Nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia

COVID-19 is a multifaceted disease and respiratory failure is a common manifestation. Interestingly, several reports are suggesting that many patients with COVID-19 pneumonia seem to present less respiratory effort and experience less dyspnea when exposed to acute respiratory failure and hypoxemia, a phenomenon called “silent,” “happy,” or even “apathetic” hypoxemia. We present a personal view exploring potential pathways associated with this intriguing clinical feature. We also suggest that “nondyspnogenic acute hypoxemic respiratory failure” is a more accurate terminology to describe this clinical finding in COVID-19, as hypoxemia may not be the only trigger for dyspnea in patients with pneumonia associated with respiratory failure. Acute hypoxemic respiratory failure is a common clinical manifestation in patients with pneumonia caused by the new severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and is a marker of in-hospital mortality (1, 2). The autonomic nervous system orchestrates a complex respiratory and cardiovascular response during a hypoxemic stress. Besides the lung and cardiovascular manifestations documented in patients with the new coronavirus disease 2019 (COVID-19) (3), there is growing evidence suggesting that SARS-CoV-2 is a neurotropic virus and may invade the peripheral and central nervous system (CNS) by several routes, with widespread brain injury, including the respiratory and cardiovascular autonomic centers (4, 5). In clinical practice, acute hypoxemic respiratory syndromes, such as those caused by bacterial or viral pneumonia, are generally accompanied by dyspnea sensation (6–8). In a cohort of 395 patients with community-acquired pneumonia, 94% of those with severe pneumonia presented with dyspnea (7). Interestingly, several anecdotal reports are suggesting that patients with COVID-19 pneumonia have an atypical nondyspnogenic response to acute hypoxemic respiratory failure (9–11). Some argue that these patients present with less respiratory effort and experience less dyspnea even when exposed to critical hypoxemia, a phenomenon called “silent,” “happy,” or even “apathetic” hypoxemia (11–13). The term “silent hypoxemia” has been criticized because dyspnea is a complex and multifactorial symptom not only dependent on systemic hypoxemia (14). Previous studies in healthy humans suggest that hypoxemia per se is generally well tolerated and hypoxemia associated with acute respiratory failure may be only a marker of a more complex respiratory pathophysiology and not the determinant cause of dyspnea (15–17). Moreover, in controlled human experiments, respiratory effort is not necessarily associated with dyspnea sensation (18). Therefore, in this review, we prefer to use the term nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia to describe the apparently comfortable status of patients with COVID-19, despite marked acute hypoxemic respiratory failure (9, 10). Nondyspnogenic acute hypoxemic respiratory failure is not an expected feature in clinical practice when assisting patients with pneumonia. Conversely, nondyspnogenic respiratory failure is more common in chronic conditions, such as chronic pulmonary obstructive disease and pulmonary fibrosis, and can also be seen in high altitude sickness (19). The limited understanding of the complex mechanisms involved in dyspnea sensation and of the neuropathology associated with SARS-CoV-2 infection is a barrier to explain why patients with severe hypoxemia may present to the emergency department without any physical discomfort and almost asymptomatic. Two initial hypotheses have been speculated to explain the installation of nondyspnogenic acute hypoxemic respiratory failure in these circumstances: the association of iso/hypocapnia, preventing the uncomfortable feelings of air hunger (19); and the maintenance of pulmonary mechanics (total dead space, lung compliance, and resistance) in near-normal range in the first stages of respiratory failure, thus not increasing significantly the respiratory effort (19, 20). Although both mechanisms are biologically plausible, they fail to address why acute respiratory failure in COVID-19 pneumonia seems to be peculiarly undersensed by these patients. To integrate the current knowledge regarding SARS-CoV-2 infection with the peculiar nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia, we hypothesize a different mechanism related to an early and complex interaction between SARS-CoV-2 infection and the peripheral and central nervous system disturbing the activation of brain regions responsible for dyspnea sensation during acute hypoxemic respiratory failure.