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INTRODUCTION
Endemic in > 100 countries in the world, malaria is the major public health problem in Africa south of the Sahara, where it takes its largest toll on very young children. An estimated 515 (range, 300–600) million clinical cases occur per year, with > 1 million deaths. About 90% of all malaria deaths in the world occur in Africa south of the Sahara.1,2
One of the major challenges for the effective monitoring and evaluation of the impact of malaria control tools is the inaccuracy of the epidemiologic information of malaria as a result of underreporting, especially in highly endemic areas, such as Gabon. The epidemiology of malaria varies considerably between countries and regions, and this variation needs to be taken into account in malaria control programs.3 In fact, the pattern of patients’ clinical manifestation is influenced by many factors such as endemicity of infections, geographical location, availability and accessibility to health care facilities, effectiveness of drugs, and age.4–6 Severe malaria presents a particularly wide spectrum of clinical and biologic manifestations. Therefore, standard criteria were developed by the World Health Organization (WHO) to characterize high-risk malaria in children.4 Thus far, there is rare site comparison from neighboring urban and rural areas concerning the different clinical phenotypes of malaria according to these WHO criteria for severe malaria. The aim of this study was to compare clinical and biologic aspects of hospitalized patients suffering from malaria in urban and rural pediatric wards in Gabon.
MATERIALS AND METHODS
Study areas.
The study was simultaneously conducted in two areas from January 2001 to December 2002 within the frame of the Severe Malaria in African Children (SMAC) studies.
Urban area.
The Malaria Clinical Research Unit (MCRU) located in the General Hospital of Libreville (the largest public referral hospital in Gabon) is linked to the Department of Parasitology, Mycology, and Tropical Medicine of the “Université des Sciences de la Santé” of Libreville. This unit works closely with a well-established emergency department, the two pediatric wards, and the National Blood Transfusion Center. Libreville is a high year-round transmission area of Plasmodium falciparum malaria. The plasmodial indexes rise to 64.9% (percentage of Plasmodium falciparum carriers in 100 inhabitants living in the same place) in the urban zone such as Libreville.7
Rural area.
The Medical Research Unit of the Albert Schweitzer Hospital is located in Lambaréné, 250 km from Libreville. As in Libreville, this area is characterized by a high year-round transmission of P. falciparum, with a plasmodial indexes rise to 64.9% and a mean entomologic inoculation rate of 50 infective bites per person per year.7–9 This unit works closely with the pediatric ward but without an emergency room as structured in Libreville.
Study design and eligibility criteria.
In this prospective observational study involving two sites in Gabon, children included in the study met the following criteria: 1–120 months of age with diagnosis of “non per os” falciparum malaria (all patients hospitalized for malaria and treated with intravenous quinine in a 10% glucose infusion).
Inclusion in the study was prior to written informed consent from children’s parents or guardians. Each inclusion involved a basic physical exam and assessment of various established prognostic features in falciparum malaria based on WHO severe malaria definition,4 such as Blantyre coma score (BCS) ≤ 2, repeated observed seizures, hypoglycemia (< 2.2 mmol/ L), severe anemia (hemoglobin concentration of < 5 g/dL), respiratory distress defined as the presence of abnormalities in respiratory rate, rhythm (Kussmaul or Cheyne-Stokes breathing), and signs of distress such as nasal flaring, subcostal, or intercostal recession, prostration, and repeated vomiting. During hospitalization, the patients were followed to determine the outcome (died or survived). Using the WHO clinical malaria revised definition, we divided all the malaria cases into two groups. The patients were classified in moderate or severe malaria groups according to the clinical state at the admission. They were included in the moderate group when they did not fulfill the standard WHO 2000 definition for severe malaria with a Blantyre coma score between 3 and 4.
Laboratory evaluation.
Once a child was hospitalized, the following laboratory tests were performed: parasitemia was quantified on thick blood smears (stained with 20% Giemsa solution at pH 7.2) by calculating the average parasitemia per microscopic field of a fixed amount of blood (10 μL) spread on a fixed area (1.8 cm2),10 and the hemoglobin level (g/dL) and glucose level (mmol/L) were determined from capillary or venous blood.
Outcome.
Primary outcome for comparisons between sites was the clinical outcome (died versus survived). The secondary outcome was malaria severity (number of symptoms qualifying for severe malaria or presence of WHO severe malaria criteria).
Management of patients.
In both sites, the treatment of the patients consisted of intravenous quinine (25 mg quinine di-hydrochloride/kg/24 hours) in a 10% glucose infusion for 3 days, followed by a single dose of sulfadoxine-pyrimethamine in Lambaréné and oral quinine in Libreville when the patients were able to tolerate oral medication. Seizures were controlled with diazepam (0.3 mg/kg intravenously or 0.5 mg/kg intrarectal). Severe anemia was corrected by transfusion of packed red cells (15 mL/kg over 4 hours). Adjunct treatment was given as required.
Ethical issue.
The study protocol was approved by the ethics committee of the International Foundation of the Albert Schweitzer Hospital in Lambaréné and the Gabonese Ministry of Health. Written informed consent was obtained from all children, parents, and/or guardians.
Data management and statistical analysis.
The demographic, clinical, and laboratory data for each patient were recorded using the same concise medical record forms in both areas. Complete manual review was done to validate data. Data were entered in SPSS 11.5 (SPSS, Chicago, IL) for descriptive and comparative statistical analysis. Comparison of data within a group was carried out by χ2 tests and non-parametric analyses (Kruskal-Wallis and Wilcoxon signed rank tests). For smaller samples, the Yate correction or the Fisher exact test was used to assess differences between the groups. Geometric mean of parasitemia (asexual parasites per microliter of blood) was calculated, and the differences between the groups was analyzed by the Wilcoxon signed rank test. A two-sided P < 0.05 was considered statistically significant. Multivariate analysis were carried out using SAS 9.0 (SAS Institute, Cary, NC) to determine the most important predictor of fatal malaria in both sites, and the test of Wald was used for significance.
RESULTS
Baseline characteristics.
Table 1 shows the baseline characteristics of the study population. In the two areas, a total of 15,617 children (8,372 boys and 7,245 girls) were screened (all the children with malaria clinical symptoms attending the hospital wards), from whom 5,846 were positive for P. falciparum (overall rate, 37%). The proportions were 39% and 35% for Libreville and Lambaréné, respectively (P < 0.001). From the 5,846 malaria cases, 2,235 were hospitalized (38% of all malaria cases diagnosed). The hospitalized falciparum malaria proportions were 33% and 48% of all malaria cases diagnosed in Libreville and Lambaréné, respectively (P < 0.001). The mean age of the patients was 32 ± 24 and 36 ± 28 (SD) months in Libreville and Lambaréné, respectively (P = 0.001).
Malaria clinical phenotypes.
Two clinical phenotypes of malaria (moderate and severe malaria) were described according to the WHO revised standard criteria of severe malaria. From 2,235 malaria cases hospitalized in the two sites, 1,289 (58%) were diagnosed as moderate cases and 946 (42%) as severe cases. One thousand eight hundred seventy-six (1,876) of the hospitalized malaria cases were younger than 5 years old (84% of all hospitalized cases).
Moderate malaria.
A total of 1,289 moderate malaria cases were identified in the two areas: 629 (53%) and 660 (63%) of all cases in Libreville and Lambaréné, respectively (P < 0.001; Table 1). During their admission, the Blantyre coma score was between 3 and 4. In these children, seizures (notion of one convulsion observed or not) were reported in 143 (22%) and 276 children (44%) in Libreville and Lambaréné, respectively (P < 0.001). The seizures were common in children younger than 5 years old in Libreville and Lambaréné. Vomiting was reported in 345 (56%) and 391 (59%) children in Libreville and Lambaréné, respectively, and mainly reported in children younger than 5 years old (76%). Repeated vomiting and prostration were reported by the mothers at the admission to hospital. In both sites, an increasing number of moderate cases from children younger than 6 months old to between 12 and 23 months were observed. This number progressively decreased in children between 24 and 71 months of age.
Severe malaria.
A total of 946 severe malaria cases were reported in both sites: 563 cases (47%) and 383 cases (37%) of all hospitalized cases in Libreville and Lambaréné, respectively (P < 0.001). Figure 1 shows in both sites a progressive increase of severe cases from children who were 6 months old to between 12 and 23 months of age. Subsequently, the number of severe malaria cases progressively decreased in children between 24 and 120 months of age.
Severe anemia.
Five hundred fifty-five children had severe anemia (25% of all severe cases in Libreville and Lambaréné). Three hundred eighty-three and 172 children had severe anemia in Libreville and Lambaréné, respectively (P < 0.001). In both sites, this feature was most common in children younger than 5 years old (95% of all severe anemia cases). Eighty-two percent of all severe anemia cases were reported in children younger than 36 months old. The mean age of children with severe anemia was 22 and 26 months in Libreville and Lambaréné, respectively (P = 0.030).
Cerebral malaria.
One hundred ninety-nine children were comatose (21% of severe malaria cases). One hundred sixty-six cases of cerebral malaria (84% of comas) occurred in children younger than 5 years old. Coma was reported in 150 (27%) and 49 children (13%) in Libreville and Lambaréné, respectively (P < 0.001). The children with cerebral malaria were older than children with severe anemia. The mean age was 35 and 36 months in Libreville and Lambaréné, respectively (P = 0.8).
Hypoglycemia.
Hypoglycemia was reported in 211 children (32% of severe malaria cases). Among children with hypoglycemia, 82% were younger than 5 years old. Forty-three (8% of severe malaria cases) and 168 children (44% of severe malaria cases) had hypoglycemia in Libreville and Lambaréné, respectively (P < 0.001). The mean age of children with hypoglycemia was 27 and 39 months in Libreville and Lambaréné, respectively (P = 0.020).
Respiratory distress.
Respiratory distress was observed in 183 children (19% of children with severe malaria). Sixty-eight percent of cases with respiratory distress were found in children between 6 and 35 months. Respiratory distress was reported in 150 (27%) and 33 children (9%) in Libreville and Lambaréné, respectively (P < 0.001).
Parasitemia.
Geometric mean parasite density (GMPD) was 40, 750, and 39,190 parasites/μL in Libreville and Lambaréné, respectively. There was no statistically significant difference between the GMPD in the two sites (P = 0.6). A lower prevalence of children with hyperparasitemia (parasite density ≥ 250,000/μL) was seen in the severe anemia group (P < 0.001) compared with the cerebral malaria group. The age-specific parasite density showed that, on the whole, they were higher in infants, rising sharply in children between 12 and 72 months. In older children, these parasite densities decreased with increasing of age (Figure 2). when we consider the whole screened population, the children younger than 5 years old were frequently parasitized (83%), with a high prevalence in children between 12 and 47 months (50%).
Mortality.
A total of 75 deaths occurred in both sites in the course of this study, with 63 in Libreville and 12 in Lambaréné. Eighty-eight percent of deaths occurred in children younger than 5 years old. The mean age of children who died was 28 and 35 months, respectively, in Libreville and Lambaréné (P = 0.3). The total case fatality rate (CFR) was 3% for both sites (5% and 1% in Libreville and Lambaréné, respectively; P < 0.001). The CFR in moderate malaria group in both sites was 1.0% (1.6% and 0.5% in Libreville and Lambaréné, respectively, P = 0.04). In the severe malaria group, this rate was 9% and 2% in Libreville and Lambaréné, respectively (P < 0.001). When considering the severe symptoms, four symptoms presented the highest fatality rates (Table 2). The CFR in cerebral malaria was 23% and 16% in Libreville and Lambaréné, respectively (P = 0.34; Table 2). The CFR in severe malarial anemia was 8% and 1%, respectively, in Libreville and Lambaréné (P < 0.001). Table 2 shows, in the two sites, that cerebral malaria and respiratory distress were the best predictors of fatal outcome.
DISCUSSION
This prospective observational study shows two groups of patients: moderate malaria cases and severe malaria patients. Severe malaria cases were distributed in four main clinical manifestations: severe anemia, cerebral malaria, hypoglycemia, and respiratory distress. Severe anemia was the predominant clinical spectrum of severe malaria (59% of all severe cases), followed by hypoglycemia (32%), cerebral malaria (21%), and respiratory distress (19%). These manifestations particularly affect children younger than 36 months old. The clinical spectrum of malaria reflects the epidemiology of malaria in highly endemic areas.11 However, Libreville showed the highest rate of severe cases (P < 0.0001), such as severe malaria, cerebral malaria, and respiratory distresses. These figures can be explained by the high proportion of the urban child population at risk of severe malaria associated with economical difficulties to accede health cares. Children with severe anemia and hypoglycemia were younger in Lambaréné than Libreville, whereas there was no statistically significant mean age difference between children with cerebral malaria in both sites (P = 0.8). Altogether, 89% of the severe patients were younger than 5 years old. This proportion is much higher than that observed in Burkina Faso (62%)12 and approximately similar to that found in a previous study in Gabon (84%).13 Respiratory distress was observed in 27% of children with severe malaria in Libreville, whereas it was found in 9% of those in Lambaréné. The proportion of respiratory distress observed in Lambaréné was close to findings from Togo (6%)14 and Kenya (14%).15 Surprisingly, among the other manifestations of severe malaria, the prevalence of hypoglycemia is markedly higher in Lambaréné than Libreville (44% and 17%, respectively). This significant difference between these two study areas needs further analysis, because a prevalence of hypoglycemia found in Libreville seems to be more often observed in other malaria endemic areas.16 The mean hemoglobin level was also markedly different between Libreville and Lambaréné: 6.0 and 8.0 g/dL, respectively (P < 0.0001).
In our study, the overall CFR was 3%. This finding is similar to the CFR reported from Tanzania.11 However, we found a significant difference between the study areas (5% and 1%, respectively, in Libreville and Lambaréné), despite the similar malaria treatment applied in both areas at the admission. This difference may partly be explained by the limited access to health care facilities in the urban area where the referral hospital access is mostly based on financing (pay before being treated). In Lambaréné, all the inpatients were immediately treated when admitted or hospitalized. These logistic differences might lead to a more severe clinical status of patients hospitalized in Libreville despite the availability of important intensive care equipment in this area. This is supported by the fact that hemoglobin levels were lower in Libreville, where the access to blood transfusion was mostly difficult despite the existence of a well-equipped blood transfusion center. There was a significant difference in fatality rate between the clinical groups (moderate and severe malaria) in both sites. Nevertheless, the malaria case fatality rate in Gabon remains low compared with other reported case fatality rates, which range between 8% and 40%.14,17–20 In this study, the highest CFR (62% of all deaths) was seen in children between 12 and 35 months of age and mostly in girls rather than boys in the two areas. In contrast, Schellenberg and others,11 in 1999, observed the highest CFR in individuals younger than 1 year old. Similar to other studies, the highest risk of dying was observed in patients presenting with coma at admission (56%; odds ratio [OR] = 11.5, 95% confidence interval [CI] = 5.7–23.2). Hypoglycemia was shown to be a better predictor of fatal outcome mostly in Libreville than in Lambaréné compared with other complications such as cerebral malaria or respiratory distress (OR = 4.1, 95% CI = 1.9–8.4). The availability of dextrose infusion in both health facilities allowed good clinical management of hypoglycemia. In both areas, cerebral malaria associated with respiratory distress was the highest risk for fatal outcome (OR = 10.7, 95% CI = 4.8–23.8; P < 0.0001), followed by cerebral malaria associated with respiratory distress and severe anemia (OR = 2.6, 95% CI = 0.6–11.5).
Despite the difference of urbanization, the two study sites present similar malaria epidemiologic characteristics with a highest proportion of moderate and severe malaria cases in Libreville. Whereas malaria in both areas is characterized by high proportion of severe anemia, the highest case fatality rate was observed in cerebral malaria associated with respiratory distress. The main differences between the two sites was the higher proportion of hypoglycemia observed in Lambarene and the lower hemoglobin concentrations in children in Libreville at admission. The higher mortality in Libreville, despite the availability of a well-equipped intensive care unit, is also noteworthy. In fact, poor housing and the high proportion of population and drainage of surface water surrounding urban areas increase vector breeding and human contact in African cities, enhancing the risk of malarial infection and consequently severe malaria in urban areas.21
Characteristics of study population
| Libreville | Lambaréné | P | |
|---|---|---|---|
| Number of patients hospitalized with fever or notion of fever (all screened patients) | 9,338 (60%) | 6,279 (40%) | < 0.001 |
| Sex | |||
| Male | 5,106 (55%) | 3,266 (52%) | – |
| Female | 4,232 (45%) | 3,013 (48%) | < 0.001 |
| Age (months), mean ± SD | 36 ± 30 | 38 ± 32 | < 0.001 |
| Number of malaria cases hospitalized | 1,192 | 1,043 | |
| Sex | |||
| Male | 647 (54%) | 571 (55%) | 0.8 |
| Female | 545 (46%) | 472 (45%) | |
| Age (months), mean ± SD | 32 ± 24 | 36 ± 28 | < 0.001 |
| Parasitemia (parasites/μL) | |||
| Geometric mean | 40,550 | 39,190 | 0.6 |
| Range | 40–1,345,200 | 10–1,425,600 | |
| Type of malaria | |||
| Moderate | 629 (53%) | 660 (63%) | – |
| Severe | 563 (47%) | 383 (37%) | < 0.001 |
| Hemoglobin (g/dL) mean ± SD | 6.0 ± 2.5 | 8.0 ± 2.4 | < 0.001 |
| Glycemia (mmol/L) mean ± SD | 5.4 ± 1.6 | 4.0 ± 1.6 | < 0.001 |
The case fatality rates of the four main severe malaria symptoms and malaria phenotype groups
| Libreville | Lambaréné | P | |
|---|---|---|---|
| Severe anemia | |||
| Number of cases | 383 | 172 | |
| Number of deaths | 29 | 2 | |
| Case fatality rate | 8% | 1% | 0.001 |
| Cerebral malaria | |||
| Number of cases | 150 | 49 | |
| Number of deaths | 34 | 8 | |
| Case fatality rate | 23% | 16% | 0.34 |
| Hypoglycemia | |||
| Number of cases | 43 | 168 | |
| Number of deaths | 12 | 6 | |
| Case fatality rate | 28% | 4% | < 0.001 |
| Respiratory distress | |||
| Number of cases | 150 | 33 | |
| Number of deaths | 31 | 4 | |
| Case fatality rate | 21% | 12% | 0.33 |
| Hospitalized malaria cases | |||
| Number of hospitalized malaria cases | 1,192 | 1,043 | |
| Number of deaths | 63 | 12 | |
| Case fatality rate | 5% | 1% | < 0.001 |
| Moderate malaria cases | 629 | 660 | |
| Number of deaths | 10 | 3 | |
| Case fatality rate | 1.6% | 0.5% | 0.04 |
| Severe malaria cases | 563 | 383 | |
| Number of deaths | 53 | 9 | |
| Case fatality rate | 9% | 2% | 0.001 |
Severe malaria cases according to age groups in Libreville (LBV) and Lambaréné.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Severe malaria cases according to age groups in Libreville (LBV) and Lambaréné.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Severe malaria cases according to age groups in Libreville (LBV) and Lambaréné.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Parasitemia per age groups.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Parasitemia per age groups.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Parasitemia per age groups.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1015
Address correspondence to Saadou Issifou, Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, BP 118, Gabon. E-mail: issifou@lambarene.mimcom.net
Authors’ addresses: Saadou Issifou, Michel A. Missinou, Pierre Blaise Matsiegui, Sanjeev Krishna, and Peter G. Kremsner, Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, BP 118, Gabon, Telephone: 00241-581099, Fax: 00241-581196, E-mail: issifou@lambarene.mimcom.net. Saadou Issifou, Michel A. Missinou, Pierre Blaise Matsiegui, and Peter G. Kremsner, Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074 Tübingen, Germany. Eric Kendjo, Arnaud Dzeing-Ella, Frédéric A. Dissanami, and Maryvonne Kombila, Département de Parasitologie-Mycologie-Médecine Tropicale, Faculté de Médecine, Université des Sciences de la Santé, BP 4009 Libreville, Gabon. Sanjeev Krishna, Division of Cellular and Molecular Medicine, Centre for Infection, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK.
Acknowledgments: We thank the children and parents who participated in this study; the laboratory technicians in Libreville and Lambaréné; the staff of the pediatric services in Libreville and Lambaréné; and Drs Bertrand Lell, Michael Ramharter, Elie Mavoungou, and Benjamin Mordmüller for critical comments.
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