key: cord-322417-9e95m4kz
authors: Segovia-Juarez, Jose; Castagnetto, Jesús M.; Gonzales, Gustavo F.
title: High altitude reduces infection rate of COVID-19 but not case-fatality rate
date: 2020-07-15
journal: Respir Physiol Neurobiol
DOI: 10.1016/j.resp.2020.103494
sha: 
doc_id: 322417
cord_uid: 9e95m4kz

Coronavirus disease 19 (COVID-19) is a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It is suggested that life at high altitude may reduce COVID infections and case-fatality rates (cases/deaths). We study data from Peru COVID-19 pandemics, which first case was recorded on March 6th, 2020. By June 13, 2020 there were 6498 deaths, and 224,132 SARS-CoV-2 positives. Using data from 185 capitals of provinces with altitudes ranging from 3 to 4342 m, we confirm previous reports that infection with COVID-19 at high altitude is reduced. However, case-fatality rate is not dependent of altitude. We have also presented first evidence that female protection towards death by COVID-19 is reduced as altitude of residence increases.

Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A recent paper with data as of April 7th from the Tibet, Bolivia and Ecuador suggests that high-altitude (HA) may provide protection from pathogenesis of SAR-CoV-2 infection (Arias-Reyes et al, 2020). A more recent paper with data from Cusco, Peru, concluded that the disease symptoms are not different in residents at high altitude (Huamani et al, 2020). By April 28, 2020 for Cusco, Peru (3414 m) was observed 0.5 % of case-fatality rate for the native population. This value is lower that the Peruvian case-fatality rate of 2.8 % (Huamani et al, 2020). Although, the figures may support the hypothesis that life in HA may provide some protection from severe COVID-19, it is necessary to be cautious before reach to a conclusion (Burtscher et al, 2020) . In fact, analysis of infection and mortality by COVID-19 in Peru shows a different scenario.

The current study has been designed to determine COVID-19 cases, deaths by COVID-19 and case-fatality rates in Peru in an altitude range from 3 to 4,342 meters above sea level.

The COVID-19 database of the Open Data website of Peru (https://www.datosabiertos.gob.pe/group/datos-abiertos-de-covid-19) obtained on June 14, 2020 was analyzed to study COVID-19 deaths, and positive to SARS-CoV-2.

Data of population and surface areas of provinces, and altitude of capital of provinces in Peru was obtained from the Peruvian Center for Planning CEPLAN website (https://www.ceplan.gob.pe/informacion-sobre-zonas-y-departamentos-del-peru/). These individual data seem to suggest that there is not a trend for reduced casefatality rate at HA.

We have observed that, the number of cases positive for COVID-19 appears to decrease with altitude of residence ( Figure 1A ). The same pattern is observed in males and females even after adjustment by population density ( Figure 1B and 1C). The sex ratio (male/female) for positive cases of COVID-19 is maintained at any altitude of residence ( Figure 1D ). This might mean that the same proportion of men related to females have risk of being infected with COVID-19 independent of the altitude of residence.

The numbers of deaths are significantly lower as altitude of residence increase. This is observed in both sexes assessed together or after analyzing men and women separately (Figures 2A-C) . The more interesting finding is that women loss protection J o u r n a l P r e -p r o o f against death for COVID-19 at HA ( Figure 2D ). In fact, as altitude of residence increase, more women die reducing the proportion of male/female deaths as altitude increases (p<0.01)

Another important finding from our study is that the cumulative case-fatality rate (cumulative deaths/cumulative positive cases) by COVID-19 does not appear to change with altitude of residence ( Figure 3 ). This does not support the suggestion that people from the highlands might be protected from death after COVID-19 infection. This is significant since our analysis includes a broad range of altitudes (from 3 to 4,342 meters). According to the data source, the positive cases have been determined by PCR or antibody tests, and the data has been adjusted by demographic density where appropriate. Individuals may be exceedingly susceptible to COVID-19 due to concomitant high preexisting ACE2 expression and low baseline cytotoxic lymphocyte levels in the lung (Duijf, 2020) . This may occur at older than in younger ages and in males than in females, and at low than at high altitudes. The strength of the study is that includes cases and deaths occurred from a range of altitudes between 3 and 4,342 m.

One limitation of the study is that according to the classification proposed by Siddiqi and Mehra (2020) "patients with clear symptoms" represent mainly severe patients (phase II) and critically ill patients (phase III), while they are asymptomatic and mildly ill (oligosymptomatic -phase I) are mostly not reported. Then, it is not possible to conclude about severity and progression of COVID-19 based only in the study of case fatality rates. Other factors may affect the relation between the case fatality rate and the actual infection fatality rate for a specific population.

We confirm previous reports that infection with COVID-19 at HA is reduced. However, case-fatality rate was not modified by altitude. We have presented first evidence that female protection towards death by COVID-19 is reduced as altitude of residence increases.

Jose Segovia-Juarez: Methodology, Data curation, Writing and Editing. Jesus Castagnetto : Software, Visualization. Gustavo F. Gonzales: Conception, Writing-Original draft preparation, Validation, Supervision.

The authors declare that they have no conflict of interest.

J o u r n a l P r e -p r o o f

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Baseline pulmonary levels of CD8+ T cells and NK cells inversely correlate with expression of the SARS-CoV-2 entry receptor ACE2

COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2

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Vitamin D Levels and Cardiometabolic Markers in Indigenous Argentinean Children Living at Different Altitudes. Glob Pediatr Health. 6:2333794X18821942. Published

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The association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with adaptation to high altitude: A Legend of Figures Figure 1. Number of Cases (Log Positive counts/population density) according to altitude (meters) of residence in Peru: (A) All positive cases, (B) Male cases