The threat of malaria for US travelers.

Although malaria has been eradicated from most industrialized and Western countries, a number of travelers to tropical countries where the disease remains a major cause of morbidity and death present with the disease upon their return. Imported cases of malaria number about 25,000 annually, although only about 10,000 are reported, and of those, approximately 150 are fatal. (1) As per the Centers for Disease Control and Prevention 2003 annual surveillance report, there were 1,278 cases of malaria reported in the United States, of which seven were fatal. (2) These numbers are growing because of increased international travel, migration, collapse of malaria control efforts in parts of the world creating new endemic areas, as well as the spread of drug-resistant strains of malaria.

In the years dating 1990 to 2003, international tourist travelers to sub-Saharan Africa, the place where a majority of malaria infections are acquired, have increased from 15.2 million to over 30 million arrivals. (3) Chemoprophylaxis and other preventive measures continue to provide effective protection against malaria for the 30 million travelers who visit malaria-endemic regions each year, but data from different countries have shown that most of those who acquire the disease are the ones who either never took prophylaxis or those who use inadequate regimens. Special groups, such as those returning to visit families in endemic countries, are at a higher risk of acquiring the disease. The 2003 annual surveillance report from the CDC shows that of the 762 civilian travelers who presented with malaria upon their return, only 17.3% took adequate chemoprophylaxis. The majority of those who acquired malaria (53.9%) were travelers who went to visit friends and families. (2)

In a review done by Schwartz et al, (4) all cases of Plasmodium falciparum malaria in Israel and more than 95% from the USA were detected within two months after the traveler's return. A majority of those individuals never used effective prophylaxis on their trip. In contrast, up to one-third of all reported cases of malaria in both Israel and the United States were late-onset illnesses caused by Plasmodium vivax or Plasmodium ovale that occurred despite adequate blood-stage prophylaxis. Almost all cases of the late-onset malaria by P vivax and P ovale are secondary to relapse from the liver stage (hypnozoites); hence an adequate blood-stage chemoprophylaxis during the trip and shortly after return will not be adequate protection. Because of its action in the hypnozoites, a two-week course of primaquine after return from travel is effective in preventing the late-onset malaria. This will prevent relapse in a majority of cases. Physicians should be aware of this gap in coverage with currently available prophylaxis and consider malaria in a returning traveler who presented with fever despite proper prophylaxis.

The treatment of malaria has changed over the years because of declining drug sensitivity in P falciparum and a resurgence of the disease in tropical areas. Chloroquine, which is one of the most inexpensive and highly used antimalarial drugs, can no longer be relied on for prophylaxis or therapy except in some limited regions. Alternative prophylaxis and therapy recommendations must thus be adopted and continually revised based on the changing regional risk of drug-resistant malaria. Currently, atovagone/proguanil (Malarone) mefloquine and doxycycline are all approved alternatives for prophylaxis of malaria for travelers. Recently, the addition of primaquine to the list of approved medications allows travelers to take prophylaxis, which is also active against the liver stage, thereby decreasing the possibility of relapse and late onset malaria.

Because of the emergence and spreading of resistant parasite strains and the need for simpler and effective chemotherapy, the search for new medications continues. One of those new medications, artemisinin and its derivatives, are highly effective compounds against multidrug-resistant P falciparum. It has shown consistent rapid clearance of parasites and fever in patients with malaria. However because of the risk of recrudescence, it has to be combined with other antimalarial agents. Artemisinin is not recommended as a chemoprophylaxis. Another agent that is still being evaluated is Tefenoquine. Tefenoquine, which is an 8-aminoquinoline, has activity against blood-stage and liver-stage malaria parasite. Because of its long half-life, it is dosed once weekly making it an easy potential chemoprophylaxis.

In this issue of the Journal, Bledsoe reviews the important aspects of the four species of malaria that infect humans: P falciparum, P vivax, P ovale, and Plasmodium malariae. In addition, he has discussed chemoprophylaxis and available therapy. Physicians who are advising travelers on chemoprophylaxis of malaria and treating patients who present with illness after a trip to endemic areas should familiarize themselves with the basic understanding of malaria, new medications, the site of action of the existing medications, and their side effects.

References

1. Wellems TE, Miller LH. Two Worlds of Malaria. N Engl J Med 2003;349:1496-1498.

2. Eliades MJ, Shah S, Nguyen-Dinh P, et al. Malaria Surveillance--United States 2003. MMWR Surveill Summ 2003;54:25-40.

3. World Tourism Organization. Historical perspective of world tourism. International tourist arrivals, 1950-2003. Available at: http://www.worldtourism.org/facts/wtb.html. Accessed November 10, 2005.

4. Schwartz E, Parise M, Kozarsky P, et al. Delayed Onset of Malaria-Implications for Chemoprophylaxis in Travelers. N Engl J Med 2003;349:1510-1516.

5. Baird JK. Effectiveness of Antimalarial Drugs. N Engl J Med 2005;352:1565-1577.

He who loses money, loses much; He who loses a friend, loses much more,
He who loses faith, loses all.
--Eleanor Roosevelt

Dawd S. Siraj, MD, MPH & TM

From the East Carolina University, Brody School of Medicine, Greenville, NC.

Reprint requests to Dawd Siraj, MD, East Carolina University, Brody School of Medicine, 600 Moye Boulevard, Bordy 3e117, Greenville, NC 27834, Email: [e-mail]

Accepted August 24, 2005.