Human immunodeficiency virus type 1 (HIV-1) infection and malaria are among the leading public health problems worldwide. Over 40 million people are currently living with HIV/AIDS,1 and 350-500 million clinical episodes of malaria occur each year, mostly caused by Plasmodium falciparum.2,3 With the increase in international travel, malaria is becoming a growing health problem in nonendemic industrialized countries.4,5 In France, the total number of documented cases of imported malaria rose from 5109 in 1996 to 6392 in 2003, with a maximum of 8059 cases in 2000.6 More than 5000 cases of P. falciparum infection are diagnosed each year,7,8 and malaria is the most common fatal infection in returning travelers.5,9
World Health Organization (WHO) severity criteria for P. falciparum malaria were developed for use in endemic areas and were revised in 2000.10-12 Studies in countries where malaria is endemic suggest that HIV-1 infection is associated with higher parasite densities and higher rates of severe malaria,13-19 but few published studies have focused on imported malaria among patients living with HIV/AIDS. The French Hospital Database on HIV (ANRS CO4, FHDH), a prospective cohort of HIV-infected patients managed in 62 French hospitals, offers an opportunity to study this coinfection. Here we describe episodes of imported malaria diagnosed between 1996 and 2003 among patients enrolled in this cohort and risk factors for severe P. falciparum malaria.
The FHDH clinical epidemiological network was created in 1992 and involves 62 French teaching hospitals belonging to 29 HIV/AIDS treatment and information centers (Centres d'Informations et de Soins sur l'Immunodéficience Humaine).20 It is one of the largest cohorts of HIV-infected patients in the world. The only FHDH inclusion criteria are confirmed HIV infection and written informed consent. Data are collected prospectively by trained research assistants using DMI2 software (property of the French Ministry of Health). The standardized data collection form includes questions on the HIV transmission group, standard biological markers such as the CD4 cell count and the plasma HIV RNA level, pathologies occurring during follow-up [coded with the International Classification of Diseases (ICD)], antiretroviral treatments and prophylaxis, clinical trials in which the patient is enrolled, and deaths and causes of death (as recorded in the medical records). A follow-up form is completed at least every 6 months and/or at each visit or hospital admission during which a new pathology is diagnosed, a new treatment is prescribed, or a change in biological markers is noted. In each center, diagnoses are validated by an HIV expert physician.
For this analysis, we considered adult patients who were followed in the database between January 1, 1996 and December 31, 2003. All patients with a first episode of imported malaria due to P. falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium ovale recorded in the FHDH database were selected on the basis of ICD-9 codes 084.0-084.3 and ICD-10 codes B50-B53.21,22 Imported malaria was defined as malarial infection acquired in an endemic country and treated in France.23,24
The medical records of the patients thus selected were systematically reviewed. Malaria episodes had to be diagnosed by direct examination. The following data (not recorded in the FHDH) were also extracted: percentage of parasitemia upon diagnosis, the area where malaria was acquired, history of the use of chemoprophylaxis, and treatment and care of the malaria episode.
Severe P. falciparum malaria episodes were defined using WHO 2000 criteria10,11 based on one or more of the following features: unrousable coma with a Glasgow Coma Scale score of 9 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 mm Hg, despite adequate volume repletion; spontaneous bleeding and/or disseminated intravascular coagulation; repeated generalized seizures; acidemia (pH < 7.25) or acidosis (serum bicarbonate < 15 mM); macroscopic hemoglobinuria if definitively related to acute malaria; impaired consciousness; parasitemia more than 4%; and total bilirubin more than 50 μmol/L.
Age was divided into 4 groups (younger than 30, 30-39, 40-49, and older than 50 years), and 4 HIV transmission groups were analyzed (men who have sex with men, intravenous drug users, heterosexuals, and “other categories,” including transfused and hemophiliac patients and patients with unknown transmission group). The countries where malaria was acquired were divided according to the status of P. falciparum chloroquine resistance in the country of malaria acquisition as recorded in the contemporary French report on P. falciparum chemoresistance.25-32 Two geographic areas were distinguished as follows: an area with P. falciparum chemoresistance and an area with high P. falciparum chemoresistance. The appropriateness of chemoprophylaxis was analyzed according to the antimalarial drugs used and the P. falciparum chloroquine resistance in the country of acquisition.33 CD4 cell counts and plasma HIV-1 RNA values, at the time of malaria diagnosis, were those available no more than 3 months before or 3 months after the malaria episode. CD4 cell counts were categorized as follows: below 200, between 200 and 349, over 350/mm3, and “no available value” (missing data). Plasma HIV-1 RNA values were classified as follows34: below 500, between 500 and 4999, over 5000 copies/mL, and “no available value” (missing data).
The following variables were tested as potential risk factors for severe P. falciparum malaria: sex, age, origin from sub-Saharan Africa, appropriate malaria chemoprophylaxis, status of P. falciparum chloroquine resistance in the country of malaria acquisition, prior AIDS-related illness, ongoing highly active antiretroviral therapy, and the CD4 cell count and plasma HIV RNA. All variables with P values <0.20 in univariate logistic regression analyses were included in the multivariable model. Age was forced into the multivariable logistic regression as a known risk factor for severe malaria.35-37 All analyses were performed with SAS statistical software version 9.1 (SAS Institute, Cary, NC).
Imported acute malaria episodes occurred in 226 HIV-1-infected patients followed in the FHDH in 1996-2003. Thirty-six patients were subsequently excluded because of coding errors (n = 23) or unconfirmed malaria (n = 13), giving a total of 190 validated cases (84.1%). Plasmodium falciparum was the responsible species in 178 (93.7%) of these 190 patients. The 12 remaining patients were infected by P. ovale (n = 9), P. malariae (n = 2), and P. vivax (n = 1).
The baseline characteristics of the 190 patients are shown in Table 1. Ninety-one (47.8%) patients were women, of whom 12 were pregnant at the time of the episode. Median age was 37.5 years (range 18-68). Half the patients were native from an African malaria-endemic country. One hundred twenty-three patients (64%) were already enrolled in the FHDH before the malaria episode, and 29 patients (15%) had AIDS. At the time of malaria diagnosis, the median CD4 cell count was 299/mm3 (interquartile range, 162-436) (n = 172) and the median plasma HIV-1 RNA load was 4.5 log10 copies/mL (interquartile range, 3.0-5.3) (n = 142). All the 178 HIV-1-infected patients with P. falciparum malaria had returned from a country with P. falciparum chloroquine resistance, of whom half had returned from an area with a high prevalence of P. falciparum chloroquine resistance. For instance in 2003, 13 patients returned from a country of high chemoresistance (Cameroun, Benin, Republic Democratic of Congo, Nigeria, Central African Republic, and Ghana) and 13 patients returned from a country of P. falciparum chloroquine resistance (Côte d'Ivoire, Burkina Faso, Mali, and Guinee).
Prescribed malaria chemoprophylaxis was appropriate in 44 cases (23%), but only 20 of these patients reported good adherence.
Treatment and outcome are shown in Table 2. Eighteen patients (10%), all infected by P. falciparum, required intensive care. Two thirds of patients were treated with quinine. Complications occurred in 36 patients, representing 20% of the entire population. One patient with concomitant pneumococcal pneumonia and P. falciparum malaria died. Elevated transaminase activity of unknown origin was observed in a patient infected by P. ovale.
Severe Plasmodium falciparum Malaria
Sixty-five (36.5%) of the 178 episodes of P. falciparum malaria were severe, including 4 cases involving pregnant women. WHO criteria for severe malaria at hospital admission are shown in Table 3. The most frequent manifestations were acidosis, prostration, jaundice, renal failure, and cerebral malaria.
Table 4 shows factors associated with severe malaria. In univariate analysis, CD4 cell count and plasma HIV-1 RNA load at malaria diagnosis were associated with severity. Compared with patients with CD4 >350, odds ratio (OR) estimates were similar for patients with CD4 in the range 200-350 [OR = 2.73; 95% confidence interval (CI): 1.22 to 6.12] and CD4 below 200 (OR = 2.63; 95% CI: 1.18 to 5.86). Thereafter, the first 2 categories of CD4 cell count were collapsed to reduce the number of strata. No difference of severity was observed for patients presenting a HIV viral load in the range 500-5000 copies/mL at malaria episode compared with patients with HIV viral load below 500 copies/mL (OR = 0.57; 95% CI: 0.13 to 2.59) whereas patients with an HIV viral load greater than 5000 copies/mL were more likely to be diagnosed with severe malaria (OR = 2.32; 95% CI: 0.89 to 6.06). Three additional variables with P value <0.20 were also retained as follows: sex, origin from sub-Saharan Africa, and status of P. falciparum chloroquine resistance in the country of malaria acquisition. In the final model, including the retained variable and adjusted for age, the risk of severe malaria was lower in women (OR = 0.50; 95% CI: 0.24 to 1.01) and in patients returning from a country with a high prevalence of chemoresistance as compared with patients returning from a country with a lower prevalence of chemoresistance (OR = 0.50; 95% CI: 0.25 to 0.99), while origin from sub-Saharan Africa was not associated with severity (OR = 0.69; 95% CI: 0.35 to 1.35). The risk of severe malaria was associated with lower CD4 cell count (OR for <350 versus ≥350, 2.58; 95% CI: 1.19 to 5.57). The association between severity and plasma HIV-1 RNA load was no more observed (OR for ≥5000 versus <500, 2.14; 95% CI: 0.74 to 6.22).
We performed an additional analysis restricted to the 114 patients enrolled in FHDH before malaria onset, of whom 37 (32.5%) had a severe malaria episode. The results of a multivariable analysis including prior CD4 cell count and prior HIV viral load, both measured 3 months before the malaria episode, and the same additional variables as in the initial analysis (sex, origin, status of P. falciparum chloroquine resistance in the country of malaria acquisition, and age) confirmed that patients with prior CD4 below 350 cells/mm3 had a higher risk of severe imported malaria episode (OR for <350 versus ≥350, 2.27; 95% CI: 0.88 to 5.85) whereas no association was observed between prior high HIV-1 RNA viral load and severity (OR for ≥5000 versus <500, 0.47; 95% CI: 0.16 to 1.39).
In this study of HIV-infected patients with imported malaria, most cases were due to P. falciparum. Nearly all the patients acquired malaria in sub-Saharan African countries. Half the patients had returned from an area with a high prevalence of P. falciparum chloroquine resistance. Chemoprophylaxis was frequently lacking. One third of P. falciparum episodes were severe. Severe malaria was associated with lower CD4 cell counts, while the risk was lower among women and among patients returning from a country with a high prevalence of chemoresistance.
Our study is based on the FHDH database, a large prospective hospital cohort study of HIV/AIDS. We used a strict definition of malaria cases, with systematic review of the medical records and confirmation of the diagnosis by direct examination in each case. On the other hand, some episodes may not have been reported in the FHDH.
Using WHO severity criteria, one third of our patients with P. falciparum malaria presented with severe malaria. These criteria, which have been developed for endemic populations, can be applied to imported malaria.5,8,9 The most frequent severity criteria were acidosis, prostration, hyperbilirubinemia, acute renal failure, and cerebral malaria as in recent French studies of HIV-seronegative adults.9,38
The risk of severe malaria was significantly lower among women (OR = 0.50; 95% CI: 0.24 to 1.01) whereas other authors have reported that women are more likely than men to have severe malaria. However, these latter studies were performed in sub-Saharan Africa where difficult access to health care may have contributed to this observation.39,40 In addition, the current literature suggests that pregnant women are at an increased risk of severe malaria,16 but the number of pregnant women in our study was too small to confirm these results.
Half the patients presenting an episode of imported malaria came from a country endemic with malaria, mainly sub-Saharan African country. To be native from a country endemic with malaria did not seem to modify the risk of severe malaria. However, we could not distinguish between recent and long-term immigrants while their immune status could be different.
Plasmodium falciparum was the most frequent causative species in this study, and the area of travel was mainly sub-Saharan Africa, as in other studies of imported malaria in France.6-8
The risk of severe malaria was associated with lower CD4 cell counts in our HIV-1-infected population. These findings are consistent with previous studies in malaria-endemic areas14,15,17,41 and with the results of a systematic review,18 suggesting an interaction between HIV infection and malaria.
Our study is the first to show an association between low CD4 cell counts and the severity of imported P. falciparum malaria in HIV-1-infected adult patients in a nonendemic industrialized country. This association was confirmed when the study was restricted to the subgroup of patients enrolled in FHDH before malaria onset and used CD4 cell count performed at least 3 months before malaria episode. The corresponding OR was 2.27 in this restricted analysis as compared with 2.58 in the original analysis and did not reach statistical significance, probably because of a diminished power. In Uganda, Whitworth and Hewitt17 observed an increased frequency of P. falciparum hyperparasitemia in HIV-1-infected adults compared with HIV-seronegative adults, and this association was more pronounced in patients with lower CD4 cell counts. In a study in South Africa, Grimwade et al15 observed higher rates of parasitemia in HIV-infected women with immunosuppression. Cohen et al41 reported a higher risk of severe malaria in HIV-infected patients with lower CD4 cell counts.19
Interestingly, the risk of severe malaria was lower among patients returning from countries with a high prevalence of P. falciparum chemoresistance. The aim of this study was not to examine the relationship between malaria severity, parasite multiplication, and virulence. There is no consensus regarding the relationship between the clinical manifestations of P. falciparum malaria, an indicator of virulence, and fitness of drug-resistant parasites,42-51 with some studies pointing to a greater virulence of resistant strains compared with susceptible strains in areas of high levels of P. falciparum chemoresistance48,49 whereas other studies advance arguments in favor of more virulence in susceptible strains.45,46 Future studies are needed to assess factors which contribute to the precise levels of the pathogenesis of severe P. falciparum malaria and to the susceptibility of the chloroquine resistance.
In conclusion, our results show that severe malaria in HIV-1-infected patients is associated with decreased CD4 cell count. In contrast, the risk seems lower when P. falciparum infection occurs in areas of high chemoresistance. All travelers, and especially HIV-1-infected patients departing for endemic countries, should systematically receive counseling and antimalarial chemoprophylaxis to reduce the risk and the severity of acute malaria whatever be their country of destination.
The authors are grateful to all the participants and research assistants of the French Hospital Database on HIV.
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