Abstract
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.
Highlights
Accepted: 24 November 2021Increasing 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]
Persistent anosmia observed among long COVID-19 patients may be involved by a cascade of effects generated by dysautonomia leading to Angiotensin-Converting Enzyme 2 receptor (ACE2) antibodies enhancing a persistent immune activation
The possible mechanisms of SARS-CoV-2 invading the central nervous system (CNS) may explain the hallmarks of COVID-19 infection, such as anosmia and ageusia, which manifest the viral entry into the CNS [28]
Summary
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]. 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. COVID-19 patients with or without hospitalization often reported anosmia as one of the predominant persisting symptoms [7,9,10,11]. 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]. Recent studies have shown that these symptoms are the manifestation of a dysautonomia in long COVID-19 patients [16]. We review evidence suggesting that dysautonomia could be responsible for anosmia occurring in long COVID-19 infection
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