key: cord-0854344-1y9dfobn
authors: Tan, Bai‐Hong; Zhang, Yan; Gui, Yue; Wu, Shuang; Li, Yan‐Chao
title: The possible impairment of respiratory‐related neural loops may be associated with the silent pneumonia induced by SARS‐CoV‐2
date: 2020-06-11
journal: J Med Virol
DOI: 10.1002/jmv.26158
sha: 95b4f0c79206a10c567734e0501aa91af2db8b42
doc_id: 854344
cord_uid: 1y9dfobn

As compared to many other viral pulmonary infections, there existed several peculiar manifestations in the COVID‐19 patients, including the “silence” of pneumonia in both mild and severe cases and a long intensive care unit stay for those requiring invasive mechanical ventilation. Similar silent pneumonia has been documented in the infection induced by H5N1 influenza virus HK483, and was found to result from the direct attack of the virus on the bronchopulmonary C‐fibers at the early stage and the final infection in the brainstem at the late stage. The long stay of critical patients in the intensive care unit is possibly due to the depression of central respiratory drive, which resulted in the failure to wean from the mechanic ventilation. Carotid and aortic bodies and bronchopulmonary C‐fibers are two key peripheral components responsible for the chemosensitive responses in the respiratory system, while triggering respiratory reflexes depends predominantly on the putative chemosensitive neurons located in the pontomedullary nuclei. In view of the findings for H5N1 influenza virus, the silence of pneumonia induced by SARS‐CoV‐2 may be due to the possible impairment of peripheral chemosensitive reflexes as well as the damage to the respiratory‐related central neurons. (195 words) This article is protected by copyright. All rights reserved.

in both mild and severe cases and a long intensive care unit stay for those requiring invasive mechanical ventilation. Similar silent pneumonia has been documented in the infection induced by H5N1 influenza virus HK483, and was found to result from the direct attack of the virus on the bronchopulmonary C-fibers at the early stage and the final infection in the brainstem at the late stage. The long stay of critical patients in the intensive care unit is possibly due to the depression of central respiratory drive, which resulted in the failure to wean from the mechanic ventilation. Carotid and aortic bodies and bronchopulmonary C-fibers are two key peripheral components responsible for the chemosensitive responses in the respiratory system, while triggering respiratory reflexes depends predominantly on the putative chemosensitive neurons located in the pontomedullary nuclei. In view of the findings for H5N1 influenza virus, the silence of pneumonia induced by SARS-CoV-2 may be due to the possible impairment of peripheral chemosensitive reflexes as well as the damage to the respiratory-related central neurons. (195 words)

Acute respiratory distress, coronavirus, COVID-19, nervous system Following the worldwide spread of two previously unrecognized coronaviruses (CoV), the severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), another CoV, SARS-CoV-2, emerged as a highly contagious pathogen that spreads rapidly among human beings and has caused a worldwide outbreak of severe pneumonia (COVID-19) from the beginning of 2020.

As compared to many other viral pulmonary infections, there existed several peculiar manifestations in the COVID-19 patients, including the "silence" of pneumonia in both mild and severe cases and a long intensive care unit (ICU) stay for those requiring invasive mechanical ventilation. The peculiar features are now attracting more and more attention, but the underlying mechanisms are not fully clear.

Pathological examination showed that the lungs from infected patients manifested significant pathological lesions, including alveolar exudative and interstitial inflammation, alveolar epithelium proliferation and hyaline membrane formation. This article is protected by copyright. All rights reserved.

Consistently, imaging examination reveals that most COVID-19 patients showed characteristic ground-glass opacities on chest CT scans.

The available clinical data show that COVID-19 patients, whether mild or severe, all showed bilateral distribution of patchy shadows or ground glass opacity 1, 2 . It is more surprising that similar CT abnormalities have also been observed in the asymptomatic patients with COVID-19, and there were no significant differences in individual signs, patterns, zonal predominance or extent of CT abnormalities between the asymptomatic and symptomatic patients 3 .

Although chest CT has revealed striking abnormalities in the lungs of COVID-19 patients, most of them showed only mild flu-like symptoms 1 Several researchers also noticed that despite severe hypoxemia, the mechanical characteristics of the lungs were relatively well preserved in the severe COVID-19 patients, which is rarely seen in other forms of acute respiratory distress syndrome. A possible explanation, provided by the authors, is the loss of lung perfusion regulation and hypoxic vasoconstriction 5 .

It has been noticed that the COVID-19 patients, who required invasive mechanical ventilation, were characteristic of a long ICU stay 2, 6 . These patients could not be weaned from the invasive mechanical ventilation, even though they had recovered from pneumonia 6 . Depression of central respiratory drive, resulting from the impairment of brainstem respiratory center, has been suggested as one main reason for this peculiar manifestation 6 . This article is protected by copyright. All rights reserved.

Dyspnea is known as a multi-dimensional cognitive output of respiratory sensation that is initiated by peripheral afferent fibers and processed through the brainstem to In view of the findings on H5N1 virus, it is possible that the poor sputum production and the subjective feeling lacking dyspnea in COVID-19 patients may be attributed to a possible impairment of the respiratory-related neural loops. The infection in bronchopulmonary C-fibers will attenuate hypercapnic ventilatory response, while the infection of chemosensitive neurons in the pontomedullary nuclei will abolish hypoxic ventilatory response. However, low arterial partial pressure of carbon dioxide has been detected in most cases with COVID-19, suggesting that the hypercapnic ventilatory response remains appropriate after SARS-CoV-2 infection.

Different from that reported for H5N1 virus, SARS-CoV-2 nucleic acid has also been detected in the serum, especially in critically ill patients, which dramatically increased the risk of infection of glomus cells in the carotid and aortic bodies, a major sensor monitoring O 2 + in the blood, whose afferent axons communicate with the medullary respiratory centers in response to the change of blood oxygen.

Besides the peripheral components, the poor perception of hypoxemia in the COVID-19 patients may also be attributed to a possible defective cortical processing of This article is protected by copyright. All rights reserved.

Accepted Article respiratory signals. SARS-CoV-2 genome or particles have been demonstrated in the cerebrospinal fluid or brain tissues from some COVID-19 patients, which clearly demonstrated that SARS-CoV-2 has the ability to enter the central nervous system. In a COVID-19 patient with severe anosmia and dysgeusia, abnormal MRI signals have been found in the right gyrus rectus and olfactory bulbs on the third day after the onset of the disease 8 . Ultrastructural study on samples from a postmortem patient with COVID-19

further revealed severe tissue damage involving neurons, axons and myelin sheath along the pathway from olfactory nerves to the medulla oblongata 9 .

As mentioned above, the direct infection of respiratory-related neural loops has been demonstrated to be responsible for the silence of pneumonia induced by H1N1 influenza virus. It is quite likely that this is also the case for the SARS-CoV-2 infection. Therefore, we propose that the peculiar manifestations in COVID-19 patients may be attributed to the possible impairment of peripheral chemosensitive reflexes as well as the damage to the respiratory-related central neurons. This conclusion will supplement our previous hypothesis 10 , and provide an important clue to reveal the mechanisms underlying the acute respiratory distress syndrome induced by SARS-CoV-2.

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city

Acute Respiratory Distress Syndrome

Brainstem involvement and respiratory failure in COVID-19

Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilator response in mice

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

Early postmortem brain MRI findings in COVID-19 non-survivors. PREPRINT (BELGIUM)

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients