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.
Wellcome Trust Centre for Human Genetics.
Honglei
H
Huang
Child Survival Theme, Medical Research Council Unit, The Gambia;
Readon C
RC
Ideh
Liverpool School of Tropical Medicine, United Kingdom Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast), Kilifi.
Evelyn
E
Gitau
Wellcome Trust Centre for Human Genetics.
Marie L
ML
Thézénas
Child Survival Theme, Medical Research Council Unit, The Gambia;
Muminatou
M
Jallow
Child Survival Theme, Medical Research Council Unit, The Gambia;
Bernard
B
Ebruke
Child Survival Theme, Medical Research Council Unit, The Gambia;
Osaretin
O
Chimah
Child Survival Theme, Medical Research Council Unit, The Gambia;
Claire
C
Oluwalana
Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast), Kilifi.
Henri
H
Karanja
Child Survival Theme, Medical Research Council Unit, The Gambia;
Grant
G
Mackenzie
Child Survival Theme, Medical Research Council Unit, The Gambia;
Richard A
RA
Adegbola
Wellcome Trust Centre for Human Genetics.
Dominic
D
Kwiatkowski
Wellcome Trust Centre for Human Genetics.
Benedikt M
BM
Kessler
Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast), Kilifi.
James A
JA
Berkley
Child Survival Theme, Medical Research Council Unit, The Gambia;
Stephen R C
SR
Howie
Wellcome Trust Centre for Human Genetics.
Climent
C
Casals-Pascual
D000209:Acute-Phase Proteins; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D005714:Gambia; D006242:Haptoglobins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007630:Kenya; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood*; D016778:Malaria, Falciparum / Q000150:complications; D008297:Male; D013058:Mass Spectrometry; D018410:Pneumonia, Bacterial / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D011237:Predictive Value of Tests; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000097:blood*; D012372:ROC Curve; D012131:Respiratory Insufficiency / Q000097:blood* / Q000175:diagnosis / Q000469:parasitology; D012720:Severity of Illness Index; D014841:von Willebrand Factor / Q000378:metabolism
D000209:Acute-Phase Proteins; D015415:Biomarkers; D006242:Haptoglobins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D014841:von Willebrand Factor; D002097:C-Reactive Protein
biomarkers; lipocalin-2/NGAL; malaria; pneumonia; respiratory infection