Differentiating COVID-19 Pneumonia From Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema
Authors: Stephen L. Archer, Willard W. Sharp, E. Kenneth Weir
Journal: Circulation (2020)

oronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by a droplet-borne severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).By May 1, 2020, the pandemic had resulted in ≈3.3 million infections, more than 235,000 deaths, and global disruption of trade.Although 80% of people with COVID-19 have a minor, acute respiratory infection, the mortality ranges from 2% to 7%.Patients with COVID-19 pneumonia may decompensate because of hypoxemic respiratory failure.Autopsy data show inflammation, diffuse alveolar damage, alveolar fluid accumulation, and occasional hyaline membranes, consistent with acute respiratory distress syndrome (ARDS).Understanding the causes of hypoxemia in COVID-19 is complicated by a paucity of hemodynamic and autopsy data; however, the presentation of patients with COVID-19 is atypical of ARDS in that the hypoxemia is often profound without appropriate dyspnea, occurs despite relatively preserved lung compliance, and is associated with a large intrapulmonary shunt.These traits suggest a failure of the body's homeostatic oxygen-sensing system, which includes the pulmonary circulation, carotid body, adrenomedullary cells, and neuroepithelial bodies.The homeostatic oxygen-sensing system optimizes oxygen uptake and systemic oxygen delivery.Hypoxic pulmonary vasoconstriction (HPV) is the pulmonary circulation's homeostatic response to airway hypoxia in lung diseases, such as pneumonia.HPV constricts pulmonary arteries serving hypoxic lung segments, diverting blood to better-ventilated alveoli, optimizing ventilation/perfusion matching.The carotid body senses hypoxemia, increasing respiratory drive.COVID-19 hypoxemia is variably attributed to ARDS, impaired HPV, and a high altitude pulmonary edema (HAPE) physiology (Figure).We propose that the best explanation is profound impairment of HPV and carotid body function, sometimes combined with virally induced ARDS.In pulmonary artery smooth muscle cells, a mitochondria-based, redox sensor involving NDUFS2 regulates oxygen-sensitive potassium and voltage-gated calcium channels initiating HPV. 1 HPV is inhibited by systemic vasodilators, like calcium channel blockers, and diseases, such as endotoxemia/sepsis.A similar mitochondrial mechanism accounts for oxygen-sensing in the carotid body. 1 Impaired carotid body function would impair respiratory drive and reduce dyspnea.SARS-CoV-2 infection of human cells changes expression of many proteins.It is interesting that 36% of all upregulated proteins and 19% of all downregulated proteins in SARS-CoV-2-infected cells are mitochondrial proteins. 2These include apoptosis mediators (apoptosis-inducing factor and cytochrome C) and proteins involved in aerobic metabolism (relevant to the mechanism of oxygen-sensing).These findings are associations, not proofs; however, they offer biological plausibility that SARS-CoV-2 may interfere with mitochondrial oxygen-sensing and cause mitochondrial-induced injury.Several features of COVID-19 pneumonia distinguish it from typical ARDS.Patients often display little breathlessness, despite profound hypoxemia, a