The research team, led by Franko O. Garcia-Solorzano and colleagues, registered their protocol in advance on PROSPERO and followed the PRISMA reporting guidelines, searching PubMed, Scopus, Embase, Web of Science and SciELO through August 2023. From 2,157 records initially recovered, the authors winnowed the literature down to 17 studies, most of which examined the 2020 to 2021 period of the pandemic. To qualify for inclusion, a study had to compare COVID-19 mortality rates or case fatality rates between high and low altitude populations, with the high-altitude category defined as above 1,500 meters above sea level. The included work fell into two broad types: thirteen population-based ecological studies, which compared aggregate death statistics across provinces, counties or states, and four individual-based cohort studies, which followed hospitalized patients at institutions located at different elevations. More than half of the studies, 58.8 percent, were conducted in Peru or Ecuador, two countries whose dramatic altitudinal gradients make them natural laboratories for this kind of research.

The methodological toolkit of the meta-analysis was deliberately conservative. For studies treating altitude as a dichotomous variable, the authors extracted risk ratios comparing the highest and lowest altitudes reported, along with 95 percent confidence intervals. For studies treating altitude continuously, they collected beta coefficients expressing the change in mortality per 100 meters of elevation, standardizing coefficients when the original studies used different units. All pooling was performed with random-effects models using the DerSimonian-Laird estimator, an appropriate choice given the expected heterogeneity across study sites, populations and outcome definitions. Risk of bias was assessed with the Joanna Briggs Institute critical appraisal tools, and the certainty of the pooled findings was graded using the GRADE framework, which starts observational evidence at a low baseline and can downgrade it further for bias and inconsistency.

That grading proved consequential. Every ecological study in the review carried a moderate or high risk of bias, with recurring failures to specify which COVID-19 diagnostic tests were used, a serious omission given the poor quality of many early-pandemic assays, and to control for confounders in their statistical models. Among the cohort studies, three of four had moderate risk of bias and one was rated high, with all studies showing substantial residual confounding despite identifying potential confounders. This pattern matters because ecological designs, which compare populations rather than individuals, are intrinsically limited in their ability to disentangle altitude from correlated factors such as access to health services, socioeconomic status and the quality of clinical management, and their results cannot be validly interpreted at the individual level.

The headline findings split by population type. In the primary meta-analysis of population-based studies, high altitude showed no statistically significant association with the mortality rate, the number of COVID-19 deaths per 100,000 inhabitants, with a pooled relative risk of 0.63 and a confidence interval spanning from 0.35 to 1.15. When altitude was analyzed as a continuous variable, each 100-meter increase in elevation was associated with a beta coefficient of 0.03, with a confidence interval from negative 0.62 to 0.67, again indicating no detectable gradient. The case fatality rate in the general population likewise showed no significant difference between high and low elevations, with a pooled relative risk of 1.10. However, in a sensitivity analysis that excluded the studies judged to be at high risk of bias, a different picture emerged: living at high altitude was associated with a 51 percent reduction in the mortality rate compared with low altitude, a relative risk of 0.49 with a confidence interval of 0.30 to 0.80.

The individual-based evidence told a more consistent story. Pooling the four cohort studies of hospitalized patients, the authors found that COVID-19 patients treated at high altitude had a 29 percent lower risk of death than those treated at lower elevations, with a relative risk of 0.71 and a confidence interval of 0.52 to 0.98. This result held up when the single high-risk study was excluded, with the protective association strengthening to a 33 percent reduction, relative risk 0.67, confidence interval 0.59 to 0.75. Notably, the protective effect was smaller among patients admitted to intensive care units than among hospitalized patients overall, a pattern the authors attribute to the severity of hypoxemia and the inherently elevated baseline mortality in critically ill populations, which may overwhelm any physiological advantage conferred by altitude acclimatization.

What biological mechanisms could underlie such a protective effect? The authors point to the suite of adaptations that high-altitude residents develop through chronic exposure to hypoxia, including increased ventilatory drive, higher hematocrit values, enhanced oxygen delivery at the tissue level and metabolic adjustments that improve tolerance to low oxygen availability. These adaptations could, in principle, blunt the hypoxemia produced by SARS-CoV-2 infection. A second, more molecular hypothesis involves angiotensin-converting enzyme 2, the receptor the virus uses to enter host cells. Chronic hypoxia states are associated with downregulation of ACE2 in the pulmonary epithelium, and infection rates have been correlated with the level of ACE2 expression, offering a plausible route by which altitude could reduce susceptibility. Environmental factors may contribute as well: higher ultraviolet radiation at elevation can inactivate virus, and colder temperatures may reduce the social interactions that drive transmission.

The review also flags important nuances and gaps. Some studies suggest that any protective effect may diminish above roughly 3,500 to 4,000 meters, possibly because chronic mountain illness offsets the benefits of acclimatization, and the authors caution that altitude gradients are difficult to study because each elevation band may carry its own distinct local factors, a point captured in the ecologist Christian Körner’s observation that there is no standard mountain. The heterogeneity of altitude cut-offs across studies, ranging from below 500 meters to 4,000 meters or more, further complicates comparison. The authors also note that no study has yet examined whether altitude modifies the immunological response to COVID-19 vaccination, and that ecological studies generally failed to specify how long their populations had actually lived at the altitudes recorded. A related line of evidence, meanwhile, suggests altitude may influence the proportion of asymptomatic infections, which would distort case fatality comparisons by changing the denominator of detected cases.

The GRADE assessment delivered the sobering bottom line: every outcome in the review, from population mortality rates to hospitalized case fatality, was rated as very low certainty, downgraded for risk of bias and for heterogeneity exceeding 80 percent in the pooled analyses. The authors are candid that residual confounding is almost unavoidable when comparing populations at different elevations, since altitude is inseparable from geography, climate, ethnicity, income and health system capacity. Their conclusion is measured rather than triumphant: the primary analysis suggests high altitude makes little to no difference in COVID-19 mortality in the general population, while the sensitivity analyses hint at a protective effect that remains very uncertain. What the review does establish is a roadmap for future work, calling for studies with standardized altitude definitions, rigorous confounder control and consistent outcome reporting. With hundreds of millions of people living above 1,500 meters worldwide, and with several respiratory viruses remaining on the list of pandemic threats, clarifying how elevation shapes infection outcomes is far more than an academic curiosity.

Subject of Research: The effect of high-altitude residence on COVID-19 mortality and case fatality rates

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

Article References: Garcia-Solorzano, F. O., Ortiz-Abanto, Y., Pachacama, L. F., Solis-Facho, G. V., & Taype-Rondan, A. (2026). Effect of altitude on COVID-19 mortality: A systematic review and meta-analysis. Heliyon, 12(15), Article e45528. https://doi.org/10.1016/j.heliyon.2026.e45528

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45528

Keywords: COVID-19, altitude, mortality, meta-analysis, systematic review, hypoxia, ACE2, epidemiology, Peru, Ecuador, case fatality rate, GRADE