While COVID-19 primarily affects the respiratory system, new studies are reporting on extrapulmonary manifestations, pointing to extensive involvement of multiple organ functions.1,2 And although auditory dysfunctions occur in connection with various viral diseases, it is still unclear whether COVID-19 affects hearing. Generally, the mechanisms underlying post-viral hearing impairment might be connected with either peripheral auditory dysfunction or a central nervous system (CNS) disease.3 Viruses may directly damage the inner ear structures, including hair cells, the organ of Corti, the stria vascularis, the spiral ganglion, and the auditory nerve, causing a host-immune response.4 In the case of SARS-CoV-2, its potential to cause neuro-auditory deficits should be emphasized. Since this neuroinvasive virus causes peripheral neuropathy, it could be hypothesized that SARS-CoV-2 also has the potential to cause auditory neuropathy spectrum disorder (ANSD), a hearing disorder where the outer hair cells in the cochlea are functioning but transmission along the ascending neural pathway is impaired.2,3
A few studies on auditory dysfunction and COVID-19 have been published so far. One study on a small group of asymptomatic SARS-CoV-2-positive patients found mild sensorineural hearing impairment at higher frequencies and evidence of damage to the outer hair cells.5 Two studies describe cases of sudden hearing loss.4,5 The question remains whether we can expect more people with hearing problems after the pandemic. The exact mechanisms of described hearing loss are also unknown. Some hypotheses can be drawn on SARS-CoV-2 intracellular invasion and the pathobiology of other coronaviruses, among others.
LESSONS LEARNED FROM THE ROUTES OF VIRAL ENTRY
SARS-CoV-2 can likely use different receptors and pathways to facilitate its infiltration, but the angiotensin-converting enzyme 2 (ACE2) is a key receptor that the virus hijacks for the intracellular invasion of a host.6 The abundant expression of ACE2 in arterial and venous endothelial cells and arterial smooth muscle cells in many organs suggests that SARS-CoV-2 can spread easily throughout the body once it enters the circulation.7 By attacking the vascular system, the virus can also damage the blood-brain barrier;8 similarly, the blood–labyrinth barrier can be breached, and the inner ear structures invaded by infected and activated monocytes.
Yoshimura, et al.,9 showed ACE2 expression in mouse cochlea with microarray technology and quantitative RT-PCR. The expression of the ACE2 gene was twice as much in the basal turn as the apical turn, which corresponds to the high-frequency hearing deficits in COVID-19 patients.10
As of this writing, no study investigating the presence of SARS-CoV-2 in the human inner ear has been published. Despite the expression of ACE2 in the endothelia of almost all organs of infected individuals, relatively few were found to be infected by the virus. This finding might indicate that the virus needs a co-receptor for cellular entry, which is only present in select cells. Successful SARS-CoV-2 infection depends not only on cellular ACE2 but also on transmembrane protease serine 2 (TMPRSS2), which plays a role in the fusion of SARS-CoV-2 with cells.11 The TMPRSS family of proteases is thought to be involved in the process of hearing.12 Guipponi, et al.,12 reported the expression of the TMPRSS2 gene in inner ear tissues, including the stria vascularis, modiolus, and organ of Corti.
Although the available data convincingly suggest that ACE2 is a functional receptor for SARS-CoV-2, the virus may also use basigin (Bsg) to assist in cell entry.13 Kawano, et al.,14 found strong Bsg expression in the basal cells of the stria vascularis and the capillary endothelial cells of the auditory nerve in the internal acoustic meatus in mice. The function of Bsg in the cochlea remains unknown; the glycoprotein may very well play a role in the homeostasis of the cochlea and the auditory nerve.
LESSONS LEARNED FROM OTHER CORONAVIRUSES
Most coronaviruses, including SARS-CoV-2, share similar viral structures and spread of infection. Data from animal models and previous coronavirus epidemics do not mention hearing problems but do provide valuable information on nervous system involvement. Even the common circulating human coronaviruses (HCoVs), which are not regarded as highly pathogenic in humans, are not confined to the respiratory system. As with other coronaviruses, HCoVs have neuroinvasive capabilities and can spread from the respiratory tract to the CNS. HCoVs were detected in the cerebrospinal fluid (CSF) of a patient presenting with acute disseminated encephalomyelitis.15 However, the suspected association between HCoVs and Kawasaki disease (KD)—which is accompanied in one-third of cases by mild to profound sensorineural hearing loss—was not proven.16 Hearing loss is a relatively unrecognized complication of KD, although it can be persistent. Whether KD-like symptoms currently appearing in children with COVID-19 also affect the inner ear as they do in actual KD cases remains unknown. The neuroinvasive potential of coronaviruses has been studied more extensively in patients and experimental animals infected by SARS-CoV, where the viruses spread from the respiratory tract to the CNS mainly via retrograde axonal transport from the olfactory nerve and olfactory bulb.17 Previous observations indicate that coronaviruses can rapidly propagate once set in the CNS. Once in the CSF, they can spread to the inner ear through the cochlear aqueduct, which links the scala tympani to the subarachnoid space.
EVALUATING RECENT REPORTS
The neurological phenotypes reported so far in patients with COVID-19 involved deficits in the central and peripheral nervous systems, including anosmia/hypogeusia, ageusia/hyposmia, deficits in visual function, and neuralgia.18 Autopsy reports have revealed brain tissue edema, necro-hemorrhagic encephalitis, and partial neuronal degeneration in deceased patients.19 Inner ear disease in the course of viral encephalopathy previously described in other viral infections may be similar in COVID-19.20
Potential inner ear damage may be caused not only by the virus directly but also by the systemic toxic effects of the immune reactions elicited by SARS-CoV-2. Excessive host response to the infection can cause a mass release of cytokines called a cytokine storm, which in turn can induce multiple organ failures, including the inner ear.21 An accompanying systemic inflammatory response syndrome can cause intravascular coagulation with subsequent thrombosis or hemorrhage. A similar though less intense sequence of events with hearing loss has been described in cytomegalovirus infection.22
It can be assumed that the risk of hearing damage will increase with the severity of the infection. Severely affected patients were more likely to develop neurological symptoms than patients with mild or moderate forms of the disease.18 This is also in line with the report by Mustafa,10 who only found mild sensorineural hearing impairment in asymptomatic COVID-19 patients. Of note, some COVID-19 patients mainly reported tinnitus, not hearing loss.23,24
Neuro-auditory deficits may appear in the long run. Interestingly, some neurological symptoms of SARS-CoV-2 and MERS-CoV infections, such as peripheral neuropathy, encephalitis, and Guillain–Barre syndrome (GBS), were described to occur two to three weeks after the onset of respiratory symptoms.2 GBS is an acute immune-mediated disease with central and peripheral nerve manifestations and theoretically likely to be associated with auditory neuropathy spectrum disorder, which has already been described in the course of COVID-19 but without audio-vestibular symptoms.25
Concerning olfaction, with multiple reports of loss of smell among COVID-19 patients and those from previous coronavirus epidemics, only a single case report describes persistent coronavirus-associated anosmia.27
It is also unclear if the audiovestibular symptoms are a complication of COVID-19 or side effects a medication. Attention should be paid to the ototoxicity of chloroquine and hydroxychloroquine, which are used to treat COVID-19. These ototoxic substances damage the inner ear structures, resulting in moderate to severe sensorineural hearing loss, tinnitus, and/or imbalance, which may be reversible if the medication is stopped. However, persistent auditory and vestibular dysfunctions have been reported26 though in less than one percent of COVID-19 patients, indicating that these symptoms are uncommon or that medical providers focused mainly on life-threatening symptoms.27
At present, it is difficult to say whether something may predispose hearing loss in the course of COVID-19. The male patient with SNHL described recently by Koumpa, et al.,28 suffered from bronchial asthma and was put on a ventilator for 30 days due to high work of breathing. His admission was complicated by pulmonary emboli, pneumonia, and anemia. Tinnitus and hearing loss appeared one week after extubation and leaving the intensive care unit (ICU), which is in line with the theses presented herein. Also, the patient mentioned by Degen, et al.,29 with bilateral profound sensorineural hearing loss had a history of ICU stay. These reports indicate that more attention should be paid to the presence of audiovestibular symptoms in COVID-19 patients after intensive therapy.
Of all the subjects we described, only one was found to have COVID-19 but no other symptoms apart from SNHL.30 This case is evidence that non-specific symptoms such as hearing loss could be the only sign with which to recognize a COVID-19. Moreover, nowadays it seems reasonable to perform a polymerase chain reaction (PCR) to investigate the presence of SARS-CoV-2 in each patient presenting to the otolaryngology clinic with sudden hearing problems.
Awareness of SNHL is important because a prompt course of steroid treatment may reverse the condition. Some of the described COVID-19 patients had hearing improvement after the administration of intratympanic or/and intravenous steroids.28,31 However, the latter remains debatable as it may cause systemic immunosuppressant side effects, which is especially undesirable in COVID-19 patients. In patients with severe-to-profound hearing loss, especially in steroid non-responders, an urgent magnetic resonance imaging (MRI) examination to exclude an inflammatory process in the cochlea should be done. Such inflammation can lead to soft tissue formation and further ossification of the cochlea, making insertion of a cochlear implant (CI) electrode for hearing rehabilitation challenging.32 MRI, but not computed tomography (CT), could detect early intracochlear labyrinthitis ossificans stages, allowing CI surgery in the right moment.33 In this way, Degen, et al.,29 assessed the condition of the cochlea in a patient with COVID-19 and performed urgent CI implantation under the local anesthesia. This report indicates that perhaps, as in cases of SNHL after bacterial meningitis, CI implantation should be considered prior to the development of labyrinthitis ossificans in patients with COVID-19-related severe to profound hearing loss.
Although this paper aims to draw attention to the relationship between SARS-CoV-2 infection and hearing problems, we also note reports of COVID-19 patients with vertigo or dizziness due to labyrinthitis or vestibular neuritis. However, these symptoms are more often associated with SNHL.34,35 The available data raise the possibility of SARS-CoV-2-related damage to the inner ear. Since recent studies on post-coronavirus complications involved a small number of cases, conclusions cannot be definitively established. It seems likely that hearing impairment will be found in patients with COVID-19 if we look for it carefully, specifically, and at the proper moment. Although neuro-auditory problems were not prevalent in previous coronavirus epidemics, the high proportion of the global population with SARS-CoV-2 infection increases the likelihood of early- or delayed-onset hearing impairment.
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