COVID-19 is Less Frequent at High Altitude Under Hypobaric conditions: The South-American Experience

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As a cyclodextrin (SBECD) is used in one of the most potent drug formulation against Covid-19 the readers of the Cyclodextrin News blog are also supposed to be interested in not so closely cyclodextrin-related aspects of the present pandemic, such as effect of altitude.
Historical background: An early paper published in 1952 (Kalter SS, Tepperman J. Influenza virus proliferation in hypoxic mice. Science. 1952:621–2) reported on the observation that influenza virus infection was less pronounced in hypoxic mice (kept under high altitude, low barometric pressure) than in mice kept under sea level/normal air conditions. In 1955, another similar observation was communicated on the effect of acclimatization to altitude on the susceptibility of mice to influenza A virus infection. (Berry LJ, Mitchell RB, Rubenstein D Proc Soc Exp Biol Med. 1955;88:543–8). Authors found that mice acclimatized to a simulated altitude of about 6000 m above sea level for 3 weeks, were more resistant to artificially induced infection with the PR8 strain of influenza A virus, than normal control mice. Moreover, altitude-acclimatized mice maintained at simulated altitude for the postinfection period, remained significantly more resistant than those maintained at normal atmospheric pressures. There is some indication that these results may be due to a metabolic disturbance which accompanies adaptation to altitude as shown by a reduction in the citric acid content of lung tissue of these animals compared to that of normal mice which reduces the animal’s capacity for virus synthesis.  
High Altitude and COVID-19
A highly interesting paper was recently published by Peruvian scientists on their observation and experience with the frequency of occurrence of COVID-19 as a function of the actual sea level altitudes of Peruvian residents. This South-American country has 32 million inhabitants. Approximately 32% of the population live in mountain regions higher than 2500 m above sea level. However, Peru is located in the close proximity to the equator, and so the weather is not extremely cold: humans, animal and plant species can well survive at these heights in conditions of hypobaric hypoxia. According to popular belief in Peru, asthmatics should move to high altitudes because, they say, there is no asthma there. (Rijssenbeek-Nouwens LH, Bel EH. High-altitude treatment: a therapeutic option for patients with severe, refractory asthma? Clin Exp Allergy. 2011;41:775–82)
The first case of Peruvian COVID-19 was announced on March 7, 2020 and on March 15 the country went into lockdown to curb the pandemic. Altogether over 170 039 cases of COVID-19 have been confirmed by RT-PCR tests and IgM/IgG antibodies. An analysis of national data showed that the number of cases and deaths per 100 000 inhabitants decreased as the altitude of residence increased. Adjusting for sex and region size, the data show that for every 500 m increment in altitude, the rate of cases is reduced by 22% and deaths by 40%. It is important to note that 2600 m above sea, COVID-19 mortality is estimated at less than 1/100 000 inhabitants (P<.0001). This fraction is similar to figures published in Bolivia and Ecuador, which reported 3 to 4-fold lower infection rates at high altitudes than in the lowlands. (Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Aliaga-Raudan F, Carvajal-Rodriguez F, Dutschmann M, et al. Does the pathogenesis of SAR-CoV-2 virus decrease at high-altitude? Respir Physiol Neurobiol. 2020;277:103443.)
Suggested mechanism of the above observations:
Reduced number of ACE2 receptors: Authors suggest that the phenomenon standing behind their observation is related to the reduced number of ACE2 receptors in the respiratory system of people living in hypobaric environment, under reduced oxygen pressure. So, fewer ACE2 receptors would explain the lower incidence of COVID-19 in high-altitude populations, and also the lower mortality rate, because if fewer ACE2 receptors are circulating, the viral load received by infected subjects, an essential factor in the course of the disease, will be lower. (Chu CM, Poon LL, Cheng VC, Chan KS, Hung IF, Wong MM, et al. Initial viral load and the outcomes of SARS. CMAJ. 2004;171:1349–52.)
Increase of Erythropoietin level:
Another possible factor could be that hypobaric hypoxia increases production of erythropoietin (EPO), a multifunctional cytoprotective hormone, which decreases inflammation caused by septic shock and mitigates endotoxemic microvascular damage, which could also play a role in the lower COVID-19 mortality among patients living at high altitudes. (Stoyanoff TR, Rodríguez JP, Todaro JS, Colavita JP, Torres AM, Aguirre MV. Erythropoietin attenuates LPS-induced microvascular damage in a murine model of septic acute kidney injury. Biomed Pharmacother. 2018;107:1046–55.) The above observations could be further supported with similar study results based on the pandemic statistics on other high-altitude population, such as data from Himalayan, Tibetian etc. residents.  

For more detail, see: Accinelli RA, Leon-Abarca JA. En la altura la COVID-19 es menos frecuente: la experiencia del Perú. Arch Bronconeumol. 2020.    

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