Putative Role of the Lung-Brain Axis in the Pathogenesis of COVID-19-Associated Respiratory Failure: A Systematic Review

Abstract

The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other organs may be damaged as well, including the heart, kidneys, and brain. Current evidence reports a high frequency of neurological manifestations in COVID-19, with significant prognostic implications. Importantly, emerging literature is showing that the virus may spread to the central nervous system through neuronal routes, hitting the brainstem and cardiorespiratory centers, potentially exacerbating the respiratory illness. In this systematic review, we searched public databases for all available evidence and discuss current clinical and pre-clinical data on the relationship between the lung and brain during COVID-19. Acknowledging the involvement of these primordial brain areas in the pathogenesis of the disease may fuel research on the topic and allow the development of new therapeutic strategies.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; brainstem; neurological COVID; neuropathology; neurophysiology; respiratory failure; systematic review.

Figure 1

Anatomy of the lung–brain axis. Sensory inputs from the respiratory tract convey to the central nervous system through cranial nerves, delivering information about special sensation from the nose (olfactory (I) nerve) and somatic sensation from the upper respiratory mucosa (trigeminal (V) nerve), large airways (glossopharyngeal (IX) nerve), and the lungs (vagus (X) nerve). In addition, the IX nerve also transports inputs from the carotid bulb, essential for gas exchange and breathing regulation. Afferent signals converge on the nucleus of the tractus solitarius (NTS) in the pontomedullary region of the brainstem, allowing tight monitoring of the respiratory function and surveillance on potential noxious stimuli. In the NTS, some neuronal populations belong to the dorsal respiratory group (DRG), which receives information from peripheral chemoreceptors about gases’ status, lung mechanisms, and tissue damage. Further modulation of the DRG function comes from the higher cortical structures through the pontine respiratory group (PRG) station. The DRG then conveys signals to the ventral respiratory group (VRG), including the preBötzinger complex, which, through efferent connections to cranial and spinal motoneurons, is responsible for the spontaneous rhythmic pattern of respiration.

Figure 2

Flow diagram of the literature research, screening, selection and final inclusion in the final analysis.

Figure 3

Neurophysiological findings in our series of COVID-19 patients with myoclonus. (A): Generalized periodic discharges, with a right hemisphere predominance, mainly recorded at the parasagittal and midline regions (unpublished data). (B): black arrows indicate waxing and waning myoclonic jerks. Note that these movements do not temporally correlate with periodic lateralized discharges at EEG, without a prominent proximal-to-distal gradient of appearance; all these features suggest a sub-cortical origin of the myoclonus (surface poly-EMG recorded from the right sternocleidomastoid, extensor carpi radialis longus, and tibialis anterior muscles; unpublished data). (C): Blink Reflex (eight superimposed traces) recorded in a COVID-19 patient (top) and a non-COVID-19 patient (bottom). In the former, ipsilateral RII responses had markedly prolonged latencies and contralateral RII were absent, suggesting a pontomedullary lesion (modified with permission from [40]).