Respiratory Drive, Dyspnea, and Silent Hypoxemia: A Physiological Review in the Context of COVID-19

Abstract

Infection with SARS-CoV-2 in select individuals results in viral sepsis, pneumonia, and hypoxemic respiratory failure, collectively known as COVID-19. In the early months of the pandemic, the combination of novel disease presentation, enormous surges of critically ill patients, and severity of illness lent to early observations and pronouncements regarding COVID-19 that could not be scientifically validated owing to crisis circumstances. One of these was a phenomenon referred to as "happy hypoxia." Widely discussed in the lay press, it was thought to represent a novel and perplexing phenomenon: severe hypoxemia coupled with the absence of respiratory distress and dyspnea. Silent hypoxemia is the preferred term describing an apparent lack of distress in the presence of hypoxemia. However, the phenomenon is well known among respiratory physiologists as hypoxic ventilatory decline. Silent hypoxemia can be explained by physiologic

SARS-CoV-2 Neuroinvasion, Inflammatory Neurodegeneration and Alzheimer's Disease

“…"Long COVID" or "post-COVID-19 syndrome" is emerging as a complex long-term disorder with extended and heterogeneous symptoms in both systemic human physiology and in neurological complications for each individual COVID-19 patient. It is our opinion that the remarkable ubiquity of the ACE2R, the primary receptor for the SARS-CoV-2 virus on multiple cell membrane types of the human host, is probably the reason for the widespread systemic involvement of SARS-CoV-2 invasion, and enrichment of the ACE2R in the limbic regions of the human brain in AD patients is probably why AD patients suffer from an increased incidence and susceptibility to COVID-19 infection (Kallet et al, 2019;Ahmad and Rathore, 2020;Magusali et al, 2021;Sun et al, 2021;Lukiw et al, 2022;Stefanou et al, 2022;Visco et al, 2022). Like many neurotropic viruses with RNA genomes, SARS-CoV-2 has a remarkably broad neuroinvasive capacity and neurons appear to be directly targeted by a particularly virulent infection (Song et al, 2020;Choe et al, 2022;Lukiw et al, 2022).…”

“…Long-lasting neurological consequences after SARS-CoV-2 infection negatively impacts the brain and CNS in anatomical regions known to be targeted by neurodegenerative events, as is observed throughout all phases of the AD continuum (Lingor et al, 2022;Lukiw et al, 2022;Piekut et al, 2022;Sirin et al, 2022;Szabo et al, 2022). Pre-existing neurological conditions and pathological interactions among the brain, central and peripheral nervous systems (CNS, PNS) and respiratory, cardiovascular and endocrine systems further modulate and/or impact the severity and long-term sequelae of the post-COVID-19 syndrome period (Kallet et al, 2019;Horn et al, 2021;Zuin et al, 2021;Molina-Molina and Hernández-Argudo, 2022;Sanyaolu et al, 2022;Stefanou et al, 2022;Visco et al, 2022). Our recent appreciation that many intractable and invariably fatal neurodegenerative disorders including AD that involve protein misfolding, aggregation and spread are prion disorders provides another dimension for the invasion of SARS-CoV-2, however the interaction between viral structure and infectivity and changes in protein conformation and aggregation are not well understood (Carlson and Prusiner, 2021;Lukiw, 2022b).…”

“…SARS-CoV-2 invasion also causes overall worsening of underlying and existing chronic cardiac, respiratory and other pathological disorders that include atrial fibrillation, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis/bronchiectasis, emphysema, interstitial lung disease, pleural effusion, pulmonary fibrosis, lung cancer, pre-existing pneumonia, metabolic syndrome and venous thromboembolic diseases (alphabetically ordered; https://www.unitypoint.org/homecare/article.aspx? id=2448b930-1451-43e4-8634-c0c16707c749; last accessed 27 May 2022; Kallet et al, 2019;Lee et al, 2021;Zuin et al, 2021;Stefanou et al, 2022;Visco et al, 2022). It has been observed that about ∼75% of hospitalized COVID-19 patients have at least one COVID-19-associated comorbidity and COVID-19 patients with underlying chronic illnesses are more likely be affected with a more adverse and unfavorable prognosis (Chiner-Vives et al, 2022;Crivelli et al, 2022;Kirtipal et al, 2022).…”

Silent Hypoxemia in the Emergency Department: A Retrospective Cohort of Two Clinical Phenotypes in Critical COVID-19

“…Another mechanism behind this clinical presentation is attributable to the idiosyncratic action of SARS-CoV-2 on the receptors involved in chemosensitivity to oxygen [ 8 , 32 ]. Respiratory response to a decrease in oxygen blood tension is quantified by the hypoxic ventilatory response, a fundamental physiological response to hypoxia, which aligns with physiology, regardless of the cause of hypoxemia, and is largely mediated by the carotid chemoreceptors and regulated based on pCO 2 [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Hypocapnia induces respiratory alkalosis, increasing arterial oxygen saturation [ 16 , 17 ].…”

“…Others associate it with the neuro-invasive potential of the virus [ 15 ]. Further hypotheses include chemoreflex dysregulation similar to high-altitude exposure and other hypoxic response and decline mechanisms [ 16 , 17 ].…”