title: Responses to Bacteria, Virus, and Malaria Distinguish the Etiology of Pediatric Clinical Pneumonia.
abstract: BACKGROUND
  Plasma-detectable biomarkers that rapidly and accurately diagnose bacterial infections in children with suspected pneumonia could reduce the morbidity of respiratory disease and decrease the unnecessary use of antibiotic therapy.
  
  
  OBJECTIVE
  Using 56 markers measured in a multiplexed immunoassay, we sought to identify proteins and protein combinations that could discriminate bacterial from viral or malarial diagnoses.
  
  
  METHODS
  We selected 80 patients with clinically diagnosed pneumonia (as defined by the World Health Organization) who also met criteria for bacterial, viral, or malarial infection based on clinical, radiographic, and laboratory results. Ten healthy community control subjects were enrolled to assess marker reliability. Patients were subdivided into two sets: one for identifying potential markers and another for validating them.
  
  
  RESULTS
  Three proteins (haptoglobin, tumor necrosis factor receptor 2 or IL-10, and tissue inhibitor of metalloproteinases 1) were identified that, when combined through a classification tree signature, accurately classified patients into bacterial, malarial, and viral etiologies and misclassified only one patient with bacterial pneumonia from the validation set. The overall sensitivity and specificity of this signature for the bacterial diagnosis were 96 and 86%, respectively. Alternative combinations of markers with comparable accuracy were selected by support vector machine and regression models and included haptoglobin, IL-10, and creatine kinase-MB.
  
  
  CONCLUSIONS
  Combinations of plasma proteins accurately identified children with a respiratory syndrome who were likely to have bacterial infections and who would benefit from antibiotic therapy. When used in conjunction with malaria diagnostic tests, they may improve diagnostic specificity and simplify treatment decisions for clinicians.
authors.affiliation: 1 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Valim
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Rushdy
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: 3 Barcelona Institute for Global Health, Barcelona Center of International Health Research, and Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|4 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lanaspa
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.|5 Bioinformatics Program, Boston University, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 4 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.|6 National Institute of Health, Health Ministry, Maputo, Mozambique.
authors.forename: Sozinho
authors.initials: S
authors.lastname: Acácio
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.|7 Massachusetts General Hospital, Boston, Massachusetts.|8 Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gillette
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Almendinger
authors.affiliation: 1 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.|8 Harvard Medical School, Boston, Massachusetts.|9 Brigham and Women's Hospital, Boston, Massachusetts; and.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.affiliation: 3 Barcelona Institute for Global Health, Barcelona Center of International Health Research, and Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|4 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.
authors.forename: Lola
authors.initials: L
authors.lastname: Madrid
authors.affiliation: 1 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Karell
authors.initials: K
authors.lastname: Pellé
authors.affiliation: 10 Richard M. Fairbanks School of Public Health and School of Medicine, Indiana University, Indianapolis, Indiana.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Harezlak
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Jacob
authors.initials: J
authors.lastname: Silterra
authors.affiliation: 3 Barcelona Institute for Global Health, Barcelona Center of International Health Research, and Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|4 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Alonso
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.|5 Bioinformatics Program, Boston University, Boston, Massachusetts.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.affiliation: 1 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: 2 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiegand
authors.affiliation: 3 Barcelona Institute for Global Health, Barcelona Center of International Health Research, and Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|4 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
mesh_terms: D015415:Biomarkers / Q000097:blood; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006242:Haptoglobins / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D007223:Infant; D008288:Malaria / Q000097:blood* / Q000150:complications; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D011014:Pneumonia / Q000097:blood / Q000209:etiology; D018410:Pneumonia, Bacterial / Q000097:blood; D011024:Pneumonia, Viral / Q000097:blood*; D053701:Receptors, Interleukin-10 / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D006242:Haptoglobins; D053701:Receptors, Interleukin-10; D047889:Receptors, Tumor Necrosis Factor, Type II; D020781:Matrix Metalloproteinase 1
keywords: bacteria; biomarkers; immunoassay; pneumonia