Next Article in Journal
Impact of Bariatric Surgery on Adipose Tissue Biology
Next Article in Special Issue
Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems
Previous Article in Journal
Aetiology of Heart Failure, Rather than Sex, Determines Reverse LV Remodelling Response to CRT
Previous Article in Special Issue
Changes in EEG Recordings in COVID-19 Patients as a Basis for More Accurate QEEG Diagnostics and EEG Neurofeedback Therapy: A Systematic Review
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Dysautonomia and Implications for Anosmia in Long COVID-19 Disease

Department of Clinical Research and Innovation, Foch Hospital, 92150 Suresnes, France
J. Clin. Med. 2021, 10(23), 5514;
Received: 13 November 2021 / Revised: 22 November 2021 / Accepted: 24 November 2021 / Published: 25 November 2021
(This article belongs to the Special Issue Long-Term COVID-19: The Lasting Health Impacts of COVID-19)


Long COVID-19 patients often reported anosmia as one of the predominant persisting symptoms. Recent findings have shown that anosmia is associated with neurological dysregulations. However, the involvement of the autonomic nervous system (ANS), which can aggregate all the long COVID-19 neurological symptoms, including anosmia, has not received much attention in the literature. Dysautonomia is characterized by the failure of the activities of components in the ANS. Long COVID-19 anosmia fatigue could result from damage to olfactory sensory neurons, leading to an augmentation in the resistance to cerebrospinal fluid outflow by the cribriform plate, and further causing congestion of the glymphatic system with subsequent toxic build-up in the brain. Studies have shown that anosmia was an important neurologic symptom described in long COVID-19 in association with potential COVID-19 neurotropism. SARS-CoV-2 can either travel via peripheral blood vessels causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction, or reach the systemic circulation and take a different route to the blood–brain barrier, damaging the blood–brain barrier and leading to neuroinflammation and neuronal excitotoxicity. SARS-CoV-2 entry via the olfactory epithelium and the increase in the expression of TMPRSS2 with ACE2 facilitates SARS-CoV-2 neurotropism and then dysautonomia in long COVID-19 patients. Due to this effect, patients with anosmia persisting 3 months after COVID-19 diagnosis showed extensive destruction of the olfactory epithelium. Persistent anosmia observed among long COVID-19 patients may be involved by a cascade of effects generated by dysautonomia leading to ACE2 antibodies enhancing a persistent immune activation.

1. Introduction

Increasing numbers of patients convalescent with SARS-CoV-2 have complained of symptoms months after acute infection and have not returned to their initial health state prior to infection, leading us to suspect a long COVID-19 disease [1]. The observed symptoms are associated with disability, debilitating fatigue, breathlessness, headaches, muscle and/or joint pain, brain fog, memory loss, sensation of pressure on the chest, palpitations, nausea, anosmia, dramatic mood swings in combination with exercise intolerance and a relapsing-remitting pattern of recurrence [2]. Anosmia is commonly observed in mild as well as more severe COVID-19 [3,4,5,6]. Recent studies have shown that anosmia was one of the main symptoms observed in long COVID patients [7]. Anosmia presents spontaneous improvement over a two- or three-week period during acute COVID-19 infection. However, many COVID-19 patients remain anosmic for longer duration periods [8]. Moreover, long COVID-19 patients with or without hospitalization often reported anosmia as one of the predominant persisting symptoms [7,9,10,11].
Recent findings have shown that anosmia is associated with neurological dysregulations [12]. Indeed, the main common symptoms attributable to central nervous system (CNS) involvement include headache, anosmia, and dysgeusia [5,6]. Anosmia could be a result of viral interaction with non-neuronal cells of the mucosal surfaces in the olfactory epithelium and olfactory bulb [13,14]. However, the involvement of the autonomic nervous system (ANS), which can aggregate all these neurological symptoms (including anosmia) in long COVID-19 infection, has not received much attention in the literature [15]. Currently, recent studies have shown that these symptoms are the manifestation of a dysautonomia in long COVID-19 patients [16]. Here, we review evidence suggesting that dysautonomia could be responsible for anosmia occurring in long COVID-19 infection.

2. Dysautonomia in Long COVID-19 Patients

Dysautonomia is characterized by either the failure or the increased activities of the sympathetic or parasympathetic components in the ANS. Dysautonomia presents several clinical symptoms, such as fatigue, anosmia, orthostatic hypotension, dysfunction in heart rate variability, appearance of impotence, dysfunction of bladder, and damage to bowel functions. Dysautonomia could be acute or chronic, as well as progressive but also reversible and is associated with many pathologies, including alcoholism, diabetes, or Parkinson’s disease. Dysautonomia is also associated with viral infections, including hepatitis C virus, HIV, or Epstein–Barr virus [15]. Several etiologies can explain dysautonomia in long COVID-19 patients, such as neurotropism, hypoxia, and inflammation [9]. Nevertheless, it remains unclear whether dysautonomia associated with long COVID-19 directly results from the autonomic-virus pathway or post-infectious immune-mediated processes.

3. SARS-CoV-2, Blood–Brain Barrier and Anosmia

SARS-CoV-2 can lead to neuronal damages by affecting the nervous system as anosmia and ageusia were among the predominant persisting neurological symptoms described [17]. Indeed, similarly to other zoonotic coronaviruses, including Middle East respiratory syndrome-related coronavirus and SARS-CoV-1, SARS-CoV-2 possesses the capacity for neurological virulence [18]. COVID-19 infection may be responsible for invasion of the central nervous system (CNS) by a direct hematogenous and neural propagation [19]. SARS-CoV-2 in the airways may pass by the epithelial barrier invading blood and lymph circulation and then propagating towards the CNS. The diameter of the SARS-CoV-2 virus is 60 to 140 nm, which allows it to translocate through the blood–brain barrier (BBB) and gain entry into the CNS [20]. However, the neurobiological mechanisms of SARS-CoV-2 remain unclear despite the high prevalence of observed neurological complications being documented [21,22]. The processes contributing to neurological symptoms may include toxic or metabolic complications to respiratory disease, as well as consequences of the anti-SARS-CoV-2 immune response, such as cytokine release syndrome and excessive immune activation [23].
SARS-CoV-2 gains entry to the CNS by penetrating the BBB. Several possible pathways may explain this phenomenon: invasion and infection by vascular endothelial cells and invasion and infection by pericytes embedded in endothelial membrane [24]. Moreover, SARS-CoV-2 can infect macrophages and monocytes recruited across the BBB [25]. In parallel, SARS-CoV-2 can infect vascular endothelial cells to invade the BBB [26]. The S protein on SARS-CoV-2 can disrupt the BBB by interacting with brain endothelial cells and leading to cell damages and a reduction in BBB integrity [27]. The possible mechanisms of SARS-CoV-2 invading the CNS may explain the hallmarks of COVID-19 infection, such as anosmia and ageusia, which manifest the viral entry into the CNS [28].

4. Anosmia and Dysautonomia

One of the main explanations is that a larger area of the olfactory epithelium is damaged, with a more profound epithelium destruction including death of numerous olfactory receptor neurons [29]. Long COVID-19 anosmia fatigue could result from damage to olfactory sensory neurons, leading to an augmentation in the resistance to cerebrospinal fluid outflow by the cribriform plate, and further causing congestion of the glymphatic system with subsequent toxic build-up in the brain [30].
Recent studies have shown that anosmia was an important neurologic symptom described in long COVID-19 in association with possible COVID-19 neurotropism [9,31]. The dissemination throughout olfactory nerve projection by the infection of the nasal mucosa and sustentacular cells is a possible process of COVID-19 neuropathogenesis. Moreover, in the olfactory bulb of post-mortem COVID-19 patients, viral RNA has been observed [32].
The glossopharyngeal afferents, innerving the carotid body and the vagal afferents and implicated in the respiratory tract, have a major role in the monitoring of the organelle process and in controlling homeostasis through the activation of the ANS. Theses neurons are the primary sensory inputs of several reflex loops controlling many key functions, including heart rate, blood pressure, and airway caliber [33]. Pulmonary receptors expressed on afferent vagal nerve terminals in the lung present mechanical or chemical stimuli, translocating in the brainstem by small-diameter myelinated (Aδ) or unmyelinated (C)-fiber nerve axons. Vagal C-fiber afferents innervate the larynx response to laryngeal discomfort whereas the afferent information arrives from the vagal and glossopharyngeal nerves to merge at the nucleus of the tractus solitarius (NTS), a major site of critical homeostasis signaling [33]. The biological phenomenon underlying the anosmia in COVID-19 patients remains unclear. However, the observed disassociation may be observed in patients showing lesions in the glossopharyngeal or vagus nerves due to cranial nerve affections [34]. Dysautonomia may enhance afferent baroreflex failure [9]. This mechanism generates numerous damages at the afferent baroreceptor pathway, starting from baroreceptors in carotid bodies to the vagal and glossopharyngeal nerve fibers, and then progressing to the NTS [15].

5. ACE2 Hypothesis in Long COVID-19

The SARS-CoV-2 virus contains a simple strain RNA as genetic material and is composed of three protein structures: the spike, the envelope, and the membrane. The spike binds to the Angiotensin-Converting Enzyme 2 receptor (ACE2) and both the envelope and the membrane implicate the genetic material [35]. Several studies have observed that there is a genetic variation in the human receptor for the virus, ACE2, in the European population, increasing this receptor expression. Europeans could be more predisposed to anosmia in comparison to Asians, precisely because they may mainly have receptors for the entry of the SARS-CoV-2 virus [36,37].
Moreover, the SARS-CoV-2 virus invades cells through ACE2 in association with TMPRSS2 (a protease-mediating S-protein cleavage). The main targets of SARS-CoV-2 are non-neuronal cells. Furthermore, the average recovery of smell is two weeks, a time span not compatible with the regeneration of neuronal cells [38,39]. Soluble platelet-derived growth factor receptor β (sPDGFRβ) has been proposed as a new candidate biomarker of blood–brain barrier function [40,41,42]. sPDGFRβ is mainly expressed in brain pericytes [43], a cell type with ACE2 expression as well as the viral cofactor TMPRSS2, making pericytes a possible target for COVID-19 infection [44].
ACE2 is the viral receptor for the SARS-CoV-2 virus and is expressed as both a membrane-bound form and a soluble form. The biological role of ACE2 is to transform the octapeptide angiotensin II (Ang II) to angiotensin (1–7). Ang II binds to AT1 receptor to generate an immune stimulation [45,46]. Ang (1–7) binds to the Mas receptor to inhibit the process of inflammation [47]. The increased levels of ACE2 protein are associated with decreased effects modulated by the stimulation of the AT1 receptor including immune stimulation (i.e., augmented ACE2 activity leads to inflammation inhibition). The link between SARS-CoV-2 and ACE2 leads to a decrease in the activity of this enzyme [48,49]. The immune system is enhanced in long COVID-19 infection. For instance, antinuclear [50], antiphospholipid [51] and anti-interferon [52] antibodies have been found after infection [53]. Antibodies against ACE2 may downregulate the activity of both soluble and membrane-bound ACE2 activating the receptors for Ang II and stimulating the immune system [53,54,55]. These recent findings showed that the ACE2 antibodies in the plasma could decrease the activity of ACE2. This downregulation could mainly damage the ACE2 enzyme that is tissue-bound as well as the activity of soluble ACE2. This provides a possible process for damage to the balance of angiotensin peptides to increase Ang II and to activate the immune system. Thus, two pathways of evidence can support the hypothesis that anti-idiotypic antibodies can enhance long COVID-19 symptoms [53,54,56].

6. ACE2 and Dysautonomia in Long COVID-19

ACE2 was observed in neurons of the brain [57] as neuropilin-1 receptor (NRP-1) was found in both the olfactory system [58] and neurons of the olfactory epithelium [59]. The ACE2 receptors are expressed in the brain and glial cells and SARS-CoV-2 acts via neuronal as well as non-neuronal pathways [60]. Several studies have suggested that the SARS-CoV-2 virus enters via the olfactory epithelium and affects the expression of both TMPRSS2 and ACE2 to facilitate SARS-CoV-2 neurotropism [13,61]. Moreover, SARS-CoV-2 exhibits neuroinvasive capacity in an ACE2-dependent manner to induce neuronal death [57] leading to the initiation of a neurotropism in these patients [62,63]. Other studies have shown that SARS-CoV-2 can damage the integrity of choroid plexus epithelium in the brain organoids of hippocampal-like regions [64]. Moreover, a second possible route of brain invasion by the SARS-CoV-2 virus could be a viral entry mediated by both ACE2 and NRP-1 [59,65]. Thus, the SARS-CoV-2 virus can either travel via peripheral blood vessels causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction, or reach the systemic circulation and take a different route to the blood–brain barrier, damaging the blood–brain barrier leading to neuroinflammation and neuronal excitotoxicity [66,67]. COVID-19 neural invasion via the peripheral nervous system nerve terminal leads to viral replication and retrograde transportation to soma leading to invasion of the central nervous system, and subsequent neurological manifestations for a long period post infection [60].

7. ACE2, Anosmia and Long COVID-19

Recent studies have shown an association between the expression of ACE2 receptor and age [68]. ACE2 receptors become more prevalent in adults than in children [37,61], explaining that young people exhibit a less severe prognosis [69,70].
Moreover, women are more likely to develop olfactory disorders than men in COVID-19 disease [5,70,71]. A possible explanation could be that incomplete X chromosome inhibition may contribute to overexpression of ACE2 [29]. A recent study has shown that anosmia, one of the main symptoms of long COVID-19, was more likely increased with aging and female gender [11]. Chen et al., observed that ACE2 immunohistochemical expression was 200 to 700 times greater in the sustentacular cells of the olfactory neuroepithelium than it was in nasal or tracheal epithelia [66]. Another study showed high levels of expression of both ACE2 and TMPRSS2 on the sustentacular cells of the olfactory epithelium [13]. This previous study has shown the absence of ACE2 expression on olfactory sensory neurons [13]. A post-mortem study of two patients with anosmia presented focal atrophy of the olfactory epithelium, leukocytic infiltration of the lamina propria and evidence of axonal damage in the olfactory nerve fibers [72]. Patients with anosmia persisting 3 months after COVID-19 diagnosis showed extensive destruction of the olfactory epithelium [73].
Another possible pathway could be the interaction between ACE2 receptor and adipose tissue in obese COVID-19 patients [74,75]. ACE2 is highly expressed in adipose tissue, especially in visceral fat, suggesting an essential role for this tissue in determining COVID-19 disease severity and duration [76,77]. However, this possible link remains unclear in long COVID-19 patients and should be investigated.

8. Conclusions

Persistent anosmia observed among long COVID-19 patients may be involved via a cascade of effects generated by dysautonomia leading to ACE2 antibodies enhancing a persistent immune activation.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.


  1. Carfì, A.; Bernabei, R.; Landi, F. Gemelli Against COVID-19 Post-Acute Care Study Group Persistent Symptoms in Patients After Acute COVID-19. JAMA 2020, 324, 603–605. [Google Scholar] [CrossRef] [PubMed]
  2. Goërtz, Y.M.J.; Van Herck, M.; Delbressine, J.M.; Vaes, A.W.; Meys, R.; Machado, F.V.C.; Houben-Wilke, S.; Burtin, C.; Posthuma, R.; Franssen, F.M.E.; et al. Persistent Symptoms 3 Months after a SARS-CoV-2 Infection: The Post-COVID-19 Syndrome? ERJ Open Res. 2020, 6. [Google Scholar] [CrossRef] [PubMed]
  3. Gerkin, R.C.; Ohla, K.; Veldhuizen, M.G.; Joseph, P.V.; Kelly, C.E.; Bakke, A.J.; Steele, K.E.; Farruggia, M.C.; Pellegrino, R.; Pepino, M.Y.; et al. Recent Smell Loss Is the Best Predictor of COVID-19 Among Individuals With Recent Respiratory Symptoms. Chem. Senses 2021, 46, bjaa081. [Google Scholar] [CrossRef] [PubMed]
  4. Giacomelli, A.; Pezzati, L.; Conti, F.; Bernacchia, D.; Siano, M.; Oreni, L.; Rusconi, S.; Gervasoni, C.; Ridolfo, A.L.; Rizzardini, G.; et al. Self-Reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-Sectional Study. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2020, 71, 889–890. [Google Scholar] [CrossRef][Green Version]
  5. Lechien, J.R.; Chiesa-Estomba, C.M.; De Siati, D.R.; Horoi, M.; Le Bon, S.D.; Rodriguez, A.; Dequanter, D.; Blecic, S.; El Afia, F.; Distinguin, L.; et al. Olfactory and Gustatory Dysfunctions as a Clinical Presentation of Mild-to-Moderate Forms of the Coronavirus Disease (COVID-19): A Multicenter European Study. Eur. Arch. Oto-Rhino-Laryngol. Off. J. Eur. Fed. Oto-Rhino-Laryngol. Soc. EUFOS Affil. Ger. Soc. Oto-Rhino-Laryngol. Head Neck Surg. 2020, 277, 2251–2261. [Google Scholar] [CrossRef]
  6. Liotta, E.M.; Batra, A.; Clark, J.R.; Shlobin, N.A.; Hoffman, S.C.; Orban, Z.S.; Koralnik, I.J. Frequent Neurologic Manifestations and Encephalopathy-Associated Morbidity in COVID-19 Patients. Ann. Clin. Transl. Neurol. 2020, 7, 2221–2230. [Google Scholar] [CrossRef]
  7. Augustin, M.; Schommers, P.; Stecher, M.; Dewald, F.; Gieselmann, L.; Gruell, H.; Horn, C.; Vanshylla, K.; Cristanziano, V.D.; Osebold, L.; et al. Post-COVID Syndrome in Non-Hospitalised Patients with COVID-19: A Longitudinal Prospective Cohort Study. Lancet Reg. Health Eur. 2021, 6, 100122. [Google Scholar] [CrossRef]
  8. Altundag, A.; Saatci, O.; Sanli, D.E.T.; Duz, O.A.; Sanli, A.N.; Olmuscelik, O.; Temirbekov, D.; Kandemirli, S.G.; Karaaltin, A.B. The Temporal Course of COVID-19 Anosmia and Relation to Other Clinical Symptoms. Eur. Arch. Oto-Rhino-Laryngol. 2021, 278, 1891–1897. [Google Scholar] [CrossRef]
  9. Barizien, N.; Le Guen, M.; Russel, S.; Touche, P.; Huang, F.; Vallée, A. Clinical Characterization of Dysautonomia in Long COVID-19 Patients. Sci. Rep. 2021, 11, 14042. [Google Scholar] [CrossRef]
  10. Graham, E.L.; Clark, J.R.; Orban, Z.S.; Lim, P.H.; Szymanski, A.L.; Taylor, C.; DiBiase, R.M.; Jia, D.T.; Balabanov, R.; Ho, S.U.; et al. Persistent Neurologic Symptoms and Cognitive Dysfunction in Non-Hospitalized COVID-19 “Long Haulers”. Ann. Clin. Transl. Neurol. 2021, 8, 1073–1085. [Google Scholar] [CrossRef]
  11. Sudre, C.H.; Murray, B.; Varsavsky, T.; Graham, M.S.; Penfold, R.S.; Bowyer, R.C.; Pujol, J.C.; Klaser, K.; Antonelli, M.; Canas, L.S.; et al. Attributes and Predictors of Long COVID. Nat. Med. 2021, 27, 626–631. [Google Scholar] [CrossRef]
  12. 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. [Google Scholar] [CrossRef]
  13. Brann, D.H.; Tsukahara, T.; Weinreb, C.; Lipovsek, M.; Van den Berge, K.; Gong, B.; Chance, R.; Macaulay, I.C.; Chou, H.-J.; Fletcher, R.B.; et al. Non-Neuronal Expression of SARS-CoV-2 Entry Genes in the Olfactory System Suggests Mechanisms Underlying COVID-19-Associated Anosmia. Sci. Adv. 2020, 6, eabc5801. [Google Scholar] [CrossRef]
  14. Fodoulian, L.; Tuberosa, J.; Rossier, D.; Boillat, M.; Kan, C.; Pauli, V.; Egervari, K.; Lobrinus, J.A.; Landis, B.N.; Carleton, A.; et al. SARS-CoV-2 Receptors and Entry Genes Are Expressed in the Human Olfactory Neuroepithelium and Brain. iScience 2020, 23, 101839. [Google Scholar] [CrossRef]
  15. Eshak, N.; Abdelnabi, M.; Ball, S.; Elgwairi, E.; Creed, K.; Test, V.; Nugent, K. Dysautonomia: An Overlooked Neurological Manifestation in a Critically Ill COVID-19 Patient. Am. J. Med. Sci. 2020, 360, 427–429. [Google Scholar] [CrossRef]
  16. Dani, M.; Dirksen, A.; Taraborrelli, P.; Torocastro, M.; Panagopoulos, D.; Sutton, R.; Lim, P.B. Autonomic Dysfunction in “Long COVID”: Rationale, Physiology and Management Strategies. Clin. Med. Lond. Engl. 2020. [Google Scholar] [CrossRef]
  17. Balcom, E.F.; Nath, A.; Power, C. Acute and Chronic Neurological Disorders in COVID-19: Potential Mechanisms of Disease. Brain J. Neurol. 2021, awab302. [Google Scholar] [CrossRef]
  18. Moldofsky, H.; Patcai, J. Chronic Widespread Musculoskeletal Pain, Fatigue, Depression and Disordered Sleep in Chronic Post-SARS Syndrome; a Case-Controlled Study. BMC Neurol. 2011, 11, 37. [Google Scholar] [CrossRef][Green Version]
  19. Desforges, M.; Le Coupanec, A.; Stodola, J.K.; Meessen-Pinard, M.; Talbot, P.J. Human Coronaviruses: Viral and Cellular Factors Involved in Neuroinvasiveness and Neuropathogenesis. Virus Res. 2014, 194, 145–158. [Google Scholar] [CrossRef]
  20. Alam, S.B.; Willows, S.; Kulka, M.; Sandhu, J.K. Severe Acute Respiratory Syndrome Coronavirus 2 May Be an Underappreciated Pathogen of the Central Nervous System. Eur. J. Neurol. 2020, 27, 2348–2360. [Google Scholar] [CrossRef]
  21. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Lancet Lond. Engl. 2020, 395, 497–506. [Google Scholar] [CrossRef][Green Version]
  22. Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020, 77, 683–690. [Google Scholar] [CrossRef][Green Version]
  23. Vabret, N.; Britton, G.J.; Gruber, C.; Hegde, S.; Kim, J.; Kuksin, M.; Levantovsky, R.; Malle, L.; Moreira, A.; Park, M.D.; et al. Immunology of COVID-19: Current State of the Science. Immunity 2020, 52, 910–941. [Google Scholar] [CrossRef]
  24. Zubair, A.S.; McAlpine, L.S.; Gardin, T.; Farhadian, S.; Kuruvilla, D.E.; Spudich, S. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol. 2020, 77, 1018–1027. [Google Scholar] [CrossRef]
  25. Jafarzadeh, A.; Chauhan, P.; Saha, B.; Jafarzadeh, S.; Nemati, M. Contribution of Monocytes and Macrophages to the Local Tissue Inflammation and Cytokine Storm in COVID-19: Lessons from SARS and MERS, and Potential Therapeutic Interventions. Life Sci. 2020, 257, 118102. [Google Scholar] [CrossRef]
  26. Paniz-Mondolfi, A.; Bryce, C.; Grimes, Z.; Gordon, R.E.; Reidy, J.; Lednicky, J.; Sordillo, E.M.; Fowkes, M. Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). J. Med. Virol. 2020, 92, 699–702. [Google Scholar] [CrossRef][Green Version]
  27. Buzhdygan, T.P.; DeOre, B.J.; Baldwin-Leclair, A.; Bullock, T.A.; McGary, H.M.; Khan, J.A.; Razmpour, R.; Hale, J.F.; Galie, P.A.; Potula, R.; et al. The SARS-CoV-2 Spike Protein Alters Barrier Function in 2D Static and 3D Microfluidic in-Vitro Models of the Human Blood-Brain Barrier. Neurobiol. Dis. 2020, 146, 105131. [Google Scholar] [CrossRef]
  28. Chakravarty, N.; Senthilnathan, T.; Paiola, S.; Gyani, P.; Castillo Cario, S.; Urena, E.; Jeysankar, A.; Jeysankar, P.; Ignatius Irudayam, J.; Natesan Subramanian, S.; et al. Neurological Pathophysiology of SARS-CoV-2 and Pandemic Potential RNA Viruses: A Comparative Analysis. FEBS Lett. 2021. [Google Scholar] [CrossRef]
  29. Butowt, R.; von Bartheld, C.S. Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection. Neurosci. Rev. J. Bring. Neurobiol. Neurol. Psychiatry 2020. [Google Scholar] [CrossRef]
  30. Wostyn, P. COVID-19 and Chronic Fatigue Syndrome: Is the Worst yet to Come? Med. Hypotheses 2021, 146, 110469. [Google Scholar] [CrossRef]
  31. Pouga, L. Encephalitic Syndrome and Anosmia in COVID-19: Do These Clinical Presentations Really Reflect SARS-CoV-2 Neurotropism? A Theory Based on the Review of 25 COVID-19 Cases. J. Med. Virol. 2021, 93, 550–558. [Google Scholar] [CrossRef]
  32. Meinhardt, J.; Radke, J.; Dittmayer, C.; Franz, J.; Thomas, C.; Mothes, R.; Laue, M.; Schneider, J.; Brünink, S.; Greuel, S.; et al. Olfactory Transmucosal SARS-CoV-2 Invasion as a Port of Central Nervous System Entry in Individuals with COVID-19. Nat. Neurosci. 2021, 24, 168–175. [Google Scholar] [CrossRef] [PubMed]
  33. Burki, N.K.; Lee, L.-Y. Mechanisms of Dyspnea. Chest 2010, 138, 1196–1201. [Google Scholar] [CrossRef]
  34. González-Duarte, A.; Norcliffe-Kaufmann, L. Is “happy Hypoxia” in COVID-19 a Disorder of Autonomic Interoception? A Hypothesis. Clin. Auton. Res. Off. J. Clin. Auton. Res. Soc. 2020, 30, 331–333. [Google Scholar] [CrossRef] [PubMed]
  35. Gupta, K.; Mohanty, S.K.; Mittal, A.; Kalra, S.; Kumar, S.; Mishra, T.; Ahuja, J.; Sengupta, D.; Ahuja, G. The Cellular Basis of Loss of Smell in 2019-NCoV-Infected Individuals. Brief. Bioinform. 2021, 22, 873–881. [Google Scholar] [CrossRef] [PubMed]
  36. Gourtsoyannis, J. COVID-19: Possible Reasons for the Increased Prevalence of Olfactory and Gustatory Dysfunction Observed in European Studies. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2020, ciaa685. [Google Scholar] [CrossRef]
  37. Somekh, I.; Yakub Hanna, H.; Heller, E.; Bibi, H.; Somekh, E. Age-Dependent Sensory Impairment in COVID-19 Infection and Its Correlation with ACE2 Expression. Pediatr. Infect. Dis. J. 2020, 39, e270–e272. [Google Scholar] [CrossRef]
  38. Bryche, B.; St Albin, A.; Murri, S.; Lacôte, S.; Pulido, C.; Ar Gouilh, M.; Lesellier, S.; Servat, A.; Wasniewski, M.; Picard-Meyer, E.; et al. Massive Transient Damage of the Olfactory Epithelium Associated with Infection of Sustentacular Cells by SARS-CoV-2 in Golden Syrian Hamsters. Brain. Behav. Immun. 2020, 89, 579–586. [Google Scholar] [CrossRef]
  39. Eshraghi, A.A.; Mirsaeidi, M.; Davies, C.; Telischi, F.F.; Chaudhari, N.; Mittal, R. Potential Mechanisms for COVID-19 Induced Anosmia and Dysgeusia. Front. Physiol. 2020, 11, 1039. [Google Scholar] [CrossRef]
  40. Sagare, A.P.; Sweeney, M.D.; Makshanoff, J.; Zlokovic, B.V. Shedding of Soluble Platelet-Derived Growth Factor Receptor-β from Human Brain Pericytes. Neurosci. Lett. 2015, 607, 97–101. [Google Scholar] [CrossRef][Green Version]
  41. Miners, J.S.; Kehoe, P.G.; Love, S.; Zetterberg, H.; Blennow, K. CSF Evidence of Pericyte Damage in Alzheimer’s Disease Is Associated with Markers of Blood-Brain Barrier Dysfunction and Disease Pathology. Alzheimers Res. Ther. 2019, 11, 81. [Google Scholar] [CrossRef][Green Version]
  42. Nation, D.A.; Sweeney, M.D.; Montagne, A.; Sagare, A.P.; D’Orazio, L.M.; Pachicano, M.; Sepehrband, F.; Nelson, A.R.; Buennagel, D.P.; Harrington, M.G.; et al. Blood-Brain Barrier Breakdown Is an Early Biomarker of Human Cognitive Dysfunction. Nat. Med. 2019, 25, 270–276. [Google Scholar] [CrossRef]
  43. Lindahl, P.; Johansson, B.R.; Levéen, P.; Betsholtz, C. Pericyte Loss and Microaneurysm Formation in PDGF-B-Deficient Mice. Science 1997, 277, 242–245. [Google Scholar] [CrossRef]
  44. Edén, A.; Simrén, J.; Price, R.W.; Zetterberg, H.; Gisslén, M. Neurochemical Biomarkers to Study CNS Effects of COVID-19: A Narrative Review and Synthesis. J. Neurochem. 2021, 159, 61–77. [Google Scholar] [CrossRef]
  45. Nataraj, C.; Oliverio, M.I.; Mannon, R.B.; Mannon, P.J.; Audoly, L.P.; Amuchastegui, C.S.; Ruiz, P.; Smithies, O.; Coffman, T.M. Angiotensin II Regulates Cellular Immune Responses through a Calcineurin-Dependent Pathway. J. Clin. Invest. 1999, 104, 1693–1701. [Google Scholar] [CrossRef][Green Version]
  46. Ruiz-Ortega, M.; Lorenzo, O.; Suzuki, Y.; Rupérez, M.; Egido, J. Proinflammatory Actions of Angiotensins. Curr. Opin. Nephrol. Hypertens. 2001, 10, 321–329. [Google Scholar] [CrossRef]
  47. Simões e Silva, A.C.; Silveira, K.D.; Ferreira, A.J.; Teixeira, M.M. ACE2, Angiotensin-(1-7) and Mas Receptor Axis in Inflammation and Fibrosis. Br. J. Pharmacol. 2013, 169, 477–492. [Google Scholar] [CrossRef][Green Version]
  48. Kuba, K.; Imai, Y.; Rao, S.; Gao, H.; Guo, F.; Guan, B.; Huan, Y.; Yang, P.; Zhang, Y.; Deng, W.; et al. A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury. Nat. Med. 2005, 11, 875–879. [Google Scholar] [CrossRef]
  49. Verma, S.; Abbas, M.; Verma, S.; Khan, F.H.; Raza, S.T.; Siddiqi, Z.; Ahmad, I.; Mahdi, F. Impact of I/D Polymorphism of Angiotensin-Converting Enzyme 1 (ACE1) Gene on the Severity of COVID-19 Patients. Infect. Genet. Evol. J. Mol. Epidemiol. Evol. Genet. Infect. Dis. 2021, 91, 104801. [Google Scholar] [CrossRef]
  50. Fujii, H.; Tsuji, T.; Yuba, T.; Tanaka, S.; Suga, Y.; Matsuyama, A.; Omura, A.; Shiotsu, S.; Takumi, C.; Ono, S.; et al. High Levels of Anti-SSA/Ro Antibodies in COVID-19 Patients with Severe Respiratory Failure: A Case-Based Review: High Levels of Anti-SSA/Ro Antibodies in COVID-19. Clin. Rheumatol. 2020, 39, 3171–3175. [Google Scholar] [CrossRef]
  51. Zhang, Y.; Cao, W.; Jiang, W.; Xiao, M.; Li, Y.; Tang, N.; Liu, Z.; Yan, X.; Zhao, Y.; Li, T.; et al. Profile of Natural Anticoagulant, Coagulant Factor and Anti-Phospholipid Antibody in Critically Ill COVID-19 Patients. J. Thromb. Thrombolysis 2020, 50, 580–586. [Google Scholar] [CrossRef] [PubMed]
  52. Bastard, P.; Rosen, L.B.; Zhang, Q.; Michailidis, E.; Hoffmann, H.-H.; Zhang, Y.; Dorgham, K.; Philippot, Q.; Rosain, J.; Béziat, V.; et al. Autoantibodies against Type I IFNs in Patients with Life-Threatening COVID-19. Science 2020, 370, eabd4585. [Google Scholar] [CrossRef] [PubMed]
  53. Arthur, J.M.; Forrest, J.C.; Boehme, K.W.; Kennedy, J.L.; Owens, S.; Herzog, C.; Liu, J.; Harville, T.O. Development of ACE2 Autoantibodies after SARS-CoV-2 Infection. PLoS ONE 2021, 16, e0257016. [Google Scholar] [CrossRef] [PubMed]
  54. Patel, S.K.; Juno, J.A.; Lee, W.S.; Wragg, K.M.; Hogarth, P.M.; Kent, S.J.; Burrell, L.M. Plasma ACE2 Activity Is Persistently Elevated Following SARS-CoV-2 Infection: Implications for COVID-19 Pathogenesis and Consequences. Eur. Respir. J. 2021, 57, 2003730. [Google Scholar] [CrossRef]
  55. Wang, E.Y.; Mao, T.; Klein, J.; Dai, Y.; Huck, J.D.; Jaycox, J.R.; Liu, F.; Zhou, T.; Israelow, B.; Wong, P.; et al. Diverse Functional Autoantibodies in Patients with COVID-19. Nature 2021, 595, 283–288. [Google Scholar] [CrossRef]
  56. Yelin, D.; Wirtheim, E.; Vetter, P.; Kalil, A.C.; Bruchfeld, J.; Runold, M.; Guaraldi, G.; Mussini, C.; Gudiol, C.; Pujol, M.; et al. Long-Term Consequences of COVID-19: Research Needs. Lancet Infect. Dis. 2020, 20, 1115–1117. [Google Scholar] [CrossRef]
  57. Song, E.; Zhang, C.; Israelow, B.; Lu-Culligan, A.; Prado, A.V.; Skriabine, S.; Lu, P.; Weizman, O.-E.; Liu, F.; Dai, Y.; et al. Neuroinvasion of SARS-CoV-2 in Human and Mouse Brain. J. Exp. Med. 2021, 218, e20202135. [Google Scholar] [CrossRef]
  58. Kawakami, A.; Kitsukawa, T.; Takagi, S.; Fujisawa, H. Developmentally Regulated Expression of a Cell Surface Protein, Neuropilin, in the Mouse Nervous System. J. Neurobiol. 1996, 29, 1–17. [Google Scholar] [CrossRef]
  59. Cantuti-Castelvetri, L.; Ojha, R.; Pedro, L.D.; Djannatian, M.; Franz, J.; Kuivanen, S.; van der Meer, F.; Kallio, K.; Kaya, T.; Anastasina, M.; et al. Neuropilin-1 Facilitates SARS-CoV-2 Cell Entry and Infectivity. Science 2020, 370, 856–860. [Google Scholar] [CrossRef]
  60. Kumar, R.; Harilal, S.; Sabitha, M.; Pappachan, L.K.; Roshni, P.R.; Mathew, B. Current Perspective of COVID-19 on Neurology: A Mechanistic Insight. Comb. Chem. High Throughput Screen. 2021. [Google Scholar] [CrossRef]
  61. Bilinska, K.; Jakubowska, P.; Von Bartheld, C.S.; Butowt, R. Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age. ACS Chem. Neurosci. 2020, 11, 1555–1562. [Google Scholar] [CrossRef]
  62. Ramani, A.; Müller, L.; Ostermann, P.N.; Gabriel, E.; Abida-Islam, P.; Müller-Schiffmann, A.; Mariappan, A.; Goureau, O.; Gruell, H.; Walker, A.; et al. SARS-CoV-2 Targets Neurons of 3D Human Brain Organoids. EMBO J. 2020, 39, e106230. [Google Scholar] [CrossRef]
  63. Yang, L.; Han, Y.; Nilsson-Payant, B.E.; Gupta, V.; Wang, P.; Duan, X.; Tang, X.; Zhu, J.; Zhao, Z.; Jaffré, F.; et al. A Human Pluripotent Stem Cell-Based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell 2020, 27, 125–136. [Google Scholar] [CrossRef]
  64. Pellegrini, L.; Albecka, A.; Mallery, D.L.; Kellner, M.J.; Paul, D.; Carter, A.P.; James, L.C.; Lancaster, M.A. SARS-CoV-2 Infects the Brain Choroid Plexus and Disrupts the Blood-CSF Barrier in Human Brain Organoids. Cell Stem Cell 2020, 27, 951–961. [Google Scholar] [CrossRef]
  65. Daly, J.L.; Simonetti, B.; Klein, K.; Chen, K.-E.; Williamson, M.K.; Antón-Plágaro, C.; Shoemark, D.K.; Simón-Gracia, L.; Bauer, M.; Hollandi, R.; et al. Neuropilin-1 Is a Host Factor for SARS-CoV-2 Infection. Science 2020, 370, 861–865. [Google Scholar] [CrossRef]
  66. Chen, M.; Shen, W.; Rowan, N.R.; Kulaga, H.; Hillel, A.; Ramanathan, M.; Lane, A.P. Elevated ACE-2 Expression in the Olfactory Neuroepithelium: Implications for Anosmia and Upper Respiratory SARS-CoV-2 Entry and Replication. Eur. Respir. J. 2020, 56, 2001948. [Google Scholar] [CrossRef]
  67. He, L.; Mäe, M.A.; Muhl, L.; Sun, Y.; Pietilä, R.; Nahar, K.; Liébanas, E.V.; Fagerlund, M.J.; Oldner, A.; Liu, J.; et al. Pericyte-Specific Vascular Expression of SARS-CoV-2 Receptor ACE2—Implications for Microvascular Inflammation and Hypercoagulopathy in COVID-19 patients. BioRxiv 2020. [Google Scholar] [CrossRef]
  68. Lecarpentier, Y.; Vallée, A. The Key Role of the Level of ACE2 Gene Expression in SARS-CoV-2 Infection. Aging 2021, 13, 14552–14556. [Google Scholar] [CrossRef]
  69. Beltrán-Corbellini, Á.; Chico-García, J.L.; Martínez-Poles, J.; Rodríguez-Jorge, F.; Natera-Villalba, E.; Gómez-Corral, J.; Gómez-López, A.; Monreal, E.; Parra-Díaz, P.; Cortés-Cuevas, J.L.; et al. Acute-Onset Smell and Taste Disorders in the Context of COVID-19: A Pilot Multicentre Polymerase Chain Reaction Based Case-Control Study. Eur. J. Neurol. 2020, 27, 1738–1741. [Google Scholar] [CrossRef]
  70. Zahra, S.A.; Iddawela, S.; Pillai, K.; Choudhury, R.Y.; Harky, A. Can Symptoms of Anosmia and Dysgeusia Be Diagnostic for COVID-19? Brain Behav. 2020, 10, e01839. [Google Scholar] [CrossRef]
  71. Rojas-Lechuga, M.J.; Izquierdo-Domínguez, A.; Chiesa-Estomba, C.; Calvo-Henríquez, C.; Villarreal, I.M.; Cuesta-Chasco, G.; Bernal-Sprekelsen, M.; Mullol, J.; Alobid, I. Chemosensory Dysfunction in COVID-19 out-Patients. Eur. Arch. Oto-Rhino-Laryngol. 2021, 278, 695–702. [Google Scholar] [CrossRef]
  72. Kirschenbaum, D.; Imbach, L.L.; Ulrich, S.; Rushing, E.J.; Keller, E.; Reimann, R.R.; Frauenknecht, K.B.M.; Lichtblau, M.; Witt, M.; Hummel, T.; et al. Inflammatory Olfactory Neuropathy in Two Patients with COVID-19. Lancet Lond. Engl. 2020, 396, 166. [Google Scholar] [CrossRef]
  73. Vaira, L.A.; Hopkins, C.; Sandison, A.; Manca, A.; Machouchas, N.; Turilli, D.; Lechien, J.R.; Barillari, M.R.; Salzano, G.; Cossu, A.; et al. Olfactory Epithelium Histopathological Findings in Long-Term Coronavirus Disease 2019 Related Anosmia. J. Laryngol. Otol. 2020, 134, 1123–1127. [Google Scholar] [CrossRef]
  74. Al-Benna, S. Association of High Level Gene Expression of ACE2 in Adipose Tissue with Mortality of COVID-19 Infection in Obese Patients. Obes. Med. 2020, 19, 100283. [Google Scholar] [CrossRef]
  75. Al Heialy, S.; Hachim, M.Y.; Senok, A.; Gaudet, M.; Abou Tayoun, A.; Hamoudi, R.; Alsheikh-Ali, A.; Hamid, Q. Regulation of Angiotensin- Converting Enzyme 2 in Obesity: Implications for COVID-19. Front. Physiol. 2020, 11, 555039. [Google Scholar] [CrossRef]
  76. Krams, I.A.; Luoto, S.; Rantala, M.J.; Jõers, P.; Krama, T. COVID-19: Fat, Obesity, Inflammation, Ethnicity, and Sex Differences. Pathog. Basel Switz. 2020, 9, e887. [Google Scholar] [CrossRef] [PubMed]
  77. Krams, I.A.; Jõers, P.; Luoto, S.; Trakimas, G.; Lietuvietis, V.; Krams, R.; Kaminska, I.; Rantala, M.J.; Krama, T. The Obesity Paradox Predicts the Second Wave of COVID-19 to Be Severe in Western Countries. Int. J. Environ. Res. Public. Health 2021, 18, 1029. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Vallée, A. Dysautonomia and Implications for Anosmia in Long COVID-19 Disease. J. Clin. Med. 2021, 10, 5514.

AMA Style

Vallée A. Dysautonomia and Implications for Anosmia in Long COVID-19 Disease. Journal of Clinical Medicine. 2021; 10(23):5514.

Chicago/Turabian Style

Vallée, Alexandre. 2021. "Dysautonomia and Implications for Anosmia in Long COVID-19 Disease" Journal of Clinical Medicine 10, no. 23: 5514.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop