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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 68
| Issue : 5 | Page : 989-993 |
Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress
Calixto Machado1, Phillip A DeFina2, Mauricio Chinchilla1, Yanín Machado1, Yazmina Machado1
1 Institute of Neurology and Neurosurgery, Department of Clinical Neurophysiology, Havana, Cuba
2 International Brain Research Foundation, Inc. Chief Executive Officer, 227 Rte. 206, Flanders, New Jersey, United States
| Date of Web Publication | 27-Oct-2020 |
Correspondence Address:
Dr. Calixto Machado
Institute of Neurology and Neurosurgery Department of Clinical Neurophysiology 29 y D, Vedado, La Habana 10400
Cuba
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.299165
Background: A terrible pandemic, Covid-19, has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS). A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by respiratory center dysfunction.
Objective: To discuss that ARDS can be caused by SARS-CoV-2 infection of the respiratory center in the brainstem.
Materials and Methods: I reviewed literature about SARS-CoV-2 mechanisms to infect the respiratory center in the brainstem.
Results and Conclusions: An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which have been found in the brains of patients and experimental models, where the brainstem was severely infested. Recent studies have provided tremendous indication of the incidence of acute respiratory failure due to SARS-CoV-2 infection of the brainstem. SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem. Hence, the virus infection causes respiratory center dysfunctions, leading to ARDS in COVID-19 patients. I conclude that acute ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.
Keywords: Acute respiratory distress syndrome, brainstem, coronavirus, COVID-19, pandemic, respiratory center, SARS-CoV-2
Key Message: ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.
How to cite this article:
Machado C, DeFina PA, Chinchilla M, Machado Y, Machado Y. Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress. Neurol India 2020;68:989-93 |
How to cite this URL:
Machado C, DeFina PA, Chinchilla M, Machado Y, Machado Y. Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress. Neurol India [serial online] 2020 [cited 2023 Dec 3];68:989-93. Available from: https://www.neurologyindia.com/text.asp?2020/68/5/989/299165 |
A terrible pandemic, Covid-19,[1],[2],[3],[4] has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS).[5],[6],[7],[8],[9] A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by CNS affection.[10],[11],[12]
An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which has been found in the brains of patients and experimental models, where the brainstem was severely infested.[10],[11],[12],[13],[14],[15],[16],[17],[18] Recent studies have provided tremendous indication of the incidence of acute respiratory failures in COVID-19 due to SARS-CoV-2 infection of the brainstem.[6],[14],[19],[20]
Therefore, the potential neuroinvasion of SARS-CoV-2 must prompt physician to be aware of the possible failure of the central regulation of the breathing process, which undoubtedly contributes to the mortality of the Covid-19 patients.
This review article was reviewed and approved by the Ethics Committee of the Institute of Neurology and Neurosurgery, on 05-01-2020.
Brainstem dysfunction in SARS-CoV-2 infection as a potential cause of ARDS
The most characteristic and challenging symptoms of Covid-19 are related to ARDS.[21],[22],[23],[24] Wang et al. reported that about 46–65% of the patients admitted in the intensive care units (ICUs) required mechanical ventilation in a brief period of time and died because of respiratory distress. According to these data, about 89% of the patients in ICUs could not breathe by their own, worsening in a short period of time and dying due to respiratory failure.[25],[26]
It has been discussed that SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem, through trans-synaptic spread. Hence, the virus infection to the respiratory center results in an ARDS in COVID-19 patients. Up to date no specific lung-directed treatment for ARDS is available, remaining mechanical ventilation as the backbone of treatment for this condition[19],[27],[28],[29],[30] [Figure 1]. | Figure 1: Schematic illustration showing how SARS-CoV-2 infects the respiratory center in the brainstem. SARS-CoV-2 may follow a route entering through the olfactory mucosa in the upper nasal cavity. Through olfactory axons it traverses the cribriform plate, projecting to the olfactory epithelium and olfactory bulb. The virus further migrates to other parts of the brain by trans-synaptic spread, finally targeting the respiratory center. There, it mainly alters the pre-Bötzinger complex function, causing dysregulation of the rhythmic breathing pattern, finally leading to respiratory failure
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It has been widely supported that lesions in the medulla and pons can cause respiratory center dysfunction, like in congenital central hypoventilation syndrome,[31] or severe brain injury,[32] which results in damage of respiratory control function.[33],[34],[35],[36],[37],[38]
The breathing mechanism controlled by the CNS is an involuntary (autonomous) process enforced by pacemaker cells in respiratory centers in the brainstem. The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is composed of three major respiratory groups of neurons, two in the medulla and one in the pons. The ventral (VRG) and dorsal (DRG) respiratory groups are located in the medulla. In the pons, the pontine respiratory group includes two areas known as the pneumotaxic center and the apneustic center.[6],[7],[14],[39],[40],[41]
The pre-Bötzinger complex, a projection of the Botzinger complex, plays an important role in regulating respiration in mammals. It is one of the four cell groups of the VRG. It is theorized that the pre-Bötzinger complex is the main location of the rhythmic pattern generation network involved in breathing movements. Rhythmogenesis, the generation of rhythm, is modulated by membrane properties and synaptic interactions occurring in interneurons, intrinsically bursting pacemaker neurons, and follower neurons within the pre-Bötzinger complex. The rhythmic discharges of the pre-Bötzinger pacemaker neurons are changed by the pneumotaxic center (nucleus parabrachialis), which may play a role in alternating between inspiration and expiration. This intrinsic network is regulated by a huge range of neurotransmitters, amino acids, and chemical signals, such as adenosine, GABA, and glycine.[42],[43],[44]
Afferent axons from the carotid and aortic bodies in the glossopharyngeal nerve contain chemoreceptor cells, and vagal afferent nerves from receptors in the lung communicate with the medulla and pons respiratory control centers to coordinate inspiration and expiration; meanwhile, the efferent fibers from the nucleus ambiguous and the nucleus of the solitary tract innervates the airway smooth muscle, glands, and blood vessels. Such neuroanatomic network indicates that the death of infected animals or patients, due to respiratory failure, may be triggered by dysfunction of the respiratory center in the brainstem.[6],[45],[46],[47],[48],[49] Destruction of neurons in the medulla and pons leads to ARDS, coma, or death.[24]
The hypoxia in COVID-19, which should stimulate of the pre-Bötzinger complex via chemoreceptors area is predictable to cause an augmented respiratory rate and depth that has been frequently reported in COVID-19 patients. In contrast, Covid-19 patients suffering deep hypoxia ostensibly appear to be asymptomatic with even deceptive cyanosis, but very frequently progress to respiratory failure, requiring mechanical ventilation. The final clinical picture is characterized by an important increment of respiratory rate, as high as 38/min, profound hypoxia with low PCO2 levels, without any dyspnea until late in the evolution of the disease. Impairment to vagal receptors in the lungs and perhaps mechanoreceptors in the respiratory muscles, sending neural information to the sensorimotor cortex, might explain the absence of dyspnea feeling. On the contrary, COVID-19 patients retain the control over voluntary breathing, suggesting that the neocortical projections to the spinal motor neurons are not damaged in this disease.[14],[50]
Bulfamante et al. described ultrastructural autopsy findings in a Covid-19 case, who required mechanical ventilation due to a severe ARDS. These authors studied three different anatomic regions: the olfactory nerve, the gyrus rectus, and the brainstem at the level of the medulla oblongata. In these anatomic structures, they found severe and widespread tissue damage in the neurons, glia, nerve axons, and myelin sheath. Furthermore, they remarkably observed numerous viral particles referable to SARS-Cov-2 invasion. At the medulla oblongata, these authors found asymmetrical axonal swelling and disruption of the myelin sheath, and viral particles with size suspicious for a viral particle was also found in the periaxonal matrix near the outer surface of a myelin sheath. As this patient also suffered anosmia and ageusia, and considering the ultrastructural damage findings in the olfactory bulb, the authors concluded that a direct virus invasion through the olfactory mucosa to the respiratory center was the cause of ARDS.[51]
Hence, it can be argued that SARS-CoV-2 invades the brainstem in early phases of the disease, leading to respiratory failure, even when hypoxemic influence has not come to effect. A wide-ranging or considerable loss of the neurons in the pre-Bötzinger complex region would lead to a neurogenic acute respiratory arrest in spite of moderate hypoxic and hypocapnia levels, as has been reported in COVID-19 patients with involvement of the brainstem at the level of the medulla oblongata.[14],[50],[52],[53]
Other possible routes of SARS-CoV-2 infection have been proposed, like viral invasion via retrograde routing from the lungs through the vagal nerve to the cardiorespiratory center in the brainstem and viral invasion through the bloodstream. Nonetheless, direct viral invasion of the brain through the olfactory mucosa and the olfactory pathways seem to be an effective way for the virus to cause ARDS.[10],[51]
| » Conclusion | |  |
SARS-CoV-2 infection of the brainstem can deeply damage the respiratory center, triggering functional deviations that affect involuntary respiration regulation, leading to ARDS refractory to treatments, which is the main cause of death in Covid-19 patients.
Hence, serial neurological examinations are recommended, with an exhaustive exploration of brainstem reflexes, even in asymptomatic patients. As neuroimaging techniques are not always available to use in ventilated patients in the ICU setting, ancillary tests, such as brainstem auditory and somatosensory, evoked potentials, quantitative EEG, transcranial Doppler, can be used to monitor brain function in severe-acute Covid-19 patients.[10]
Therefore, acute ARDS in Covid-19 can be explained by brainstem dysfunction, due to direct SARS-CoV-2 invasion, suggesting the needs of more specific and aggressive treatments with the direct participation of neurologists and neurointensivists.[10],[11],[12],[54]
Future research is needed to comprehend the route of virus entry (neural or through the bloodstream), trans-synaptic spread, neuronal damage, and brain affected areas, including a detailed pathological assessment of the respiratory center in the brainstem.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » References | | |
| 1. | Bavishi C, Maddox TM, Messerli FH. Coronavirus disease 2019 [COVID-19] infection and renin angiotensin system blockers. JAMA Cardiol 2020. doi: 10.1001/jamacardio.2020.1282.  |
| 2. | Al-Quteimat Om Msc B, Amer Am R. Ph M. SARS-CoV-2 outbreak: How can pharmacists help? Res Social Adm Pharm 2020. doi: 10.1016/j.sapharm.2020.03.018. |
| 3. | Bonate PL. COVID-19: Opportunity arises from a world health crisis. J Pharmacokinet Pharmacodyn 2020;47:119-20. |
| 4. | Caly L, Druce J, Roberts J, Bond K, Tran T, Kostecki R, et al. Isolation and rapid sharing of the 2019 novel coronavirus (SAR-CoV-2 from the first patient diagnosed with COVID-19 in Australia. Med J Aust 2020;212:459-63. |
| 5. | Federico A. Brain awareness week, CoVID-19 infection and neurological sciences. Neurol Sci 2020;41:747-8. |
| 6. | Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020;92:552-5. |
| 7. | Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun 2020;87:18-22. |
| 8. | Das G, Mukherjee N, Ghosh S. Neurological inights of COVID-19 pandemic. ACS Chem Neurosci 2020;11:1206-9. |
| 9. | Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, et al. COVID-19 presenting as stroke. Brain Behav Immun 2020;87:115-9. |
| 10. | Machado C. Severe Covid-19 cases: Is respiratory distress partially explained by central nervous system involvement?. Med Rev 2020;22:38-41. |
| 11. | Machado C. Reader response: COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology. 2020. doi: 10.1212/WNL.0000000000009700. |
| 12. | Machado C. Reader response: Neurologists and COVID-19: A note on courage in a time of uncertainty. Neurology. 2020;94:855-7. |
| 13. | Conde G, Quintana Pajaro LD, Quintero Marzola ID, Ramos Villega Y, Mascote Salazarb LT. Neurotropism of SARS-CoV 2: Mechanisms and manifestations. J Neurol Sci. 2020;412:116824. doi: 10.1016/j.jns.2020.116824. |
| 14. | Baig AM. Computing the effects of SARS-CoV-2 on respiration regulatory mechanisms in COVID-19. ACS Chem Neurosci 2020. doi: 10.1021/acschemneuro.0c00349. |
| 15. | Freni F, Meduri A, Gazia F, Nicastro V, Galletti C, Aragona P, et al. Symptomatology in head and neck district in coronavirus disease [COVID-19]: A possible neuroinvasive action of SARS-CoV-2. Am J Otolaryngol 2020;41:102612. |
| 16. | Ahmed MU, Hanif M, Ali MJ, Haider MA, Kherani D, Memon GM, et al. Neurological manifestations of COVID-19 (SARS-CoV-2): A review. Front Neurol 2020;11:518. |
| 17. | Mawhinney JA, Wilcock C, Haboubi H, Roshanzamir S. Neurotropism of SARS-CoV-2: COVID-19 presenting with an acute manic episode. BMJ Case Rep 2020;13. doi: 10.1136/bcr-2020-236123. |
| 18. | Hascup ER, Hascup KN. Does SARS-CoV-2 infection cause chronic neurological complications? Geroscience. 2020:1-5. doi: 10.1007/s11357-020-00207-y. |
| 19. | Gandhi S, Srivastava AK, Ray U, Tripathi PP. Is the collapse of the respiratory center in the brain responsible for respiratory breakdown in COVID-19 patients? ACS Chem Neurosci 2020;11:1379-81. |
| 20. | Roman GC, Spencer PS, Reis J, Buguet A, Faris MEA, Katrak SM, et al. The neurology of COVID-19 revisited: A proposal from the environmental neurology specialty group of the world federation of neurology to implement international neurological registries. J Neurol Sci 2020;414:116884. doi: 10.1016/j.jns.2020.116884. |
| 21. | Cao Y, Liu X, Xiong L, Cai K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis. J Med Virol 2020. doi: 10.1002/jmv.25822. |
| 22. | Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not lead to a “Typical” acute respiratory distress syndrome. Am J Respir Crit Care Med 2020;201:1299-300. |
| 23. | Zhou M, Zhang X, Qu J. Coronavirus disease 2019 [COVID-19]: A clinical update. Front Med 2020;14:126-35. |
| 24. | Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. |
| 25. | Wang J, Hajizadeh N, Moore EE, McIntyre RC, Moore PK, Veress LA, et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series. J Thromb Haemost 2020;18:1752-5. |
| 26. | Wang L, He W, Yu X, Hu D, Bao M, Liu H, et al. Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up. J Infect. 2020;80:639-45. |
| 27. | Sellner J, Taba P, Ozturk S, Helbok R. The need for neurologists in the care of COVID-19 patients. Eur J Neurol 2020. doi: 10.1111/ene.14257. |
| 28. | Coolen T, Lolli V, Sadeghi N, Rovai A, Trotta N, Taccone FS, et al. Early postmortem brain MRI findings in COVID-19 non-survivors. Neurology 2020. doi: 10.1212/WNL.0000000000010116. |
| 29. | Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg 2020;194:105921. doi: 10.1016/j.clineuro.2020.105921. |
| 30. | Galougahi MK, Ghorbani J, Bakhshayeshkaram M, Naeini AS, Haseli S. Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: The first report. Acad Radiol 2020;27:892-3. |
| 31. | Fisher M, Smeiles C, Jnah AJ, Ruiz ME, Difiore T, Sewell K. Congenital central hypoventilation syndrome: A case-based learning opportunity for neonatal clinicians. Neonatal Netw 2019;38:217-25. |
| 32. | Wienke A, Walter O. Loss of the sense of taste and smell after head and brain injury. Laryngorhinootologie 2001;80:752. |
| 33. | Machado C, Gutierrez JV. Anosmia and ageusia as initial or unique symptoms after sars-cov-2 virus infection (Review article). Preprints 2020;2020040272. doi: 10.20944/preprints202004.0272.v1. |
| 34. | Estevez-Baez M, Machado C, Garcia-Sanchez B, Rodriguez V, Alvarez-Santana R, Leisman G, et al. Autonomic impairment of patients in coma with different Glasgow coma score assessed with heart rate variability. Brain Inj 2019;33:496-516. |
| 35. | Estevez-Baez M, Carricarte-Naranjo C, Jas-Garcia JD, Rodriguez-Rios E, Machado C, Montes-Brown J, et al. Influence of heart rate, age, and gender on heart rate variability in adolescents and young adults. Adv Exp Med Biol 2019;1133:19-33. |
| 36. | Estevez-Baez M, Machado C, Montes-Brown J, Jas-Garcia J, Leisman G, Schiavi A, et al. Very high frequency oscillations of heart rate variability in healthy humans and in patients with cardiovascular autonomic neuropathy. Adv Exp Med Biol 2018;1070:49-70. |
| 37. | Machado C, Estevez M, Perez-Nellar J, Schiavi A. Residual vasomotor activity assessed by heart rate variability in a brain-dead case. BMJ Case Rep 2015;2015. doi: 10.1136/bcr-2014-205677. |
| 38. | Machado C, Estevez M, Rodriguez R, Perez-Nellar J, Chinchilla M, DeFina P, et al. Zolpidem arousing effect in persistent vegetative state patients: Autonomic, EEG and behavioral assessment. Curr Pharm Des 2014;20:4185-202. |
| 39. | Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-2. |
| 40. | Rissel R, Gosling M, Ruemmler R, Ziebart A, Hartmann EK, Kamuf J. Bronchoalveolar lavage and oleic acid-injection in pigs as a double-hit model for acute respiratory distress syndrome (ARDS). J Vis Exp 2020. doi: 10.3791/61358. |
| 41. | Holt PG. The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage. J Allergy Clin Immunol 2015;136:15-22. |
| 42. | Guyenet P. How does CO2 activate the neurons of the retrotrapezoid nucleus? J Physiol 2012;590:2183-4. |
| 43. | Basting TM, Burke PG, Kanbar R, Viar KE, Stornetta DS, Stornetta RL, et al. Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis. J Neurosci 2015;35:527-43. |
| 44. | Guyenet PG, Bayliss DA, Stornetta RL, Kanbar R, Shi Y, Holloway BB, et al. Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus. J Physiol 2018;596:3029-42. |
| 45. | Ceccarelli M, Berretta M, Venanzi Rullo E, Nunnari G, Cacopardo B. Differences and similarities between severe acute respiratory syndrome [SARS]-CoronaVirus (CoV) and SARS-CoV-2. Would a rose by another name smell as sweet? Eur Rev Med Pharmacol Sci 2020;24:2781-3. |
| 46. | Chang L, Zhao L, Gong H, Wang L, Wang L. Severe acute respiratory syndrome coronavirus 2 RNA detected in blood donations. Emerg Infect Dis 2020;26:1631-3. |
| 47. | Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: Early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun 2005;19:334-44. |
| 48. | Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, Kida H, et al. The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 2004;41:101-7. |
| 49. | Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:1-9. |
| 50. | Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]. J Med Virol 2020;92:699-702. |
| 51. | Bulfamante G, Chiumello D, Canevini MP, Priori A, Mazzanti M, Centanni S, et al. First ultrastructural autoptic findings of SARS -Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol 2020;86:678-9. |
| 52. | Baig AM. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther 2020;26:499-501. |
| 53. | Baig AM. Updates on what ACS reported: Emerging evidences of COVID-19 with nervous system involvement. ACS Chem Neurosci 2020;11:1204-5. |
| 54. | Machado C. Reader response: Tapia syndrome at the time of the COVID-19 pandemic: Lower cranial neuropathy following prolonged intubation. Neurology 2020. doi: 10.1212/WNL.0000000000010011. |
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