Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review

Abstract

BackgroundSevere malaria remains a major cause of pediatric hospital admission across Africa. Invasive bacterial infection (IBI) is a recognized complication of Plasmodium falciparum malaria, resulting in a substantially worse outcome. Whether a biological relationship exists between malaria infection and IBI susceptibility remains unclear. We, therefore, examined the extent, nature and evidence of this association.MethodsWe conducted a systematic search in August 2012 of three major scientific databases, PubMed, Embase and Africa Wide Information, for articles describing bacterial infection among children with P. falciparum malaria using the search string ‘(malaria OR plasmodium) AND (bacteria OR bacterial OR bacteremia OR bacteraemia OR sepsis OR septicaemia OR septicemia).’ Eligiblity criteria also included studies of children hospitalized with malaria or outpatient attendances in sub-Saharan Africa.ResultsA total of 25 studies across 11 African countries fulfilled our criteria. They comprised twenty cohort analyses, two randomized controlled trials and three prospective epidemiological studies. In the meta-analysis of 7,208 children with severe malaria the mean prevalence of IBI was 6.4% (95% confidence interval (CI) 5.81 to 6.98%). In a further meta-analysis of 20,889 children hospitalised with all-severity malaria and 27,641 children with non-malarial febrile illness the mean prevalence of IBI was 5.58 (95% CI 5.5 to 5.66%) in children with malaria and 7.77% (95% CI 7.72 to 7.83%) in non-malaria illness. Ten studies reported mortality stratified by IBI. Case fatality was higher at 81 of 336, 24.1% (95% CI 18.9 to 29.4) in children with malaria/IBI co-infection compared to 585 of 5,760, 10.2% (95% CI 9.3 to 10.98) with malaria alone. Enteric gram-negative organisms were over-represented in malaria cases, non-typhoidal Salmonellae being the most commonest isolate. There was weak evidence indicating IBI was more common in the severe anemia manifestation of severe malaria.ConclusionsThe accumulated evidence suggests that children with recent or acute malaria are at risk of bacterial infection, which results in an increased risk of mortality. Characterising the exact nature of this association is challenging due to the paucity of appropriate severity-matched controls and the heterogeneous data. Further research to define those at greatest risk is necessary to target antimicrobial treatment.

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

“…Mathematical modelling suggests that this can explain the low levels of superinfections in young children 11 , but this mechanism cannot account for observed reductions in the risk of primary malaria infection in children with IDA. It has also been speculated that transient peaks in nontransferrin-bound iron caused by administration of highly absorbable iron supplements 12 could promote intra-erythrocytic parasite growth 13 or bacterial septicemia (a common cause of death in malaria patients 14–16 ) but definitive evidence is absent.…”

Immunology, epidemiology and mathematical modelling towards a better understanding of invasive non-typhoidalSalmonelladisease and rational vaccination approaches

“…Malaria, malarial anaemia and hemolysis exert suppressive effects on phagocyte-mediated cellular immunity and have been epidemiologically associated with a higher risk of iNTS disease [13,[64][65][66]. Plasmodium organisms metabolize the heme portion of human hemoglobin to ferriprotoporphyrin IX and then via the heme polymerase to the insoluble pigment hemozoin, which is released from ruptured erythrocytes and phagocytosed by monocytes, macrophages and neutrophils.…”

Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children

“…About 6.5% of invasive bacterial infections (IBIs) occur in P. falciparum-infected children (6, 7); however, in view of the low sensitivity of blood cultures, P. falciparum infection might account for more than 50% of IBIs in children living in settings of malaria endemicity (8).…”