High-Altitude Pulmonary Edema in the Context of COVID-19
Eduardo Garrido 1,*, Javier Botella de Maglia 2, Oriol Sibila 3, Gustavo Zubieta-Calleja 4
Hypobaria and Biomedical Physiology Unit, University of Barcelona, Hospitalet de Llobregat, Spain
Intensive Care Unit, University and Polytechnic Hospital La Fe, Valencia, Spain
Pneumology and Respiratory Allergy Department, Hospital Clinic, Barcelona, Spain
High Altitude Pulmonary and Pathology Institute, La Paz, Bolivia
* Correspondence: Eduardo Garrido
Academic Editor: Yan Sanders
Special Issue: Oxygen Transport Physiology and COVID at High Altitude
Received: July 18, 2022 | Accepted: August 31, 2022 | Published: September 09, 2022
OBM Genetics 2022, Volume 6, Issue 3, doi:10.21926/obm.genet.2203163
Recommended citation: Garrido E, Botella de Maglia J, Sibila O, Zubieta-Calleja G. High-Altitude Pulmonary Edema in the Context of COVID-19. OBM Genetics 2022;6(3):6; doi:10.21926/obm.genet.2203163.
© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
High-altitude pulmonary edema (HAPE) and COVID-19 pneumonia are different diseases, but HAPE-susceptible individuals (whose susceptibility often has a genetic basis) can also suffer from severe COVID-19. We hypothesized that certain pathogenic mechanisms might overlap if such a coincidence occurs, since these patients could react to alveolar hypoxia with a more intense and heterogeneously distributed pulmonary vasoconstriction than non-HAPE-susceptible patients. It is also not known how future altitude acclimatization might affect lowlanders with COVID-19 pulmonary sequelae, and how the loss of adaptation to chronic hypoxia might differ by genetic lineage among highland natives who have recovered from severe COVID-19 around the world. Although the incidence of CoV-2 in high-altitude locations seems to be lower, a correct differential diagnosis of both conditions is essential, especially in high-altitude areas where health resources are scarce, considering that there is sometimes a similarity between COVID-19 pneumonia and HAPE.
Altitude; genetics; hypoxia; pulmonary edema; COVID-19
The outbreak of CoV-2 disease (COVID-19) led to the publication of many scientific studies that investigated various aspects of this disease. Due to certain similarities between COVID-19 pneumonia and high-altitude pulmonary edema (HAPE), the therapeutic utility of nifedipine, sildenafil, tadalafil, and acetazolamide was initially considered . However, due to differences in the pathophysiology of both conditions and the mechanisms of action of these drugs, these medications might be not only useless but even harmful to patients suffering from COVID-19 pneumonia, as stated by other researchers [2,3].
HAPE is a life-threatening disease of non-cardiogenic etiology and is caused by exaggerated pulmonary hypertension in response to hypobaric hypoxia. The overall incidence rate is around 6% in those lowlanders who rapidly reach high altitudes but increases to 15% at the height of 5,500 m ; the incidence rate increases up to 60% if there is a history of HAPE . The clinical symptoms might be confused with those of pneumonia, considering that even cyanosis and fever may be present . However, it often differs from typical COVID-19 pneumonia, as it does not involve silent initial changes but rather acute alveolar edema, although both conditions may have radiological similarities (Figure 1).
Figure 1 High-altitude pulmonary edema shows a typical radiological chest pattern (diffuse and asymmetric bilateral opacities, like cotton wool blotches), which resembles the chest pattern of many cases of COVID-19 pneumonia. (Image from Zubieta-Calleja et al.  reproduced with permission from Bentham Sci. Publ.].
It is assumed that there is a genetic predisposition to HAPE, but few genetic polymorphisms (JAK2, HRG, and CYP1B1) possibly associated with HAPE-susceptible individuals have been identified . Prolyl hydroxylase domain protein 2 (EGLN1) and HIF-1α inhibitory factor (HIF1AN) are also associated with the pathophysiology of HAPE , and abnormally elevated levels of HIF-1α are considered to be a HAPE susceptibility marker . Additionally, angiotensin II type 1 receptor (AT1R) gene polymorphisms might be associated with HAPE susceptibility , and A1166C AT1R polymorphism is also associated with COVID-19 severity . Interestingly, a slightly elevated plasma concentration of B-type natriuretic peptide might be related to an exaggerated pulmonary vascular response in hypoxia-susceptible individuals , as well as poor outcomes in COVID-19 patients .
As the two conditions are different and without known genetic analogies, we hypothesized that certain pathogenic mechanisms of both conditions might overlap in cases of COVID-19 pneumonia affecting HAPE-susceptible individuals, a scenario that has not been investigated yet. Such patients might respond to alveolar hypoxia with a pulmonary vasoconstriction stronger and more heterogeneously distributed than expected, causing alveolar edema in larger areas of the lungs. This might impair ventilation/perfusion mismatch and gas exchange, which might worsen hypoxemia and the course of the disease. A study proposed that severe cases of respiratory failure in COVID-19 might benefit from hyperbaric oxygen therapy . Some individuals with endogenous susceptibility to HAPE might be found among these patients, however, we consider that in the setting of an intensive care unit, several complexities might challenge the management of a COVID-19 patient inside a hyperbaric chamber.
People with COVID-19 sequelae (residual fibrosis, pulmonary hypertension, bronchiectasis) might be prone to further difficulties when acclimatizing to high altitude, but such possibility has not been studied. With the probable exception of ethnic groups of Tibetan lineage, who have a singular genetic adaptation to hypoxia and develop an attenuated hypoxic pulmonary hypertension , it is unpredictable whether other high-altitude dwellers, especially Andean natives, will increase their risk of suffering from the re-entry HAPE when returning to their place of residence after recovering from COVID-19 pneumonia in a hospital at lower altitudes.
In a small group of highlanders, patients with COVID-19 pneumonia hospitalized at an altitude of 4,150 m, those with lower serum hematocrit and erythropoietin (EPO) levels had a higher mortality rate . Interestingly, based on the oxygen transport triad concept, high-altitude residents suffering pneumolysis caused by SARS-CoV-2 recovered with higher hematocrit levels that before being affected by the COVID-19 disease . The term hypoxia paradox was proposed due to the concomitance of profound hypoxemia and low plasma concentrations of EPO, having been observed that patients with severe COVID-19 and worse prognosis improved considerably after treatment with recombinant EPO analogs .
The combination of COVID-19 pneumonia and high-altitude hypoxia can be detrimental, but, overall, there appears to be a lower prevalence, severity, and mortality of COVID-19 in some populations living in high altitudes, an intriguing fact that needs to be confirmed . Such a pattern might be associated with environmental factors, the downregulation of angiotensin-converting enzyme II, as well as a lower prevalence of certain comorbidities, such as diabetes mellitus, obesity, and hypertension which might protect individuals living at high altitudes against CoV-2 infection, especially those residing at more than 3,000 m above sea level [20,21]. We argue that larger epidemiological studies are needed to confirm whether this benefit of highlanders is exclusively due to their genetic and/or phenotypic adaptations to chronic hypoxia since other aspects related to health, social customs, or demographic distribution might also play a significant role.
Finally, considering that some HAPE patients might onset with non-specific insidious symptoms, and given that there might also be radiological features similar to COVID-19 pneumonia, a differential diagnosis should be carefully performed at high altitudes during the SARS-CoV-2 pandemic to implement the most appropriate therapeutic strategy under conditions of environmental hypoxia, especially in isolated mountainous areas where health resources are scarce.
Dr. Garrido and Dr. Botella de Maglia have proposed the main ideas, have made the selection of the search for scientific documents and written the manuscript; Dr. Sibila and Dr. Zubieta-Calleja have elaborated the concepts and consequences of COVID-19 pneumonia in relation to altitude.
The authors have declared that not competing conflict of interest exist.
- Solaimanzadeh I. Acetazolamide, nifedipine and phosphodiesterase inhibitors: Rationale for their utilization as adjunctive countermeasures in the treatment of coronavirus disease 2019 (COVID-19). Cureus. 2020; 12: e7343. [CrossRef]
- Luks AM, Freer L, Grissom CK, McIntosh SE, Schoene RB, Swenson ER, et al. COVID-19 lung injury is not high altitude pulmonary edema. High Alt Med Biol. 2020; 21: 192-193. [CrossRef]
- Archer SL, Sharp WW, Weir EK. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema: Therapeutic implications. Circulation. 2020; 142: 101-104. [CrossRef]
- Bärtsch P, Swenson ER. Acute high-altitude illnesses. N Engl J Med. 2013; 368: 2294-2302. [CrossRef]
- Bärtsch P, Maggiorini M, Mairbäurl H, Vock P, Swenson E. Pulmonary extravascular fluid accumulation in climbers. Lancet. 2002; 360: 571-572. [CrossRef]
- Rabold M. High-altitude pulmonary edema: A collective review. Am J Emerg Med. 1989; 7: 426-433. [CrossRef]
- Eichstaedt CA, Benjamin N, Grünig E. Genetics of pulmonary hypertension and high-altitude pulmonary edema. J Appl Physiol. 2020; 128: 1432-1438. [CrossRef]
- Sharma K, Mishra A, Singh HN, Parashar D, Alam P, Thinlas T, et al. High-altitude pulmonary edema is aggravated by risk loci and associated transcription factors in HIF-prolyl hydroxylases. Hum Mol Genet. 2021; 30: 1734-1749. [CrossRef]
- Soree P, Gupta RK, Singh K, Desiraju K, Agrawal A, Vats P, et al. Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers. Sci Rep. 2016; 6: 26468. [CrossRef]
- Hotta J, Hanaoka M, Droma Y, Katsuyama Y, Ota M, Kobayashi T. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest. 2004; 126: 825-830. [CrossRef]
- Izmailova O, Shlykova O, Vatsenko A, Ivashchenko D, Dudchenko M, Koval T, et al. Allele С (rs5186) of at1r is associated with the severity of COVID-19 in the Ukrainian population. Infect Genet Evol. 2022; 98: 105227. [CrossRef]
- Khatri R, Gupta RK, Vats P, Bansal V, Kumar Yadav A, Reddy PK, et al. Subclinical elevated B-type Natriuretic Peptide (BNP) indicates endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals. Life Sci. 2020; 260: 118408. [CrossRef]
- Zinellu A, Sotgia S, Carru C, Mangoni AA. B-Type Natriuretic Peptide concentrations, COVID-19 severity, and mortality: A systematic review and meta-analysis with meta-regression. Front Cardiovasc Med. 2021; 8: 690790. [CrossRef]
- Geier MR, Geier DA. Respiratory conditions in coronavirus disease 2019 (COVID-19): Important considerations regarding novel treatment strategies to reduce mortality. Med Hypotheses. 2020; 140: 109760. [CrossRef]
- Storz JF, Scott GR. Phenotypic plasticity, genetic assimilation, and genetic compensation in hypoxia adaptation of high-altitude vertebrates. Comp Biochem Physiol A Mol Integr Physiol. 2021; 253: 110865. [CrossRef]
- Viruez-Soto A, López-Dávalos MM, Rada-Barrera G, Merino-Luna A, Molano-Franco D, Tinoco-Solorozano A, et al. Low serum erythropoietin levels are associated with fatal COVID-19 cases at 4,150 meters above sea level. Respir Physiol Neurobiol. 2021; 292: 103709. [CrossRef]
- Zubieta-Calleja G, Zubieta-DeUrioste N, Venkatesh T, Das KK, Soliz J. COVID-19 and pneumolysis simulating extreme high-altitude exposure with altered oxygen transport physiology; multiple diseases, and scarce need of ventilators: Andean Condor’s-eye-view. Rev Recent Clin Trials. 2020; 15: 347-359. [CrossRef]
- Begemann M, Gross O, Wincewicz D, Hardeland R, Daguano Gastaldi V, Vieta E, et al. Addressing the 'hypoxia paradox' in severe COVID-19: Literature review and report of four cases treated with erythropoietin analogues. Mol Med. 2021; 27: 120. [CrossRef]
- Millet GP, Debevec T, Brocherie F, Burtscher M, Burtscher J. Altitude and COVID-19: Friend or foe? A narrative review. Physiol Rep. 2021; 8: e14615. [CrossRef]
- Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Aliaga-Raudan F, Carvajal-Rodríguez F, Dutschmann M, et al. Does the pathogenesis of SAR-CoV-2 virus decrease at high-altitude? Respir Physiol Neurobiol. 2020; 277: 103443. [CrossRef]
- Seclén SN, Nunes-Robles E, Yovera-Aldana M, Arias-Chumpitaz A. Incidence of COVID-19 infection and prevalence of diabetes, obesity and hypertension according to altitude in Peruvian population. Diabetes Res Clin Pract. 2020; 169: 108463. [CrossRef]