It is not clear whether HIV itself is an independent risk factor for severe Plasmodium falciparum malaria. Studies done in countries where malaria is endemic suggested that, relative to HIV-negative adults, adults with advanced HIV-1 disease were at an increased risk of contracting malaria, that they had higher parasitemia and more severe clinical illness, and that they did not benefit as much from antimalarial therapy [1–3]. Because of the global increase in travel to tropical destinations where malaria is endemic, malaria has become a serious health problem for travelers to the developing world [4,5], and the incidence of imported malaria is on the increase in France [6–8].
Here we studied the respective impact of HIV-1 infection and immunodeficiency on the severity of imported P. falciparum malaria in adults returning from endemic areas, based on data from the French Hospital Database on HIV (FHDH-ANRS CO4, an ongoing prospective cohort of HIV-infected patients managed in 62 French hospitals) , the Bichat Claude Bernard University hospital parasitological and virological databases, and the French National Reference Centre of malaria chemosensibility (CNRCP) .
HIV-1-infected patients with a first episode of P. falciparum malaria were selected on the basis of International Classification of Diseases (ICD-10 code B50) between 2000 and 2003, and CD4 cell counts at time of malaria diagnosis were those available no more than 3 months before or 3 months after the malaria episode in the FHDH-ANRS CO4 cohort. CNRCP is in charge of epidemiological surveillance of P. falciparum malaria chemoresistance and advises the authorities on public health measures and case management. Persons diagnosed with P. falciparum malaria at Bichat Claude Bernard University Hospital (Paris, France) in the same time period and who tested negative for HIV-1 infection were selected from the parasitological and virological databases.
Malaria episodes had to be diagnosed by direct examination. The medical records of all selected patients were systematically reviewed. The following data were extracted: geographic origin, country of malaria acquisition, use of chemoprophylaxis, percentage of parasitemia upon diagnosis, clinical symptoms, treatment care, follow-up, and issue of the malaria episode.
We used three definitions to classify severity (Table 1). First, the World Health Organization (WHO) 2000 criteria [11,12], based on one or more of the following features: unrousable coma with a Glasgow Coma Scale score of 11 or less; severe anemia with hemoglobin (<5 g/dl); renal failure (serum creatinine >265 μmol/l); pulmonary edema with acute respiratory distress syndrome or acute lung injury; hypoglycemia (blood glucose <2.2 mm/l); circulatory collapse or shock with systolic blood pressure <80 mmHg despite adequate volume repletion; spontaneous bleeding and/or disseminated intravascular coagulation; repeated generalized seizures; acidemia (pH <7.25) or acidosis (serum bicarbonate <15 mmol/l); macroscopic hemoglobinuria if definitively related to acute malaria; impaired consciousness; parasitemia more than 4%; and total bilirubin more than 50 μmol/l. The second definition was the adaptation of the WHO 2000 to imported malaria by French recommendations 2007 for clinical practice of management and prevention of imported P. falciparum malaria [13,14]. The latter criteria were used to derive a broad definition, comprising signs and symptoms with high prognostic value and those with low prognostic value but requiring admission to an ICU, and a strict definition comprising only signs and symptoms with high prognostic value.
To determine the respective influence of HIV-1 infection and immunodepression on the severity of imported malaria, we used a combined variable and divided the patients into three groups (HIV-seronegative, HIV-infected with CD4 cell counts ≥350/μl, and HIV-infected with CD4 cell counts <350/μl). Age was divided into three classes (<30, 30–50, and >50 years).
The countries where malaria was acquired were classified as areas of chemoresistance versus high P. falciparum chemoresistance, as stated in the contemporary French report on P. falciparum chemoresistance . Patient origin was dichotomized as sub-Saharan Africa versus other origins . Use of malaria chemoprophylaxis was reported by the patients  and was coded according to the contemporary French report on P. falciparum chemoresistance in the country of acquisition [18–21].
The rates of severe malaria were calculated according to each variable. In addition to HIV infection and immune status, the following variables were tested as potential risk factors for severe P. falciparum malaria: sex, age, origin, area of travel, and use of malaria chemoprophylaxis. The interaction between HIV-1 infection and immune status and each of the other variables was systematically tested. All variables with P values less than 0.20 were included in a multivariable logistic model. All analyses were done with SAS statistical software version 9.1 (SAS Institute, Cary, North Carolina, USA).
We studied 265 patients with a first episode of imported P. falciparum malaria, of whom 104 were infected by HIV-1. Among these latter patients, 41 (39%) had CD4 cell counts at least 350/μl and 63 (61%) had CD4 cell counts less than 350/μl. At malaria diagnosis, 11 HIV-infected patients (11%) had already had an AIDS-defining event. The median CD4 cell counts in the 104 HIV-infected patients was 296/μl [interquartile range (IQR), 196–436] and the median plasma HIV-1 RNA load was 4.6 log10 copies/ml (IQR, 2.6–5.3; n = 94). Among HIV-infected patients, 50 (48%) were on antiretroviral therapy and 23 (22%) were receiving cotrimoxazole.
Half of episodes occurred among women, of whom 18 were pregnant at the time of the malaria episode. The HIV-infected and HIV-negative patients did not differ with respect to sex or age (Table 2). Most of the patients originated from sub-Saharan Africa. All patients acquired P. falciparum infection while traveling in sub-Saharan Africa and half the patients had returned from an area with a high prevalence of P. falciparum chloroquine resistance. In the three groups, the use of antimalarial chemoprophylaxis was reported as poor, but was lower among HIV-infected patients than among HIV-negative patients. Depending on the criteria used, 21% (WHO), 17% (broad criteria), and 11% (strict criteria) of episodes of imported P. falciparum malaria among HIV-negative patients were classified as severe, compared with 40% (WHO), 32% (broad criteria), and 28% (strict criteria) of episodes among HIV-infected patients. According to level of immunodepression of HIV-infected patients, the rate of severe episodes ranged from 22 (CD4 cell counts ≥350/μl) to 51% (CD4 cell counts <350/μl) using WHO criteria, from 15 (CD4 cell counts ≥350/μl) to 41% (CD4 cell counts <350/μl) using the broad 2007 French recommendations definition, and from 12 (CD4 cell counts ≥350/μl) to 38% (CD4 cell counts <350/μl) using the strict 2007 French recommendations definition.
Ninety-six HIV-infected patients (92%) were hospitalized, of whom 16 (15%) were admitted to an ICU, compared with 136 HIV-negative patients (85%), of whom 13 (8%) were admitted to an ICU. There was no difference between these two groups in terms of treatment, with more than two-third of patients treated with intravenous quinine. Complications occurred in 21 HIV-infected patients (20%) and in seven HIV-negative patients (4%). The only death involved an HIV-infected patient with concomitant Pneumococcal pneumonia.
Patients with severe malaria and dysfunction of several organ or metabolic systems are described in Table 3 according to HIV infection and immunological status. This table gives the frequency of features for malaria severity by number of patients with severe malaria episode in each group, respectively in the 34 HIV-negative patients, in the nine HIV-infected patients with CD4 cell counts at least 350/μl and in the 32 HIV-infected patients with CD4 cell counts less than 350/μl. The presented criteria are not exclusive, as a patient could have one or more features of malaria severity, the total would be greater than 100%. This table shows that the groups are comparable in terms of presence of different criteria of malaria severity. The most frequent criterion of severity was hyperparasitemia, which was associated with other criteria in all but six of the patients concerned. Hyperparasitemia was greater than 15% for 17 patients (n = 7, n = 4, and n = 6, respectively for HIV-negative, HIV-infected patients with CD4 cell counts ≥350/μl, and HIV-infected patients with CD4 cell counts <350/μl). Organ dysfunction and clinical manifestations mainly consisted of impaired consciousness, renal failure, and jaundice, and did not differ between HIV-infected and HIV-negative patients.
Whatever the severity criteria used, the episode was significantly more likely to be severe in HIV-infected patients with CD4 cell counts <350/μl than in HIV-negative patients and in HIV-infected without immunodepression (Table 4). Multivariable analyses using the three definitions of severity yielded similar estimates. After adjustment for potential confounding factors, HIV-infected patients with immunodepression (CD4 cell counts <350/μl) were at a significantly higher risk of severe malaria than HIV-negative patients, with odds ratios (ORs) of 3.5 [95% confidence interval (CI) 1.8–6.8; WHO], 3.2 (95% CI 1.6–6.5; broad criteria), and 4.7 (2.1–10.0; strict criteria). In contrast, HIV-infected patients with high CD4 cell counts (>350/μl) were not more at risk than HIV-seronegative patients (OR 0.7–0.9).
The increased risk of severe malaria among HIV-infected patients with immunodepression was confirmed when the analyses were restricted to HIV-seronegative patients and a subgroup of 71 HIV-infected patients with available CD4 cell counts obtained measured 3 months before the malaria episode (see Supplementary Table), with ORs of 2.7 (95% CI 1.1–6.5; WHO), 2.8 (95% CI 1.1–7.1; broad criteria), and 4.7 (95% CI 1.8–12.5; strict criteria).
No interaction between HIV-1 infection and immune status and each of the other variables was found to be significant. In our study, 23 (22%) HIV-infected patients were receiving cotrimoxazole. No protective effect of cotrimoxazole on severe malaria was observed in the subgroup of HIV-infected patients with CD4 cell counts <350/μl (using the WHO 2000 criteria for example: OR for patients not receiving cotrimoxazole versus patients receiving cotrimoxazole, 1.20; 95%CI 0.33–4.42).
The present study estimates the respective effects of HIV infection and immunodepression on the severity of imported malaria in adult patients returning from malaria-endemic areas. We found that, compared with HIV-negative patients, the risk of severe malaria was significantly higher in HIV-infected patients with immunodepression (CD4 cell counts <350/μl) but not in HIV-infected patients with higher CD4 cell counts (>350/μl). Similar results were obtained with three different definitions of severe malaria [11–13,15].
We compared two contemporary series of patients with a confirmed diagnosis of imported P. falciparum malaria, either HIV-infected patients (FHDH-ANRS CO4 cohort) or HIV-negative patients (CNRCP) so that the recommendations and the pattern of resistance were the same for HIV-infected and HIV-negative patients. Immune status was assessed using CD4 cell level at the time of the malaria episode, and a threshold of 350/μl was used to define immunodepression . We also confirm the impact of HIV infection with immunodepression on the risk of severe malaria in the subgroup of HIV-infected patients with an available CD4 cell count measured 3 months before the malaria episode. One limitation of this study is that we had no information on the duration of residence in France among people originating from sub-Saharan Africa. Second, 18 women were pregnant, of whom 10 were HIV-negative (no cases of severe malaria) and eight were HIV-infected (three cases of severe malaria), but the numbers were too small to examine the possible relationship between pregnancy, HIV infection, and malaria severity. However, a sensitivity analysis conducted after excluding these 18 pregnant women did not affect our result. Third, cotrimoxazole has been reported to protect against malaria [22,23]. We were not able to confirm its impact on the severity of the malaria episode but our number of participants in this subgroup analysis was too small. Finally, delay between the first symptoms of the malaria episode and its diagnosis is probably one of determinants of malaria severity that could not be assessed in the study due to lack of information available.
Previous studies in malaria-endemic areas have found a relationship between HIV infection and severity of malaria. A study in Zimbabwe , comparing HIV-infected and HIV-uninfected patients with an episode of malaria, showed that HIV infection doubled the risk of severity. An observational cohort study conducted in South Africa yielded a similar conclusion .
Focusing only on imported P. falciparum malaria, we found that the risk of severe malaria in HIV-infected patients was restricted to those with CD4 cell counts below 350/μl.
The risk of severe malaria episodes was significantly lower in people originating from sub-Saharan Africa in our study, as previously observed in HIV-seronegative patients [16,17,24]. This apparent protection is probably due to persistent acquired immunity to P. falciparum after several years of nonexposure in sub-Saharan Africa [24–27].
Insecticide-treated bed nets (ITNs) and other malaria preventive methods, which significantly reduce the risk of malaria [23,28–31], could not be studied here for their possible preventive effect on severe imported malaria. Only 37, 24, and 19% of our HIV-negative, HIV-infected patients with CD4 cell counts at least 350/μl, and HIV-infected patients with CD4 cell counts 350/μl reported using an adequate antimalarial chemoprophylaxis. As expected [17,32], the risk of severe malaria was higher among patients who did not use an adequate chemoprophylaxis.
In summary, compared with HIV-negative patients, imported P. falciparum malaria is more severe in immunodepressed HIV-infected patients (CD4 cell counts <350/μl) but not in HIV-infected patients with higher CD4 cell counts, and fewer than one in four HIV-infected patients in the study reported using chemoprophylaxis. Imported malaria is almost entirely preventable. The relationship observed here between HIV infection with immunodepression and the severity of imported P. falciparum malaria highlights the need to tailor preventive messages on the use of effective antimalarial prophylaxis, ITNs, and other malaria preventive methods when visiting endemic areas, including for people originating from sub-Saharan Africa.
The authors are grateful to all the participants and research assistants of the French Hospital Database on HIV.
C.M., D.C., and S.M. designed and planned the study and developed the protocol. C.M., M.G., and D.C. did the statistical analyses. C.M., D.C., M.G., S.H., J.L., and S.M. interpreted the final data analyses and wrote the article. All authors read and critically commented on the paper. D.C. is the guarantor.
The French Hospital Database on HIV is supported by Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.
C.M. is supported by the SIDACTION doctoral fellowship.
None of the authors has any conflict of interest to declare.
Members and institutions of Clinical Epidemiology Group of the French Hospital Database on HIV (FHDH ANRS CO4) are as follows:
Scientific committee: S Abgrall, F Barin, M Bentata, E Billaud, F Boué, C Burty, A Cabié, D Costagliola, L Cotte, P De Truchis, X Duval, C Duvivier, P Enel, L Fredouille-Heripret, J Gasnault, C Gaud, J Gilquin, S Grabar, C Katlama, MA Khuong, JM Lang, AS Lascaux, O Launay, A Mahamat, M Mary-Krause, S Matheron, JL Meynard, J Pavie, G Pialoux, F Pilorgé, I Poizot-Martin, C Pradier, J Reynes, E Rouveix, A Simon, P Tattevin, H Tissot-Dupont, JP Viard, N Viget.
DMI2 (name of a software used to record data in the FHDH cohort) coordinating center.
French Ministry of Health (A Pariente-Khayat, Valérie Salomon), Technical Hospitalization Information Agency, ATIH (N Jacquemet, A Rivet).
Statistical analysis center: INSERM U943 (S Abgrall, D Costagliola, S Grabar, M Guiguet, I Kousignian, E Lanoy, L Lièvre, M Mary-Krause, V Potard, H Selinger-Leneman).
CISIH Paris area: CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: E Bouvet, B Crickx, JL Ecobichon, C Leport, S Matheron, C Picard-Dahan, P Yeni), CISIH de Paris-Centre Ouest (Hôpital Européen Georges Pompidou: D Tisne-Dessus, L Weiss; GH Tarnier-Cochin: D Salmon, D Sicard; Hôpital Saint-Joseph: I Auperin, J Gilquin; Hôpital Necker adultes: L Roudière, JP Viard), CISIH de Paris-Sud (Hôpital Antoine Béclère: F Boué, R Fior; Hôpital de Bicêtre: JF Delfraissy, C Goujard; Hôpital Henri Mondor: C Jung, Ph Lesprit; Hôpital Paul Brousse), CISIH de Paris-Est (Hôpital Saint-Antoine: N Desplanque, JL Meynard, MC Meyohas, O Picard; Hôpital Tenon: J Cadranel, C Mayaud, G Pialoux), CISIH de Pitié-Salpétrière (GH Pitié Salpétrière: F Bricaire, S Herson, C Katlama, A Simon), CISIH de Saint-Louis (Hôpital Saint-Louis: JP Clauvel, JM Decazes, L Gerard, JM Molina; GH Lariboisière-Fernand Widal: M Diemer, P Sellier), CISIH 92 (Hôpital Ambroise Paré: H Berthé, C Dupont; Hôpital Louis Mourier: C Chandemerle, E Mortier; Hôpital Raymond Poincaré: P de Truchis), CISIH 93 (Hôpital Avicenne: M Bentata, P Honoré; Hôpital Jean Verdier: V Jeantils, S Tassi; Hôpital Delafontaine: D Mechali, B Taverne).
CISIH Outside Paris area: CISIH Auvergne-Loire (CHU de Clermont-Ferrand: F Gourdon, H Laurichesse; CHRU de Saint-Etienne: A Fresard, F Lucht); CISIH de Bourgogne-Franche Comté (CHRU de Besançon; CHRU de Dijon; CH de Belfort: P Eglinger, JP Faller; CHRU de Reims); CISIH de Caen (CHRU de Caen: C Bazin, R Verdon), CISIH de Grenoble (CHU de Grenoble), CISIH de Lyon (Hôpital de la Croix-Rousse: A Boibieux, D Peyramond; Hôpital Edouard Herriot: JM Livrozet, JL Touraine; Hôtel-Dieu: L Cotte, C Trepo), CISIH de Marseille (Hôpital de la Conception: I Ravaux, H Tissot-Dupont; Hôpital Nord: JP Delmont, J Moreau; Institut Paoli Calmettes: JA Gastaut; Hôpital Sainte-Marguerite: I Poizot-Martin, F Retornaz, J Soubeyrand; CHG d'Aix-En-Provence: T Allegre, PA Blanc; Centre pénitentiaire des Baumettes: A Galinier, JM Ruiz; CH d'Arles; CH d'Avignon: G Lepeu; CH de Digne Les Bains: P Granet-Brunello; CH de Gap: JP Esterni, L Pelissier; CH de Martigues: R Cohen-Valensi, M Nezri; CHI de Toulon: S Chadapaud, A Laffeuillade), CISIH de Montpellier (CHU de Montpellier: J Reynes; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois: T May, C Rabaud), CISIH de Nantes (CHRU de Nantes: E Billaud, F Raffi), CISIH de Nice (Hôpital Archet 1: P Pugliese, C Pradier; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes: C Arvieux, C Michelet), CISIH de Rouen (CHRU de Rouen: F Borsa-Lebas, F Caron), CISIH de Strasbourg (CHRU de Strasbourg: P Fraisse, JM Lang, D Rey; CH de Mulhouse), CISIH de Toulouse (CHU Purpan: E Arlet-Suau, L Cuzin, P Massip, MF Thiercelin Legrand; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: Y Yasdanpanah), CISIH de Tours (CHRU de Tours; CHU Trousseau).
Overseas: CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: R Pradinaud, M Sobesky), CISIH de Martinique (CHRU de Fort-de-France), CISIH de La Réunion (CHD Félix Guyon: C Gaud, M Contant).
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