Malaria in Long-Term Travelers
By Lin H. Chen, MD
Assistant Clinical Professor, Harvard Medical School, Director, Travel Resource Center, Mount Auburn Hospital, Cambridge, MA
Dr. Chen reports no consultant, stockholder, speaker’s bureau, research, or other financial relationship with any company having ties to this field of study.
At the 54th annual meeting of the american Society of Tropical Medicine and Hygiene held in Washington, DC, on December 11-15, 2005, a symposium was devoted to Malaria in Long-Term Travelers, with Drs. Monica Parise, Patricia Schlagenhauf, and Alan Magill as guest speakers. The clinical pre-meeting course, Anti-Malaria Chemoprophylaxis, also included a presentation by the associate editor on Prevention of Malaria in Long-Term Travelers. Travel Medicine specialists face many questions associated with long-term travel. Most existing guidelines, including those of the US Centers for Disease Control and Prevention, focus on preventing malaria in the short-term travelers. What is the risk of acquiring malaria with long stays? Are drugs for malaria chemoprophylaxis safe for long-term use? What are the strategies travelers actually adapt? What is the possibility of harboring hypnozoites from P. vivax (and to a lesser degree, P. ovale) that may later cause relapses, especially following a long stay in risk areas? Is there a role for presumptive anti-relapse therapy in such travelers (PART, also known as terminal prophylaxis)?
There is currently no consensus on the definition of long-term travel. However, UK guidelines, written by Hughes and colleagues on behalf of the Advisory Committee on Malaria Prevention, regarded travel for > 6 months as long-term.1 Long-term travelers may include urban expatriates and diplomats, as well as missionaries, rural expatriates, field researchers, Peace Corps volunteers, students, and backpackers; thus, their risks may vary greatly from one another. Available data show that the risk of acquiring malaria increases as the stay is prolonged.2,3 At the same time, data show that the use of personal protective measures (long clothes, air-conditioning, repellents, insecticides, mosquito nets, coils) is simply abysmal.4,5
Anecdotally, many long-term travelers abandon continuous chemoprophylaxis. One of the reasons cited for discontinuation is the fear of potential side effects from chemoprophylaxis drugs, although other reasons also contribute to discontinuation of chemoprophylaxis. (see Table 1) In the United States, doxycycline is labeled for up to 4 months of continuous use as malaria chemoprophylaxis. Otherwise, there is no specific restriction on the duration of use in the label of chloroquine, hydroxychloroquine, mefloquine, atovaquone-proguanil, or primaquine. There is some variation in other countries’ guidelines, and confusion may arise when a traveler is overseas. The safety of malaria chemoprophylaxis in clinical trials provides some reassurance, as shown in Table 2.
Nonetheless, many travelers choose to take chemoprophylaxis intermittently or only during the high transmission season, or rely solely on standby emergency treatment (SBET, also referred to as emergency self-treatment). While these alternative strategies may be acceptable in certain geographic regions with very clearly defined transmission seasons, they are inappropriate for most of sub-Saharan Africa, which is felt to generally have high levels of transmission. Note that SBET has been recommended by the World Health Organization since 1988 for travel to certain destinations: areas with low malaria transmission but without reliable diagnostic and therapeutic facilities (parts of SE Asia), high risk areas for P. falciparum where chemoprophylaxis drugs may not be effective, and remote areas, to be prescribed along with chemoprophylaxis (parts of East and Central Africa).6
The new Swiss-German-Austrian guidelines for malaria chemoprophylaxis have shifted to favor SBET, a move considered by many experts to be bold. These new guidelines continue to recommend continuous chemoprophylaxis for high-risk areas including sub-Saharan Africa, some provinces in Brazil, Indonesia, and Oceania. In other regions, the Swiss-German-Austrian guidelines recommend SBET with chloroquine, mefloquine, or atovaquone-proguanil or artemether-lumefantrine, based on the resistance patterns. The argument for the change in recommendations is that the benefit of chemoprophylaxis should be > 10 times greater than the risk of adverse events. The results from this shift in Swiss-German-Austrian recommendations may help to guide future strategies for malaria prevention, and may especially benefit long-term travelers. For now, SBET should be considered in addition to continuous chemo-prophylaxis for most long-term travelers.
Finally, some studies have shown that P. vivax causes from one-quarter to over one-half of malaria cases in travelers.7,8 P. vivax, along with P. ovale, have dormant liver stage parasites called hypnozoites that may cause relapses. Primaquine is the only causal prophylaxis against the hypnozoites, whereas chloroquine, mefloquine, doxycycline, and atovaquone-proguanil are only suppressive prophylaxis. Primaquine is indicated as primary anti-malaria prophylaxis, radical cure, as well as presumptive anti-relapse therapy (PART, or terminal prophylaxis). For long-term travelers, primaquine may be especially useful for the following situations: long stay in areas with high-risk for P. vivax, stay in low-risk areas with intermittent visits to areas with high-risk for P. vivax, and as PART in combination with other chemoprophylaxis regimen to be administered after departing from P. vivax risk areas. It may also be used for travelers who cannot tolerate other anti-malarials. Testing for adequate levels of G6PD must be done before prescribing primaquine, because life-threatening hemolytic anemia can occur in G6PD-deficient individuals. Although the original FDA approval for primaquine was 15 mg daily for 14 days, the current CDC recommendation is 30 mg daily for 14 days. The higher dose is important for tropical strains of P. vivax. Clinicians in the United States need to advise travelers that the use of primaquine as primary chemoprophylaxis is off label.
In summary, prevention of malaria in long-term travelers should be individualized. Guidelines for long-term travelers should be developed such that they are consistent, in order to minimize confusion for the travelers. Travel medicine specialists should emphasize the importance of personal protective measures, particularly for long-term travelers. Continuous chemoprophylaxis along with SBET is the safest strategy for long-term travelers, and travelers should be encouraged to have medication for at least the initial several months. Establishing reliable medical care at destination is crucial in preventing malaria in long-term travelers. With reliable local medical expertise at the destination, long-term travelers may obtain appropriate advice regarding malaria and seek timely treatment if necessary.
References
- Hughes C, et al. Malaria Prophylaxis for Long-Term Travelers. Commun Dis Public Health. 2003;6:200-208.
- Phillips-Howard PA, et al. Risk of Malaria in British Residents Returning from Malarious Areas. BMJ. 1990;300:499-503.
- Adera T, et al. Risk Factors for Malaria Among Expatriates Living in Kampala, Uganda: The Need for Adherence to Chemoprophylactic Regimens. Am J Trop Med Hyg. 1995;52:207-212.
- Weber R, et al. Knowledge, Attitudes and Practices of Business Travelers Regarding Malaria Risk and Prevention. J Travel Med. 2003;10:219-224. Erratum in: J Travel Med. 2003;10:312
- Schoepke A, et al. Effectiveness of Personal Protection Measures Against Mosquito Bites for Malaria Prophylaxis in Travelers. J Travel Med. 1998;5:188-192.
- WHO. Stand-By Emergency Treatment. In: International Travel and Health. Available at www.who.int/ith/chapter07_03.html. Accessed March 29, 2004.
- Schwartz E, Sidi Y. New Aspects of Malaria Imported from Ethiopia. Clin Infect Dis. 1998;26:1089-1091.
- Eliades MJ, et al. Malaria Surveillance—United States, 2003. MMWR Surveill Summ. 2005;54:25-40.
- Lobel HO, et al. Long-Term Malaria Prophylaxis with Weekly Mefloquine. Lancet. 1993;341:848-851.
- Shanks GD, et al. Doxycycline for Malaria Prophylaxis in Australian Soldiers Deployed to United Nations Missions in Somalia and Cambodia. Mil Med. 1995,160:443-445.
- Overbosch D. Post-Marketing Surveillance: Adverse Events During Long-Term Use of Atovaquone/Proguanil for Travelers to Malaria-Endemic Countries. J Travel Med. 2003;10:S16-S20.
- Fryauff DJ, et al. Randomised Placebo-Controlled Trial of Primaquine for Prophylaxis of Falciparum and Vivax Malaria. Lancet. 1995;346:1190-1193.
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