A 27-year-old previously healthy white man living in New York City with no prior otologic history, and no active medical problems presented with sudden left-sided hearing loss and rotational vertigo. During the six days prior to the audiovestibular symptoms, he experienced what he described as “extreme fatigue with an intense headache.” He was febrile with a temperature of 102°F (38.9°C) and experienced repeated shaking and chills. COVID-19 testing was positive.

A growing number of patients with COVID-19 who experience some form of sensorineural hearing loss (SNHL), tinnitus, and/or dizziness are being reported. We studied adult patients who developed audiovestibular dysfunction within three weeks of COVID-19 diagnosis in 6 clinical centers in the US from May 2020 to May 2021. A total of ten patients met these criteria (Table 1).

Table 1: Clinical Characteristics of Study Patients.

It is not rare for a virus to affect the auditory system.  Although coronaviruses, including SARS-CoV-2, were already known to be a common cause of middle ear infection [1, 2], their role in inner ear infection was not previously studied. To examine the underlying molecular mechanisms of new-onset hearing loss, tinnitus, and/or dizziness in COVID-19 patients, we studied human and mouse inner ear tissue. We also generated some of the first human cellular models of infectious inner ear disease.

How could SARS-CoV-2 affect the inner ear?

Presumed mechanisms of virally-induced audiovestibular symptoms include direct invasion and damage of inner ear structures [3], immune-mediated damage and inflammation, including neuroinflammation [4, 5], and reactivation of latent virus within the inner ear [6].

Our work suggests that hair cells may be particularly vulnerable to infection by SARS-CoV-2 in the human inner ear (Figure 1) because known cofactors for infection are present in virus-accessible locations within hair cells. By contrast, these cofactors are less available to facilitate virus entry in other cell types. In Schwann cell precursors, for example, FURIN and ACE2 expression is restricted to the nucleus.

Figure 1: Surgical specimens of human peripheral vestibular organs from the inner ear include vestibular hair cells, supporting cells, Schwann cells, and vestibular neurons. SARS-CoV-2 entry-related proteins (ACE2, TMPRSS2, and FURIN) are expressed in MYO7A+ hair cells, especially in their apical region. At 48 hours post-infection, we observed viral double-stranded RNA (dsRNA) in hair cells and not in vestibular neurites.

How to cope with COVID-19-induced hearing loss?

Although glucocorticoids are a class of medications that can potentially reverse sudden hearing loss, there are currently no pharmacologic therapies FDA-approved for SNHL. So far, successful medical treatments of SNHL in animal models have not translated to humans [7, 8], and the human inner ear is not amenable to tissue biopsy on which to test promising drugs. Progress in understanding and treating human SNHL is stagnated by the lack of human in vitro models for hearing restoration. We propose to address this major unmet need by developing robust and reproducible models of human inner ear cells in two dimensions (2D) and three dimensions (3D). 3D inner ear organoids are three-dimensional organized structures mimicking inner ear epithelium that can be generated from human induced pluripotent stem cells (Figure 2). Human vestibular tissue and the inner ear organoids share structural and functional similarities. Our expandable cellular models of the inner ear can be used in future studies to test new pharmacologic therapies for auditory and vestibular diseases in a high-throughput fashion.

Figure 2: 3D inner ear vestibular organoids containing MYO7A+ hair cells express SARS-CoV-2 entry receptor ACE2. At 72 hours post-infection, we observed dsRNA staining, strongly suggesting that the virus targeted hair cell-like cells and MAP2-expressing neurons in the organoids.

Although continued research is necessary to understand SARS-CoV-2 pathogenesis and transmission in the inner ear, our data support a causative link between SARS-CoV-2 and audiovestibular dysfunction. Pursuing this relationship is important to understanding and ultimately combating the ever-growing list of COVID-19-related clinical manifestations. Based on the clinical, human in vitro, and animal evidence presented here, we advocate that health care providers monitor both for signs and symptoms of audiovestibular impairment in COVID-19 patients.

References

[1] Massa, H.M., Cripps, A.W. & Lehmann, D. Otitis media: viruses, bacteria, biofilms, and vaccines. Med J Aust 191, S44-49 (2009).

[2] Frazier, K.M., Hooper, J.E., Mostafa, H.H. & Stewart, C.M. SARS-CoV-2 Virus Isolated From the Mastoid and Middle Ear: Implications for COVID-19 Precautions During Ear Surgery. JAMA Otolaryngol Head Neck Surg (2020).

[3] Nomura, Y., Kurata, T. & Saito, K. Cochlear changes after herpes simplex virus infection. Acta Otolaryngol 99, 419-427 (1985).

[4] Greco, A., et al. Sudden sensorineural hearing loss: an autoimmune disease? Autoimmun Rev 10, 756-761 (2011).

[5] Merchant, S.N., Durand, M.L. & Adams, J.C. Sudden deafness: is it viral? ORL J Otorhinolaryngol Relat Spec 70, 52-60; discussion 60-52 (2008).

[6] Chen, X., Fu, Y.Y. & Zhang, T.Y. Role of viral infection in sudden hearing loss. J Int Med Res 47, 2865-2872 (2019).

[7] Muurling, T. & Stankovic, K. M. Metabolomic and network analysis of pharmacotherapies for sensorineural hearing loss. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society and European Academy of Otology and Neurotology 35, 1-6, doi:10.1097/MAO.0000000000000254 (2014).

[8] Crowson, M. G., Hertzano, R. & Tucci, D. L. Emerging Therapies for Sensorineural Hearing Loss. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society and European Academy of Otology and Neurotology 38, 792-803, doi:10.1097/MAO.0000000000001427 (2017).

For details see Jeong et al., Communications Medicine, 2021.

https://www.nature.com/articles/s43856-021-00044-w