Delayed Onset of Malaria — Implications for Chemoprophylaxis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Schwartz et al. (Oct. 16 issue)1 report that a substantial proportion of cases of malaria in returned travelers are characterized by a late onset. The authors conclude that the usual chemoprophylactic agents do not prevent such cases and suggest switching to agents such as primaquine or atovaquone–chloroguanide for prophylaxis. However, we believe that other considerations — including tolerability and cost for the millions of travelers who remain malaria-free — are just as important.
The U.S. government recorded more than 18 million trips to malaria-prone continents by citizens in 1995.2 Conservatively, assuming that only 20 percent of these trips involved travel to malarious areas, we calculated that there were 22.5 million such trips during the period of the study by Schwartz et al. Given that they report 987 cases of late-onset malaria, the estimated incidence of late-onset malaria among U.S. travelers to malarious areas is 4.4 cases per 100,000 trips. An effective intervention would thus be required in approximately 23,000 persons to prevent one case. These are broad estimates only, but they illustrate our point: very few travelers taking chemoprophylaxis ever have late-onset malaria. It is imperative that they not be put at unnecessary risk.
Graham Brown, M.B., B.S., Ph.D.
Joe Torresi, M.B., B.S., Ph.D.
Shaun Flint, M.B., B.S.
Centre of Clinical Research Excellence in Infectious Diseases
3050 Parkville, Australia
References
Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria: implications for chemoprophylaxis in travelers. N Engl J Med 2003;349:1510-1516.
Government Bureau of Transport Statistics. Travel between the United States and foreign countries: 1990, 1995, and 2000. (Accessed December 15, 2003, at http://www.bts.gov/publications/us_international_travel_and_transportation_trends/excel/table1.xls.)
To the Editor: Schwartz et al. showed that most cases of malaria in Israel and the United States occurring more than two months after travel to endemic areas were caused by Plasmodium vivax or P. ovale, as one would expect. They suggest that new agents that act against the hypnozoite stage could be attractive chemotherapeutic alternatives. Although I agree that such new agents would be chemotherapeutic alternatives, I do not think that they are really needed. One has to recognize that it is malaria caused by P. falciparum that is a fatal disease. Recommendations for the protection of travelers to areas where the disease is endemic rightly focus on prevention of this infection and should continue to do so. The development of effective and affordable drugs for the treatment of and prophylaxis against falciparum malaria is what is truly needed for millions of people in both developed and developing countries. The non-falciparum malarias are relatively mild illnesses and are easily treatable, if recognized. The focus should not be on prophylaxis against them, but rather on their prompt recognition in returned travelers.
Nabin K. Shrestha, M.D.
B.P. Koirala Institute of Health Sciences
Dharan, Nepal
nksmd@yahoo.com
The authors reply: Although we agree that tolerability and cost are important factors in the choice of antimalarial chemoprophylactic agents (as we state in our article), the usual agents used (blood schizonticides) do not prevent late relapses, and we stand by our opinion that liver-stage prophylaxis provides the most complete chemoprophylactic protection. In addition, Brown and colleagues misquote us in stating that we recommend that travelers change to atovaquone–chloroguanide as the drug of choice for prophylaxis against malaria. Although this drug combination does have liver-stage activity, data on whether it will prevent the establishment of hypnozoites are still limited, and we therefore did not mention it in Table 3 of our report.
The issue of the level of risk of malarial infection and the recommendation of chemoprophylaxis depends on the risk for the individual traveler, and the safety, efficacy, and cost of the drug and is subject to varying recommendations in different countries. However, this issue holds true for the prevention of both primary infection and late infection and was not part of the scope of our report.
We agree with Dr. Shrestha that P. falciparum is the most deadly form of malaria. However, travelers are instructed that they are taking malarial prophylaxis, not falciparum prophylaxis, and the occurrence of late infection can therefore lead to decreased trust in health care providers and to reduced adherence to chemoprophylactic regimens. Moreover, our experience has been that travelers are often willing to pay to prevent all malarial infections, including P. vivax, which may cause significant morbidity even though it is not a fatal illness. We already have drugs that effectively prevent blood-stage infections, including that of P. falciparum, but as we showed in our report, the main reason that P. falciparum infections were not prevented was the lack of adherence to the chemoprophylactic regimen.
Our main conclusion was that efforts to prevent malaria should be targeted to the liver stage. This approach may prevent all malarial infections and enhance adherence, which is a major issue among travelers, since chemoprophylaxis can be discontinued on departure from the malarious area. In the future, we hope to see more drugs with this mode of action.
Eli Schwartz, M.D.
Chaim Sheba Medical Center
Tel Hashomer 52621, Israel
elischwa@post.tau.ac.il
Monica Parise, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
The U.S. government recorded more than 18 million trips to malaria-prone continents by citizens in 1995.2 Conservatively, assuming that only 20 percent of these trips involved travel to malarious areas, we calculated that there were 22.5 million such trips during the period of the study by Schwartz et al. Given that they report 987 cases of late-onset malaria, the estimated incidence of late-onset malaria among U.S. travelers to malarious areas is 4.4 cases per 100,000 trips. An effective intervention would thus be required in approximately 23,000 persons to prevent one case. These are broad estimates only, but they illustrate our point: very few travelers taking chemoprophylaxis ever have late-onset malaria. It is imperative that they not be put at unnecessary risk.
Graham Brown, M.B., B.S., Ph.D.
Joe Torresi, M.B., B.S., Ph.D.
Shaun Flint, M.B., B.S.
Centre of Clinical Research Excellence in Infectious Diseases
3050 Parkville, Australia
References
Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria: implications for chemoprophylaxis in travelers. N Engl J Med 2003;349:1510-1516.
Government Bureau of Transport Statistics. Travel between the United States and foreign countries: 1990, 1995, and 2000. (Accessed December 15, 2003, at http://www.bts.gov/publications/us_international_travel_and_transportation_trends/excel/table1.xls.)
To the Editor: Schwartz et al. showed that most cases of malaria in Israel and the United States occurring more than two months after travel to endemic areas were caused by Plasmodium vivax or P. ovale, as one would expect. They suggest that new agents that act against the hypnozoite stage could be attractive chemotherapeutic alternatives. Although I agree that such new agents would be chemotherapeutic alternatives, I do not think that they are really needed. One has to recognize that it is malaria caused by P. falciparum that is a fatal disease. Recommendations for the protection of travelers to areas where the disease is endemic rightly focus on prevention of this infection and should continue to do so. The development of effective and affordable drugs for the treatment of and prophylaxis against falciparum malaria is what is truly needed for millions of people in both developed and developing countries. The non-falciparum malarias are relatively mild illnesses and are easily treatable, if recognized. The focus should not be on prophylaxis against them, but rather on their prompt recognition in returned travelers.
Nabin K. Shrestha, M.D.
B.P. Koirala Institute of Health Sciences
Dharan, Nepal
nksmd@yahoo.com
The authors reply: Although we agree that tolerability and cost are important factors in the choice of antimalarial chemoprophylactic agents (as we state in our article), the usual agents used (blood schizonticides) do not prevent late relapses, and we stand by our opinion that liver-stage prophylaxis provides the most complete chemoprophylactic protection. In addition, Brown and colleagues misquote us in stating that we recommend that travelers change to atovaquone–chloroguanide as the drug of choice for prophylaxis against malaria. Although this drug combination does have liver-stage activity, data on whether it will prevent the establishment of hypnozoites are still limited, and we therefore did not mention it in Table 3 of our report.
The issue of the level of risk of malarial infection and the recommendation of chemoprophylaxis depends on the risk for the individual traveler, and the safety, efficacy, and cost of the drug and is subject to varying recommendations in different countries. However, this issue holds true for the prevention of both primary infection and late infection and was not part of the scope of our report.
We agree with Dr. Shrestha that P. falciparum is the most deadly form of malaria. However, travelers are instructed that they are taking malarial prophylaxis, not falciparum prophylaxis, and the occurrence of late infection can therefore lead to decreased trust in health care providers and to reduced adherence to chemoprophylactic regimens. Moreover, our experience has been that travelers are often willing to pay to prevent all malarial infections, including P. vivax, which may cause significant morbidity even though it is not a fatal illness. We already have drugs that effectively prevent blood-stage infections, including that of P. falciparum, but as we showed in our report, the main reason that P. falciparum infections were not prevented was the lack of adherence to the chemoprophylactic regimen.
Our main conclusion was that efforts to prevent malaria should be targeted to the liver stage. This approach may prevent all malarial infections and enhance adherence, which is a major issue among travelers, since chemoprophylaxis can be discontinued on departure from the malarious area. In the future, we hope to see more drugs with this mode of action.
Eli Schwartz, M.D.
Chaim Sheba Medical Center
Tel Hashomer 52621, Israel
elischwa@post.tau.ac.il
Monica Parise, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333