developing malaria because they often believe they are immune to infection and disease.

In 2009, the species most commonly reported to cause disease was P. falciparum. Data on the use of preventive antimalarial medications were available for 611 US citizens with imported malaria in 2009: 25% reported taking prophylactic antimalarial medication, and of these, 10% did not use an agent recommended by the CDC. Of those who reported using an appropriate medication (n=103; 66%), information on adherence was available for 91, of whom 55% reported nonadherence (ie, at least some missed doses) with chemoprophylaxis. Thus, of the malaria cases reported to the CDC in 2009, most did not use appropriate chemoprophylaxis, including 80% of pediatric cases.

Most US clinicians likely have little or no diagnostic and treatment experience with malaria, and presenting symptoms of children with malaria are often nonspecific. An adequate travel history may not be taken or recent travel may not be discussed with clinicians. Taylor and colleagues recently reviewed the medical literature from 1950 to 2010 to determine the predictive value of clinical findings for diagnosing acute malaria in travelers returning from endemic areas. Seven studies were evaluated, and the presence of fever, splenomegaly, hyperbilirubinemia and thrombocytopenia were found to increase the likelihood of diagnosing malaria.

Gutman and Guarner recently published a retrospective review of 50 confirmed cases of malaria in children in the Atlanta area. Most of these children had visited family and friends in endemic countries. Of the 50 cases reviewed, 10 children used chemoprophylaxis, and only five children used a medication appropriate for the region where they traveled. Three children presented with symptoms 8 to 12 months after returning to the United States. In another study, Schwartz and colleagues evaluated cases of US and Israeli travelers with late-onset malaria. Of 2,822 cases of malaria diagnosed in US travelers during a 7-year period, late-onset (longer than 2 months) illness developed in 35%, mostly due to P. vivax and P. ovale. These Plasmodium species have persistent liver stages, which can result in symptomatic disease months or years after infection.

Chemoprophylaxis

It is vital that travelers to countries where malaria is endemic use appropriate prophylactic antimalarial agents and other preventive measures (eg, use of topical insect repellents, mosquito bed netting). However, this may not occur with many travelers. Information on appropriate chemoprophylactic agents is available on the CDC (www.cdc.gov/travel) and WHO (www.who.org) websites. Agent choice depends upon geographic area traveling to, type of travel planned (eg, time planned outdoors), geographic resistance patterns, patient age, trip duration, medical history and concomitant medications, and medication costs.

Clinicians can choose from at least six chemoprophylactic agents: atovaquone-proguanil, chloroquine phosphate, doxycycline, hydroxychloroquine sulfate, mefloquine and primaquine. The mechanisms and sites of action differ for some of these antimalarials. Most are classified as blood-stage schizonticides because they interrupt asexual schizogony (mitotic division) in red blood cells, thus preventing clinical episodes of malaria. Mefloquine (Lariam, Roche) and atovaquone-proguanil (Malarone, GlaxoSmithKline) are blood-stage schizonticides. Primaquine is a tissue-stage schizonticide and kills liver schizonts and dormant hypnozoites. In many areas of sub-Saharan Africa, P. falciparum is responsible for most cases of malaria, and blood-stage active agents are likely to be effective. In areas where P. vivax and P. ovale more commonly occur, liver-stage prophylaxis with primaquine would provide additional protection.

Additional agent-specific considerations can also be important when choosing chemoprophylaxis for an individual traveler. Pregnant women should not use atovaquone-proguanil or doxycycline. Mefloquine is best not used in those with a history of some psychiatric disorders (such as depression), seizure disorders or cardiac conduction abnormalities. Primaquine should not be used in those with glucose-6-phosphate dehydrogenase deficiency.

Malaria vaccine

Although a commercially available vaccine for malaria is not available, preliminary data from studies of a newly developed malaria vaccine have recently been published (see story on page 22). This vaccine, RTS,S/AS01, has been developed by GlaxoSmithKline and is being evaluated in a randomized, double blind, phase 3, multicenter trial in seven sub-Saharan African countries. In this trial, RTS,S/AS01 was given to infants and children aged 6 to 12 weeks and children aged 5 to 17 months, and then it was compared with nonmalaria. The primary endpoint was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6,000 children aged 5 to 17 months who received all three doses. In the first 14 months after the first dose of vaccine, first episodes of clinical malaria in these 6,000 children was reduced in the treatment group for an efficacy of 55.8% in the per-protocol population. Results of vaccine efficacy in the younger population are expected to be published soon. Because vaccine cost is likely to be a significant consideration for use of the vaccine in developing countries, GlaxoSmithKline has indicated that it intends to market the vaccine as inexpensively as possible. The Bill & Melinda Gates Foundation has contributed $200 million to assist in the development of this vaccine.

For more information:

• Baird JK. N Engl J Med. 2005;352:1565-1577.
• Freedman DO. N Engl J Med. 2008;359:603-612.
• Griffith KS. JAMA. 2007;297:2264-2277.
• Gutman J. J Travel Med. 2010;17:334-338.
• Schwartz E. N Engl J Med. 2003;349:1510-1516.
• Taylor SM. JAMA. 2010;304:2048-2056.
• The RTS,S Clinical Trials Partnership. N Engl J Med. 2011;doi:10.1056/NEJMoa1102287.

Edward A. Bell, PharmD, BCPS, is professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. Bell is also a member of the Infectious Diseases in Children Editorial Board. Disclosure: Dr. Bell reports no relevant financial disclosures.

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