During the 1996–2003 period, 27,085 malaria cases were reported to CNREPIA; 21,888 of these patients had P. falciparum malaria, which constituted the study population. Included were 20,436 (93.4%) uncomplicated cases, 825 (3.8%) severe cases, 433 (2%) asymptomatic cases, 161 (0.7%) cases of hyper-reactive malarial splenomegaly, and 33 (0.1%) unspecified cases. Cases attributable to species other than P. falciparum and cases attributable to species combinations that included P. falciparum were not considered in the analysis (no fatal cases of imported malaria due to Plasmodium species other than P. falciparum were reported during the study period). The annual number of malaria cases reported by the network increased until 1999–2000, then stabilized at ≈3,000 cases per year (Table 1). Most patients were male (sex ratio M:F = 1.7), and the median (range) age was 29.0 (0–96) years. Most patients had acquired malaria in Africa: 59.2% in West Africa, 26.2% in central Africa, 11.2% in Madagascar and the Comoros Islands, and 0.9% in East Africa (Table 2, Table A1, available from www.cdc.gov/EID/content/13/6/883-appT.htm). Others (2.5%) had returned mainly from French Guiana, Haiti, India, Sri Lanka, Thailand, and Indonesia. African travelers were most numerous (44.6%), followed by European travelers (26.5%), African residents (12.9%), and European expatriates living in Africa (5.4%); “others” represented 10.6%. Few patients (30.4%) reported taking effective chemoprophylaxis, and more than half the patients had not taken any. The median duration of stay was 32 days (interquartile range 21–62). The median time from return to symptom onset was 6 days (interquartile range 1–12), and 10% of patients had their first symptoms before returning to France. The median time from symptom onset to diagnosis was 3 days (interquartile range 1–6). Compared with Europeans, Africans were more likely to seek care at a hospital (73.0% vs. 62.7%, p<0.001). Diagnoses were fairly evenly distributed between spring-summer (55.5%) and fall-winter (45.5%). At diagnosis, 7.9% of patients had high-level parasitemia (>5% of parasitized erythrocytes).

To our knowledge, this is the largest retrospective study aimed at identifying risk factors for fatal imported malaria. France has large numbers of migrants of African origin. Those populations are particularly at risk of acquiring malaria when visiting friends and relatives (15–17). Migrants of African origin travel for longer periods in highly malaria-endemic areas (globally, 75% of malaria infections and 89% of P. falciparum infections in travelers are acquired in sub-Saharan Africa [18]), are less likely to have pretravel encounters with a healthcare provider, and are therefore unlikely to take antimalarial prophylaxis (18). These factors explain why France, in comparison with many other European countries or the United States, has so many malaria cases and why the country appears to receive disproportionally high numbers of malaria-infected returning travelers from Africa (19), rather than from Asia or South America. As a result, P. falciparum is overrepresented in imported malaria in France in comparison with other industrialized countries. The case-fatality rate (4.4 per 1,000 cases) is among the lowest in the World Health Organization (WHO) 2004 Computerized Information System for Infectious Diseases database, probably because of the large proportion of African migrants in our study population.

The following characteristics were independently associated with death from falciparum malaria, according to multivariate analysis: older age, origin in an area not endemic for malaria, infection in East Africa, and no effective chemoprophylaxis. Increasing age has also been a risk factor for fatal falciparum malaria in smaller studies (10,11,13,20,21). As has been reported elsewhere (21), we found a gradual increase in risk over the entire age spectrum, resulting in particularly high risk among elderly patients. This factor should be taken into account when offering pretravel health advice, particularly as the age of international travelers increases.

Severe malaria and death were particularly frequent among nonimmigrants, as previously reported in smaller series (6–8,13,22). These results are consistent with the hypothesis of persistent acquired immunity, even after several years of nonexposure, which may partially protect African immigrants from fatal malaria, as previously shown for severe forms of malaria (23). Genetic factors, selected at the population level over centuries of exposure to the parasite, may also partly explain the relative protection of African immigrants compared with Europeans (24,25).

Except for the Comoros Islands (0.5 cases per 1,000 cases of falciparum malaria), countries accounting for large numbers of cases in this study (Senegal, Cameroon, Mali, and Côte d’Ivoire) had similar case-fatality rates (3.2 to 5.4 cases per 1,000 cases of falciparum malaria). Most travelers returning from the Comoros Island were migrants; few were European tourists. East African countries such as Djibouti, Kenya, Mozambique, and Tanzania accounted for fewer cases but a disproportionate number of fatalities (34.1 cases per 1,000). Ben-Ami et al. recently reported a high rate of severe malaria (6 of 29 cases, including 1 death) among patients who visited Mombasssa, Kenya (26). More generally, Krause et al. reported that falciparum malaria acquired in Africa had a higher case-fatality rate than falciparum malaria acquired elsewhere (11). During the period of our study, an increase in malaria deaths, probably related to higher levels of drug resistance, was seen in residents of East Africa but not in those of West Africa (27). Those observations are not necessarily linked, but particular attention should be paid to travelers returning from these areas. Further studies are needed to confirm and explain these findings.

The risk for death was higher when prophylaxis was absent or ineffective than when appropriate prophylaxis was taken. On the basis of interview data, only 2 authentic failures of prophylaxis were suspected among our patients, but drug and metabolite concentrations were not assayed. These results are consistent with those of Krause et al., who reported that study participants who had taken chemoprophylaxis with chloroquine-proguanil were less likely to die than those who had not taken chemoprophylaxis (11). These results once again underline the importance of recommending antimalarial prophylaxis for travelers to malaria-endemic areas (28).

Bruneel et al. reported that platelet counts were significantly lower in patients who eventually died of P. falciparum–infected patients than in survivors (8) and that leukocyte counts also tended to be higher. In our population, a platelet count <50×10⁹/L was associated with increased risk of dying; this effect was particularly marked at counts <10×10⁹/L. Disseminated intravascular coagulation, which is associated with marked thrombocytopenia, was frequent in patients who later died (Table 3). Leukocyte counts >10×10⁹ cells/L were also associated with increased mortality, ]and the effect was particularly marked at counts >15×10⁹ cells/L. Hyperleukocytosis in this setting may be related to cytokine or cortisol release or to bacterial (especially nosocomial) infections, which were frequent in our patients who eventually died (Table 3). Bruneel et al. found that hyperparasitemia (>5%), a WHO severity criterion, was weakly linked to death. Although the number of circulating parasitized erythrocytes may not accurately reflect the number of adherent red cells in deep organ capillaries, which are the source of most clinical complications (29), hyperparasitemia appeared to be an important predictor of death in our series. However, parasitemia and some biologic data (hemoglobin, platelet counts, and leukocyte counts) could not be included in our multivariate analysis because an excessive amount of data were missing. In particular, hemoglobin, platelet count, and leukocyte count data were missing for more than half the patients.

A limitation of our study is that our network for collecting data accounted for only 50%–55% of total malaria cases imported to France. Two annual exhaustive studies (National Quality Control Survey [30]; F. Legros, unpub. data) suggest that representativeness of our sites was correct. Thus, risk factors associated with death in imported malaria would not likely differ for cases not seen in our network.

Severe and fatal malaria, even though it is eminently preventable, continues to be seen in areas that are not endemic for malaria (31,32). Fatal cases are rare in patients who take appropriate prophylaxis. With the current increases in intercontinental travel, numbers of elderly travelers, risk for transmission in malaria-endemic areas, and drug-resistant strains of P. falciparum (16,33), the numbers of fatal cases of imported malaria should be carefully monitored in the coming years in France and other industrialized countries. Preventive measures remain necessary for all travelers, including those from Africa, for whom adherence is often poor (34). Posttravel care should also be reinforced to reduce the interval between symptom onset and diagnosis (35,36).