Discovery and Validation of Biomarkers to Guide Clinical Management of Pneumonia in African Children

Background Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and pneumonia from others causes, such as viruses. Molecular tools could improve diagnosis and management. Methods We conducted a mass spectrometry–based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (n = 204) and age-, sex-, and neighborhood-matched controls (n = 186). Independent validation was conducted in 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with Plasmodium falciparum malaria, and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUC). Results Lipocalin 2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUC, 0.71 [95% confidence interval, .64–.79]) and highly predictive of bacteremia (78% [64%–92%]), pneumococcal bacteremia (84% [71%–98%]), and “probable bacterial etiology” (91% [84%–98%]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the World Health Organization definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUC, 99% [95% confidence interval, 99%–100%]) and Kenyan children (82% [74%–91%]). Conclusions Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies

Discovery and validation of biomarkers to guide clinical management of pneumonia in African children

Background. Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing between severe pneumonia from other causes of respiratory distress like malaria, and between bacterial pneumonia and pneumonia from others causes such as viruses. Molecular tools could improve diagnosis and management.Methods. We conducted a mass spectrometry-based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (N=204) and age, sex and neighborhood-matched controls (N=186). Independent validation was conducted on 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with P. falciparum malaria and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUROC).Results. Lipocalin-2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUROC: 0.71 [95% CI, 0.64-0.79]) and highly predictive of bacteremia (AUROC 78% [95% CI, 64-92%]); pneumococcal bacteremia (AUROC 84% [95% CI, 71-98%]); and ‘probable bacterial etiology’ (AUROC: 91% [95%CI 84-98]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the WHO definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUROC: 99% [95%CI 99-100%]) and in Kenyan children (AUROC: 82% [95% CI, 74-91%]).Conclusions. Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia, and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies

Childhood pneumonia and crowding, bed-sharing and nutrition: a case-control study from The Gambia.

SETTING: Greater Banjul and Upper River Regions, The Gambia. OBJECTIVE: To investigate tractable social, environmental and nutritional risk factors for childhood pneumonia. DESIGN: A case-control study examining the association of crowding, household air pollution (HAP) and nutritional factors with pneumonia was undertaken in children aged 2-59 months: 458 children with severe pneumonia, defined according to the modified WHO criteria, were compared with 322 children with non-severe pneumonia, and these groups were compared to 801 neighbourhood controls. Controls were matched by age, sex, area and season. RESULTS: Strong evidence was found of an association between bed-sharing with someone with a cough and severe pneumonia (adjusted OR [aOR] 5.1, 95%CI 3.2-8.2, P < 0.001) and non-severe pneumonia (aOR 7.3, 95%CI 4.1-13.1, P < 0.001), with 18% of severe cases estimated to be attributable to this risk factor. Malnutrition and pneumonia had clear evidence of association, which was strongest between severe malnutrition and severe pneumonia (aOR 8.7, 95%CI 4.2-17.8, P < 0.001). No association was found between pneumonia and individual carbon monoxide exposure as a measure of HAP. CONCLUSION: Bed-sharing with someone with a cough is an important risk factor for severe pneumonia, and potentially tractable to intervention, while malnutrition remains an important tractable determinant

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis

BACKGROUND: The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS: We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS: We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION: Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING: WHO; Bill and Melinda Gates Foundation