In Search of a Neurotologic Profile in COVID-19 — A Study in Health Care Workers

Introduction COVID-19 is an emerging disease and the neurotologic symptoms are still not well understood. Furthermore, the development of a neurotological profile and its associated factors can help the clinician in the diagnosis and treatment of this disease. The objective is to determine the neurotologic manifestations experienced by COVID-19 positive health care workers and their associated factors. Methods A symptoms survey was administered to health care workers who were positive to COVID-19 from September to October 2020. An informed consent form was digitally signed and Google Forms software was used for the survey. Frequencies and percentages were used for categorical variables, and associated clinical features were reported with odds ratios. Results We included 209 COVID-19 positive health care workers, 55.5% (n = 116) were women, and 44.5% (n = 93) were men. Fifty-three percent of patients were 20 to 30 years old and 56.4% had at least one comorbidity. The prevalence of neurotological manifestations was 18.6% (n = 39/209), the most frequent symptoms were vertigo (61.5%, n = 24/39), tinnitus (43.5%, n = 17/39), imbalance (43.5%, n = 17/39), and one case of facial paralysis (2.5%, n = 1/39). Neurotological manifestations were associated predominantly with asthenia (p = 0.021), loss of smell (p = 0.002) and taste dysfunction (p = 0.002). Conclusion The most common neurotological manifestations were vertigo, tinnitus and imbalance. Clinical features associated with a neurotologic profile were asthenia, hyposmia and dysgeusia.


Introduction
A new species of coronavirus caused an epidemic outbreak of atypical pneumonias in late December 2019 in Wuhan, China, becoming rapidly a global health problem [1]. SARS-CoV-2 infection (Severe Acute Respiratory Syndrome Coronavirus 2) affects the central nervous and peripheral nervous systems, and muscle; these neurogenic properties explain many of the coronavirus manifestations [2].
Additionally, histologic studies have confirmed the capacity of SARS CoV-2 virus to infect the nervous system. Reverse transcription-polymerase chain reaction (RT-PCR) has detected SARS-CoV genomic sequences in cerebral spinal fluid and brain tissue specimens, also edema and focal degeneration of neurons have been observed in the brains of SARS CoV-2 autopsies [2,3].
Coronaviruses have both hematogenous and neuro-invasive properties and can produce excitotoxicity, neurodegeneration and apoptosis [4]. Through these mechanisms, they can affect central and peripheral nervous systems. COVID-19 manifestations vary in severity and presentation depending on the genetic and nongenetic factors of the host, among other variables [5].
The objective of this study was to determine the prevalence of neurotological manifestations in COVID-19positive health care workers and to analyze their association with other clinical symptoms.

Materials And Methods
A descriptive and analytical cross-sectional study was conducted using a survey. The survey was administered through Google Forms from September 15 to October 19, 2020. Information about the otorhinolaryngologic and neurotologic symptoms was obtained from positive SARS-CoV-2 RT-PCR (Reverse Transcriptase -Polymerase Chain Reaction) health care workers.
The version of the survey used is available at figshare [15]. To be included in the study, all participants underwent confirmatory RT-PCR for SARS-COV-2. The survey included 28 sociodemographic questions regarding the participants' occupation, institution, gender, and age, followed by questions on complementary testing (IgG and IgM antigens, chest computed tomography), comorbidities, symptoms and their duration, with an emphasis on otorhinolaryngological and neurotological manifestations. Some questions allowed the selection of multiple answers.
Informed consent was digitally signed by all participants. Data was managed anonymously, as indicated by the Declaration of Helsinki.
For the analysis, the population was divided into two groups: patients with neurotological manifestations, and patients without neurotological manifestations. Patients were classified in the neurotological group if they presented with at least one neurotologic manifestation such as imbalance, vertigo, tinnitus, subjective hearing loss and/or facial paralysis; therefore, some patients had more than one neurotological manifestation.
The results were collected automatically through Google Forms and then transferred to an Excel database for descriptive analysis using Statistical Software for Social Sciences (SPSS, Inc., Version 21, IBM Corp., Armonk, NY, USA). Categorical variables were described as frequencies and percentages, and associations as odds ratios and confidence intervals. A p-value <0.05 was considered statistically significant.

FIGURE 1: Neurotologic symptoms in COVID-19 positive health care workers.
The group with no neurotologic manifestations had 170 participants and the group with neurotological manifestations had 39 subjects.
There was no difference between baseline demographic variables and neurotologic profile, except for the nursing personnel that showed an increased prevalence of neurotological manifestations (35.9% vs. 11.2%, p = 0.007) ( Table 1). 2022    We found otolaryngologic symptoms associated with a neurotologic profile, such as loss of smell (p = 0.002) and loss of taste (p = 0.002) ( Table 3).   Additionally, patients with hyposmia or anosmia were 4.31 times more likely to present a neurotologic complication, as well as those with dysgeusia were 3.79 times more prone to present neurotologic symptoms (

Discussion
We present a study that explores neurotological symptoms and their associated clinical variables in a population of health care workers.

Neurotological manifestations
The SARS-CoV-2 can invade the central and peripheral nervous systems, producing in this manner, a wide range of neurological manifestations; from mild symptoms such as loss of smell to others of greater complexity, such as encephalopathy [16][17][18].
Furthermore, there is a viral neurotropism in SARS-CoV-2 [2]. Direct invasion of the central nervous system by this virus may occur by two routes: hematogenous and via axonal transport. The axonal invasion could lead to the damage of the cranial nerves, for example, the olfactory nerve [19][20][21].
Unfortunately, in the literature there are mainly case reports and surveys when reporting for the audiovestibular assessment of patients with COVID-19 [25], probably due to the contagious nature of the disease, as this precludes more exhaustive research, at least in the beginning of the pandemic, when vaccines were not readily available.
In the study of Viola et al., 38.2% of patients with dizziness had migraine [14]; among our respondents, there was a significant association between headache and neurotological manifestations.
We have reported one case of facial paralysis. This is relevant since current literature suggests that facial paralysis might be the only or the first finding of COVID-19 [12,13,26,27]. Egilmez et al. found in their study that most patients with facial paralysis have a grade 4 on House-Brackmann scale at first admission, and after 2-5 weeks of steroid treatment 37.5% recovered [27].
Other more severe neurological manifestations are encephalitis, Guillain-Barré, cerebrovascular events, etc. [28], this should be considered when evaluating a patient with COVID-19. There is a controversy regarding whether the presence of neurotological symptoms justifies the use of chest CT scan to rule out clinically silent lung disease [11]; interestingly, in our study, there was no significant relationship between positive CT scan and neurotological symptoms (p = 0.407), which leads us to the conclusion that nervous system involvement is not synonymous of pulmonary involvement.

Otorhinolaryngological symptoms and the neurotologic profile
Loss of smell and taste have been described as clinical features of COVID-19 that persist even after the disease is resolved [29,30]. In our study, almost half of the surveyed population presented anosmia (45%), which is similar to previous studies [29][30][31]. This clinical symptom is more frequent in patients with mildmoderate disease and it has also been considered the strongest predictor of positivity. In our study, loss of smell was associated with a neurotological profile (87.2% vs. 61.2%, p = 0.002).
Probably the invasion of one cranial nerve such as olfaction, could lead to a similar invasion of other cranial nerves (cochlear and/or vestibular), but this remains unknown [19,20].
The main limitation of our study is that it merely relies on a survey; therefore, more prospective studies are necessary to expand our knowledge on this disease. Our research group decided to perform a survey on health care workers because it minimizes bias, since health care workers are more aware of the clinical manifestations of this disease than the general population.
This is a study that explores the neurotologic symptoms of COVID-19 population and could probably reveal, by the creation of a neurotologic profile, the clinical features associated with a neurotologic presentation.
COVID-19 positive health care workers presented with scant but diverse neurotologic manifestations. The main clinical features associated with neurotologic symptoms were asthenia, smell and taste disorders.

Conclusions
The most common neurotological manifestations were vertigo, tinnitus and imbalance. Clinical features associated with a neurotologic profile of symptoms were asthenia, hyposmia and dysgeusia.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Universidad Autonoma de Sinaloa issued approval 0000. Ethics committee approval was exempt due to the fact that this is a survey. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.