Results from the ANOVA regional analysis clearly indicated a difference between incidence, case-fatality, and mortality rates. Amazónica had the highest incidence yet the lowest case-fatality and mortality rates. Compared to the other regions, Amazónica had the highest poverty level and proportion of males which are believed to be positively associated with higher COVID-19 morbidity and mortality (31, 32) and lowest population density, which is associated with lower incidence (31), potentially contradicting our observations. The high incidence rate in the Amazónica region may be explained by case misclassification with reports showing concern for potential dengue cases being diagnosed as COVID-19 (33). Specifically in Ecuador, dengue misclassification and underreporting is a current concern during the COVID-19 pandemic (34). This could explain the significantly higher incidence rate in the Amazónica, yet lowest morality statistics. Furthermore, it is well known due to the lack of sufficient health care facilities in the Amazónica, most morbidity indicators are underreported. Conversely, the Costa region held the lowest incidence rate and highest case-fatality and mortality rate. Although the Costa region’s mortality rate was not statistically different than the Sierra region, the case-fatality rate was significantly higher. Since case-fatality rate is an indicator based on the number of deaths and the number of cases, not taking into account the population, it is important to acknowledge the differences in the number of case deaths varying from region to region. The high CFR in the Costa region may be due to a higher population density than both other regions. However, one of the strongest risk factors found in the literature for COVID-19 mortality, advanced age (2, 32), was significantly the highest in the Sierra region. This could indicate not only altitude differences but also resource-oriented healthcare factors which could explain the higher mortality statistics in the Costa region (35, 36).
In both the correlation analysis and the linear model, altitude was a protective factor against COVID-19 mortality. Based on standardized estimates, altitude was the factor with the highest effect on mortality rates followed by population density and identifying as White. The rest of the covariates in the model were not statistically significant nor had large effect on mortality rate. While, race (Other) was statistically significant in the correlation analysis, the proportion of the population identifying as “Other” was too small to be clinically relevant. White race fit the model best and therefore included in the model. Deemed COVID-19 risk factors, the covariates lack of significance may be due to lack of statistical power.
Several hypotheses have been proposed as possible explanations for the protective nature of altitude. One hypothesis focuses on the effects of chronic hypoxia in high altitude environments (37). Specifically, examining the effects of chronic hypoxia on Angiotensin-converting enzyme 2 (ACE2), the enzyme SARS-CoV-2 binds to enter host cells. Under conditions of chronic hypoxia, Angiotensin-converting enzyme 1 (ACE1) is upregulated by Hypoxia inducible factor 1 (HIF-1) in human pulmonary artery smooth muscle cells shifting the balance of the oxygen sensitive renin–angiotensin system (RAS) away from the vasodilator ACE2 and towards the vasoconstrictor ACE1. This process markedly decreases ACE2 expression in the pulmonary artery smooth muscle cells (17, 18). Due to SARS-CoV-2 utilization of the ACE2 receptor for cellular entry, it is hypothesized populations living in constant hypoxia may be less susceptible to SARS-CoV-2 infection. Additionally, HIF-1, activated in chronic hypoxia, may ameliorate a COVID-19 infection (38). In addition to biological mechanisms that may be affected by living in higher altitudes, environmental factors are also theorized reasons for the observed negative correlation between altitude and COVID-19 mortality. A possible explanation of decreased SARS-CoV-2 infection rates in populations at high elevation is a higher level of O3 (ozone). Considered a disinfecting agent, ozone disrupts the reproductive cycle via peroxidation, affecting virus-to-cell contact and damaging the viral capsid (15, 39). Further suggesting the potential impact ozone may have on SARS-CoV-2 transmission, one study, conducted from January to March 2020, showed a statistically significant negative correlation between ambient average ozone levels and number of confirmed cases (40). Lastly, another common element found in high altitudes an increase of ultraviolet (UV) radiation. UV radiation was found to effectively eliminate SARS-CoV (41), suggesting a similar effect for SARS-CoV-2. However, studies on this hypothesis are limited and a recent study found no association between UV radiation and COVID-19 cases (42). In addition to the sterilization effect of UV radiation, UV radiation’s effect on Vitamin D production is also an area of interest. Vitamin D is theorized to help maintain a healthy immune system and its deficiency is associated with increased risk of respiratory infectious diseases (43–46). This is further supported by recent studies examining finding a protective effect of Vitamin D3 against COVID-19 (47, 48). Lastly, there may be behavioral factors affecting the relationship between COVID-19 mortality and altitude. Numerous other socioeconomic and lifestyle factors could explain the differences seen in regard to the infectivity and mortality in high altitude populations. A recent publication cautioned the researchers against associating altitude to decreased COVID-19 pathogenicity based solely on altitude arguing factors such as population density, access to commodities, clinical care, and ability to “social distance” may all be contributing to the observed reduced pathogenicity (49). Health benefits of communities living in high altitude is not new knowledge, with high altitude associated with higher levels of physical activity, lower rates of obesity, cardiovascular disease, and cancer (50–52).
Limitations in the study mainly include lack of access to smaller unit-sized data and individual data. This study is an ecological study, focusing on province-level data, and should be noted that there may be individual cities that may be influential or leveraging the results. Regardless, of the limitations, altitude was significantly protective against COVID-19 mortality rate in both the correlation analysis and final model.