Malaria-Related Deaths among U.S. Travelers, 19632001

Malaria is an enormous global public health problem, responsible for up to 500 million febrile illnesses and approximately 1 million deaths each year (1). The burden of disease is primarily in sub-Saharan Africa, where approximately 90% of all malaria-related deaths occur in children younger than 5 years of age (1). In contrast, nearly 1500 cases of malaria are reported each year in the United States (2). Almost all infections are acquired outside of the United States since indigenous transmission of malaria was interrupted in the United States in the late 1940s (3). Although some cases occur in refugees and immigrants, U.S. travelers overseas are now the largest group of persons given a diagnosis of malaria. In 2000 (the most recent year for which U.S. Department of Commerce data are available), approximately 27.7 million U.S. travelers visited countries affected by malaria (4), and 825 cases of imported malaria among U.S. civilians were reported to the National Malaria Surveillance System (NMSS) (2). Despite attempts at increasing awareness of malaria among travelers and health care workers, malaria-related deaths among travelers occur nearly every year. A previous review of mortality from Plasmodium falciparum malaria in travelers between 1959 and 1987 was published in 1990 (5); no systematic review has been conducted since. We therefore performed a systematic review of malaria deaths in the United States from 1963 (the first year for which complete case reports are still available) through 2001 (the last year for which data are complete) to describe trends, elucidate risk factors, and identify potential public health actions to prevent future malaria-related deaths among U.S. travelers. Methods Malaria is a notifiable disease in the United States. Malaria cases (including fatal cases) are reported to the NMSS, which is administered by the Centers for Disease Control and Prevention (CDC) Malaria Branch. The NMSS is a passive case detection system that relies on U.S. state and local health departments and health care providers to report laboratory-confirmed malaria cases. Cases diagnosed outside the United States or one of its territories are not included. The CDC publishes an annual summary of malaria surveillance in the United States as a supplement to Morbidity and Mortality Weekly Report, which includes case summaries of all fatal malaria cases. We reviewed and screened all fatal cases that occurred between 1963 and 2001, and we included only U.S travelers in our review. We defined a malaria-related death in a U.S. traveler as 1) a death reported to NMSS and subsequently published in the annual surveillance summary for which malaria was a direct or indirect cause of death, 2) a malaria diagnosis and death that occurred in the United States or one of its territories, 3) death from a malarial infection that was acquired outside of the United States or one of its territories, and 4) death of a U.S. resident who traveled abroad for any nonmilitary purpose for any length of time at any point before onset of malaria. We abstracted cases that met these inclusion criteria and entered them into a database (Epi-Info 6.01, CDC, Atlanta, Georgia). We used Stata software, version 7 (Stata Corp., College Station, Texas), for all statistical analyses. We also used several definitions. We defined time to seeking care as the number of days between symptom onset and first visit to a medical provider (coded as unknown if treatment-seeking details were not available in the case summary), time to diagnosis as the number of days between the first visit to a medical provider and the diagnosis of malaria (coded as unknown if these dates were not specified), time to treatment as the number of hours between a diagnosis of malaria and the initiation of antimalarial treatment, appropriateness of chemoprophylaxis regimen as the extent to which CDC recommendations published at the time of travel were followed, and appropriateness of treatment as the determination based on the most recent recommendation from The Medical Letter for that year. We coded adherence to chemoprophylaxis as adherent or nonadherent if this was specifically mentioned; if not, we coded this as unknown. We defined a preventable death as one in which the person 1) took no chemoprophylaxis, 2) took (or was prescribed) inappropriate chemoprophylaxis, 3) took the correct chemoprophylaxis but did not completely adhere to the prescribed regimen, 4) delayed seeking medical care for more than 2 days after the onset of symptoms, 5) sought medical care but did not receive a diagnosis on the day of initial presentation with malaria, 6) was given a diagnosis of malaria but treatment began more than 1 day after diagnosis, or 7) was treated with an antimalarial drug that was inappropriate for the infecting species and region of acquisition. Results From 1963 to 2001, 185 malaria-related deaths were reported to the CDC: 123 (66.5%) occurred among U.S. travelers, 31 (16.8%) occurred among refugees and visitors, 17 (9.2%) occurred among military personnel, and 14 (7.6%) occurred among unknown or other groups (percentages add to 100.1% because of rounding) (Figure 1). The number of deaths among U.S. travelers has remained relatively constant over time, varying between 0 and 10 deaths (median, 3). Among the 123 U.S. travelers, 49 (39.8%) were women and the median age was 51 years (mean, 48.7 years [range, 12 to 91 years]). Most deaths (114 [92.7%]) were attributed to P. falciparum, 4 (3.3%) were attributed to P. vivax, 2 (1.6%) were attributed to P. malariae, and 1 (0.8%) was attributed to P. ovale. In 2 (1.6%) cases, the species was not determined or not reported. The percentage of erythrocytes infected with P. falciparum was reported for 46 cases (mean, 21.4% [range, 1% to 60%]). Figure 1. Number of malaria deaths among travelers, refugees or visitors, and military in the United States, 19632001. Estimated Case-Fatality Rate, Species of Infection, and Origin of Infection The estimated case-fatality rate for U.S. travelers with reported cases of imported malaria (all species) was 0.9% (range, 0% to 4.4% by year). For 1985 to 2001, the only years for which complete computerized data are available, the case-fatality rate was 1.3% for P. falciparum, 0.06% for P. vivax, 0.3% for P. malariae, and 0.3% for P. ovale. These case-fatality rates are probably an overestimate (particularly for nonP. falciparum malaria) because deaths are more likely to be reported than nonfatal cases. Most fatal cases (93 cases [75.6%]) were acquired in Africa: Kenya (25 cases), Nigeria (15 cases), and Liberia (10 cases) were the most probable frequent origins of infections, accounting for 40.6% of fatal cases. The duration of stay varied widely (<1 day to 23 years), with a median stay of 22 days. Tourism was the most frequently identified motive for travel (17.9%), with business (16.3%), missionary work (13.8%), and visiting friends or relatives (11.4%) as the next most common reasons. During the most recent years reviewed (1989 to 2001), the relative importance of these travel motives shifted: Visiting friends and relatives is now the most frequently reported motive for travel among fatal cases (21.3%), followed by business (19.2%), missionary work (10.6%), and tourism (8.5%). Use of Chemoprophylaxis Nearly half of persons (n= 57 [46.3%]) took no chemoprophylaxis, and information on the use of chemoprophylaxis was not available for an additional 32 persons (26%). Of the 34 persons who reported taking chemoprophylaxis, 12 (35.3%) took a drug or drug combination that was inappropriate for the region of travel, and 20 (58.8%) took an appropriate chemoprophylactic drug. Information was insufficient in 2 individuals to determine whether the drug regimen was appropriate. Of the 20 persons who took an appropriate drug, 6 (30%) did not adhere to the prescribed regimen. No information on adherence was available for an additional 7 persons (35%). Therefore, 7 of 123 individuals (5.7%) were known to take appropriate chemoprophylaxis and adhere to the regimen. The reasons these individuals became ill with malaria is not known, but the most likely reasons are unreported nonadherence to the recommended regimen and malabsorption of the antimalarial drug. Table 1 summarizes the chemoprophylaxis regimens currently recommended by the CDC (6). Table 1. Drugs Used in the Prophylaxis of Malaria Presenting Symptoms Fever was the most common presenting symptom, reported for 77.2% of fatal cases, followed by chills (45.9%) (Table 2). Although the classic symptoms of fever and chills or sweats were very common, 23 persons (18.7%) presented with no history of these symptoms. Symptom onset ranged from 18 days before return to 4 years after return (median, 5 days after return; P. ovale was the infecting species for the case 4 years after return). One woman, a 91-year-old who died after developing P. malariae infection, became symptomatic an unknown number of years after traveling to China. Table 2. Presenting Symptoms of 123 U.S. Travelers Who Died of Malaria, 19632001 Time to Seeking Care and Diagnosis Forty-six persons (37.4%) waited more than 1 day after symptom onset before seeking medical care (median, 4.5 days [range, 2 to 28 days]). We could not determine the timing of care-seeking for 58 persons (47.2%). Of the 90 individuals for whom the case report provides adequate information, 61 (67.8%) did not obtain a diagnosis of malaria on the same day as the medical visit. The time to diagnosis ranged from 1 day to 17 days (median, 4 days). In 4 persons, the species was initially misidentified. Diagnosis of P. malariae infection was later changed to P. falciparum infection in 2 cases, P. vivax infection was later changed to P. falciparum infection in 1 case, and P. falciparum infection was later corrected to P. vivax infection in 1 case. In 22 of the 123 U.S travelers (17.9%), malaria was diagnosed only at autopsy. Delay in Initiati