HIV Infection, Malnutrition, and Invasive Bacterial Infection among Children with Severe Malaria
James A. Berkley
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Philip Bejon
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Tabitha Mwangi
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Samson Gwer
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Kathryn Maitland
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Thomas N. Williams
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Shebe Mohammed
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Faith Osier
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Samson Kinyanjui
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Greg Fegan
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Brett S. Lowe
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Mike English
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Norbert Peshu
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Kevin Marsh
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Charles R. J. C. Newton
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who were admitted to the hospital
, 26% of inpatient
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Centre for Clinical Vaccinology and Tropical Medicine
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Health Organization (WHO) criteria for cerebral ma-
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Nairobi Kenya Medical Research Institute (KEMRI)-Wellcome Trust Collaborative Research Programme, Kenyatta National Hospital
, Nairobi,
Kenya
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ease is due to malaria. For example, in Malawi, another
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Centre for Geographic Medicine Research
, Kilifi
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Institute of Child Health, University College London
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London, United Kingdom
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Infectious Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine
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Department of Paediatrics and Wellcome Trust Centre for Clinical Tropical Medicine, Imperial College
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Department of Paediatrics, University of Oxford
,
Oxford
(See the editorial commentary by Breman on pages 344-5) Background. Human immunodeficiency virus (HIV) infection, malnutrition, and invasive bacterial infection (IBI) are reported among children with severe malaria. However, it is unclear whether their cooccurrence with falciparum parasitization and severe disease happens by chance or by association among children in areas where malaria is endemic. Methods. We examined 3068 consecutive children admitted to a Kenyan district hospital with clinical features of severe malaria and 592 control subjects from the community. We performed multivariable regression analysis, with each case weighted for its probability of being due to falciparum malaria, using estimates of the fraction of severe disease attributable to malaria at different parasite densities derived from cross-sectional parasitological surveys of healthy children from the same community. Results. HIV infection was present in 133 (12%) of 1071 consecutive parasitemic admitted children (95% confidence interval [CI], 11%-15%). Parasite densities were higher in HIV-infected children. The odds ratio for admission associated with HIV infection for admission with true severe falciparum malaria was 9.6 (95% CI, 4.919); however, this effect was restricted to children aged 1 year. Malnutrition was present in 507 (25%) of 2048 consecutive parasitemic admitted children (95% CI, 23%-27%). The odd ratio associated with malnutrition for admission with true severe falciparum malaria was 4.0 (95% CI, 2.9-5.5). IBI was detected in 127 (6%) of 2048 consecutive parasitemic admitted children (95% CI, 5.2%-7.3%). All 3 comorbidities were associated with increased case fatality. Conclusions. HIV, malnutrition and IBI are biologically associated with severe disease due to falciparum malaria rather than being simply alternative diagnoses in co-incidentally parasitized children in an endemic area. Falciparum malaria is a common cause of severe illness among children in sub-Saharan Africa [1]. Human immunodeficiency virus (HIV) infection, malnutrition, and invasive bacterial infection (IBI) are reported among children with severe malaria [2-16]. However, it is unclear whether these conditions are actually associated with severe malaria among children living in areas where malaria is endemic. The clinical signs of severe malaria have been carefully defined, but even when they are supported by Plasmodium falciparum parasitemia, not all severe discause of death was found during postmortem examinations of 23% of children who fulfilled the World
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planation is that, in areas of endemicity, asymptomatic malaria
parasites are observed among children who present with
nonmalarial conditions. The alternative explanation is that severe
malaria is associated with other conditions, either biologically
or through shared risk factors.
Direct comparison of comorbidities between malaria slide
positive and -negative, hospitalized patients is inappropriate
for 2 reasons: (1) among slide-positive cases, not all disease is
due to malaria; and (2) among slide-negative cases, HIV
infection, malnutrition, and IBI themselves may be causes of (or
be strongly associated with) severe disease. Rather, longitudinal
studies or comparisons with children in the community must
be undertaken.
Studies of severe malaria usually exclude parasitemic children
with clinical evidence of other illnesses, such as malnutrition,
meningitis, or pneumonia. However, this approach assumes a
priori that parasitemia is coincidental and excludes the
possibility of the actual coexistence of severe malaria with other
diseases.
There is no gold standard to determine, in an individual
child, that severe disease is or is not due to malaria in an
area where malaria is endemic. Therefore, malarial parasitemia
should always be treated in seve (...truncated)