title: Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.
abstract: Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: James J
authors.initials: JJ
authors.lastname: Gilchrist
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Heath
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Department of Microbiology, College of Medicine, University of Malawi, Blantyre, Malawi Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom.
authors.forename: Chisomo L
authors.initials: CL
authors.lastname: Msefula
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Department of Microbiology, College of Medicine, University of Malawi, Blantyre, Malawi Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom.
authors.forename: Esther N
authors.initials: EN
authors.lastname: Gondwe
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom.
authors.forename: Wilson
authors.initials: W
authors.lastname: Mandala
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: MacLennan
authors.affiliation: Department of Paediatrics, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Molyneux
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Department of Paediatrics, College of Medicine, University of Malawi, Blantyre, Malawi Centre for International Child Health, University of Melbourne and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Graham
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom calman.maclennan@ndm.ox.ac.uk.
authors.forename: Calman A
authors.initials: CA
authors.lastname: MacLennan
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood*; D005260:Female; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008264:Macrophages / Q000276:immunology; D008295:Malawi; D008297:Male; D044342:Malnutrition / Q000150:complications; D009504:Neutrophils / Q000276:immunology; D012480:Salmonella Infections / Q000401:mortality* / Q000473:pathology*; D018805:Sepsis / Q000401:mortality* / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D016207:Cytokines