Lower Incidence of COVID-19 at High Altitude: Facts and Confounders

Hypoxia

The unique exposure for high altitude residents is that of chronic hypobaric hypoxia, which evokes many immediate and sustained compensations to increase tissue oxygen delivery and enhance oxygen utilization by both nongenomic and genomic mechanisms. Thus it can be argued that high-altitude residents may be somewhat tolerant to the consequences of more hypoxemia and systemic tissue hypoxia developing as a result of COVID-19 infection and subsequent lung injury. However, because high-altitude residents already have lower baseline arterial oxygenation than sea level residents, it could make their disease-related hypoxemia worse for any given degree of developing lung dysfunction despite any preexisting adaptations to hypoxia. Although impossible to test in humans, cell and tissue culture techniques or animal models mimicking clinically relevant COVID-19 could be used to test this hypothesis.

One aspect of high-altitude hypoxia with particular relevance to COVID-19 is possible hypoxia-mediated differences in tissue expression of ACE-2 that could afford protection against the virus in people living in mountainous areas. SARS-CoV-2 entry into human cells is through binding of its exterior spike protein to ACE-2 and subsequent internalization to access cell machinery for its replication (Lu et al., 2020; Zhou et al., 2020). ACE-2 is widely present in many human organs (Baig et al., 2020) with particularly high expression in the upper and lower respiratory tract epithelia, vascular endothelium, myocardium, renal tubules, gastrointestinal tract epithelium, testes, and central nervous system. This expression helps to explain the particular morbidity of COVID-19 including acute respiratory distress syndrome, coagulopathy and thromboembolism, myocarditis, acute kidney injury, diarrhea, anosmia, encephalitis, and orchitis (Cardona Maya et al., 2020; Menni et al., 2020; Wadman et al., 2020).

The pathophysiological rationale to quantitatively link the expression level of ACE-2 to differences in viral susceptibility, symptomology, and outcomes in those infected with SARS-CoV-2 at high altitude was suggested by Arias-Reyes et al. (2020). These authors proposed that SARS-CoV-2 may be less virulent at high altitude owing to hypoxia-induced downregulation of ACE-2 expression providing fewer receptors for the virus, but data supporting this contention are not consistent or convincing. Zhang et al. (2009) reported a blunted expression of ACE-2 in cell lines exposed to severe hypoxia (2% oxygen) over 12 days. A similar observation was made by Dang et al. (2020) when rats were exposed to the hypoxia equivalent of ∼4500 m altitude over 45 days.

However, other studies in different models have reported that hypoxia upregulates ACE-2. Oarhe et al. (2015) found that hypoxia (1%) in fetal lung fibroblasts increased ACE-2 expression by twofold (Oarhe et al., 2015). Hampl et al. (2015) showed that rats exposed to 10% oxygen for 2 weeks had a doubling of lung tissue ACE-2 content (Hampl et al., 2015). Joshi et al. (2019) demonstrated that human hematopoietic stem cells respond to 1% oxygen with an increase in mRNA and ACE-2 protein (Joshi et al., 2019). Most importantly, it needs to be emphasized that there are currently no human or animal data characterizing ACE-2 expression during hypoxic conditions along the epithelium of the upper and lower respiratory tracts, where the virus first infects humans through inhalation. Furthermore, any such experimental observations on hypoxia exposure may not be relevant to genetically adapted high-altitude populations such as Tibetans, Sherpas, Andeans, Ethiopian highlanders, or those not of these ethnic groups, who were born and raised at high altitude. Thus far, there are no published data that genetically or highly adapted high-altitude residents have downregulated ACE-2 expression. With multiple variants of the ACE-2 gene found by single nucleotide polymorphism analysis present across the world (Cao et al., 2020), high-altitude populations might conceivably have protective variants. Such information may become available with completion of the COVID-19 Host Genetics Initiative (Ganna, 2020) now underway.

Any direct association of altitude and possible differences in ACE-2 expression may oversimplify a very complex interaction. First, it is well established that ACE-2 is a key element of the renin–angiotensin system (RAS) promoting vasodilation and maintenance of normal capillary integrity and affording cytoprotective anti-inflammatory, antioxidative, and antithrombotic actions in the lungs and other organs (Kuba et al., 2005). ACE-2 acts by catalyzing the formation of angiotensin 1–7, which opposes the opposite actions of angiotensin II (Xie et al., 2006; Lakatta, 2018), particularly in severe acute lung disease such as that present in patients with COVID-19. Second, it remains unclear whether any modest differences in ACE-2 expression, which depend on circumstances such as age (Bunyavanich et al., 2020), host genetics (Ghafouri-Fard et al., 2020), smoking status (Berlin et al., 2020; Zhang et al., 2020), air pollution (Aztatzi-Aguilar et al., 2015; Frontera et al., 2020), and drugs affecting the RAS (Gao et al., 2020; Vaduganathan et al., 2020), translate into differing degrees of susceptibility to SARS-CoV-2 infection. Indeed, regardless of the inference that individuals with reduced ACE-2 expression may be less susceptible to severe infection, there appears to be a paradoxical relationship between virally mediated membranous ACE-2 downregulation and a predisposition to suffer more severe forms of COVID-19 lung injury, perhaps related to decreased angiotensin 1–7 production (Zambelli et al., 2015; Cheng et al., 2020; Peiró and Moncada, 2020).

Thus, the potential positive or negative impact of ACE-2 upregulation or downregulation in COVID-19 pathogenesis and differing expression levels among populations should be critically examined, as currently there is no definitive clinical evidence in humans. The best evidence against any pertinent disease modifying effect of differences in ACE-2 expression relates to the widespread use of angiotensin receptor blockers and ACE inhibitors. Therapeutic use of these drugs, while having been reported in some studies, but not all, to increase ACE-2 expression has led to fear regarding their continued usage during the pandemic (Bavishi et al., 2020; Patel and Verma, 2020). The concern is unjustified because their administration does not appear to cause any increased risk for COVID-19 in patients on these medications for their intended use in heart disease, hypertension, diabetes, and chronic kidney disease (Amat-Santos et al., 2020; Khera et al., 2020).

Other environmental factors

The high-altitude environment has higher ultraviolet (UV) radiation and is generally drier and colder. Atmospheric measurements suggest that the general distribution of UV energy below the ozone layer is 3%–5% of total sunlight energy in the <400 nm wavelength range. Of this UV radiation ∼95% is UV-A (wavelength: 315–400 nm), 5% is UV-B (280–315 nm), and 0% is in the germicidal UV-C (200–280 nm). Because a UV wavelength of 254 nm is most cidal for SARS-CoV-2 and other viruses (Sangripanti and Lytle, 2020), it would be predicted that sunlight should not cause significant UV inactivation of SARS-CoV-2. Arguably, there might be some impact of the lesser killing efficiency of higher UV-B wavelengths in sunlight, particularly if the amount of UV-B at higher altitudes is greater than at sea level. Another benefit of greater UV radiation at high altitude will be possibly higher vitamin D levels, which afford protection against several other viral and bacterial infections by T cell enhancement (Grant et al., 2020). Thus, UV radiation might, theoretically, contribute to slowing the spread of the virus as some groups have suggested (Cadnum et al., 2020; Hamzavi et al., 2020; Keil et al., 2020), but this needs to be examined carefully. However, any action of UV radiation will only be relevant to the outdoor environment and most viral transmission occurs indoors, where people congregate in closer quarters and spend many hours of the day.

The lower water content and humidity present at high altitudes may hasten viral desiccation and inactivation as a possible benefit. Conversely, the generally colder temperatures at high altitude, which decline by ∼0.6°C/100 m, may increase COVID-19 risk. The incidence of COVID-19 reportedly declined with increasing temperature in the United States (Sehra et al., 2020) and China (Shi et al., 2020). The reported peak incidence of SARS-CoV-2 in a range of 5°C–15°C with humidity range of 3–10 g/m³ further highlights the niche of higher viral infection rates (Huang et al., 2020). However, a consensus is yet to be reached on this topic, because a further analysis incorporating meteorological data from different Chinese cities found that both temperature and UV radiation were not significantly associated with viral transmission (Yao et al., 2020).

Air pollution may be a factor in greater susceptibility to the virus (Brandt et al., 2020; Fattorini and Regoli, 2020) and in general many mountainous areas have less pollution related to industry and automobiles. However, this may be countered by biomass burning for heating and cooking, which can make the indoor environmental conditions problematic along with outdoor air quality in valley regions prone to meteorological inversions (Thakur et al., 2020). Personal pollution exposure in the form of tobacco smoking may be a risk factor for greater COVID-19 rates (Alqahtani et al., 2020; Engin et al., 2020), but this has not been found in all studies (Rossato et al., 2020). Smoking increases airway epithelium expression of ACE-2 (Leung et al., 2020; Zhang et al., 2020) and this may be further driven independently by airway nicotine exposure (Russo et al., 2020).