Comment

Malaria and bacteraemia in African children

Interactions between dierent infections and their aggregate eect on an individual are poorly understood and understudied. Investigation of the broader eect of specic interventions, such as vaccination, can help to provide some insight into these associations and their underlying mechanisms, but such studies also expose our ignorance or misconceptions about the pathogenesis of these links. Malaria infection has long been suspected to predispose an individual to bacterial infection, especially those with Gram-negative bacteria, such as non-typhoidal salmonella infections,1,2 which are a major cause of morbidity and mortality in young children in many parts of Africa,3 but proof of a direct cause and eect has not been established. In The Lancet, Anthony Scott and colleagues4 provide the strongest evidence yet that malaria is an important risk factor for bacteraemia in African children. The investigators have taken advantage of a unique set of data collected over 9 years on the Kenyan coast in a population at high risk of both malaria and bacteraemia. During the study period, the prevalence of malaria in the study area decreased substantially as a result of widespread use of eective control interventions,5 with malaria admissions to the district hospital also decreasing. Paediatric hospital admissions with bacteraemia decreased in parallel with the decrease in admissions for malaria. This eect was seen for all Gramnegative bacteria, including non-typhoidal salmonella. A similar pattern has been seen in The Gambia, where a decrease in the incidence of non-typhoidal salmonella in young children has accompanied a decrease in the incidence of malaria.6 The decrease in hospital admissions for malaria or bacteraemia seen in coastal Kenya could be coincidentaleg, both might be a consequence of an overall improvement in health care in the study area, or they could be causally related. Scott and colleagues have used an imaginative approach to tease out the nature of this association. At the beginning of the studya time when malaria was prevalent in the study areaScott and colleagues reported that the haemoglobin genotype for the sickle-cell trait (HbAS) was strongly associated with protection against admission to hospital with bacteraemia (adjusted odds ratio 036, 95% CI 020065). With a series of yearly case-control studies, they have shown that as the incidence of malaria decreased, so did the protective eect of the sickle-cell trait against bacteraemia until the OR reached unity. The obvious conclusion from this nding is that malaria infection predisposes an individual to Gram-negative bacteraemia, and that the decrease in paediatric admissions to the district hospital in Kili, Kenya, with Gram-negative bacterial infections was directly related to the reduction in malaria transmission in the surrounding area. The investigators considered other possible explanations for their ndings, but identication of another confounder, which would have to have decreased in parallel with malaria and be associated in some way with HbAS, is dicult. We agree with Scott and co-workers conclusion that their ndings provide strong evidence that malaria predisposes directly to Gram-negative bacteraemia. Acceptance of this conclusion has important scientic and public health implications. For instance, how might malaria predispose to acute Gram-negative bacterial infections? Several possible explanations have been suggested to explain this apparent association. Observations in the eld and experiments in animals suggest that anaemia is a key factor,7,8 but how this eect is mediated is not known. Since the 1970s, malaria has been known to impair the immune response to some antigens,9 but the mechanism underlying this eect is still not fully understood.10 The malaria pigment haemozoin, produced on digestion of haemoglobin, is taken up by macrophages of the reticuloendothelial
Published Online September 7, 2011 DOI:10.1016/S01406736(11)61146-X See Online/Articles DOI:10.1016/S01406736(11)60888-X

www.thelancet.com Published online September 7, 2011 DOI:10.1016/S0140-6736(11)61146-X

Karel Prinsloo/AP/Press Association Images

Comment

system and impairs their function11 so that impairment of antigen processing by macrophages might be an important factor. However, none of these possible explanations account for the fact that the eect seems to be largely restricted to Gram-negative bacteria. The results of the Kenyan study might encourage further research into the way in which malaria modulates the overall function of the immune system and increases susceptibility to other infections. The public health implications of the ndings of this study are substantial. The outcome of malaria control programmes is often greater than would be expected from studies of the burden of malaria in a study community. This occurrence has been noted with largescale malaria control programmes, as seen in Guyana in the 1960s,12 and in controlled trials in African children of chemoprophylaxis and insecticide-treated bednets.13 The results of this important study described by Scott and colleagues lend more support to the belief that the control of malaria, by whatever means, will have an even greater eect on child survival than might have been expected, and provides added justication for continuation of the investment needed to eectively control and ultimately eliminate this infection. *Stephen Obaro, Brian Greenwood
Division of Paediatric Infectious Diseases, Department of Paediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA (SO); and Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK (BG) stephen.obaro@hc.msu.edu
We declare that we have no conicts of interest.

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Mabey DC, Brown A, Greenwood BM. Plasmodium falciparum malaria and Salmonella infections in Gambian children. J Infect Dis 1987; 155: 131921. Green SD, Cheesbrough JS. Salmonella bacteraemia among young children at a rural hospital in western Zaire. Ann Trop Paediatr 1993; 13: 4553. Morpeth SC, Ramadhani HO, Crump JA. Invasive non-typhi salmonella disease in Africa. Clin Infect Dis 2009; 49: 60611. Scott JAG, Berkley JA, Mwangi I, et al. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 2011; published online Sept 7. DOI:10.1016/S0140-6736(11)60888-X. Okiro EA, Hay SI, Gikandi PW, et al. The decline in paediatric malaria admissions on the coast of Kenya. Malar J 2007; 6: 151. Mackenzie G, Ceesay SJ, Hill PC, et al. A decline in the incidence of invasive non-typhoidal salmonella infection in The Gambia temporally associated with a decline in malaria infection. PLoS One 2010; 5: e10568. Kaye D, Gill FA, Hook EW. Factors inuencing host resistance to salmonella infections: the eects of hemolysis and erythrophagocytosis. Am J Med Sci 1967; 254: 20515. Roux CM, Butler BP, Chau JY, et al. Both hemolytic anemia and malaria parasite-specic factors increase susceptibility to nontyphoidal Salmonella enterica serovar typhimurium infection in mice. Infect Immun 2010; 78: 152027. Williamson WA, Greenwood BM. Impairment of the immune response to vaccination after acute malaria. Lancet 1978; 1: 132829. Cunningtion AJ, Riley EM. Suppression of vaccine responses by malaria: insignicant or overlooked. Expert Rev Vaccines 2010; 9: 40929. Schwarzer E, Turrini F, Ulliers D, Giribladi G, Ginsburg H, Arese P. Impairment of macrophage function after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malaria pigment. J Exp Med 1992; 176: 103341. Gigliogli G. Changes in the pattern of mortality following the eradication of hyperendemic malaria from a highly susceptible community. Bull World Health Organ 1972; 46: 181202. Alonso PL, Lindsay SW, Armstrong JRM, et al. The eect of insecticide-treated bednets on mortality of Gambian children. Lancet 1991; 337: 1499502.

www.thelancet.com Published online September 7, 2011 DOI:10.1016/S0140-6736(11)61146-X