Malaria Update From the 50th Annual Meeting of the ASTMH
December 1, 2001
Malaria Update From the 50th Annual Meeting of the ASTMH
Conference Coverage
By Frank J. Bia, MD, MPH
Source: Symposium 3: Malaria in Travelers. Steffen R, Parise M, Keystone J, Newman RD. Am J Trop Med Hyg. 2001;65(suppl). No. 3. 26.
Synopsis: This symposium on malaria in travelers was a superb update by several experienced individuals in clinical tropical medicine. It provided an equally knowledgeable audience with considerable information regarding the current state of the art in malaria prophylaxis and treatment. It also increased audience awareness of the larger role being played by immigrants returning home from North America or Europe to visit friends and relatives in developing countries—so-called VFRs.
The CDC has expanded its recommended geographic regions requiring malaria prophylaxis to include southern Uzbekistan. In this hemisphere, hurricane damage in Central America has made both urban and rural Belize malaria risk areas once more, and Costa Rica is also back on the list for malaria chemoprophylaxis. These are a few of the changes appearing in the 200l edition of the CDC "yellow book."
Chloroquine and proguanil are no longer listed as an effective combination option for prevention of chlorquine-resistant malaria. Primaquine, when used alone, has still not been suggested for sole primary prophylaxis. Reluctance is not related to the efficacy of primaquine, but to concerns about potential G6PD deficiency and hemolysis in recipients who might not be tested for this abnormality, and the potential for similar consequences in a G6PD deficient fetus.
New information regarding Malarone® (atovaquone/proguanil) prophylaxis in children is available. Monica Parise highlighted an abstract presented at these meetings describing a recent study in children from Gabon.1 It was aimed at determining the potential effects of malaria prophylaxis on antibody responses to typhoid and cholera vaccines in Gabonese children. Malarone® had no documented effect upon antibody responses after vaccination and was found to be highly effective in the prevention of Plasmodium falciparum in children weighing between 11 and 40 kg. Moreover, in this randomized, double-blind, placebo-controlled study, 330 pediatric subjects received prophylaxis for falciparum malaria either with Malarone® or matching placebo for up to 12 weeks. There was a single case of P falciparum in the atovaquone/proguanil arm, vs. 31 in the placebo arm giving Malarone® a protective efficacy of 97%. This confirms similar data obtained last year in Iryan Jaya. The same group of investigators demonstrated that atovaquone/proguanil is both efficacious and safe for the treatment of falciparum malaria in young children, under age 3, weighing between 5 and 11 kg.2 Cure rates were 95% compared to 51% for amodiaquine in a study of 200 Gabonese children. The incidence of adverse events was similar for both treatment groups.
Malarone® is an effective causal prophylactic combination, which makes it useful for short-term travel since it can be discontinued 1 week after leaving a malarious area. However, this combination does not eliminate hypnozoite forms of P vivax or P ovale. When used alone for prophylaxis against P vivax, efficacy is only 81%, and as sole therapy for vivax malaria, one can expect a 74% relapse rate. Terminal prophylaxis with primaquine is necessary if there has been a significant exposure to these relapsing forms of malaria.
How long can Malarone® be used safely? The CDC has no recommended upper time limit although, to date, Malarone® has only been studied for as long as 20 weeks. There are insufficient safety data available to recommend Malarone® for use in pregnancy; however, both chloroquine and mefloquine (Lariam®) are now considered safe for use during any trimester of pregnancy.
Jay Keystone offered a cogent presentation of an increasing problem now being appreciated in travel medicine. By 1999, the reported rate of malaria in Canada was 5-10 times the reported per-capita rate in the United States.3 In the same year, nearly half a million people of south Asian origin were living in Canada and about 30,000 returned home for visits annually. Much of the imported malaria in Canada (30-80%) was being accounted for by travelers to India. From 1989 to 1996, 30% of imported malaria in Italy was observed in immigrants revisiting their country of origin.4 If you provide care to immigrants, who reside in the developed world and return home to a developing country to visit friends and relatives (VFRs), be aware of the unique role these individuals and their families play in malaria morbidity. The falciparum malaria attack rates for travelers to India, for example, differ considerably between those who return to visit friends and family (331 per 100,000) and those on business trips (38 per 100,000). Unfortunately, VFRs account increasingly for a significant proportion of imported malaria, now termed VFR-associated malaria. By 1996, surveillance of malaria imported into the United Kingdom showed that 56% was VFR-associated malaria and 96% was caused by P falciparum. This group of travelers is growing and represents an increasing proportion of travelers, now 40%; they also tend to avoid taking malaria prophylaxis. Whereas 55% of nonimmune travelers take prophylaxis, only 11% of those we would classify as VFRs do so. They may think of themselves as less likely to become seriously ill because their malaria tends to be less severe than in other travelers, and they have faster parasite clearance times. This group generally does not seek pre-travel advice, and more than half are not even aware of a malaria risk. Of those VFRs surveyed in Canada who did intend to use antimalarial agents, only 24% had been prescribed a drug regimen that was officially recommended by various health agencies.
When they do seek advice what happens? In one survey, 54% did so but only 7% used a recommended regimen, which represents a serious disconnect between the health care system and the needs of travelers. This group tended to consult their primary care physician, who may or may not represent the optimal source for such consultations. Keystone pointed to a clear need for strategies that increase cultural acceptance and awareness of risks associated with travel home to the malarious regions of the developing world. Lack of resources and cost of family visits will also inhibit this group from obtaining the preventive care they require. These problems might be alleviated by creative fee structures for traveling families and groups. Country-specific, culturally sensitive literature, which directly addresses travel issues for VFRs, may be part of the answer. The clinic at Toronto General has just such material, which was demonstrated in his presentation.
Dr. Robert Newman of the CDC summarized the issue of deaths in US travelers—deaths that are both significant in number and totally preventable. To put his figures in perspective, the bottom line is this: 1 in 100 US travelers who contracts malaria dies. Between 1963 and 2001, the CDC data concerning the 177 documented US-based malaria deaths showed a majority (115) were among travelers and 97% were attributable to P falciparum, as would be expected. Of these fatal infections in travelers, 76% were acquired in east or west Africa. What attributes characterized this unfortunate group? Half took no chemoprophylaxis, and of those who did, at least 10% took inappropriate agents. More than one third delayed 2 or more days in seeking care for their illness, and often those who did experienced a delay in diagnosis. In 18%, the diagnosis was only made at autopsy! Of these 115 deaths, 26% had received no specific malaria therapy; one sixth died at home or outside the hospital, and 87% of deaths were considered preventable.
What can be learned from these preventable malaria deaths in US travelers? Health providers can even get in the way of a malaria diagnosis, if they tell travelers who present with fevers on return from abroad that such fevers are unlikely to be caused by malaria. They may not obtain malaria smears quickly enough, nor persist in obtaining a diagnosis of malaria. Often they don’t get the relevant travel history. They may have prescribed antimalarial agents that are no longer effective for prophylaxis, producing a false sense of security based upon assumptions about low malaria risk for their patients. Travelers may not have sufficient understanding of malaria as an emergency for which delays in diagnosis and therapy may be paid for in high morbidity and mortality rates. Travelers may even have to push their own providers into considering this diagnosis.
References
1. Faucher J-F, et al. Plasmodium falciparum prophylaxis with atovaquone and proguanil when administered in combination with typhoid and cholera vaccines in Gabonese children. Am Soc Trop Med Hyg. 2001;65(suppl). No. 3. 345. Abstract 580.
2. Borrmann S, et al. Alovaquone and proguanil versus amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in children weighing > 5 and < 11 kg in Gabon. Am Soc Trop Med Hyg. 2001;65(suppl): No 3. 432. Abstract 813.
3. Dos Santos CC, et al. Survey of use of malaria prevention measures by Canadians visiting India. CMAJ. 1999;160(2):195-200.
4. Castelli F, et al. Malaria in migrants. Parassitologia. 1999;41:261-265.
Dr. Bia, Professor of Medicine and Laboratory Medicine; Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine, is Editor of Travel Medicine Alert.