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

Abstract

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.

Robust classification of bacterial and viral infections via integrated host gene expression diagnostics

“…Procalcitonin has been studied extensively in the setting of sepsis diagnosis but cannot distinguish between noninfected individuals and those with viral infections (58). Protein-panel assays have been shown to discriminate bacterial from viral infections but cannot discriminate patients with noninfectious inflammation (59, 60). Thus, all of these classifiers have certain strengths and weaknesses that will become more apparent with further prospective testing and direct comparison.…”

Challenges in the diagnosis of paediatric pneumonia in intervention field trials: recommendations from a pneumonia field trial working group

“…Host-response biomarkers, such as C-reactive protein, interleukin(IL)-6, and procalcitonin, have been increasingly used to assist the diagnosis of a variety of infectious diseases, including pneumonia and sepsis. [66][67][68][69][70][71] A meta-analysis of 6708 adults with acute respiratory infection found that the use of procalcitonin to guide therapy was associated with a 17% reduced risk of mortality and a 2·4-day reduction in antibiotic exposure compared with controls, without increasing adverse outcomes. 72 However, data in children are scarce, and early studies have conflicting results.…”

“…77 Few studies in low-income and middle-income countries have investigated the consistency of hostresponse biomarkers in childhood pneumonia diagnoses. 68,69,78,79 Certain conditions complicate the definition of an optimal threshold of host-response biomarkers for diagnosis. For example, not all bacterial infections cause host-response biomarkers to rise, or to rise to the same degree.…”

“…Two studies compared biomarker testing for pneumonia (as defined by WHO) and radiographical findings. 68,69 Erdman and colleagues 68 studied how biomarker testing using C-reactive protein and Chitinase 3-like-1 predicted radiological findings in 155 children who had pneumonia (as defined by WHO) in Tanzania. Valim and colleagues 69 selected 80 children with pneumonia (as defined by WHO), along with ten healthy controls, and identified how combinations of Review biomarkers (including haptoglobin, tumour necrosis factor receptor 2 or IL-10, and tissue inhibitor of metalloproteinases 1) classified patients by bacterial, malarial, and viral causes.…”

Advances in the diagnosis of pneumonia in children

“…[122][123][124][125][126][127][128][129] Several other biomarkers, including the combination of haptoglobin, tumor necrosis factor (TNF) receptor 2, or interleukin 10, and tissue inhibitor of metalloproteinases 1, 130 have shown promise for the classification of children with bacterial pneumonia but require further evaluation.…”