The Association Between Hypoxemia and Mortality in Children With Lower Respiratory Infections in Low- and Middle-income Countries: Updated Systematic Review and Meta-analysis

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Abstract RATIONALE: Lower respiratory infections (LRIs), including pneumonia, with low blood oxygen levels (hypoxemia) are a leading cause of death in children globally, with the highest pediatric hypoxemia burden in low- and middle-income countries (LMICs). World Health Organization Integrated Management of Childhood Illnesses (IMCI) guidelines used in LMICs recommend hospitalization for children with hypoxemia, defined as an arterial oxyhemoglobin saturation (SpO2) <90%. While a SpO2<90% is associated with mortality, higher hypoxemia thresholds (e.g., SpO2<94%), also have mortality associations. This systematic review and meta-analysis aimed to estimate the association between hypoxemia and mortality in children with LRI in LMICs and evaluate LRI mortality risk using different hypoxemia thresholds. METHODS: To update a systematic review and meta-analysis of literature through 2015, we searched databases (MEDLINE, Embase, LILACS, Global Index Medicus, Web of Science, Scopus) for peer-reviewed research from January 2015 to August 2023. We included observational studies from LMICs reporting the association between hypoxemia and death in children under five years with LRI. The Quality in Prognosis Studies (QUIPS) tool, with minor adaptations, assessed study quality. Two reviewers independently conducted title and abstract screening, full text review, data extraction, and quality assessment. Included studies were pooled with those from the prior meta-analysis. Potential bias and small study effects were evaluated using funnel plots, Begg and Egger tests, and leave-one-out analysis. We used restricted maximum likelihood random effects models to estimate pooled odds ratios by pre-defined hypoxemia subgroups using the inverse-weighting method. RESULTS: 5,489 unique records were identified; 16 new studies met inclusion criteria and contributed data to the meta-analysis. Combined with 16 studies from the prior meta-analysis, data from 45,975 participants from 32 studies were included. Studies were published between 1993-2023 and most were from Africa (17/32, 51.1%) and South Asia (12/32, 37.5%). Hypoxemia of any definition was associated with a 5.35-fold (95% confidence interval (CI) 4.27-6.70) higher odds of LRI death than those without hypoxemia. The OR of LRI death for a SpO2<90%, compared to 90%-100%, was 6.11 (95% CI 4.42-8.44), and for <95%, versus 95%-100%, was 4.22 (95% CI 3.14-5.66). When restricted to SpO2 90-94%, versus 95%-100%, the OR of LRI death remained elevated (2.81(95% CI 1.77-4.46)). CONCLUSIONS: Hypoxemia is strongly associated with LRI death in children in LMICs. Alternative hypoxemia thresholds with a SpO2 above 90% also have an elevated LRI mortality risk and should be carefully considered for inclusion in LRI care management algorithms for children in LMICs.

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