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.

Etiology of severe childhood pneumonia in the Gambia, West Africa, determined by conventional and molecular microbiological analyses of lung and pleural aspirate samples.

Molecular analyses of lung aspirates from Gambian children with severe pneumonia detected pathogens more frequently than did culture and showed a predominance of bacteria, principally Streptococcus pneumoniae, >75% being of serotypes covered by current pneumococcal conjugate vaccines. Multiple pathogens were detected frequently, notably Haemophilus influenzae (mostly nontypeable) together with S. pneumoniae.

Serotype analysis of Streptococcus pneumoniae in lung and nasopharyngeal aspirates from children in the Gambia by MassTag PCR.

Streptococcus pneumoniae strains comprise >90 serotypes. Here we describe establishment of a MassTag PCR assay designed to serotype S. pneumoniae and demonstrate its utility in tests using 31 paired lung aspirate and nasopharyngeal aspirate samples from children with pneumonia in the Gambia. Serotypes 1, 5, and 14 in were implicated in 90% of lung infections. With 5 exceptions, serotypes found in lung aspirates were also found in nasopharyngeal aspirates.

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 & Melinda Gates Foundation.

Congenital malformations: Prevalence and characteristics of newborns admitted into Federal Medical Center, Asaba.

Background: Congenital malformations account for a significant cause of perinatal mortality and morbidity. Understanding the burden and pattern of congenital malformation is key in monitoring the trend and improving the health care of neonates especially those in low-income countries. Objective: This was a prospective cross-sectional study to determine the prevalence and characteristics of congenital malformations among neonates admitted to the neonatal unit. Method: All newborns with congenital malformation admitted into the neonatal unit of Federal Medical Center, Asaba whose parents gave consent were recruited for the study for a 1-year period from January 2020 to December 2020. Appropriately indicated laboratory and radio-diagnostic investigations were done to confirm internal anomalies. Data were collected using a structured questionnaire and analyzed with a statistical package for social sciences version 26.0. Results: The total admission for the period was 752 with 46 of the neonates (6.1%) having congenital malformation. The predominant system affected was the cardiovascular system (57%), central nervous system (33%), and digestive system (30%). Atrioventricular septal defect (31%) and patent ductus arteriosus (31%) were the commonest types of cardiovascular malformation. A significant number of newborns with congenital anomalies died (43.5%). Conclusion: Congenital malformation was seen among one in 18 neonates affecting mostly the cardiovascular and central nervous system. A high index of suspicion, early complete physical examination, and radio-diagnostic investigations are relevant for the complete evaluation of CM in neonates. Advanced maternal age was associated with the presence of multiple organ anomalies.

Zinc as an adjunct therapy in the management of severe pneumonia among Gambian children: randomized controlled trial.

BACKGROUND: The benefit of zinc as an adjunct therapy for severe pneumonia is not established. We assessed the benefit of adjunct zinc therapy for severe pneumonia in children and determined whether the study children were zinc deficient. METHODS: This was a randomized, parallel group, double-blind, placebo-controlled trial with an allocation ratio of 1:1 conducted in children with severe pneumonia to evaluate the efficacy of daily zinc as an adjunct treatment in preventing 'treatment failure' (presence of any sign of severe pneumonia) on day-5 and day-10 and in reducing the time to resolution of signs of severe pneumonia. Six hundred and four children 2-59 months of age presenting with severe pneumonia at six urban and rural health care facilities in The Gambia were individually randomised to receive placebo (n = 301) or zinc (n = 303) for seven days. To determine if the study children were zinc deficient, supplementation was continued in a randomly selected subgroup of 121 children from each arm for six months post-enrolment, and height-gain, nutritional status, plasma zinc concentrations, and immune competence were compared. RESULTS: Percentage of treatment failure were similar in placebo and zinc arms both on day 5 (14.0% vs 14.1%) and day 10 (5.2% vs 5.9%). The time to recovery from lower chest wall indrawing and sternal retraction was longer in the placebo compared to zinc arm (24.4 vs 23.0 hours; P = 0.011 and 18.7 vs 11.0 hours; P = 0.006 respectively). The time to resolution for all respiratory symptoms of severity was not significantly different between placebo and zinc arms (42.3 vs 30.9 hours respectively; P = 0.242). In the six months follow-up sub-group, there was no significant difference in height gain, height-for-age and weight-for-height Z-scores, mid upper arm circumference, plasma zinc concentrations, and anergy at six months post-enrolment. CONCLUSIONS: In this population, zinc given as an adjunct treatment for severe pneumonia showed no benefit in treatment failure rates, or clinically important benefit in time to recovery from respiratory symptoms and showed marginal benefit in rapidity of resolution of some signs of severity. This finding does not support routine use of zinc as an adjunct treatment in severe pneumonia in generally zinc replete children. TRIAL REGISTRATION: ISRCTN33548493.

The exposure of infants and children to carbon monoxide from biomass fuels in The Gambia: a measurement and modeling study.

Smoke from biomass fuels is a risk factor for pneumonia, the leading cause of child death worldwide. Although particulate matter (PM) is the metric of choice for studying the health effects of biomass smoke, measuring children's PM exposure is difficult. Carbon monoxide (CO), which is easier to measure, can be used as a proxy for PM exposure. We measured the exposure of children ≤ 5 years of age in The Gambia to CO using small, passive, color stain diffusion tubes. We conducted multiple CO measurements on a subset of children to measure day-to-day exposure variability. Usual CO exposure was modeled using a mixed effects model, which also included individual and household level exposure predictors. Mean measured CO exposure for 1181 children (n=2263 measurements) was 1.04 ± 1.46 p.p.m., indicating that the Gambian children in this study on average have a relatively low CO exposure. However, 25% of children had exposures of 1.3 p.p.m. or higher. CO exposure was higher during the rainy months (1.33 ± 1.62 p.p.m.). Burning insect coils, using charcoal, and measurement done in the rainy season were associated with higher exposure. A parsimonious model with fuel, season, and other PM sources as covariates explained 39% of between-child variation in exposure and helped remove within-child variability.