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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immigrants account for a large proportion of cases of imported malaria in France. For example, among the 7,000 cases of imported malaria that occurred in France in 1999, 83% were due to P. falciparum and 63% involved immigrants.8 We formulated the hypothesis that if protection actually disappears within a few months or years of non-exposure, then Europeans (naive individuals) and Africans living in Europe (individuals previously exposed to malaria) will behave similarly during a malaria attack. Therefore, we investigated the possible long-term persistence of immunity despite cessation of exposure by comparing malaria attacks between European and African patients presenting with attacks of P. falciparum malaria following short stays in Africa.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasmodium falciparum density in blood was expressed as the percentage of parasitized red blood cells. Severe and complicated malaria was defined according to 1990 World Health Organization (WHO) criteria and its diagnosis required at least one major criterion or two minor criteria.9
Treatment and follow-up.
Each patient was seen before and after treatment by one of the study physicians, who collected standardized medical and biologic data. African patients were asked to state the frequency of travel to their home country, and the date of the last trip. The decision to hospitalize a patient was taken by the individual physicians according to clinical and biologic findings. Treatment was administered as recommended by the French Ministry of Health at the time of diagnosis. Uncomplicated malaria was treated with halofantrine (500 mg every six hours for three doses) or with oral quinine (8 mg/kg three times a day for seven days) if halofantrine was contraindicated. Patients with severe or complicated malaria, and those who vomited, were given intravenous quinine. Clinical follow-up included a full physical examination daily, and temperature measurement twice a day. Blood smears were examined every day until parasite clearance, and systematically on day 7. The time required for parasite clearance was calculated from the beginning of specific treatment until the disappearance of asexual forms from thick blood films. The clearance of fever was calculated from the outset of specific treatment until a temperature 
37.2°C (99°F) was maintained for at least 24 hours. In vitro chloroquine activity was assessed on blood samples before treatment. Antibody levels to P. falciparum were measured using an immunofluorescence method using a thick blood smear of mature asexual stages from an in vitro culture of P. falciparum.10 This study was reviewed and approved by the hospital ethical committee, and informed consent was obtained from all patients (or the accompanying person).
Statistical analysis. For univariate analysis, the chi-square test and Fisher’s exact test, when necessary, were used to compare the distribution of qualitative variables between patient groups. Continuous variables were compared using a t-test. Data were analyzed using Epi-Info software version 6 (Centers for Disease Control and Prevention, Atlanta, GA). P values < 0.05 were considered significant. Multivariate analyses (logistic and linear regressions) were performed using BMDP software (BMDP Statistical Software, Inc., Los Angeles, CA) procedures 2R and LR.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Characteristics of the stays in endemic areas.
Table 1
shows the characteristics of the stays in endemic countries and the prophylactic measures used. Both Africans and Europeans were generally infected in west or central Africa (most frequently Cameroon or Côte d’Ivoire). The length of stay in the endemic country was higher among the Africans than the Europeans (mean ± SD = 38 ± 21 days versus 23 ± 14 days; P < 0.0001), and stays in urban areas were also more frequent among the Africans (32.9% versus 13.5%; P = 0.0005). Prophylactic measures, whatever the type, were more frequently used by Europeans than by Africans.
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for the two groups of patients. The interval from symptom onset to diagnosis was similar, as was the proportion of patients who had treated themselves before presenting to the hospital. However, at diagnosis, severe and complicated malaria was less frequent and the mean parasite density was lower in Africans than in Europeans. Hemoglobin levels were lower in Africans, while white blood cell and platelet levels were higher. Treatments were similar in the two groups. Following treatment, fever and parasite clearance times were shorter in Africans than in Europeans.
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and 4. They show that after adjustment on all other covariates, severe malaria remained more frequent in Europeans than in Africans, whereas parasite density was more elevated and temperature clearance time was significantly longer. Conversely, the effect of geographic origin on parasite clearance time disappeared when parasite density was taken into account.
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), and this difference persisted after adjustment on other covariates (P = 0.0002, by linear regression). Indeed, 77.3% of Africans had reciprocal titers 
256, compared with only 52.4% of Europeans (P = 0.0003). Median titers among patients originating from Africa did not differ according to the duration of residence in Europe. When adjusted on other variables, there was no relationship between antibody titers and any of the outcome variables.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The African patients reported less frequent use of prophylactic measures against malaria (chemoprophylaxis, repellents, bed nets, and air conditioning) than European patients during their stay in Africa. As suggested by these differences in the characteristics of the stay and in the socioeconomic status, the Europeans can be expected to have better housing and living conditions in which there are less exposed to mosquito bites compared with the Africans, and that they might therefore have received a larger inoculum of P. falciparum sporozoites. Although the latter is thought to be related to more severe disease, the African patients were less likely than the Europeans to have severe and complicated malaria.11–13 Conversely, the fact than Africans spent more time exclusively in an urban environment (where sporozoite exposure is often lower than in rural areas) than the Europeans might produce the opposite result.
In our study, the rate of severe and complicated malaria is higher than that usually reported in imported malaria.14,15 Such a difference can be explained by the high prevalence of P. falciparum malaria imported in France and because we used the 1990 WHO classification including major and minor criteria. A high proportion of patients had two minor criteria such as obnubilation, icterus, hyperbilirubinemia, or hyperparasitemia. This could lead to an over-estimation of severe forms. Nevertheless in two studies comparing data between Africans and Europeans, a lower prevalence of complicated malaria is found in Africans (3.7% versus 6.3% and 1.3% versus 9.2%, respectively) as in our report.14,15
Several other factors may explain this difference in malaria disease expression between African immigrants and Europeans, including differences in their genetic background, or differences in the P. falciparum strains infecting the two groups. Various genetic factors affecting red blood cells, such as the sickle-cell trait, 
- and ß-thalassemia, and glucose-6-phosphate dehydrogenase deficiency, are more frequent in African populations and have been linked to decreased susceptibility to malaria.16–20 Unfortunately, the hemoglobin status of our patients was not characterized. In our study population, the sickle cell trait is undoubtedly the most frequent hemoglobinopathy, since it occurs in 15-20% of the population from sub-Saharan Africa. However, even if the trait was fully effective in preventing severe disease, this would achieve a maximum rate of severe and complicated malaria of 5.4% in Africans who do not have the sickle cell trait. Therefore, this cannot account for the difference of this rate when compared with Europeans (15.2%). Alternatively, it has been suggested that selected parasite strains may be more virulent than others.13,21 However, since both groups of patients were infected in various parts of Africa over a six-year period, it is unlikely that virulence differed between the two groups. The possible relationship between infection with human immunodeficiency virus (HIV) and a higher severity of malaria cannot be excluded.22 This information was not available in our study, but there is no reason to believe that our findings are due to a higher HIV prevalence in the European patients than in the African patients.
This apparent existence of residual immune memory after several years in a non-endemic area is surprising because malaria immunity has been reported to wane rapidly after the end of exposure to the parasite.4–7 However, during the acute phase of the malaria attacks, antibody levels to P. falciparum were higher in the African patients than in the European patients. Given that the antibody level were measured a mean of 10–12 days after symptom onset in both groups, a malaria attack could have boosted immunity in Africans who were exposed prior to residence in France compared with Europeans without previous exposure. Although such antibodies do not by themselves confer protection against malaria, but rather simply indicate previous contact with malarial antigens, this higher antibody level in Africans might be an argument for the existence of residual immune memory. Interestingly, antibody levels during the acute phase were unrelated to the length of residency in Europe.
Thus, when taken together, our data strongly suggest the persistence of a specific immune response in African patients removed from the risk of exposure to P. falciparum. Literature on this topic is poor. As previously states, no convincing demonstration is available to support the classic assertion regarding disappearance of immunity within a few months or years of non-exposure. Conversely, the results of a few studies are consistent with our findings. An in vitro study showed that humoral and cellular responses to defined P. falciparum antigens persisted in migrants from west Africa who spent up to 13 years in France without returning to their native country.23 Two studies conducted in Nigeria and Sudan showed that long-term drug prophylaxis in children did not diminish protective immunity after termination of drug distribution.24,25 Moreover, such long-term persistence of anti-malarial immunity is consistent with observations in the highlands of Madagascar (which are a non-endemic area for malaria) during the 1987 malaria outbreak. Individuals more than 40 years old who had spent their childhood in a malaria hyperendemic area before implementation of a control program were protected more against clinical P. falciparum malaria than were younger subjects, despite being submitted to a similar risk of infective mosquito bites; they also had stronger humoral and cellular immune responses to P. falciparum antigens.26 These differences were attributed to a difference in past exposure to malaria parasites.
Most of the African patients in our study had previously visited their country of origin since migrating to Europe, and these visits, despite their low frequency (once every five years on average) may have contributed to maintenance of long-term immune memory. Nevertheless, we observed no difference between patients who had rarely returned to their native countries and those who had made more frequent visits, although this may have been due to inadequate statistical power.
In conclusion, imported malaria in African adult migrants is less severe (lower parasite density and lower frequency of severe and complicated disease) and more readily cured (shorter parasite and fever clearance times) than it is in Europeans. This difference may be related to long-term persistence of immune memory. However, travel physicians must continue to recommend optimal anti-malaria prophylaxis for all patients visiting endemic areas.
Received July 30, 2003. Accepted for publication August 2, 2004.
Financial support: This work was supported by the Institut de Médecine et d’Epidémiologie Africaine (Paris, France).
Authors’ addresses: Olivier Bouchaud, Sabine Kony, Rémy Durand, Ricarda Schiemann, Pascal Ralaimazava, Jean-Pierre Coulaud, and Jacques Le Bras, Institut de Médecine et d’Epidémiologie Africaine, 16 Rue Henri Huchard, 75018 Paris, France, Telephone: 33-1-44-85-63-00, Fax: 33-1-44-85-63-04, E-mail: imea{at}bichat.inserm.fr. Michel Cot and Philippe Deloron, Institut de Recherche pour le Développement, Unité de Recherche 010, Mother and Child Health in the Tropics, Faculté de Pharmacie, 4 Avenue de l’Observatoire, 75005 Paris, France, Telephone: 33-1-53-73-96-22, Fax: 33-1-53-73-96-17, E-mail: philippe.deloron{at}ird.fr.
Reprint requests: Olivier Bouchaud, Service des Maladies Infectieuses et Tropicales, Hôpital Avicenne, 125 Rue de Stalingrad, 93009 Bobigny, France, Telephone: 33-1-48-95-54-21, Fax: 33-1-48-95-54-28, E-mail: olivier.bouchaud{at}avc.ap-hop-paris.fr.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-thalassaemia are the result of natural selection by malaria. Nature 321: 744–750.[Medline]
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  A. D Smith, D. J Bradley, V. Smith, M. Blaze, R. H Behrens, P. L Chiodini, and C. J M Whitty Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006 BMJ, July 3, 2008; 337(jul03_2): a120 - a120. [Abstract] [Full Text] [PDF]
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