title: Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study.
abstract: BACKGROUND
  Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance.
  
  
  METHODS
  We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis.
  
  
  RESULTS
  Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5-98.8), 80.8% specificity (72.6-87.1), positive likelihood ratio 4.9 (3.4-7.1), negative likelihood ratio 0.083 (0.022-0.32), and misclassification rate 0.20 (standard error 0.038).
  
  
  CONCLUSIONS
  In Tanzanian children with WHO-defined clinical pneumonia, combinations of host biomarkers distinguished between end-point pneumonia, other infiltrates, and normal chest x-ray, whereas clinical variables did not. These findings generate pathophysiological hypotheses and may have potential research and clinical utility.
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Erdman
authors.affiliation: Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland; Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: D'Acremont
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kyla
authors.initials: K
authors.lastname: Hayford
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nimerta
authors.initials: N
authors.lastname: Rajwans
authors.affiliation: Amana Regional Referral Hospital, Dar es Salaam, United Republic of Tanzania.
authors.forename: Mary
authors.initials: M
authors.lastname: Kilowoko
authors.affiliation: St-Francis Hospital, Ifakara, United Republic of Tanzania.
authors.forename: Esther
authors.initials: E
authors.lastname: Kyungu
authors.affiliation: St-Francis Hospital, Ifakara, United Republic of Tanzania.
authors.forename: Philipina
authors.initials: P
authors.lastname: Hongoa
authors.affiliation: Department of Radiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Leonor
authors.initials: L
authors.lastname: Alamo
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Streiner
authors.affiliation: Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland; Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland; Infectious Disease Service, University Hospital, Lausanne, Switzerland.
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D054392:Adipokines / Q000097:blood*; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D002116:Calcitonin / Q000097:blood*; D015740:Calcitonin Gene-Related Peptide; D002675:Child, Preschool; D000071451:Chitinase-3-Like Protein 1; D015331:Cohort Studies; D000071063:Endoglin; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005334:Fever; D006801:Humans; D007223:Infant; D037102:Lectins / Q000097:blood*; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D011014:Pneumonia / Q000097:blood / Q000175:diagnosis* / Q000000981:diagnostic imaging; D011498:Protein Precursors / Q000097:blood*; D012372:ROC Curve; D011859:Radiography; D042787:Receptor, TIE-2 / Q000097:blood; D011956:Receptors, Cell Surface / Q000097:blood; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D013636:Tanzania; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D054392:Adipokines; D015703:Antigens, CD; D015415:Biomarkers; C000606589:CALCA protein, human; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; C064206:ENG protein, human; D000071063:Endoglin; D037102:Lectins; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; D002116:Calcitonin; D002097:C-Reactive Protein; D042787:Receptor, TIE-2; D015740:Calcitonin Gene-Related Peptide