Commentaries on Viewpoint: Nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia.

: Barreto-Filho et al. (1) proposed a potential mechanism of dysregulation of ventilatory control in patients affected by COVID-19 (disease caused by the newly discovered SARS-CoV-2) and a lack of awareness during acute hypoxemic respiratory failure. Although the physiopathology of COVID-19 is largely unknown, the fact that SARS-CoV-2 may affect the control of minute ventilation raises important considerations that need to be addressed.

The SARS-CoV-2 invasion of central and peripheral respiratory neural networks may cause different effects on the control of respiratory frequency (fR) and tidal volume (VT), with important implications for patients who recovered from the COVID-19 disease. Indeed, although VT appears to be mainly influenced by chemical stimuli, fR seems to be substantially regulated by central command and group III/IV muscle afferent feedback inputs (2,3). Consequently, the chemosensitivity damage induced by SARS-CoV-2 might be more evident in VT rather than fR responses. Moreover, the inflammatory damage induced by the SARS-CoV-2 in the central respiratory neurons may also be extended to the subregion of the medial parabrachial complex, an area known to be involved in the control of expiratory and inspiratory duration (4). Lastly, the SARS-CoV-2 invasion of skeletal muscle tissues may cause neuromuscular damage (5) and affect the neural activity of group III/IV muscle afferents, which, in turn, may contribute to the dysregulation of fR (2). Therefore, it is highly advised to consider the effects of SARS-CoV-2 on fR and VT separately. Further studies are certainly required to better understand the effects of SARS-CoV-2 on the ventilatory control system.

: We appreciate the attempt of Barreto-Filho et al. (1) to provide insight into the mechanisms underlying the nondyspnogenic acute hypoxemic respiratory failure observed in some patients with COVID-19. Understanding the pathophysiology of this manifestation is important for COVID-19 clinical management. Here, we make a simple suggestion that may help address this issue from both physiological and clinical points of view.

We have recently pointed out that respiratory frequency (fR) and tidal volume (VT) may be regulated by different inputs during exercise (2), and that this feature extends to nonexercise conditions (3,4). Unlike VT, fR may not be substantially regulated by metabolic inputs, as shown in human and animal studies (2,3). Hence, it is conceivable that SARS-CoV-2 may affect VT and fR by acting preferentially on chemical and nonchemical pathways, respectively. The differential control of fR and VT has implications for the interpretation of respiratory signs and symptoms, as the components of dyspnea may be associated with different ventilatory responses (4). An example is the preferential increase in VT associated with the occurrence of air hunger in patients with metabolic acidosis (e.g., Kussmaul’s breathing) (4). However, despite the importance of respiratory monitoring in patients with COVID-19 and other diseases, the abundance of available technological solutions is currently not accompanied by an effective use of respiratory devices in clinical settings (4,5). We urgently need to improve the everyday measurement of fR and VT for managing COVID-19 and understanding the ventilatory responses associated with nondyspnogenic acute hypoxemic respiratory failure.