During the 1996–2003 study period, 27,085 malaria cases were reported to CNREPIA. Of these, 21,888 cases were P. falciparum malaria (the study population), among which 20,431 (93.3%) were uncomplicated, 832 (3.8%) were severe, 433 (2%) were asymptomatic, 160 (0.7%) showed hyperreactive malarial splenomegaly, and 32 (0.1%) were unspecified. Among the 21,888 P. falciparum cases, 96 deaths (case-fatality rate [CFR] of 0.4%) were related to malaria. The annual number of malaria cases reported by the network increased to ≈3,000 cases up to 1999–2000 and then incidence began to regularly decrease. The CFR of severe P. falciparum malaria was higher during 2000–2003 than before, reaching 15.3% in 2003 (Table 3).

Most patients were male (sex ratio M:F = 1.7), and the median age was 29.6 (range 0–96) years. 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%. Most patients (97.5%) became infected with malaria in Africa: 59.2% in western Africa, 26.2% in central Africa, 11.2% in Madagascar and the Comoros Islands, and 0.9% in eastern Africa (Table 4; Table A1). Others (2.5%) had returned mainly from French Guiana, Haiti, India, Sri Lanka, Thailand, and Indonesia. Almost one third of the patients (30.4%) stated they had taken an appropriate chemoprophylaxis, whereas more than half stated they had not. The median duration of stay was 32 days (interquartile range [IQR] 21–62 days). The median time from return to symptom onset was 6 days (IQR 1–12 days), and 11% of patients had their first symptom before returning to France. The median time from symptom to diagnosis was 3 days (IQR 1–6 days). Most patients went to a hospital first (69.4%) and, compared with Europeans, Africans were more likely to do so (73% vs. 62.7% p<0.001). At the time of diagnosis, 7.9% of patients had high-level parasitemia (>5% of parasitized erythrocytes). Seventy-five percent of patients were hospitalized, and the median hospitalization length was 3 days (range 0–169 days). Laboratory results for 13.1% of patients revealed low platelet counts (<50 × 10⁹ cells/L); 6% of patients had low hemoglobin levels (<8 g/dL).

With a mean of >4,000 cases per year during the study period, France is the country reporting the highest number of imported malaria cases; >80% of cases are caused by P. falciparum, the species responsible for almost all severe cases and death in travelers. African travelers are particularly at risk of acquiring malaria when visiting friends and relatives. Together with African residents who declare malaria during a stay in France, African travelers accounted for 57.5% of imported malaria cases in our series. These populations, either immune or possessing residual immunity, are less likely to acquire severe cases of malaria (9), which may explain why the total proportion of severe cases in our series, fluctuating according to years from 2.5% to 5.3% (mean 3.8%), appears lower than those reported in previous studies (3–5,7,10–12).

We identified 7 risk factors independently associated with severe imported P. falciparum malaria; 4 were the same as those associated with fatal imported malaria (older age, being a native from an area where malaria is nonendemic, infection occurring in East Africa, and absence of appropriate chemoprophylaxis), and 3 were new risk factors (first visit was to a general practitioner, time to diagnosis 4–12 days, and diagnosis during the fall–winter season). Increasing age is a well-recognized risk factor for severe (3–6,17) and fatal P. falciparum malaria (2,4,14,18,19). For persons >45 years of age, age appeared more as an increased risk factor rather than a gradual increase over the entire age spectrum. This finding is contrary to what has already been reported for death, or for severe cases in another study, which included only European patients (2,3). Severe malaria was particularly frequent among nonimmigrants, as previously reported in a smaller series (7–9,12). These results are consistent with the hypothesis of persistent acquired immunity, even after several years of nonexposure (12), which may partly protect African travelers from severe malaria (9,12).

Genetic factors may also partly explain the relative protection of African travelers compared with Europeans, as noted by Lewis et al. (8). Five countries, Côte d’Ivoire, Cameroon, Senegal, Mali, and the Comoros Islands, accounted for the largest numbers of malaria cases; case severity rates varied between 1.4% and 4.8%. Travelers returning from the Comoros Islands were almost exclusively migrants who were visiting friends and relatives, which may explain the particularly low proportion of severe cases observed for this country. Conversely, countries in eastern Africa such as Djibouti, Kenya, Mozambique, and Tanzania accounted for fewer cases but displayed a disproportionately high number of severe cases (10.6%–16.7%). This observation confirmed what has been reported for CFR (2).

As suggested by a preliminary study (17), a relationship between P. falciparum drug-resistance level and severity of imported cases may exist. Because countries in eastern Africa usually harbor high proportions of drug-resistant P. falciparum strains (20,21), further specific studies are required to assess this point. The risk of severe malaria was higher when antimalarial chemoprophylaxis was absent or inappropriate. These results are in agreement with previous observations (5,6,8) and advocate strengthening the message of prevention through the use of antimalarial chemoprophylaxis. Even when this prophylaxis fails to prevent malaria because of lack of observance, drug resistance, or pharmacologic hazards, antimalarial chemoprophylaxis may confer a degree of protection against the severe form of malaria.

Management of patients who had uncomplicated malaria was not standardized among the different hospitals of our network. Depending on local procedures or on individual evaluations, patients were hospitalized, usually for the duration of their treatment, or were treated on an outpatient basis. Nevertheless, each patient with severe malaria needed to be hospitalized in an intensive care unit (exceptions to this rule depend on local medical practice). The odds of severe malaria developing were increased by 40% when the patient’s initial visit was to a general practitioner rather than to a hospital. This effect remained after controlling for time to diagnosis and suggests that this association was not due to a simple delay of diagnosis.

Time between onset of symptoms and diagnosis of 4–12 days was associated with an increased risk of severe malaria. Shorter delays of diagnosis enabled prompt treatment of malaria episodes and probably prevented their potential evolution towards severity. Diagnosis >12 days postsymptom onset usually reflected controlled parasitemia and uncomplicated malaria. These data emphasized once again the need for early diagnosis and prompt therapy. The higher severity found during the fall–winter season has been related previously to a potential mismanagement of malaria patients initially misdiagnosed with influenza (22,23). However, delay in diagnosis does not totally explain higher severity because the association between seasons and severity was not reduced after time to diagnosis was controlled for in multivariate analysis. Moreover, the influenza season in France is shorter than the fall–winter season considered in our analysis. Multivariate analysis in another study (E. Seringe et al., unpub. data) showed that malaria episodes around the end of the transmission season in areas where malaria is endemic were significantly associated with an increased risk of death (OR for each additional month away from the end of the malaria season 0.75, 95% CI 0.64–0.87; p<0.001). If one considers the geographic origin of the largest number of imported malaria cases, the end of the transmission season matched the French winter season. An additional factor, symptom onset before return to France, was marginally independently associated with severe malaria (OR 1.20, 95% CI 1.01–1.50; p = 0.03). Repatriations for medical reasons, including malaria infections, may partially explain this result.

This study has several limitations. Our surveillance network accounted for only 50%–55% of total malaria cases (uncomplicated, severe, or fatal) imported to France. Two annual exhaustive studies (National Quality Control Survey [24]) and F. Legros (unpub. data) suggest that our corresponding sites had a correct representation of patients. Thus, it is unlikely that factors associated with severity in imported malaria would be different among cases not seen in our network. From 2000 through 2003, the CFR in patients infected with P. falciparum and the percentage of severe cases have increased from 0.3% to 0.7% (p<0.0001) and from 2.5% to 4.5% (p = 0.3) respectively, whereas the CFR of severe cases remained stable (from 14.3% to 15.3%). These figures may be caused by fluctuations over time but may also be partially explained by the revision of WHO criteria for severe malaria in 2000. This revision may have led to a better categorization of severe cases, judging by the increased odds of death associated with severity after the 2000 reclassification (OR 1.84, 95% CI 1.20–2.90). However, no interaction was identified between year of diagnosis and relevant associations and all analyses were adjusted for the year of diagnosis.

Biological data were not introduced in multivariate analysis, first, because of a large number of missing data (59% and 60% of missing data in severe cases for platelet counts and hemoglobinemia, respectively) and, second, because parasitemia (10% of missing data), hemoglobin, and platelet counts are directly or indirectly part of the definition of severe malaria. Thus, parasitemia, although strongly associated with severe forms of malaria in univariate analysis, was not introduced in the final multivariate model because it is in the causal pathway between several factors and disease. For instance, delay to diagnosis leads to high parasitemia, which itself leads to severe forms of malaria. Adjusting for high parasitemia in the final model would make the relationship between delay to diagnosis and severe malaria disappear.

Treatment of severe malaria may have varied according to the physicians. Detailed French guidelines for the management of severe P. falciparum malaria were available (25). These guidelines strongly recommended a quinine-loading dose but did not recommend exchange transfusion. Intravenous artesunate was not used in France during the study period.

The clinical course of P. falciparum malaria is unpredictable and may result in severe illness and death. Although the acquisition of P. falciparum malaria among travelers to countries where malaria is endemic can never be completely avoided, our data suggest that severe malaria may largely be prevented. Pretravel health advice promoting the compliant use of antimalaria chemoprophylaxis for every traveler, with a particular focus on nonimmune travelers and elderly persons, is essential. In addition, increased vigilance of travelers in reporting symptoms and of physicians in providing prompt diagnosis and treatment is required to reduce any delay in patient management.