Geographic components of SARS-CoV-2 expansion: a hypothesis
JAppl Physiol 129: 257-262, 2020. doi:10.1152/japplphysiol.00362.2020.
Kelsey E. Joyce,1 kej764 at student.bham.ac.uk). Samuel R. Weaver,1 and Samuel J. E. Lucas1
1 School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom
Submitted 8 May 2020; accepted in final form 16 July 2020
Possible Reasons include
- UVB ==> Vitamin D ==> stronger immune system
- UVB inhibit viral reporduction
- Less air polution (thus more UVB)
- Lungs used to working harder (less Oxygen)
- Healthier people (perhaps due to increased Vitamin D)
- Less ACE-2
- Under reporting
VitaminDWiki Items in both categories UV and Virus are listed here:
- UV provides the best explanation of COVID-19 variation in Italy (74 pcnt) – Nov 2020
- More UVB, less Coronavirus – including SARS-CoV-2 – Aug 2020
- Less COVID-19 at high altitude due to more Vitamin D or other possible reasons – July 2020
- Far fewer COVID-19 deaths in the summer (Europe, Canada)
- High-altitude Cusco, Peru has far lower rate of COVID-19 than others (high UVB and Vitamin D) - June 2020
- Influenza Virus aerosols killed by 10 minutes of sunlight (far faster if use UV-C) – Nov 2019
- Influenza Virus aerosols killed by 10 minutes of sunlight (faster if use UVB, UVCC– Nov 2019
- Ultraviolet light kills cold and flu viruses, and generates Vitamin D in the skin
- Cities at high altitude (Peru) have far less COVID-19 infection Aug 14, preprint FREE PDF
- Increased UVB and Vitamin D at high altitude are not even mentioned as possible mechanisms
- See on VitaminDWiki High-altitude Cusco, Peru has far lower rate of COVID-19 than others (high UVB and Vitamin D) - June 2020
- Does COVID-19 have a fear of hights? -(or just a fear of the increased VItamin D generated at high altitudes) WP May 31
- Cusco Peru (11,000 feet) - Vitamin D is not mentioned. yet there may be 50% more UVB-generated Vitamin D at that altiude
- "In one peer-reviewed study, published in the journal Respiratory Physiology & Neurobiology, researchers from Australia, Bolivia, Canada and Switzerland looking at epidemiological data from Bolivia, Ecuador and Tibet found populations living above 3,000 meters (9,842 feet) reported significantly lower levels of confirmed infections than their lowland counterparts"
- Hypothesis: Colorado has the best UV (and thus best health) in the US
- Decreased mortality with sun and or altitude
- 40 percent less likely to gain weight if live at high altitude (no mention of UVB nor vitamin D) – April 2014
- High-altitude sheep had higher levels of vitamin D and better bones – Feb 2013
The emergence of COVID-19 infection (caused by the SARS-CoV-2 virus) in Wuhan, China in the latter part of 2019 has, within a relatively short time, led to a global pandemic. Amidst the initial spread of SARS-CoV-2 across Asia, an epidemiologic trend emerged in relation to high altitude (HA) populations. Compared with the rest of Asia, SARS-CoV-2 exhibited attenuated rates of expansion with limited COVID-19 infection severity along the Tibetan plateau. These characteristics were soon evident in additional HA regions across Bolivia, central Ecuador, Nepal, Bhutan, and the Sichuan province of mainland China. This mini-review presents a discussion surrounding attributes of the HA environment, aspects of HA physiology, as well as, genetic variations among HA populations which may provide clues for this pattern of SARS-CoV-2 expansion and COVID-19 infection severity. Explanations are provided in the hypothetical, albeit relevant historical evidence is provided to create a foundation for future research.
The emergence of COVID-19 infection (caused by SARS- CoV-2) in Wuhan, China in the latter part of 2019 has, within a relatively short time, led to a global pandemic (13, 39, 81). Amidst the initial outbreak of COVID-19 and its expansion throughout mainland China, an epidemiologic trend emerged relative to high altitude (HA) populations. Lower transmission rates and reduced severity of COVID-19 infections were initially noted on the Qinghai-Tibetan plateau during the virus,s rapid spread across Asia (49, 85). Growing evidence in support of similar trends have now been shown in Bolivia (1); Peru, Argentina, and Chile (24); HA regions of central Ecuador (1, 63); remote villages in Papua (78); the Sichuan province of mainland China (46, 91); Nepal and Bhutan (3); and Himalayan regions of India including Arunachal Pradesh and Ladakh (24). While it is acknowledged the pandemic is still in its early stages in some of these regions, the disproportionate spread of SARS-CoV-2 deserves further attention. The objective of this short review is to examine environmental and physiological factors associated with HA in regards to the disparate incidence and severity of COVID-19 infections between high- and low- altitude populations. The discussion is presented in the hypothetical, albeit historical evidence is provided with the intention of creating a foundation for future epidemiologic investigations of COVID-19 among HA populations.
HA is associated with a reduced partial pressure of oxygen and concomitantly reduced arterial oxygenation. HA populations exhibit greater respiratory function evident in their superior ventilatory responses to hypoxia (71) and greater vital and total lung capacities (26). They display improved oxygen transport across the alveolar-arterial gradient and also utilize oxygen more effectively within cardiac tissue (44). Taken together, HA natives’ ability to resist SARS-CoV-2 could be attributed to superior responses to hypoxemia with consequentially less strain on the heart in acute respiratory distress, which is critical if infection progresses (29, 81).
Hypoxic conditions have also been associated with down- regulation and suppression of several RNA and DNA viruses (e.g., adenovirus and influenza), which are often culprits of respiratory infections (45, 79). Mechanisms by which hypoxia inhibits viral replication can vary between viruses and require further investigation with regards to SARS-CoV-2. Nevertheless, adaptations associated with HA acclimatization have been linked to viral infection resistance and attributed to reductions in citric acid buildup that are believed to reduce viral synthesis in lung tissue (8). Similarly, associations between altitude- hypoxia and the restriction of M-ycobacterium tuberculosis growth in whole blood and the augmentation of anti-mycobacterial cellular immunity (28) have been identified. Such effects are consistent with the HA-induced amplifications in cell- mediated immunity (increased PHA-blasts, lymphocyte migration index, and DNCB response) observed over 30 years earlier (17) and parallel the lower prevalence and reduced severity of tuberculosis (TB) infections at HA (62, 74).
SARS-CoV-2 may encounter similar immune challenges in hosts at HA which could explain the higher proportion of asymptomatic COVID-19 cases at HA (46, 49), as well as, the overall lower incidence and attenuated severity of symptomatic cases at HA (1, 63, 91). Genetic differences between the immunologic or inflammatory responses of lowlanders and highlanders (22, 90) may also be of interest given the apparent variability in immune and inflammatory responses to SARS- CoV-2 and the associated severity of cOvID-19 infection (36, 39,50,65).
Whether the summation of these factors has significant benefits in regards to COVID-19 remains to be investigated fully; however, it is clear that HA populations exhibit unique physiological and health profiles that may have the potential for protection against the development and severity of COVID-19 infection. Investigations surrounding the immune and inflammatory responses to SARS-CoV-2 among lowlanders and HA natives are required. The recent emergence of dexamethasone as a successful treatment strategy for severe COVID-19 infection (38) aligns with its common use at HA, which targets problematic inflammation and capillary leak that accompany severe HA illness (e.g., HA cerebral edema) (43). Dexamethasone therefore presents a unique method for exploring HA-associated distinctions that may mitigate (or exacerbate) inflammatory responses to SARS-CoV-2.
Numerous environmental characteristics associated with HA may also explain physiological findings and may be important in the future impact of COVID-19. Significant differences between highlanders and lowlanders are observed among the most commonly identified comorbidities (10) of COVID-19, with residence at higher elevation associated with lower incidence of cardiovascular disease and mortality (60), diabetes mellitus (83), obesity (84), and metabolic syndrome (51), which have all been linked to higher risk of severe COVID-19 infection and mortality (88). In contrast, hypertension appears to be higher in HA populations (2, 58, 61), although it is not possible to determine whether this puts these populations at a greater risk for COVID-19 infection, as there is still wide debate about whether the association between hypertension and COVID-19 embodies a causal relationship, or if it is simply indicative of the age and wider health status of those who are worst affected by COVID-19 (32, 70).
Pollution has also been associated with increased risk and severity of COVID-19 infections in high-pollution lowland areas (e.g., Lombardy, Italia, and New York, NY) (20, 96), and may relate to the emerging issue of hypercoagulability among COVID-19 patients (73). Reduced air pollution at HA (10, 31) is therefore of particular interest as is HA,s possible mitigation of hypercoagulability via increases in fibrinolytic activity following two weeks of exposure (18).
Incidence patterns may also be mediated by differences in the levels of vitamin D, which are elevated at HA (47, 97). Indeed, the potential role of vitamin D in mortality among COVID-19 patients is being explored (33, 64). Ultraviolet (UV) radiation which increases alongside elevation should also be considered with respect to mortality in COVID-19, as increased radiation may help to inhibit viral replication (19).
Similar to other zoonotic viruses (e.g., H1N1 influenza) (23, 52), factors such as temperature and humidity can influence SARS-CoV-2 infectivity (89) although the links appear to be quite dynamic (15). Lower temperatures and hypobaric-hyp- oxia at HA (above ~2,000 m) could, in part, explain the lower incidence of infections at HA, as they render the environment uninhabitable to non-human living vectors (e.g., Aedes xxxx mosquitos, flies, or other pests) (12, 53); however, recent evidence indicates that Aedes mosquitos do not pose a threat to SARS-CoV-2 transmission (86). Nevertheless, there has been evidence of an altitude “cut-off” for COVID-19 infections (~2,500 m) (1), which echoes the aforementioned insect line (12, 53). Thus, contributions from other insects whose inhabitancy is similarly thwarted at HA (e.g., flies) (75) should be considered, particularly, given their potentiation of fecal-oral transmission (67a) and the emerging evidence suggesting fecal-oral spread of SARS-CoV-2 (9, 57, 67, 87). Also of note are the lower incidences of viruses exhibiting fecal-oral transmission (e.g., gastrointestinal viruses) at HA (4), notwithstanding that fecal-oral transmission can also occur via several alternate pathways to the mouth (35).
Consistent and specific reporting of COVID-19 infections (e.g., residence vs. reporting facility altitude or geographic coordinates) will be important in evaluating links between HA-related climatic factors and SARS-CoV-2 transmission or COVID-19 infection severity and, ultimately, to help confirm or deny altitude protection against SARS-CoV-2.
The relationships between angiotensin-converting enzyme 2 (ACE2) expression and COVID-19 pathogenesis and mortality are undoubtedly complex with conflicting arguments within current research. Nonetheless, it has been suggested that changes in the level and activity of the ACE2 protein can alter COVID-19 outcomes (92). ACE2, a homolog of angiotensinconverting enzyme (ACE), is the primary infection route for SARS-CoV-2 (37, 95). Despite being crucial for viral entry, upregulation of ACE2 expression appears to confer protection against SARS-CoV-related lung injury (16,41). Similarly, pro- vs anti-inflammatory imbalance (ACE-angiotensin II-ATI imbalance) associated with low ACE2 expression [e.g., with old age or in diabetes mellitus, DM (14)] has the potential to predispose patient’s lungs to acute injury (34, 72) and could perpetuate the “cytokine storm”（76) observed in COVID-19 (56) that is known to confer poor outcomes, particularly, among the elderly and those with DM (94).
Acute upregulation of ACE2 appears possible with hypoxic exposures (21, 93). Likewise, prevention of ACE2 downregulation seems plausible (59). By limiting SARS-CoV-2-induced ACE2 depletion that ensues following receptor binding (92), ACE2 upregulation may thereby attenuate associated pulmonary inflammation and lung damage (41, 77). Clinical recommendations for the continuance of ACE inhibitor and angiotensin receptor blocker (ARB) therapies (30), which both upregulate ACE2, are consistent with ACE2-upregulation being beneficial. Whether hypoxia directly or indirectly translates into a definitive physiological advantage over SARS-CoV-2 via ACE2 involvement remains unclear. Careful evaluations of pulmonary ACE2 in humans in response to various durations and intensities of hypoxic exposures would be helpful in determining the relevance of ACE2 in this context.
Genomic ancestry supports genetic links between the anti- COVID-19 display among HA populations. In HA regions such as Ladakh, Arunachal Pradesh, Manipur, and Mizoram, the Tibeto-Burman genetic composition predominates and COVID-19 infections have been limited (24). Similarly, higher fractions of Paleo-Eskimo ancestry in HA regions of Peru and Mexico have been accompanied by considerably lower death rates (24). Together with the genetic differences known to exist between HA populations (Andean vs. Tibetan) (5), it is conceivable that evolutionary components may also exist with regards to anti-COVID-19 displays. Analyses of existing genetic data from various HA populations would be useful to further investigate this.
Population and ethnic differences in a number of genes related to ACE2 have also been suggested as having a potential role in COVID-19. Support can be provided by the differences in relative binding affinities for SARS-CoV-2 between ACE2 allelic variants (40), as well as in gene-variant dependent effects on viral internalization processes that appear to influence susceptibility to SARS-CoV-2 (7). Ethnic variations in the expression of ACE2 (11) have also been highlighted. Genetic variability in ACE2 among HA populations may help to modulate resistance and susceptibility to viral infection; however, investigations into the dynamics of pulmonary ACE2 expression across a range of genetic profiles in response to SARS-CoV-2 are required to better understand the significance of ACE2 genetic variation as it relates to COVID-19 infection.
Relative frequency of the ACE gene,s deletion allele (D; vs. the insertion allele, I) parallels reductions in ACE2 expression and has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) (55) and SARS-CoV-1 (48). Consistent with this are the higher numbers of COVID-19 cases among black populations (27, 66), who exhibit relatively low I allelic frequency (68), as well as the lower incidence and severity of infections among HA populations, who exhibit high I allelic frequency (82). In contrast, Delanghe and colleagues suggest that a higher I allele frequency may actually be detrimental to COVID-19 outcomes within European populations (25). These conflicting epidemiologic data emphasize the complexity of the relationships between COVID-19 and ACE genotype or ACE2. Nevertheless, given the potential impact of ACE polymorphisms on resultant ACE2 and COVID-19 outcomes, it is clear the duo warrant further exploration.
Alternative gene variants also differ between ethnic groups (42), such as angiotensin II type 1 receptor (or the AGTR1 gene), and thus deserve attention; notwithstanding that SARS- CoV-2 infection is distinctly different from existing pathophysiological variability between AGTR1 gene variants (54). Genes related to vascular inflammation (69) may also be worthy of investigation, although a complex relationship between components of the vasoregulatory axis and SARS-CoV-2 is likely.
We acknowledge there are a number of limitations to this perspective. Underreporting in HA regions is possible, although unlikely for symptomatic infections as low notifications for other severe respiratory infections have accurately reflected actual cases (80). Disparities in tracking and tracing capacities between high- and low-altitude regions may allow the higher proportion of asymptomatic cases at HA (46) to go undetected; however, this would further support the argument for reduced case severity at HA. Actions that aid testing and reporting efforts in HA regions could improve comparisons (high vs. low altitude) related to COVID-19 infections.
It is also acknowledged that HA can exacerbate certain respiratory infections (4) and may be contraindicated in those with severe existing disease (54). Under no circumstances is the presented evidence intended to justify HA exposure for prophylactic use or treatment against COVID-19.
The transmission of SARS-CoV-2 and severity of CO- VID-19 infections may embody a clinal pattern specifically related to HA with subsequent physiological advantages over COVID-19 being possible among HA populations. Future research could benefit from utilizing existing genetic and physiological data pertaining to HA populations to evaluate presented theories related to the prevalence of SARS-CoV-2 and severity of COVID-19 among HA populations.
- Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Aliaga-Rad- uan F, Carvajal-Rodriguez F, Dutschmann M, Schneider-Gasser EM, Zubieta-Calleja G, Soliz J. Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude? Respir Physiol Neurobiol 277: 103443, 2020. doi:10.1016/j.resp.2020.103443.
- Aryal N, Weatherall M, Bhatta YKD, Mann S. Blood pressure and hypertension in people living at high altitude in Nepal. Hypertens Res 42: 284-291, 2019. doi:10.1038/s41440-018-0138-x.
- Asim M, Sathian B, van Teijlingen E, Mekkodathil A, Subramanya SH, Simkhada P. COVID-19 pandemic: public health implications in Nepal. Ne'pal J Epidemiol 10: 817-820, 2020. doi:10.3126/nje.v10i1. 28269.
- Basnyat B, Cumbo TA, Edelman R. Infections at high altitude. Clin Infect Dis 33: 1887-1891, 2001. doi:10.1086/324163.
- Beall CM. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA 104, Suppl 1: 8655-8660, 2007. doi:10.1073/pnas.0701985104.
- Benetti E, Tita R, Spiga O, Ciolfi A, Birolo G, Bruselles A, Doddato G, Giliberti A, Marconi C, Musacchia F, Pippucci T, Torella A, Trezza A, Valentino F, Baldassarri M, Brusco A, Asselta R, Mirella B, Furini S, Seri M, Nigro V, Matullo G, Tartaglia M, Mari F, Renieri A, Pinto A. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population (Preprint). medRxiv 2020. doi:10.1101/2020.04.03.20047977.
- Berry LJ, Mitchell RB, Rubenstein D. Effect of acclimatization to altitude on susceptibility of mice to influenza A virus infection. Proc Soc Exp Biol Med 88: 543-548, 1955. doi:10.3181/00379727-88-21646.
- 9. Bonato G, Dioscoridi L, Mutignani M. Faecal-oral transmission of SARS-COV-2: practical implications. Gastroenterology. doi:10.1053/j. gastro.2020.03.066.
- Burtscher M. Effects of living at higher altitudes on mortality: a narrative review. AgingDis 5: 274-280, 2013. doi:10.14336/AD.2014.0500274.
- Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 6: 11, 2020. doi:10.1038/s41421-020-0147-1.
- Cetron M. Revision to CDC’s Zika travel notices: minimal likelihood for mosquito-borne Zika virus transmission at elevations above 2,000 meters. MMWR Morb Mortal Wkly Rep 65: 267-268, 2016. doi:10.15585/mmwr. mm6510e1.
- Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, Tsoi HW, Lo SK, Chan KH, Poon VK, Chan WM, Ip JD, Cai JP, Cheng VC, Chen H, Hui CK, Yuen KY. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395: 514-523, 2020. doi:10.1016/S0140-6736(20)30154-9.
- Chen J, Jiang Q, Xia X, Liu K, Yu Z, Tao W, Gong W, Han J-DJ. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell. doi:10.1111/acel.13168.
- Chen L-D. Effects of ambient temperature and humidity on droplet lifetime - A perspective of exhalation sneeze droplets with COVID-19 virus transmission. Int J Hyg Environ Health 229: 113568, 2020. doi:10. 1016/j.ijheh.2020.113568.
- Cheng H, Wang Y, Wang GQ. Organ-protective effect of angiotensinconverting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol 92:726-730,2020.doi:10.1⑻2/jmv.25785.
- Chohan IS, Singh I. Cell mediated immunity at high altitude. Int J Siometeorol 23:21-30,1979.doi:10.1⑻7/BF01553374.
- Chohan IS. Blood coagulation changes at high altitude. Def Sci J 34: 361-379, 1984. doi:10.14429/dsj.34.6083.
- Conti P, Gallenga CE, Tete G, Caraffa A, Ronconi G, Younes A, Toniato E, Ross R, Kritas SK. How to reduce the likelihood of corona- virus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1. J Biol Regul Homeost Agents 34, 2020. doi:10.23812/ Editorial-Conti-2.
- Conticini E, Frediani B, Caro D. Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy? Environ Pollut 261: 114465, 2020. doi:10.1016/j.envpol. 2020.114465.
- Cooke M, Cruttenden R, Mellor A, Lumb A, Pattman S, Burnett A, Boot C, Burnip L, Boos C, O’Hara J, Woods D. A pilot investigation into the effects of acute normobaric hypoxia, high altitude exposure and exercise on serum angiotensin-converting enzyme, aldosterone and cortisol. J Renin Angiotensin Aldosterone Syst 19: 1470320318782782, 2018. doi:10.1177/1470320318782782.
- Crawford JE, Amaru R, Song J, Julian CG, Racimo F, Cheng JY, Guo X, Yao J, Ambale-Venkatesh B, Lima JA, Rotter JI, Stehlik J, Moore LG, Prchal JT, Nielsen R. Natural selection on genes related to cardiovascular health in high-altitude adapted Andeans. Am J Hum Genet 101: 752-767, 2017. doi:10.1016/j.ajhg.2017.09.023.
- da Costa ACC, Code^o CT, Krainski ET, Gomes MFDC, Nobre AA. Spatiotemporal diffusion of influenza A (H1N1): starting point and risk factors. PLoS One 13: e0202832, 2018. doi:10.1371/journal. pone.0202832.
- Das R, Ghate SD. Investigating the likely association between genetic ancestry and COVID-19 manifestation (Preprint). medRxiv 2020. doi:10. 1101/2020.04.05.20054627.
- Delanghe JR, Speeckaert MM, De Buyzere ML. The host’s angiotensinconverting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin Chim Acta 505: 192-193, 2020. doi:10. 1016/j.cca.2020.03.031.
- Droma T, McCullough RG, McCullough RE, Zhuang JG, Cymerman A, Sun SF, Sutton JR, Moore LG. Increased vital and total lung capacities in Tibetan compared to Han residents of Lhasa (3,658 m). Am J PhysAnthropol 86: 341-351, 1991. doi:10.1002/ajpa.1330860303.
- Dyer O. Covid-19: Black people and other minorities are hardest hit in US. BMJ 369: m1483, 2020. doi:10.1136/bmj.m1483.
- Eisen S, Pealing L, Aldridge RW, Siedner MJ, Necochea A, Leybell I, Valencia T, Herrera B, Wiles S, Friedland JS, Gilman RH, Evans CA. Effects of ascent to high altitude on human antimycobacterial immunity. PLoS One 8: e74220 74220, 2013. doi:10.1371/journal.pone.0074220.
- Elias B, Shen C, Bar-Yam Y. Respiratory Health for Better COVID-19 Outcomes Cambridge, MA: New England Complex Systems Institute (April 18, 2020). https://necsi.edu/respiratory-health-for-better-covid-19- outcomes.
- Essig M, Matt M, Massy Z. The COVID-19 outbreak and the angiotensin-converting enzyme 2: too little or too much? Nephrol Dial Transplant 35: 1073-1075, 2020. doi:10.1093/ndt/gfaa113.
- Faeh D, Gutzwiller F, Bopp M; Swiss National Cohort Study Group. Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation 120: 495-501, 2009. doi: 10.1161/CIRCULATIONAHA.108.819250.
- Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 8: e21, 2020. doi:10.1016/S2213-2600(20)30116-8.
- Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 12: 1626, 2020. doi:10.3390/nu12040988.
- Gu H, Xie Z, Li T, Zhang S, Lai C, Zhu P, Wang K, Han L, Duan Y, Zhao Z, Yang X, Xing L, Zhang P, Wang Z, Li R, Yu JJ, Wang X, Yang P. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep 6: 19840, 2016. doi: 10.1038/srep19840.
- Heller L, Mota CR, Greco DB. COVID-19 faecal-oral transmission: Are we asking the right questions? Sci Total Environ 729: 138919, 2020. doi:10.1016/j.scitotenv.2020.138919.
- Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med 58: 1021-1028, 2020. doi:10.1515/ cclm-2020-0369.
- Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271-280.e8, 2020. doi:10.1016/j.cell.2020.02.052.
- Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie K, Haynes R, Landray MJ; Randomised Evaluation of COVID-19 Therapy (RECOVERY) Collaborative Group. Effect of dexamethasone in hospitalized patients with COVID-19: Preliminary Report (Preprint). MedRxi'v 2020. doi:10.1101/2020.06.22.20137273.
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395: 497-506, 2020. doi:10.1016/ S0140-6736(20)30183-5.
- Hussain M, Jabeen N, Raza F, Shabbir S, Baig AA, Amanullah A, Aziz B. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J Med Virol. doi:10.1002/jmv.25832.
- Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436: 112-116, 2005. doi:10.1038/nature03712.
- Jin T, Ren Y, Zhu X, Li X, Ouyang Y, He X, Zhang Z, Zhang Y, Kang L, Yuan D. Angiotensin II receptor 1 gene variants are associated with high-altitude pulmonary edema risk. Oncotarget 7: 77117-77123, 2016. doi:10.18632/oncotarget.12489.
- Joyce KE, Lucas SJE, Imray CHE, Balanos GM, Wright AD. Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema. Expert Opin Pharmacother 19: 1891-1902, 2018. doi:10.1080/14656566.2018.1528228.
- Julian CG, Moore LG. Human Genetic Adaptation to High Altitude: Evidence from the Andes. Genes (Basel) 10: 150, 2019. doi:10.3390/ genes10020150.
- Kalter SS, Tepperman J. Influenza Virus Proliferation in Hypoxic Mice. Science 115: 621-622, 1952. doi:10.1126/science.115.2997.621.
- Kong W, Wang Y, Hu J, Chughtai A, Pu H; Clinical Research Collaborative Group of Sichuan Provincial People’s Hospital. Comparison of clinical and epidemiological characteristics of asymptomatic and symptomatic SARS-CoV-2 infection: A multi-center study in Sichuan Province, China. TravelMed InfectDis. doi:10.1016/j.tmaid.2020.101754.
- Ku YC, Liu ME, Ku CS, Liu TY, Lin SL. Relationship between vitamin D deficiency and cardiovascular disease. World J Cardiol 5: 337-346, 2013. doi:10.4330/wjc.v5.i9.337.
- Kuba K, Imai Y, Rao S, Jiang C, Penninger JM. Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. J Mol Med (SerlJ 84:814-820,2006.doi:10.1⑻7/s00109-006-0094-9.
- Lei Y, Lan Y, Lu J, Huang X, Silang B, Zeng F. Clinical features of imported cases of coronavirus disease 2019 in Tibetan patients in the Plateau area (Preprint). medRxiv 2020. doi:10.1101/2020.03.09.20033126.
- Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, Shi J, Zhou M, Wu B, Yang Z, Zhang C, Yue J, Zhang Z, Renz H, Liu X, Xie J, Xie M, Zhao J. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 146: 110-118, 2020. doi:10.1016/j.jaci. 2020.04.006.
- Lopez-Pascual A, Bes-Rastrollo M, Sayon-Orea C, Perez-Cornago A, Dfaz-Guti4rrez J, Pons JJ, Martfnez-Gonzdlez MA, Gonzdlez-Muni- esa P, Martfnez JA. Living at a geographically higher elevation is associated with lower risk of metabolic syndrome: Prospective analysis of the SUN Cohort. Front Physiol 7: 658, 2017. doi:10.3389/fphys.2016. 00658.
- Lowen AC, Mubareka S, Steel J, Palese P. Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathog 3: 1470-1476, 2007. doi:10.1371/journal.ppat.0030151.
- Lozano-Fuentes S, Hayden MH, Welsh-Rodriguez C, Ochoa-Martinez C, Tapia-Santos B, Kobylinski KC, Uejio CK, Zielinski-Gutierrez E, Monache LD, Monaghan AJ, Steinhoff DF, Eisen L. The dengue virus mosquito vector Aedes aegypti at high elevation in Mexico. Am J Tro~p Med Hyg 87: 902-909, 2012. doi:10.4269/ajtmh.2012.12-0244.
- Luks AM, Freer L, Grissom CK, McIntosh SE, Schoene RB, Swenson ER, Hackett PH. COVID-19 lung injury is not high altitude pulmonary edema. High Alt Med Biol 21: 192-193, 2020. doi:10.1089/ham.2020.
- Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, Humphries SE, Hill MR, Laurent GJ. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 166: 646-650, 2002. doi:10.1164/rccm.2108086.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395: 10331034, 2020. doi:10.1016/S0140-6736(20)30628-0.
- Meng X, Huang X, Zhou P, Li C, Wu A. Alert for SARS-CoV-2 infection caused by fecal aerosols in rural areas in China. Infect Control Hosp Epidemiol 41: 987, 2020. doi:10.1017/ice.2020.114.
- Mingji C, Onakpoya IJ, Perera R, Ward AM, Heneghan CJ. Relationship between altitude and the prevalence of hypertension in Tibet: a systematic review. Heart 101: 1054-1060, 2015. doi:10.1136/heartjnl- 2014-307158.
- Mohamed TL, Nguyen HT, Abdul-Hafez A, Dang VX, Dang MT, Gewolb IH, Uhal BD. Prior hypoxia prevents downregulation of ACE-2 by hyperoxia in fetal human lung fibroblasts. Exp Lung Res 42: 121-130, 2016. doi:10.3109/01902148.2016.1157712.
- Mortimer EA Jr, Monson RR, MacMahon B. Reduction in mortality from coronary heart disease in men residing at high altitude. N Engl J Med 296: 581-585, 1977. doi:10.1056/NEJM197703172961101.
- Narvaez-Guerra O, Herrera-Enriquez K, Medina-Lezama J, Chirinos JA. Systemic hypertension at high altitude. Hypertension 72: 567-578, 2018. doi:10.1161/HYPERTENSIONAHA.118.11140.
- Olender S, Saito M, Apgar J, Gillenwater K, Bautista CT, Lescano AG, Moro P, Caviedes L, Hsieh EJ, Gilman RH. Low prevalence and increased household clustering of Mycobacterium tuberculosis infection in high altitude villages in Peru. Am J Trop Med Hyg 68: 721-727, 2003. doi:10.4269/ajtmh.2003.68.721.
- Ortiz-Prado E, Simbana-Rivera K, Diaz AM, Barreto A, Moyano C, Arcos V, Vasconez-Gonzalez E, Paz C, Simbana-Guaycha F, Moles- tina-Luzuriaga M, Fernandez-Naranjo R, Feijoo J, Henriquez AR, Adana L, Lopez-Cortes A, Fletcher I, Lowe R, Gomez-Barreno L.
- Epidemiological, socio-demographic and clinical features of the early phase of the COVID-19 epidemic in Ecuador (Preprint). MedRxiv 2020. doi:10.1101/2020.05.08.20095943.
- Panarese A, Shahini E. Letter: Covid-19, and vitamin D. Alimentary Pharmacol Ther 51: 993-995, 2020. doi:10.1111/apt.15752.
- Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest 130: 2202-2205, 2020. doi:10.1172/JCI137647.
- Platt L, Warwick R. Are some ethnic groups more vulnerable to CO- VID-19 than others? In: Inequality: The INFS Deaton Review. Institute for Fiscal Studies, 2020. https://www.ifs.org.uk/inequality/chapter/are-some- ethnic-groups-more-vulnerable-to-covid-19-than-others/.
- Qian Q, Fan L, Liu W, Li J, Yue J, Wang M, Ke X, Yin Y, Chen Q, Jiang C. Direct evidence of active SARS-CoV-2 replication in the intestine. Clin Infect Dis ciaa925, 2020. doi:10.1093/cid/ciaa925.
- Rozendaal JA. Houseflies. In: Vector Control - Methods for Use by Individuals and Communities. Geneva, Switzerland: WHO, 1997, chapt. 6.
- Saab YB, Gard PR, Overall AD. The geographic distribution of the ACE II genotype: a novel finding. Genet Res 89: 259-267, 2007. doi:10.1017/ S0016672307009019.
- Sato J, Kinugasa M, Satomi-Kobayashi S, Hatakeyama K, Knox AJ, Asada Y, Wierman ME, Hirata K, Rikitake Y. Family with sequence similarity 5, member C (FAM5C) increases leukocyte adhesion molecules in vascular endothelial cells: implication in vascular inflammation. PLoS One 9: e107236, 2014. doi:10.1371/journal.pone.0107236.
- Schiffrin EL, Flack JM, Ito S, Muntner P, Webb RC. Hypertension and COVID-19. AmJHypertens 33: 373-374, 2020. doi:10.1093/ajh/hpaa057.
- Slessarev M, Mardimae A, Preiss D, Vesely A, Balaban DY, Greene R, Duffin J, Fisher JA. Differences in the control of breathing between Andean highlanders and lowlanders after 10 days acclimatization at 3850 m. JPhysiol 588: 1607-1621, 2010. doi:10.1113/jphysiol.2009.186064.
- Sodhi CP, Nguyen J, Yamaguchi Y, Werts AD, Lu P, Ladd MR, Fulton WB, Kovler ML, Wang S, Prindle T Jr, Zhang Y, Lazartigues ED, Holtzman MJ, Alcorn JF, Hackam DJ, Jia H. A dynamic variation of pulmonary ACE2 is required to modulate neutrophilic inflammation in response to Pseudomonas aeruginosa lung infection in mice. J Immunol 203:3000-3012,2019. doi:10.4049/jimmunol.19⑻579.
- Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18: 844-847, 2020. doi:10.1111/jth.14768.
- Tanrikulu AC, Acemoglu H, Palanci Y, Dagli CE. Tuberculosis in Turkey: high altitude and other socio-economic risk factors. Public Health 122: 613-619, 2008. doi:10.1016/j.puhe.2007.09.005.
- Taye A, Alemayehu W, Melese M, Geyid A, Mekonnen Y, Tilahun D, Asfaw T. Seasonal and altitudinal variations in fly density and their association with the occurrence of trachoma, in the Gurage zone of central Ethiopia. Ann Trop Med Parasitol 101: 441-448, 2007. doi:10.1179/ 136485907X176544.
- Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, Toffoli B, Nguyen-Huu T-P, Head GA, Fu Y, Chin-Dusting J, Cooper ME, Tikellis C. Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ Res 107: 888-897, 2010. doi:10.1161/CIRCRESAHA.110.219279.
- Treml B, Neu N, Kleinsasser A, Gritsch C, Finsterwalder T, Geiger R, Schuster M, Janzek E, Loibner H, Penninger J, Loeckinger A. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med 38: 596-601, 2010. doi:10.1097/CCM.0b013e3181c03009.
- van Burg E, van Burg-Verhage W. Eruption of COVID-19 like illness in a remote village in Papua (Indonesia) (Preprint). medRxiv 2020. doi: 10.1101/2020.05.19.20106740.
- Vassilaki N, Frakolaki E. Virus-host interactions under hypoxia. Microbes Infect 19:193-203,2017.doi:10.1016/j.micinf.2016.10.⑻4.
- Vree M, Hoa NB, Sy DN, Co NV, Cobelens FGJ, Borgdorff MW. Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey. BMC Infect Dis 7: 109, 2007. doi:10. 1186/1471-2334-7-109.
- Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 395: 470473, 2020. doi:10. 1016/S0140-6736(20)30185-9.
- Wang Y, Lu H, Chen Y, Luo Y. The association of angiotensinconverting enzyme gene insertion/deletion polymorphisms with adaptation to high altitude: A meta-analysis. J Renin Angiotensin Aldosterone Syst 17: 1470320315627410, 2016. doi:10.1177/1470320315627410.
- Woolcott OO, Castillo OA, Gutierrez C, Elashoff RM, Stefanovski D, Bergman RN. Inverse association between diabetes and altitude: a crosssectional study in the adult population of the United States. Obesity (Silver Spring) 22: 2080-2090, 2014. doi:10.1002/oby.20800.
- Woolcott OO, Castillo OA, Torres J, Damas L, Florentini E. Serum leptin levels in dwellers from high altitude lands. High Alt Med Biol 3: 245-246, 2002. doi:10.1089/15270290260131975.
- Xi A, Zhuo M, Dai J, Ding Y, Ma X, Ma X, Wang X, Shi L, Bai H, Zheng H, Nuermberger E, Xu J. Epidemiological and clinical characteristics of discharged patients infected with SARS-CoV-2 on the Qinghai plateau. J Med Virol. doi:10.1002/jmv.26032.
- Xia H, Atoni E, Zhao L, Ren N, Huang D, Pei R, Chen Z, Xiong J, Nyaruaba R, Xiao S, Zhang B, Yuan Z. SARS-CoV-2 does not replicate in aedes mosquito cells nor present in field-caught mosquitoes from Wuhan. Virol Sin 35: 355-358, 2020. doi:10.1007/s12250-020-00251-0.
- Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, Guo Q, Sun X, Zhao D, Shen J, Zhang H, Liu H, Xia H, Tang J, Zhang K, Gong S. *Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med 26: 502-505, 2020. doi:10. 1038/s41591-020-0817-4.
- Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, Ji R, Wang H, Wang Y, Zhou Y. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis 94: 91-95, 2020. doi:10.1016/j.ijid.2020.03.017.
- Yao M, Zhang L, Ma J, Zhou L. On airborne transmission and control of SARS-Cov-2. Sci Total Environ 731: 139178, 2020. doi:10.1016/j. scitotenv.2020.139178.
- Yu J, Zeng Y, Chen G, Bian S, Qiu Y, Liu X, Xu B, Song P, Zhang J, Qin J, Huang L. Analysis of high-altitude syndrome and the underlying gene polymorphisms associated with Acute Mountain Sickness after a rapid ascent to high-altitude. Sci Rep 6: 38323, 2016. doi:10.1038/ srep38323.
- Zeng J, Peng S, Lei Y, Huang J, Guo Y, Zhang X, Huang X, Pu H, Pan L; COVID-19 Clinical Research Collaborative Group of Sichuan Provincial People's Hospital. Clinical and Imaging features of COVID-19 patients: analysis of data from high-altitude Areas. J Infect 80: e34-e36, 2020. doi:10.1016/j.jinf.2020.03.026.
- Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46: 586-590, 2020. doi:10.1007/s00134-020-05985-9.
- Zhang R, Wu Y, Zhao M, Liu C, Zhou L, Shen S, Liao S, Yang K, Li Q, Wan H. Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 297: L631-L640, 2009. doi:10.1152/ ajplung.90415.2008.
- Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395: 1054-1062, 2020. doi:10.1016/S0140-6736(20)30566-3.
- Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, Si H-R, Zhu Y, Li B, Huang C-L, Chen H-D, Chen J, Luo Y, Guo H, Jiang R-D, Liu M-Q, Chen Y, Shen X-R, Wang X, Zheng X-S, Zhao K, Chen Q-J, Deng F, Liu L-L, Yan B, Zhan F-X, Wang Y-Y, Xiao G-F, Shi Z-L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579: 270-273, 2020. doi:10.1038/s41586-020- 2012-7.
- Zhu Y, Xie J, Huang F, Cao L. Association between short-term exposure to air pollution and COVID-19 infection: evidence from China. Sci Total Environ 727: 138704, 2020. doi:10.1016/j.scitotenv.2020.138704.
- Zittermann A, Gummert JF. Sun, vitamin D, and cardiovascular disease. J Photochem Photobiol B 101: 124-129, 2010. doi:10.1016/j.jphotobiol. 2010.01.006.