No Relevant Analogy Between COVID-19 and Acute Mountain Sickness

Similarity of Hypoxia-Induced Symptoms

It may well be that illnesses causing considerable hypoxemia can cause symptoms that also occur in AMS. This does, however, not imply that similar pathways as in AMS are involved in causing hypoxemia of such illnesses. Furthermore, the cardinal symptom of AMS is headache (Roach et al., 2018), whereas this is not the case for COVID-19 (Sampaio Rocha-Filho and Voss, 2020). Recently, dexamethasone was identified as a treatment for critically ill COVID-19 patients (Recovery Collaborative Group et al., 2020). Dexamethasone is also effective in preventing and treating AMS (Johnson et al., 1984; Hackett et al., 1988; Levine et al., 1989). However, the multiple modes of action and the unclear mechanisms by which dexamethasone is beneficial in both COVID-19 and AMS do not allow the conclusion that both diseases are subject to the same pathophysiological mechanisms.

Differences in Time Course

The estimated mean incubation period for COVID-19 is reported to be 3–6 days (Tolksdorf et al., 2020), and the interval from symptom onset to the development of acute respiratory distress syndrome (ARDS) is approximately another 8–12 days (Zhou et al., 2020). This time course is significantly longer than the time course with which AMS develops. Usually, AMS symptoms develop 4–12 hours after arrival at a new altitude (Berger et al., 2019). This discrepancy in the time courses from the initial “insult” (i.e., infection vs. ascent to high altitude) to the onset of symptoms indicates distinct pathophysiological mechanisms, even if some clinical manifestations of AMS may be similar to those experienced during COVID-19 (i.e., hypoxemia, fatigue, and nausea).

Role of Inflammation

In contrast to AMS, COVID-19 is caused by a virus infection that in severe cases leads to an excessive and generalized inflammation. A growing body of clinical data suggests that the upregulation of proinflammatory cytokines is associated with COVID-19 severity and that this is a crucial determinant for the onset of (multiple-) organ dysfunction and death (Hu et al., 2020). COVID-19 primarily affects the respiratory system, with some patients progressing to ARDS (Li and Ma, 2020). AMS is a predominant neurological disorder, and it is controversial whether minor impairments of gas exchange contribute to this disease (Cremona et al., 2002; Senn et al., 2006; Dehnert et al., 2010; Berger et al., 2017; Lipman et al., 2017). The significance of inflammation in AMS is in general unclear, as previous studies found either no (Johnson et al., 1988; Kleger et al., 1996; Swenson et al., 1997; Julian et al., 2011) or only a moderate (Hartmann et al., 2000; Boos et al., 2016; Lundeberg et al., 2018; Wang et al., 2018) increase (of about 1.5- to 3.5-fold) in proinflammatory cytokines in subjects with AMS. Even if some mild inflammation is part of the pathophysiology of AMS, it does not induce organ damage and its significance in the disease's pathogenesis is far smaller than in COVID-19. The statement that both COVID-19 and AMS trigger a perfect storm in the respiratory system targeting the integrative layers of the respiratory system and injuring the lungs (Soliz et al., 2020) is not correct.

Role of Angiotensin Converting Enzyme 2

Angiotensin converting enzyme 2 (ACE2) is the enzyme that generates angiotensin 2. As the authors (Soliz et al., 2020) addressed, ACE2 in the airway epithelia and in particular the alveoli acts as a primary gateway for the cellular penetration of SARS-CoV-2, causing inflammation and local cell death. Therefore, ACE2 expression and/or polymorphism could influence both the susceptibility to SARS-CoV-2 infection and the outcome of COVID-19 disease (Devaux et al., 2020). In severe COVID-19, the presence of ACE2 in other tissues than the lung may explain why in some patients the disease progresses to multiorgan failure. Devaux et al. (2020), therefore, suggested that quantification of ACE2 and angiotensin II should be added to the biological monitoring of COVID-19 patients. There are, however, no data on the role of ACE2 in AMS. Also, aside from ACE2 there is only limited evidence to support a genetic basis for susceptibility to AMS and HACE, although this might partially be due to the subjective and unclear phenotype of AMS and the rarity and severity of HACE (MacInnis and Koehle, 2016). Thus, although ACE2 seems to be of major importance in the pathogenesis of COVID-19, there is no evidence supporting its role in the pathophysiology of AMS and HACE.

Comments to the Table Presented by Soliz et al.

This table lists symptoms and pathophysiological features purported to be shared between AMS and COVID-19. Based on the scientific literature (Hackett and Roach, 2001; Wilson et al., 2009, 2014; Bartsch and Swenson, 2013), most of these items cannot be attributed to AMS. Cough is not a symptom of AMS. Hypoxic pulmonary vasoconstriction and shortness of breath are physiological responses to altitude exposure and do not differ between those with and without AMS. In contrast, an exaggerated hypoxic pulmonary vasoconstriction is of major importance in the pathophysiology of HAPE. We are not aware of any study demonstrating lymphopenia or hemolysis in AMS. There is no clinically relevant pulmonary edema in AMS as discussed earlier. Hypoxic respiratory failure does not occur in AMS and we are not aware of reports of an impaired central respiratory network in AMS. A lower hypoxic ventilatory response may, however, be a risk factor for AMS (Richalet et al., 2012), but this characteristic is primarily due to a lower sensitivity of the peripheral chemoreceptor response to hypoxia (Bartsch et al., 2002). Brain edema is present in HACE (Hackett et al., 1998), but if present at all in AMS it is minimal and most likely not accounting for symptoms of this illness (Wilson et al., 2009, 2014; Dekker et al., 2019). Large epidemiological studies (Honigman et al., 1993; Schneider et al., 2002; Richalet et al., 2012) demonstrate that men are not more affected by AMS than women. An endothelial inflammation of lungs, heart, and kidney has not been demonstrated in AMS, and circulating markers of inflammation are not consistently found in AMS as outlined earlier. Furthermore, there is no evidence of epithelial inflammation in the bronchoalveolar lavage fluid in AMS (Schoene et al., 1988).

Erythropoietin

Soliz et al. (2020) suggest that erythropoietin could be effective for treating at least those COVID-19 patients with hypoxemia in association with low hemoglobin or low hematocrit, because of its role in long-term acclimatization at high altitude improving oxygen transport by increasing ventilation and hemoglobin. It may counteract pulmonary vasoconstriction, is neuroprotective, and has anti-inflammatory effects. Some of these postulated mechanisms of action have never been shown in humans and the transferability of these findings to the clinical situation of a hypoxemic COVID-19 patient is questionable at best. In support of their suggestion they cite on an open-labeled trial reporting that four injections of erythropoietin preceding acute exposure to 4130 m reduced severity and incidence of AMS (Heo et al., 2014). It is noteworthy that sildenafil was given in this study twice daily >2360 m for prevention of HAPE. This additional intervention precludes evaluating effects of erythropoietin on the lung. Furthermore, as the authors discuss, administration of exogenous erythropoietin is associated with an increased risk of thrombotic cardiovascular events (Jeong et al., 2010) and, therefore, in our opinion precludes consideration of its use for a disease in which thrombosis and embolism may occur in more severe cases, and for which anticoagulation is recommended (Ackermann et al., 2020; Connors and Levy, 2020; Wichmann et al., 2020).

In summary, the authors' (Soliz et al., 2020) suggestion that pathophysiological mechanisms underlying AMS may overlap with the mechanisms causing COVID-19 is not supported by scientific evidence. We feel it is important to highlight this inappropriate analogy and misconception, which could foster experimental therapies increasing the risk of patient harm.