Effect of altitude on COVID-19 mortality: A systematic review and meta-analysis

Background The global outbreak due to COVID-19 pandemic was one of the deadliest in history. While many risk factors were identified for COVID-19, the impact of environmental factors, such as high altitude, remains unclear. We aimed to assess the effect of high altitude on COVID-19 mortality. Methodology We conducted a systematic review in Web of Science, Scopus, PubMed, Embase, and SciELO, using terms related to COVID-19 and altitude. Epidemiological studies comparing mortality rate (MR) and case fatality rate (CFR) in high and low altitude sites were included. We performed a random model meta-analysis for each outcome. GRADE methodology for grading the level of certainty of our results was used. Results Out of 2157 records identified, 1132 were screened after duplicate removal, 43 full texts were assessed for eligibility, and 17 studies were included. The primary meta-analysis of ecological studies in the general population showed no significant difference in the MR of COVID-19 between high- and low-altitude populations (RR: 0.63, 95% CI: 0.35-1.15). However, after excluding studies at high risk of bias, the sensitivity analysis showed that high altitude may be a protective factor for the MR of COVID-19 (RR: 0.49, 95% CI: 0.30-0.80), while it may have no effect on the CFR of COVID-19. Furthermore, the primary meta-analysis of cohort studies in the hospitalized population revealed that high altitude may be associated with a lower CFR (RR: 0.71, 95% CI: 0.52-0.98). However, the level of certainty for all the results remains very uncertain. Conclusion The available evidence suggests that high altitude may result in little to no difference in COVID-19 mortality in the general population. Although a possible protective association was observed in hospitalized population, the overall certainty remains very low because of residual confounding and substantial heterogeneity. Future well-designed studies with standardized altitude definitions, rigorous control of confounding, and consistent outcome reporting are needed to better inform preparedness for future respiratory pandemics and geographically tailored health strategies.