Malaria among United States troops in Somalia.

PURPOSE: United States military personnel deployed to Somalia were at risk for malaria, including chloroquine-resistant Plasmodium falciparum malaria. This report details laboratory, clinical, preventive, and therapeutic aspects of malaria in this cohort. PATIENTS AND METHODS: The study took place in US military field hospitals in Somalia, with US troops deployed to Somalia between December 1992 and May 1993. Centralized clinical care and country-wide disease surveillance facilitated standardized laboratory diagnosis, clinical records, epidemiologic studies, and assessment of chemoprophylactic efficacy. RESULTS: Forty-eight cases of malaria occurred among US troops while in Somalia; 41 of these cases were P falciparum. Risk factors associated with malaria included: noncompliance with recommended chemoprophylaxis (odds ratio [OR] 2.4); failure to use bed nets (OR 2.6); and failure to keep sleeves rolled down (OR 2.2). Some patients developed malaria in spite of mefloquine (n = 8) or doxycycline (n = 5) levels of compatible with chemoprophylactic compliance. Five mefloquine failures had both serum levels > or = 650 ng/mL and metabolite:mefloquine ratios over 2, indicating chemoprophylactic failure. All cases were successfully treated, including 1 patient who developed cerebral malaria. CONCLUSIONS: P falciparum malaria attack rates were substantial in the first several weeks of Operation Restore Hope. While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred. Military or civilian travelers to East Africa must be scrupulous in their attention to both chemoprophylaxis and personal protection measures.

Malarial antibodies measured by the indirect hemagglutination test in West African children.

The indirect hemagglutination test with Plasmodium falciparum antigen was used to measure malarial antibodies in filter paper blood specimens from 527 West African children. A slight decline in antibodies was noted in 6- to 8-month-old children wh o had no malaria parasites in their blood smears. Children older than 10 months had similar antibody levels regardless of the presence or absence of demonstrated parasites in blood smears.

A study of polymorphism in the circumsporozoite protein of human malaria parasites.

We have characterized the circumsporozoite (CS) gene sequences of Plasmodium malariae China-1 CDC, isolated recently from a person who was infected 50 years ago in China, and P. vivax Chesson, isolated 48 years ago from a patient who had returned from New Guinea. These protein sequences were compared with the CS protein sequences of recently isolated P. vivax and P. malariae parasites. In a similar manner, we compared the previously characterized CS protein gene of P. falciparum clone 7G8, derived from a Brazilian isolate collected in 1980, with the CS protein genes of recent P. falciparum field isolates. In the case of the P. malariae CS protein gene, with the exception of an additional copy of major (NAAG) and minor (NDAG) repeat sequences and the presence of one copy of NDEG sequence, the China-1 CDC P. malariae parasite is similar to the Uganda-1 CDC isolate of 1982. In the nonrepeat region, changes were noted in two amino acid residues, one of which is also seen in a closely related monkey malaria parasite, P. brasilianum. In the case of P. vivax CS proteins, the nonrepeat region of the protein in Chesson strain shares identity with nearly 71% of the CS clones characterized from field isolates. In the P. falciparum CS proteins, the 7G8 CS protein sequence is identical to 75% of the genes of recent field isolates in the Th1R-N1 region. In the Th2R and Th3R regions, 34% and 55% of the CS clones analyzed, respectively, had changes at two amino acid residues.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of whole blood and serum levels of mefloquine and its carboxylic acid metabolite.

Because of the widespread presence of chloroquine-resistant Plasmodium falciparum malaria, mefloquine is now the recommended drug of choice for long-term malaria prophylaxis in these areas. Although several studies have compared plasma and whole blood concentrations of either mefloquine or its carboxylic acid metabolite, we report the first comparison of serum and whole blood levels in 86 Dutch marines taking 250 mg of mefloquine weekly for 18 weeks while deployed in western Cambodia. All samples were taken during steady-state and at 42-48 hr after the most recent dose. The concentration of mefloquine in serum (mean = 979 ng/ml) was significantly greater than in whole blood (mean = 788 ng/ml) (P < 0.00001, by paired t-test) with an overall mean ratio of 1.28. The concentration of the metabolite in serum (mean = 3,039 ng/ml) was also significantly greater than in whole blood (mean = 1,390 ng/ml) (P < 0.00001, by paired t-test) with an overall mean ratio of 2.25. These findings are similar to previous reports of plasma-to-whole blood levels. Furthermore, we report that the within-individual ratios of the metabolite concentration to the mefloquine concentration were also found to be significantly different in serum (3.79; P < 0.00001, by paired t-test) and in whole blood (2.02; P < 0.00001, by paired t-test). Appropriate attention must be given to these differences when comparing serum and whole blood concentrations of either mefloquine or its metabolite to avoid misinterpretation of their respective levels. Also, the determination of the relative mefloquine ratios in various blood fluids, as well as the documentation of the metabolite levels and their ratios, is critical to the appropriate interpretation of both chemoprophylaxis and chemotherapy, especially in the presence of resistant strains.

Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis.

In 1982, the fixed combination of pyrimethamine and sulfadoxine (Fansidar) became available in the United States, and was recommended for use in travelers at risk of acquiring chloroquine-resistant Plasmodium falciparum. Prior to that time, no reports of severe cutaneous reactions had appeared in the medical literature despite widespread use for more than 8 years in both Europe and malarious areas of the developing world. In the fall of 1984, the Centers for Disease Control received reports of 4 cases of toxic epidermal necrolysis (including 3 fatalities) among Americans who had used pyrimethamine-sulfadoxine (PYR/SDX) for the prevention of malaria. Subsequent investigation into severe cutaneous reactions associated with the use of this drug by American travelers detected 24 cases of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Twenty-three of the 24 patients concurrently used chloroquine. Seven patients died. No risk factors in the development of these reactions other than the use of PYR/SDX could be identified. Among American travelers, we estimate that these reactions occur in 1 per 5,000-8,000 users, and that fatal reactions occur in 1 per 11,000-25,000 users. This higher than expected incidence necessitates that the use of PYR/SDX for the prevention of malaria be reconsidered. In the United States it is now recommended that the routine weekly use of the drug be reserved for those travelers at highest risk of acquiring chloroquine-resistant P. falciparum, when alternate prophylactic regimens are not deemed appropriate.

Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers' health.

The effectiveness of mefloquine to prevent malaria caused by Plasmodium falciparum is influenced by the sensitivity of the malaria parasites to this drug. Concern has been raised that resistance to mefloquine may develop in sub-Saharan Africa as has been observed in Southeast Asia. Case reports, along with blood smears to confirm the diagnosis and blood samples to determine the mefloquine concentration, were provided on any Peace Corps volunteer serving in sub-Saharan Africa who was diagnosed with malaria. We defined prophylaxis failures probably due to mefloquine resistance as patients with P. falciparum malaria confirmed at the Centers for Disease Control and Prevention, reported compliance with prophylaxis, no ingestion of mefloquine between date of illness onset and date of blood drawing, and a mefloquine level > or = 620 ng/ml in blood drawn within five days of onset of illness. Between January 1, 1991 and September 6, 1996, 44 (31%) of 140 volunteers with confirmed P. falciparum had blood drawn within five days of onset of illness. Twenty-nine (66%) had not fully complied with prophylaxis. Five of 15 prophylaxis failures in four countries had mefloquine levels > or = 620 ng/ml. Failure of mefloquine prophylaxis is primarily due to noncompliance. Evidence of probable resistance to mefloquine among strains of P. falciparum was found in five Peace Corps volunteers in sub-Saharan Africa. Clusters of well-documented prophylaxis failures need to be followed-up by therapeutic in vivo studies to document parasite resistance to mefloquine. Reduced sensitivity to mefloquine does not (yet) appear to be a significant problem in sub-Saharan Africa.

Transmission of Plasmodium vivax malaria in San Diego County, California, 1986.

Between 18 June and 20 September 1986, 28 cases of Plasmodium vivax malaria were documented in Carlsbad, California, a coastal town north of San Diego. Malaria occurred in 1 local resident who had no risk factors, a second local resident who had traveled to a malarious area 9 months earlier, and 26 Mexican migrant workers (MWs). Among the 28 cases, 27 lived in a square mile marshy area where Anopheles hermsi, a newly described American species of the Anopheles maculipennis group, was known to be breeding. An investigation of MWs residing in the affected area was done to determine the extent of the outbreak and to identify risk factors for acquiring malaria. We interviewed and drew blood from 304 healthy MWs and 17 (65%) of the MWs with malaria. Fluorescent antibody titers to P. vivax greater than or equal to 1:256 occurred in 14 (82%) of the 17 MWs with malaria tested and 9 (3%) of the healthy MWs. The principal risk factor identified for contracting malaria was sleeping outside on a hillside adjacent to the marshy area. Malaria in a local resident with no malaria risk factors and the clustering in time and place of 26 cases suggest that P. vivax malaria was introduced and local transmission was sustained through several generations, producing the largest outbreak of introduced malaria in the United States since 1952.

The China I/CDC strain of Plasmodium malariae in Aotus monkeys and chimpanzees.

Five Aotus monkeys and two chimpanzees were infected with Plasmodium malariae isolated from a patient who acquired her infection approximately 50 years ago. All animals were splenectomized. The chimpanzees supported the highest parasite densities of 22,271/microliters and 18,544/microliters. Three Aotus monkeys with a previous history of infection with P. vivax had maximum parasite counts of from 1,818/microliters to 2,909/microliters, whereas two monkeys not previously infected had maximum parasite counts of 6,908/microliters. The establishment of new isolates in these animals aides the development of diagnostic probes and the identification of areas of antigenic variation within the species.

Antimalarial chemoprophylaxis in infants and children.

The evolving patterns of drug resistance in malaria parasites and changes in recommendations for malaria prevention present a challenge to physicians who advise travellers on chemoprophylaxis. Because compliance with personal protection measures is usually low, children should receive appropriate chemoprophylaxis, including breast-fed infants who are not protected through maternal chemoprophylaxis. For travel to areas where chloroquine resistance has not yet been reported (i.e. parts of Central America, the Caribbean and parts of the Middle East), chloroquine alone is sufficient for antimalarial prophylaxis. Mefloquine is the drug of choice for chemoprophylaxis in areas with chloroquine-resistant Plasmodium falciparum, and can be given to infants and young children. The combination of chloroquine and proguanil is well tolerated in children but is much less effective against drug-resistant malaria. Further research is needed to determine the best dosage regimen for antimalarial drugs used for chemoprophylaxis in children.

Use of malaria prevention measures by North American and European travelers to East Africa.

BACKGROUND: The use of preventive measures, including effective chemoprophylaxis, is essential for protection against malaria among travelers. However, data have shown that travelers and medical advisors are confused by the lack of uniform recommendations and numerous prophylactic regimens of varying effectiveness that are used. METHODS: To assess the use and type of preventive measures against malaria, we conducted a cross-sectional study in 1997 among travelers departing from the Nairobi and Mombasa airports in Kenya with European destinations. RESULTS: Seventy-five percent of the travelers studied were residents of Europe and 25% were residents of North America; all stayed less than 1 year, and visited malarious areas. Most travelers, 97.1%, were aware of the risk and 91.3% sought pretravel medical advice. Although 95.4% used chemoprophylaxis and/or antimosquito measures, only 61.7% used both regular chemoprophylaxis and two or more antimosquito measures. Compliance with chemoprophylaxis was lowest amongst those who used a drug with a daily, as opposed to, a weekly dosing schedule, stayed more than 1 month, attributed an adverse health event to the chemoprophylaxis, and were less than 40 years of age. Among US travelers, 94.6% of those taking chemoprophylaxis were taking an effective regimen, that is, mefloquine or doxycycline. Only 1.9% used a suboptimal drug regimen, such as chloroquine/proguanil. Among European travelers, 69% used mefloquine or doxycycline, and 25% used chloroquine/proguanil. Notably, 45.3% of travelers from the UK used chloroquine/proguanil. Adverse events were noted by 19.7% of mefloquine users and 16.4% of travelers taking chloroquine/proguanil. Neuropsychologic adverse events were reported by 7.8% of users of mefloquine and 1.9% of those taking chloroquine/proguanil. The adverse events, however, had a lesser impact on compliance than frequent dosing schedule. CONCLUSIONS: Health information should be targeted to travelers who are likely to use suboptimal chemoprophylaxis or may be noncompliant with prophylaxis. Uniform recommendations for effective chemoprophylaxis with simple dosing schedules are necessary to reduce rates of malaria among travelers to Africa.

Update on prevention of malaria for travelers.

Individuals from industrialized nations frequently travel to countries with malaria, so health care providers need to be familiar with current recommendations for prevention of malaria. Changes in drug susceptibility of malaria parasites and evolving knowledge of how well drugs are tolerated necessitate periodic review of guidelines for prophylaxis of malaria, especially of chloroquine-resistant Plasmodium falciparum malaria. Mefloquine is the drug of choice for chemoprophylaxis for most travelers, with doxycycline and chloroquine being less effective alternatives. Mefloquine is well tolerated at prophylactic dosages, but anecdotal reports have raised concerns about its adverse effects. Resistance to this drug has emerged in parts of Southeast Asia and may spread to other regions of the world. The major disadvantages of doxycycline are the need for daily dosing, its contraindication for young children and pregnant women, and its adverse effects. Chloroquine is effective for prophylaxis only in Central America, the Caribbean, and parts of the Middle East. Few new drugs will be available in the near future because of reduced funding for antimalarial drug research and development; therefore, the usefulness of currently available drugs needs to be prolonged by rational use. Increased efforts should be made to ensure that alternative drugs will be available for prevention of malaria.

Interpretation of IHA titres for the study of malaria epidemiology.

The results of IHA test surveys of persons with malaria parasitaemia in Ethiopia and the Philippines suggest that the antibody response may be influenced by the frequency and intensity of the antigenic stimulations and also be age-dependent. Antibody frequency distribution curves from four different areas suggest that the shape of such curves can provide some information about the endemicity of malaria. Results of similar and of parasitological surveys in Bangladesh, Ethiopia, Haiti, and the Philippines were compared and related to available malaria surveillance information. The results indicate that a serologic population profile may provide an indication of the history and status of malaria. Technical aspects of the IHA test are reviewed; it may be desirable to use homologous antigens instead of a simian Plasmodium antigen. To obtain the most useful additional epidemiological information about a malaria situation, serologic data need to be age-related, and longitudinal surveys are usually more informative than a cross-sectional survey.

A quantitative approach to recommendations on malaria prophylaxis.

In order to develop recommendations for malaria prophylaxis, a quantitative method is needed to balance the risk of Plasmodium falciparum malaria infections against the toxicity of antimalarial drugs. Using decision analysis, we estimated the expected mortality associated with three alternative regimens of prophylactic drugs for visitors to three areas with different risks of infection with chloroquine-resistant P. falciparum. The model used took into account the risks of malaria and of adverse reactions to antimalarial drugs. Estimates of the parameters used in the analysis were based on observations made on U.S. travellers. Reducing the risk of malaria infection was found to have a far greater impact on lowering the expected mortality than that of increasing the chemoprophylactic efficacy of the drugs used, thereby emphasizing the need for travellers to use anti-mosquito measures in malarious areas. The analytical method described can be used to define optimal malaria prevention strategies.

Reassessment of blood donor selection criteria for United States travelers to malarious areas.

In the United States (US), travelers who have had malaria or who have taken antimalarial chemoprophylaxis are deferred as blood donors for 3 years to prevent transfusion-transmitted malaria. To assess the impact of shortening this 3-year exclusion period, national malaria surveillance data from 1972 to 1988 were reviewed. The average annual rate of transfusion-transmitted malaria is 0.25 cases per million units of blood collected. Of 45 reported cases, 38 percent were caused by Plasmodium malariae, 29 percent by P. falciparum, 24 percent by P. vivax, and 9 percent by P. ovale. Thirty-two donors were implicated in 34 cases of transfusion-transmitted malaria. Of 30 implicated donors whose native country was identified, 23 (77%) were foreign nationals and 7 (23%) were from the US. In a review of all imported malaria cases by species and by interval between date of entry and onset of illness, 98 percent of P. falciparum, 86 percent of P. malariae, 76 percent of P. vivax, and 74 percent of P. ovale infections became symptomatic within 6 months of the patient's arrival in the US, regardless of the use of prophylaxis. Shortening to 6 months the donor exclusion period for US travelers to malarious areas would result in a minimum of 70,000 additional blood donors' being made available, with a maximum annual increase of 0.03 additional cases of transfusion-transmitted malaria. The potential benefit of bringing healthy travelers back into the donor pool after a shorter period of exclusion merits consideration by the blood banking industry.

Imported Plasmodium falciparum malaria in American travelers to Africa. Implications for prevention strategies.

Data from the US National Malaria Surveillance System were analyzed to assess characteristics of travelers who acquired Plasmodium falciparum infections in Africa and evaluate the impact of chloroquine resistance on the incidence of imported malaria. Although the number of cases acquired in East Africa has stabilized, the number of imported P falciparum infections acquired in West Africa increased threefold from 1985 to 1988, and the proportion of travelers who reported failure of chloroquine prophylaxis increased from 10% to 48%. Fifty-eight percent of patients who acquired malaria in West Africa had not used chemoprophylaxis. To curb the rising incidence of P falciparum infections in American travelers, the Centers for Disease Control revised malaria prophylaxis recommendations to include the use of mefloquine in areas of chloroquine resistance. Use of malaria protection measures by travelers to West Africa must also be improved.

Recent trends in the importation of malaria caused by Plasmodium falciparum into the United States from Africa.

National malaria surveillance data were reviewed in an analysis of the epidemiological impact of the transmission of chloroquine-resistant Plasmodium falciparum in Africa on malaria in the United States. Between 1975 and 1983, P. falciparum infections acquired by U.S. citizens who visited East Africa, especially Kenya, increased 21-fold. Estimated attack rates for P. falciparum per 100,000 U.S. travelers to Kenya rose from 21.2 cases in 1977 to 83.3 cases in 1982, a rise suggesting that the increase in imported malaria was not due to increased travel. The percentage of reported cases in U.S. citizens with P. falciparum infections acquired in East Africa who indicated having used chloroquine prophylaxis increased from 22.2% in 1978 to 75.8% in 1983; in contrast, no change in the reported use of chloroquine prophylaxis was observed in those infected in West Africa during the same period. These results suggest that chloroquine can no longer be considered a highly effective drug for prevention of malaria caused by P. falciparum in U.S. travelers to East Africa.

Evaluation of in-vitro-cultured Plasmodium falciparum as antigen for malaria serology.

A handicap in developing seroepidemiology for malaria in India is the lack of homologous antigens. Aotus monkeys, in which human plasmodia can be propagated, are not easily available in India. Other alternatives include the use of infected human blood or the in-vitro culture of Plasmodium falciparum, using the candle-jar technique of Trager & Jensen (1976). With certain modifications, the in-vitro culture technique has been established at the St John's Medical College (SJMC) to obtain a regular and high yield of P. falciparum to use as a source of antigen in serological tests. Antigens prepared from in-vitro-cultivated P. falciparum have been tested against positive and negative reference sera by the indirect haemagglutination (IHA) and immunofluorescent antibody (IFA) tests. These reference sera were also tested with the IHA test by using P. falciparum-sensitized human "O' erythrocytes received from the Center for Disease Control (CDC), Atlanta. IHA test results with both types of antigens were comparable (Spearman rank correlation coefficient, rS=0.8440, P less than 0.01). The antigen from in-vitro culture was also found suitable for use in the IFA test. The IFA titres obtained were comparable to those found at the CDC (Spearman rank correlation coefficient, rS=0.7940, P less than 0.01). These results indicate that P. falciparum parasites prepared from in-vitro continuous culture can be used as a source of antigen for use in the IHA and IFA tests for malaria.