As healthcare professionals and researchers scrambled to understand the novel coronavirus, a surprising discovery was made by Fidan et al. – the first documented case of acute otitis media (AOM) in a COVID-19 patient 
This revelation marked the beginning of an intriguing journey into the interplay between SARS-CoV-2 and the middle ear, uncovering unexpected findings that have significant implications for both the medical community and patients alike.
A Pioneering Revelation
The pivotal moment occurred when Fidan and colleagues reported the initial case of AOM in a COVID-19 patient in April 2020 . This observation was later substantiated by Frazier et al., who identified SARS-CoV-2 in the middle ears of two out of three autopsy specimens .
Further confirmation came from Jeican et al., who detected the presence of SARS-CoV-2 in four necropsy samples from the middle ear . These early findings initiated a wave of research aimed at understanding the relationship between COVID-19 and otitis media.
Remarkably High Detection Rates
Until recently, the detection of SARS-CoV-2 in the middle ear fluid (MEF) was a rare occurrence, with only one documented case of a positive PCR result .
Even more astonishing, these patients had previously tested negative for the virus in nucleic acid or antigen tests from nasopharyngeal swabs at enrollment. This suggests that SARS-CoV-2 can persist longer in the middle ear than in the nasopharynx, shedding new light on the virus’s behavior within the human body .
Prolonged Viral Persistence
Another intriguing discovery in this research is the extended duration of viral persistence in the middle ear. The virus remained detectable in the MEF for up to 45 days after a nasopharyngeal swab had yielded a negative result.
This extended persistence raises questions about the virus’s capacity to establish reservoirs within the body, which may have implications for the management of COVID-19 and its potential sequelae .
Low Rate of Viral Co-Infection
Contrary to expectations, the study found a very low rate of viral co-infection in the MEF of COVID-19 patients, with only one case (2.4%) involving co-infection with human rhinovirus (HRV). This finding is significant, given that HRV was also the sole respiratory virus detected in the MEF of the control group.
This aligns with previous studies that have consistently shown HRV to be the most prevalent virus in MEF [11, 12]. The implications of this low rate of co-infection in COVID-19-associated otitis media are yet to be fully elucidated and warrant further investigation.
Clinical Characteristics and Outcomes
Comparative analysis between the COVID-19 and control groups revealed no significant differences in age, gender, history of otitis media with effusion (OME), or severity of hearing loss. However, one notable difference was the duration of ear symptoms, which was significantly shorter in the COVID-19 group.
This discrepancy may be attributed to heightened awareness of symptoms among COVID-19 patients, prompting earlier medical attention-seeking behaviors. Encouragingly, the outcomes of patients with COVID-19-associated otitis media were generally positive, with 92.6% reporting cure or improvement after 7 to 30 days of treatment (average: 16.5 ± 6.7 days). Only two patients in the study reported no improvement after 30 days of treatment and were prepared to undergo tympanic catheterization, highlighting the overall effectiveness of the treatment strategies employed.
Current Status and Future Considerations
Although the world has witnessed a significant decline in COVID-19 cases following the implementation of vaccination campaigns and public health measures, sporadic cases still emerge, as evident in China . Furthermore, healthcare professionals continue to encounter patients with OME symptoms after their second or third COVID-19 infections in ENT clinics, underscoring the importance of ongoing research and vigilance in monitoring COVID-19-associated otitis media.
In conclusion, the discovery of COVID-19-associated otitis media has added a new dimension to our understanding of the SARS-CoV-2 virus. This unexpected interaction between the virus and the middle ear has raised important questions about viral persistence, co-infection rates, and the clinical implications for patients.
While this study provides valuable insights, several limitations, such as the small sample size and the exclusion of severely ill COVID-19 patients, necessitate further research to fully comprehend the long-term implications of SARS-CoV-2 in the middle ear. Nonetheless, these findings underscore the importance of considering otitis media as a potential symptom of COVID-19 and provide a basis for future studies and clinical guidelines in managing COVID-19-associated ear infections.
The Link Between COVID-19 and Audiovestibular Dysfunction
The temporal correlation between the onset of audiovestibular symptoms and positive COVID-19 test results strongly implicates SARS-CoV-2 infection as the root cause of these symptoms. Notably, none of the patients exhibited evidence of middle ear infection, shifting our focus towards the inner ear and the cochleovestibular nerve as likely culprits. Intriguingly, MRI scans revealed inflammation in the inner ear, cochlear, and vestibular nerves in one patient, providing tangible evidence of the virus’s potential impact.
However, it is important to acknowledge the inherent challenges in diagnosing audiovestibular dysfunction in COVID-19 patients. Universal testing for such symptoms has not been adopted, and patients with more severe manifestations of the disease may have been unable to report these issues. Additionally, those experiencing mild symptoms may have avoided medical evaluation due to fears of contracting the virus. Thus, the true prevalence of audiovestibular dysfunction in COVID-19 remains unknown.
Molecular Insights into Inner Ear Infection
To bridge this knowledge gap, we took a novel approach by developing the first human in vitro 2D and 3D models of SARS-CoV-2 otic infection derived from human induced pluripotent stem cells (hiPSCs). These models allowed us to gain unprecedented insights into the cellular mechanisms underlying audiovestibular dysfunction. Surprisingly, our data revealed that hair cells, which play a critical role in hearing and balance, appeared to be susceptible to SARS-CoV-2 infection in all human inner ear tissue models.
The Role of ACE2, TMPRSS2, and FURIN
Our findings were further bolstered by the presence of key entry factors for the virus—ACE2, TMPRSS2, and FURIN—in hair cells. These proteins were located in cellular locations accessible to viral spike proteins, strengthening the case for direct viral infection. Moreover, our study suggests that cochlear hair cells, responsible for sound detection, may also be vulnerable to SARS-CoV-2 infection, given their similarities to vestibular hair cells.
Schwann Cells and Neurons: A Complex Relationship
Intriguingly, our data showed inconsistent results regarding the infection of Schwann cells. While immature Schwann cells were not readily infected in 2D culture, mature Schwann cells in human explants exhibited signs of infection. Further investigation is needed to decipher the differences in protein expression and subcellular locations between these cell types. Additionally, alternative routes of viral entry into mature Schwann cells may exist, highlighting the complexity of the virus’s interactions within the inner ear.
The Complexity of Audiovestibular Dysfunction
Our study proposes three potential mechanisms for the audiovestibular symptoms observed in COVID-19 patients. First, the virus may directly infect and damage hair cells or nerve cells, leading to hearing loss and balance issues. Second, viral infection could trigger an inflammatory response within the inner ear, causing further damage. Third, damage to the stria vascularis, a structure critical for maintaining the inner ear’s potassium balance, could disrupt hearing.
Multiple Paths to Inner Ear Entry
The route by which SARS-CoV-2 accesses the inner ear remains a subject of intense investigation. It may enter through the central nervous system, the endolymphatic sac, or even via hematogenous spread through the stria vascularis. The possibility of traversal through the round or oval window membrane is also considered, although evidence supporting this pathway is limited.
reference link : https://www.nature.com/articles/s43856-021-00044-w#Sec27
reference link : https://www.sciencedirect.com/science/article/pii/S1201971223007099#sec0009