Responses to Bacteria, Virus, and Malaria Distinguish the Etiology of Pediatric Clinical Pneumonia

Am J Respir Crit Care Med. 2016 Feb 15;193(4):448-59. doi: 10.1164/rccm.201506-1100OC.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Keywords: bacteria; biomarkers; immunoassay; pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / blood
  • Child, Preschool
  • Diagnosis, Differential
  • Female
  • Haptoglobins / metabolism
  • Humans
  • Immunoassay
  • Infant
  • Malaria / blood*
  • Malaria / complications
  • Male
  • Matrix Metalloproteinase 1 / blood
  • Pneumonia / blood
  • Pneumonia / etiology
  • Pneumonia, Bacterial / blood
  • Pneumonia, Viral / blood*
  • Receptors, Interleukin-10 / blood
  • Receptors, Tumor Necrosis Factor, Type II / blood
  • Reproducibility of Results
  • Sensitivity and Specificity


  • Biomarkers
  • Haptoglobins
  • Receptors, Interleukin-10
  • Receptors, Tumor Necrosis Factor, Type II
  • Matrix Metalloproteinase 1