key: cord-1042711-1x00nxo8
authors: Martínez-Briseño, David; Pérez-Padilla, Rogelio; Fernández-Plata, Rosario; Castillejos-López, Manuel; Higuera-Iglesias, Anjarath Lorena
title: El impacto de la altitud en las tasas de mortalidad por COVID-19 en México
date: 2022-04-22
journal: Arch Bronconeumol
DOI: 10.1016/j.arbres.2022.03.022
sha: 476484cdb3b41ce24eab1b49066aea948e0109f2
doc_id: 1042711
cord_uid: 1x00nxo8

nan

Rosario Fernández-Plata, rosferpla@gmail.com; rosario.fernandez@iner.gob.mx and Rogelio PérezPadilla, perezpad@gmail.com; perezpad@iner.gob.mx National Institute of Respiratory Diseases "Ismael Cosío Villegas", Tlalpan 4502, Mexico City, 14080, Mexico Different studies have described a positive association between altitude and mortality from respiratory diseases. 1,2 However the impact of altitude on mortality from COVID-19 has shown opposite results, as the altitude could be protective or a risk factor for mortality. 3-5 On one side, SARS-Cov-2 interacts with human Angiotensin Converting Enzyme Receptor 2 (ACE2) 6 expressing more in adults, in men and at low altitudes, and then it has been hypothesized that Covid-19 mortality could be reduced at higher altitudes. 7-9 On the other hand, hypoxemia caused by lung diseases is expected to be more severe at higher altitudes, especially in those that have a sudden onset and therefore have a short period of time for adaptation. Hypoxemia is considered a risk factor for mortality in patients with COVID-19. 10 We carried out an exploratory ecological study to evaluate the association between altitude and mortality from COVID-19, taking socioeconomic and demographic factors into account.

Mexico is divided into 32 states and 2,468 municipalities but we only analyzed 1,926, those with at least one COVID-19 death. We utilized public information from the COVID-19 database of the Ministry of Health of Mexico and collected data at the municipal level on confirmed deaths by PCR or antigen test, the number of persons with diabetes mellitus, chronic obstructive pulmonary disease (COPD), asthma, high blood pressure, cardiovascular disease, obesity, chronic kidney disease, pneumonia and smoking status, and the average number of tests (PCR or antigen) per person from March to December 2020. 11 The frequency of deaths, comorbidities and tests per person were computed by age (5-year age groups) and stratified by gender. We also collected for each municipality, information on midyear population for 2020 12 , population density (population/km 2 ) 13 , whether the municipality is a metropolitan zone 12 , the altitude in meters above sea level divided into six 500-meter categories 14 , and two composite indicators of socioeconomic status: human development index 15 (HDI) with four categories, and marginalization level 12 (ML) with five categories. The reference categories were those with the worst socioeconomic status.

The relation between altitude and mortality from COVID-19 was evaluated by Poisson regression models stratified by gender and adjusted by age, socioeconomic status (HDI or ML), population density, the average number of tests (PCR or antigen) per individual, state of residence and if the residence was in a metropolitan area, the number of people with diabetes mellitus, chronic obstructive pulmonary disease (COPD), asthma, hypertension disease, cardiovascular disease, obesity, chronic kidney disease, pneumonia and smoking. We included municipal population as offset term in each model. Data were analyzed with Stata software version 12.

Municipalities located at <500 m and [1500-2000 m) registered the highest proportions of cases, 19.5% and 22.3%, respectively. Table S1 describes the population characteristics by altitude in the supplementary material. The cases confirmed by PCR or antigen test were 1,431,541 with 9% of deaths. Crude mortality rates per 100,000 population were estimated by altitude, and no pattern was found in women or men (tables S2 and S3). Details on mortality rates by age Page 4 of 10 J o u r n a l P r e -p r o o f 4 (tables S4 and S5) and comorbidities distribution by altitude could be found in the supplemental material (tables S6-S11).

Poisson models (Table 1) depict that the risk of death was increased between 9.6% and 14.2% in women living at 2,500 m compared to those living at <500 m.

In models adjusted by HDI, the risk of death in men was increased 8.9% and 23.8% when living at (2,000-2,500 m) and 2,500 m respectively. The risk of death was 19.3% higher in men living at 2,500 m if adjusted by ML. On the other hand, chronic exposure to moderate or high altitudes may enhance adaptive features in the lungs at the organ and cellular level, as well as modulation of ACE2 protein expression in the lung cell membrane 6 and be a protective factor for both COVID-19 incidence and mortality due to a multisystemic adaptation process to hypoxia. 4, 5 Studies carried out in Peru and Colombia reported that altitude is a protective factor for the risk of death from COVID-19. 4,5 In the Peruvian study, the mortality comparisons were made for areas at different altitudes matched by population density adjusting for only one confounder at a time. Thus, the reported relative risk (RR) could be different if multiple adjustment had been made. In Colombia, multiple linear regression models including population density and altitude were fitted for the number of deaths and fatality rate but it was not clear if altitude was or not a risk for death. Our study incorporated adjustment by confounding factors such as population density, clinical conditions, and belonging to a metropolitan area, which were not considered in a previous study performed in Mexico but which nevertheless also concluded that altitude could be a risk factor for COVID-19 mortality. 3

The main limitation of our study is the ecological design, and therefore the results may not apply at the individual level. In addition, we did not consider confounding factors that may modify the relationship between altitude and mortality from COVID-19 such as silent hypoxemia, health care resources and availability of services, climate, and air pollution. 18-20 Additionally, in Mexico firewood is still used as a source of energy to cook food, especially in rural areas, and inhalation of wood smoke is associated with impaired pulmonary function 21 ; this factor was also not considered.

In conclusion, after adjusting by several confusion factors, our results suggest that above 2,000 m in men and above 2,500 m in women, the risk of mortality increases between 8.9% and 23.8% compared to residents living at <500 m above sea level.

However, these results should be considered with caution and individual studies are recommended to confirm these findings. 

High-altitude pulmonary edema

Hypoxic induction of interleukin-8 gene 45 expression in human endothelial cells

COVID-19 with silent hypoxemia

Temperature, Humidity, and Latitude 49 Analysis to Estimate Potential Spread and Seasonality of Coronavirus Disease 2019 50 (COVID-19)

Exposure to air pollution and 52 COVID-19 mortality in the United States: A nationwide cross-sectional study

* Mortality rates were estimated using Poisson models, which were adjusted by: age, population density, number of test 66 (PRC or antigen) per individual, metropolitan zone, state of residence, the number of people with diabetes mellitus, chronic 67 obstructive pulmonary disease (COPD), asthma, hypertension disease, cardiovascular disease, obesity, chronic kidney 68 disease

HDI: Human Development Index 70 ML: Marginalization level