COVID-19 “Long-Haulers:” The Emergence of Auditory/Vestibular Problems After Medical Intervention

Authors: Robert M. DiSogra Audiology Today American Academy of Audiology

Johns Hopkins University’s Center for Systems Science and Engineering (CSSE) in the United States reported over seven million documented cases of COVID-19 and over 212,000 deaths since the virus was first identified in this country in January 2020 (2020).

Early in the pandemic, the medical profession, the Centers for Disease Control and Prevention (CDC), the National Institute of Health (NIH), and both federal and state governments worked 24/7 to develop testing protocols and intervention strategies (pharmacological management and vaccines).

Until a scientifically proven intervention strategy is identified along with a vaccine, the public continues to be advised by the CDC to wear face masks, socially distance from each other, wash their hands regularly, and avoid crowds/indoor events. This major change in our lifestyle/behavior and the associated economic impact is still with us today.

As a novel virus, no assumptions can be made about treatment or management strategies or prediction of late onset of new symptoms. Within a few months after the pandemic was declared, a variety of pharmacological interventions were proposed by the federal government—all without scientific evidence. The most popular unproven intervention strategy in the United States was the combined use of two known ototoxic drugs: hydroxychloroquine and azithromycin (Bortoli and Santiago, 2007; FDA, 2017; Prayuenyong. et al, 2020).

DiSogra (2020a) provides a detailed review of this strategy from an audiologist’s perspective. In Europe, hydroxychloroquine and chloroquine were prescribed for almost 12 percent of COVID-19 patients (Lechien et al, 2020).

Researchers attempted to determine if other FDA-approved drugs could be repurposed as an intervention strategy. A summary of several FDA-approved drugs that were being repurposed for COVID-19 patients appears in DiSogra (2020b).

Vaccines for COVID-19 are still undergoing clinical trials. The U.S. National Library of Medicine’s Clinical Trials website is monitoring over 80 COVID-19 vaccine-related clinical trials (in various phases of development) worldwide as of September 24, 2020.

COVID-19 Recovery

A self-organized group of COVID-19 “long-haul” patients, who are researchers in relevant fields (e.g., participatory design, neuroscience, public policy, data collection and analysis, human-centered design, health activism) and have intimate knowledge of COVID-19, have been working on patient-led research around the COVID experience and prolonged recoveries (Assaf et al, 2020).

To capture and share the experiences of patients suffering from prolonged or long-haul COVID-19 symptoms, survivor/researchers used a data-driven participatory-type survey and patient-centric analysis. With 640 survey respondents, many participants experienced fluctuations in the type (70 percent reporting) and intensity (89 percent reporting) of symptoms over the course of being symptomatic.

For approximately 10 percent who had recovered, the average length of time of being symptomatic was 27 days. Unrecovered respondents experienced symptoms for an average of 40 days, with a large proportion experiencing symptoms for five to seven weeks. The chance of full recovery by day 50 was smaller than 20 percent.

Most common auditory/vestibular symptoms were earaches and vertigo lasting up to eight weeks after the diagnosis. Sixty percent of the respondents reported balance issues that peaked by second week and subsided over the next four weeks. Earaches (~32 percent) and vertigo/motion sickness (~25 percent) persisted over six weeks. One patient reported hearing loss that recovered after three weeks. Subjects listed tinnitus as the second highest complaint on a write-in list of symptoms.

All patients experienced a full recovery after 90 days except for patients with pre-existing asthma. The majority of survey respondents were not hospitalized; however, a large number of participants (37.5 percent) had visited the emergency rooms or urgent care but were not admitted for further testing or overnight observation.

Auditory Symptoms After COVID-19 Treatment

For this manuscript, “auditory symptoms” is defined as hearing loss (any degree/type), earache, subjective tinnitus, or vertigo/balance problems.

Sensorineural Hearing Loss

Almufarrij et al (2020) conducted a rapid systematic review investigated audio-vestibular symptoms associated with coronavirus. They found five case reports and two cross-sectional studies that met the inclusion criteria (N=2300). No records of audio-vestibular symptoms were reported with the earlier types of coronavirus (i.e., severe-acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]).

Reports of hearing loss, tinnitus, and vertigo were rarely reported in individuals who tested positive for the SARS-CoV-2. They opined that reports of audio-vestibular symptoms in confirmed COVID-19 cases are few “with mostly minor symptoms, and the studies are of poor quality.”

Munro et al (2020) concluded that it was unclear which cases of hearing loss [and tinnitus] can be directly attributed to SARS-CoV-2 or perhaps related to the many possible causes of hearing loss associated with critical care including ototoxic mediations (Ciorba et al. 2020), local, or systematic infections, vascular disorders and auto-immune disease.

Elbiol (2020) reported only one case (N=121) of sudden hearing loss (0.6 percent). A case report of sudden hearing loss that occurred one week after hospitalization was also published by Koumpa et al (2020).

Conductive Hearing Loss

Fiden (2020) reported one COVID-19 patient with a unilateral otitis media. The conductive hearing loss was mild to moderate.

Tinnitus

Tinnitus was reported in four studies in 2020 (N = 8 patients; Cui et al, Fidan, Lechien et al, and Sun et al). The characteristics of the tinnitus and the impact on the individual were not reported.

Munro, et al (2020) followed 121 COVID-19 patients eight weeks after discharge. Sixteen (13.2 percent) patients reported a change in hearing and/or tinnitus after diagnosis of COVID-19. However, there was no pattern for the duration of the recovery.

Some patients showed no changes in tinnitus while one patient reported no tinnitus after eight weeks. There was self-reported tinnitus in eight cases with three reporting a pre-existing hearing loss. Another patient reported that their tinnitus resolved. Elibol (2020) noted that tinnitus is rarely seen in COVID-19 patients.

Liang et al (2020) attempted to identify and describe neurosensory dysfunctions (including tinnitus) of COVID-19 patients. A total of 86 patients were screened but only three (3.5 percent) were identified as having tinnitus. The average interval from onset of tinnitus was one day; while the average interval from onset of tinnitus to admission was 6 ± 5.29 days; the average duration of tinnitus was 5 ± 0 days. Finally, a non-organic component of the tinnitus (i.e., anxiety) cannot be ruled out (Xia et al, 2020). Although the current studies indicate a low incidence of tinnitus in these patients, development of tinnitus management protocol may be beneficial.

Vertigo

The Munro study (2020) identified one patient with hearing loss that also reported vertigo, which the authors concluded may have been vestibular in origin. TABLE 1 summarizes the earliest case reports and cross-sectional study designs that identified auditory/vestibular problems.

AUTHORTYPE OF STUDYNAUDITORY/VESTIBULAR SYMPTOMS
Asaaf et al, 2020Survey640Earaches (32 %)
Vertigo (60%)
Hearing Loss (0.15%)
Ciu et al, 2020Case Report20Tinnitus (N=1)
Otitis media (N=1)
Fiden, 2020Case Report1Tinnitus
Otitis media
Han et al, 2019Case Report1Vertigo
Lechien et al, 2019Cross Sectional1420Ear pain (N=358 or 25%)
Rotary vertigo (N=6 or 0.4%)
Tinnitus (N=5 or 0.3%)
Mustafa, 2020Cross Sectional20Sensorineural HL
Sriwijitalai and Wiwanitkit, 2020Case Report82Sensorineural HL (N=1 or 1.2%)
Sun et al, 2020Case Report1Sensorineural HL

TABLE 1. Summary of published case reports and cross-sectional research that identified some type of auditory/vestibular problems (adapted from Almufarrij et al, 2020).

The Mustafa study (2020) compared two groups of patients (asymptomatic SARS-CoV-2 vs. control), and the results found that the asymptomatic SARS-CoV-2 group had significantly poorer hearing thresholds at 4-8 kHz and lower amplitude transient evoked otoacoustic emissions (Mustafa, 2020). Almufarrij et al (2020) concluded that high-quality studies are required in different age groups to investigate the acute effects of coronavirus. These studies include temporary effects from medications as well as studies on long-term risks on the audio-vestibular system.

Some Intervention Strategies

Aside for re-purposed pharmaceuticals, dietary supplements are proposed as a treatment option (DiSogra, 2020c). In the Aasaf study (2020), Tylenol® (followed by an inhaler) were the top medications taken by respondents in their survey to treat symptoms. Supplements, such as vitamin C, vitamin D, zinc and electrolytes, were taken by many of the respondents over several weeks. Hot liquids were also very popular with the respondents.

Other popular entries for medications, supplements and treatments reported by participants included Mucinex®, prednisone, steroids, ginger, magnesium, steam, probiotics, oregano oil/supplements, Flonase®, and other nasal sprays.

The majority of respondents never consumed any of the following substances: smoke/vape nicotine, edible or liquid cannabis, smoke/vape recreational cannabis, consume or smoke cannabidiol-only products or consume recreational drugs. Many of the respondents said they occasionally or frequently consumed alcoholic beverages.

Conclusion

The auditory-vestibular side effects of any illness, or from a pharmaceutical, nutraceutical, noise, or trauma, as well as any psychogenic component, will always be a concern for audiologists. With COVID-19, it is still too early to predict auditory-vestibular side effects, although several studies have attempted to do so or at least guide us in our short and long-term management.

If these “long-hauler” patients can be followed more closely, a body of knowledge should emerge that will help audiologists better manage COVID-19 survivors when their auditory/vestibular symptoms result in a referral for testing. It would appear that conductive and sensorineural hearing loss, tinnitus (including its non-organic origin) and vertigo can be expected but with no predictable pattern.

Protocols for management will need to be developed; however, in the interim, an ototoxic drug monitoring protocol can serve as a reference (American Academy of Audiology, 2009). The duration of these symptoms (after the diagnosis) can last from one day to eight weeks but, again, it is still too early in the life of this pandemic to state definitively if these symptoms are temporary or permanent. Although no formal protocols have been developed, audiologists must keep in mind that the more severe, life-threatening side effects of COVID-19 will continue to get researcher’s attention.

This article is a part of the September/October 2020 Audiology Today issue.

References

Almufarrij I, Uus K, Munro KJ. (2020) Does coronavirus affect the audio-vestibular system? A rapid systematic review. Int J Audiol 59(7):487–491. 

American Academy of Audiology. (2009) Position statement and clinical practice guidelines – ototoxicity monitoring. Accessed at https://audiology-web.s3.amazonaws.com/migrated/OtoMonGuidelines.pdf_539974c40999c1.58842217.pdf.

Assaf G, Davis, H, McCorkell L, Wei H, Brooke O, Akrami A, Low R, Mercier J, Adetutu A. (2020) Report: What does COVID-19 recovery actually look like? Patient Led Res.  Accessed at https://patientresearchcovid19.com/research/report-1/#Recovery_Timecourse. Accessed online September 26, 2020.

Bortoli R, Santiago M. (2007) Chloroquine ototoxicity. Clin Rheumatol 26 (11):1809–1810 

Ciorba A, Corazzi V, Skarzynski PH, Skarzynska MB, Bianchini C, Pelucchi S, Hatzopoulos S. (2020) Don’t forget ototoxicity during the SARS-CoV-2 (Covid-19) pandemic. Int J Immunopath Pharmacol 34:1–3. 

Cui C, Yao Q, Zhang D, Zhao Y, Zhang K, Nisenbaum E, Liu X, Cao P, Zhao K, Huang X, Leng D,Liu C, Li N, Luo Y, Chen B, Casiano R,Weed D, Sargi Z, Telischi F, Lu H, Denneny III JC, Shu Y,  Liu X. (2020) Approaching otolaryngology patients during the COVID-19 pandemic. Otolaryngol Head Neck Surg 163(1):121–131

DiSogra RM. (2020a) Audiological management of COVID-19 survivors treated with hydroxychloroquine and azithromycin. Accessed September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-audiological-management-covid-19-survivors-treated

DiSogra RM. (2020b) Ototoxicity of FDA-approved drugs being re-purposed for COVID-19 treatment. Accessed on September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-ototoxicity-fda-approved-drugs-being-re-purposed-covid.

DiSogra RM. (2020c) Dietary supplements used for COVID-19 treatment. Accessed on September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-dietary-supplements-used-covid-19-treatment. Accessed online 9/24/2020

Elibol E. (2020) Otolaryngological symptoms in COVID-19. Eur Arch Otorhinolaryngol 1:1–4. Accessed online ahead of print September 24, 2020.

Fidan, V. (2020) New type of corona virus induced acute otitis media in adult. Amer J Otolaryngol 41:3 Article in Press. Accessed online September 24, 2020.

Food and Drug Administration. Aralen® chloroquine phosphate USP. 2017. www.accessdata.fda.gov/drugsatfda_docs/label/2017/006002s044lbl.pdf. Accessed online September 22, 2020.

Han W, Quan B, Guo Y, Zhang J, Lu Y, Feng G, Wu Q, Fang F, Cheng L, Jiao N, Li X, Chen Q. (2019) The course of clinical diagnosis and treatment of a case infected with coronavirus disease. J Med Virol 2(5):461–463

Johns Hopkins University Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. Accessed 9/24/2020

Koumpa FS, Forde CT, Manjaly JG. (2020) Sudden irreversible hearing loss post COVID-19. BMJ Case Reports 13(11):e238419.

Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q, Saussez S. (2019) Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease. J Intern Med 288:3, 1–10

Liang Y, Xu J, Chu M, Mai J, Lai N, Tang W, Yang T, Zhang S, Guan C, Zhong F, Yang L, Liao G. (2020) Neurosensory dysfunction: A diagnostic marker of early COVID-19. Int J Infect Dis. 98:347–352.

Mustafa MWM. (2020) Audiological profile of asymptomatic Covid-19 PCR-positive cases. AmerJ Otolaryngol 41:3.

National Library of Medicine. Clinical trials website (www.clinicaltrials.gov). Accessed September 24, 2020.

Prayuenyong P, Kasbekar AV, Baguley DM. Clinical Implications of chloroquine and hydroxychloroquine ototoxicity for COVID-19 treatment: a mini-review.” Frontiers Public Health 8 (252): 1–8

Sriwijitalai W, Wiwanitkit V. (2020) Hearing loss and COVID-19: a note. Amer J Otolaryngol. Letter to the Editor.

Sun R, Liu H, Wang X. (2020) Mediastinal emphysema, giant bulla, and pneumothorax developed during the course of COVID-19 pneumonia.” Kor J Radiol 21(5):541–544

World Health Organization. Timeline of WHO’s response to COVID-19. www.who.int/news-room/detail/29-06-2020-covidtimeline. Accessed September 24, 2020.

Xia L, Wang J, Chuan D, Fan J, Chen Z. COVID 19 associated anxiety enhances tinnitus. www.medrxiv.org/content. Accessed September 24, 2020.

Auditory Disturbances and SARS-CoV-2 Infection: Brain Inflammation or Cochlear Affection? Systematic Review and Discussion of Potential Pathogenesis

Pietro De Luca1Alfonso Scarpa1Massimo Ralli2Domenico Tassone3Matteo Simone3Luca De Campora3Claudia Cassandro4† and Arianna Di Stadio Frontiers in Medicine

Patients affected by COVID-19 present a series of different symptoms; despite some of these are common, other less likely appear. Auditory symptoms seem to be less frequent, maybe because rarer or, alternatively, because they are underestimated during the clinical investigation. The hearing impairment might be related to the central or peripheral involvement of the auditory pathways; in particular, the likelihood of thrombosis might be one of the causes. To date, the prevalence of auditory symptoms such as sudden or progressive sensorineural hearing loss and tinnitus is unclear in COVID-19 patients. However, their presence might be an early sign of thrombosis or spread of the infection into the brain. In this systematic review of the literature we investigated the presence of auditory symptoms in COVID-19 patients and discussed their potential origin and causal relationship with SARS-CoV-2. Results showed that, despite rarely, auditory impairment can appear in patients with COVID-19 and should always be investigated for an early treatment and potential indicator of involvement of the central nervous system.

Introduction

Coronavirus Disease 19 (COVID-19) has spread worldwide, negatively impacting the healthcare systems and institutions (1). COVID-19 presents several symptoms, that generally arise 2-14 days after the start of the infection. Common symptoms include fever, cough, shortness of breath, respiratory distress; furthermore, olfactory and gustatory alterations have been widely reported (23). The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is responsible of different neurological manifestations and systemic complication (4).

Despite rarely, several viral infections that determine inflammation of the cochlea can cause auditory deficits (5); the pathogenetic mechanisms of these symptoms have been widely explained and confirmed by the literature (67). Researchers have attributed their onset to the peripheral damage affecting the cochlea (6) or to the involvement of the central auditory pathways (8).

Several studies have described the presence of brain lesions as responsible of auditory impairment (911), supporting the hypothesis that SARS-CoV-2, which has neuro-invasive characteristics, might determine a central hearing loss in COVID-19 patients both in the active phase and during recovery (12). It has been shown that the virus can spread from neuroepithelium to the olfactory bulb to the brain (1315), causing loss of smell (16), persistent cough after pneumonia resolution (17), memory deficit (18), and neurocognitive problems (19).

Although the central hypothesis seems to be the most plausible, the peripheral involvement of the cochlea cannot be totally excluded.

The presence of auditory symptoms in COVID-19 might be underestimated because they are not a primary symptom of the disease, while they might be a sign of the spread of the virus in the superior auditory pathways, or of a thrombosis.

The aim of this paper is to assess the incidence of sudden sensorineural hearing loss (SSNHL) and hearing deterioration in COVID-19 patients and discuss their possible causes.

Methods

This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and statement recommendations (Figure 1). The nature of this review did not require Institutional Review Board approval.

Figure 1

FIGURE 1. Prisma diagram to illustrate the method used to select the articles.

Search Strategy

A comprehensive search strategy, developed in partnership with a medical librarian, was performed on PubMed, Scopus and Google Scholar without time restrictions. The keywords used were: “hearing loss,” “hearing impairment” “tinnitus” “audio and vestibular symptom” “sudden hearing loss,” “SARS-CoV-2” and “COVID-19”. Only articles in the English language were considered for the analysis.

Two independent investigators reviewed the articles extracted from the literature review. Duplicates were removed, then each reviewer singularly filled in an Excel data sheet (Microsoft Corporation, USA) including information extracted from the articles. Files were then compared and disagreements on the inclusion/exclusion papers were debated until complete agreement of both researchers. Only papers that received full consensus were considered.

PRISMA guidelines were followed to conduct the systematic review and the full list of references was screened for potentially relevant articles.

Study Selection Criteria

We included articles with the following characteristics: patients (0-99 years) affected by sudden sensorineural hearing loss or hearing deterioration after SARS-CoV-2 infection, written in English language, with full-text available. There were no restrictions in terms of diagnostic tools used to detect SARS-CoV-2. Suspected/unconfirmed COVID-19 patients were excluded. Selected articles were read in full to assess the study objectives and the level of evidence.

Data Extraction

A spreadsheet was filled using the data extracted from the articles read in full by the researchers. The following information were included: name of the author, year of publication, type of study, country where the study was conducted, number of subjects analyzed, patients’ characteristics, auditory results, treatment, outcome, presence or absence of the comparison group, characteristics of control groups.

Risk of Bias Assessment

The National Institutes of Health’s (NIH) quality assessment tools were used to assess the risk-of-bias checklists due to the different study designs (20). The rating of each study was categorized as: poor, fair or good (i.e., unbiased and fully described). The two authors independently gave a score to each article and any disagreement was resolved by direct comparison among the researchers.

Results

Study Selection

One-hundred seventeen records were identified (Figure 1 and Table 1). After removal of duplicates and abstract evaluation, 93 articles were excluded. Twenty-four full-text articles matched the inclusion/exclusion criteria. Five full-text articles were excluded because at high-risk of bias and the remaining 19 were included in the systematic review. The articles identified an association between SARS-CoV-2 and hearing impairment/sudden sensorineural hearing loss. All studies were published over a period of 2 years, between 2019 and 2021.

Table 1

TABLE 1. Summary of studies included in the systematic review.

Study Characteristics

Sudden Sensorineural Hearing Loss in Patients With SARS-CoV-2 Infection

Twelve full-text articles were identified (72131) (Table 2); we identified 11 case reports and 1 case series. Two studies were conducted in Turkey, two in France, two in the United Kingdom, and one in each of the following countries: Thailand, Germany, Brazil, Australia, Egypt, and United States of America. Sixteen patients (10 men and 6 women; age range 18-84 years) evaluated in these studies tested positive for COVID-19. All patients suffered from SSNHL; tinnitus was reported by four patients. Two patients suffered from vertigo, two had nausea or vomiting, and one was affected by ear fullness. Four subjects had bilateral impairment. Five patients had right SSNHL and five left SSNHL; in two studies the side of the affection was not specified. The hearing function was always (100%) assessed by pure tone audiometry (PTA); tympanometry was performed in three studies, speech audiometry and otoacoustic emissions in one, respectively. Two studies did not report the audiological assessment.

Table 2

TABLE 2. Characteristics of studies exploring sudden sensorineural hearing loss (SSNHL) in patients with COVID-19 and included in the systematic review.

Nine patients were exclusively treated by oral steroids, one subject with intratympanic steroid only; three patients were treated by combining oral steroid and intratympanic corticosteroids. In one case the treatment was not described. One patient, who did not recover, needed cochlear implant and only one patient recovered spontaneously.

Three patients completely recovered the auditory function (only one spontaneously) and five had a partial improvement; two studies did not mention the hearing outcome.

Hearing Loss in Patients With SARS-CoV-2 Infection

Seven full-text articles were identified (27323638) (Table 3). They included four prospective studies, one retrospective study, one case series, and one case report. The studies were conducted in Italy, Portugal, Iran, United Kingdom, Turkey, Egypt, and Qatar. A total of one 188 patients were evaluated. Ninety-three patients were males, 95 were females; age ranged from 0 to 82 years. Only one study did not report details about age and gender of the patients. Hearing ability was assessed by PTA by four authors, speech audiometry in one study, otoacoustic emissions in three and tympanometry in two articles. Only one author reported hearing capacity as “self-reported hearing loss” without objective assessment.

Table 3

TABLE 3. Characteristics of studies exploring hearing loss (HL) in patients with COVID-19 included in the systematic review.

Discussion

The results of our systematic review showed that, despite uncommon, the hearing function might be affected by SARS-CoV-2 infection. Because of wide differences among the studies and the lack of clinical trials, we were not able to perform a meta-analysis to clarify the real prevalence of this symptom.

Gallus et al. (32) performed a retrospective study investigating the audiological and vestibular characteristics of 48 non-hospitalized patients affected by COVID-19; after two consecutive negative RT-PCR on nasopharyngeal swabs, the doctors analyzed patients’ auditory and vestibular functions. All subjects were investigated by pure-tone audiometry, tympanometry, and cochleo-stapedius reflex. Four (8.3%) of them reported self-perception of hearing loss, in presence of normal hearing threshold at the time of testing.

Alves de Sousa et al. (33) in a prospective study showed that patients with light forms of COVID-19 had worse auditory thresholds at 1,000, 2,000, 4,000, and 8,000 Hz compared to healthy subjects, and the severity of hearing loss worsened in patients with moderate-severe forms of the disease. The results observed by Karimi-Galougahi et al. (34) and the report from Chirakkal et al. (38) confirmed the association between hearing deterioration and SARS-CoV-2 infection in a sample of five patients.

Celik et al. tested the auditory function on newborns from mothers who suffered from COVID-19 during pregnancy; 37 infants were studied by transient evoked otoacoustic emission (TEOAEs), distortion product otoacoustic emission (DPOAE), and contralateral suppression of otoacoustic emission (CLS OAE). The results were compared to healthy controls. The authors found statistically significant differences between TEOAEs (3,000 and 4,000 Hz) of infants exposed to COVID-19 infection during pregnancy compared to the ones of non-exposed newborns. Analyzing the results of CLS OAE, the authors observed similar significant statistical differences in all auditory frequencies (more significant at high frequencies) (35). Mustafa et al. used TEOAE to evaluate the hearing function in a cohort of asymptomatic COVID-19 patients; their results were compared to those of non-infected subjects. The authors identified that TEOAE amplitude was significant worse in SARS-CoV-2 positive subjects compared to the control (36). Munro et al. investigated the hearing functions of 138 adult patients with confirmed SARS-CoV-2 infection using a questionnaire; 16 (13.2%) patients referred changes in their hearing status after COVID-19 diagnosis; unfortunately, no audiological evaluation was performed to objectively assess the hearing in this cohort (37).

Sriwijtalaia and Wiwanitkit were the first to describe a correlation between COVID-19 and hearing loss (21); unfortunately, detailed data about patients’ characteristic were missing. Similarly, Degen et al. (22) described a 60-year-old man with profound SSNHL and COVID-19, but they did not report the outcome after treatment. Lang et al. (23) described a 30-year-old woman with severe unilateral SSNHL treated with oral steroids without significative improvement of the symptom. Furthermore, Lamounier et al. (24) and Koumpa et al. (25) showed that patients (one case for each author) could obtain partial recovery of their hearing function combining oral and intratympanic steroids. Guigou et al. described a 29-year-old man with bilateral SSNHL and positive to SARS-CoV-2, who obtained complete recovery of the hearing after treatment with oral corticosteroids (26). Notably, in this patient the SSNHL was the presenting symptom of COVID-19.

Chern et al. showed a case of bilateral intralabyrinthine hemorrhage in an adult woman affected by COVID-19; the patient suffered from bilateral SSNHL, aural fullness and vertigo. The magnetic resonance imaging (MRI) showed bilateral intralabyrinthine hemorrhage, which was identified as the cause of the hearing symptoms. The patient partially recovered hearing function after treatment with high-dose oral prednisone and left intratympanic dexamethasone injection (31).

Perret et al. described a case of acute labyrinthitis and SSNHL (29); the patient was treated with oral prednisone and showed progressive recovery. The oral steroid treatment was effective also for treating the hearing impairment in a patient on peritoneal dialysis program who showed SSNHL as presenting symptom of SARS-CoV-2 infection (29). An improvement of the hearing capacity was also reported by Abdel Rhman and Abdel Wahid (30); in this case the patient was treated with intratympanic steroids.

Kilic et al., speculating that hearing loss could be a presenting symptom of COVID-19, performed a real-time polymerase chain reaction (RT-PCR) in five consecutive male patients presenting with unilateral SSNHL. Only one of these subjects was positive for SARS-CoV-2, and SSNHL positively responded to COVID-19-specific treatment in the SARS-CoV-2 (739).

Finally, Jacob et al. observed a complete and spontaneous recovery of hearing in a 61-year-old woman with SSNHL and SARS-CoV-2 infection (27).

Etiopathology of Hearing Impairment in COVID-19

In patients affected by COVID-19, hearing loss and hearing disturbances might be related to a central and/or peripheral involvement of the auditory pathways. The cause can be indirectly (e.g., thrombosis) or directly (e.g., viral spread) related to SARS-CoV2.

SARS-CoV-2 infection increases the risk of systemic thrombosis (40), a condition that may determine neurological symptoms (41). Thrombosis is more common in the mild/moderate forms of the disease (42) rather than in severe ones, probably because in the latter anti-coagulant therapy is promptly administered (4243). An alteration of coagulation rate (44) could cause a macro and/or micro thrombosis, with consequent transitory ischemia and hypoxia in the auditory pathways determining the onset of hearing alterations. The thrombus, which can occlude the cochlear-vestibular artery or one of its afferent vessels (Figure 2), could determine transitory SSNHL or, in case of extremely rapid resolution, a slight hearing impairment or tinnitus. However, despite rapid resolution, transitory hypoxia into the cochlea could stress the inner ear cells and increase the concentration of reactive oxygen species (ROS), that could be responsible of additional damage of the hair cells. On the other hand, a thrombus in one of the vessels of the superior auditory pathways (Figure 2) can determine central hearing loss (45).

Figure 2

FIGURE 2. Direct Virus Effect. The image clearly shows the contiguity between the olfactory and the auditory areas. The virus can easy spread from the olfactory bulb to the olfactory area, reach the auditory area and once there inducing neuroinflammation responsible of the onset of the auditory symptoms.

Another hypothesis is that central auditory pathways—especially the auditory cortex (Figure 3)—might undergo the same inflammatory process observed in the olfactory area (16), directly caused by SARS-CoV-2. Recently, it has been confirmed that SARS-CoV2 spreads up to the olfactory bulb passing through the olfactory epithelium and lamina cribrosa (13); we speculate that the virus might, for contingency among the olfactory and auditory areas (Figure 3), determine transitory neuro-inflammation and consequent hearing symptoms. This hypothesis, although only speculative, could be supported by the clinical evidence of symptoms’ resolution using steroids.

Figure 3

FIGURE 3. Indirect Virus Effect. The images illustrates the different position of a potential trombosis, which can determine the onset of the audio-vestibular disorders because it stops the blood flow in the audiovestibular artery.

Moreover, the presence of vertigo/dizziness (4647) in patients with COVID-19 could have the same etiopathogenesis; in fact, a thrombosis in the audio-vestibular artery may alter the blood flow both in the cochlea and the vestibule explaining the presence of these symptoms (47). However, because of vestibular compensative mechanism, equilibrium disorders may be less perceived by the patients than hearing disturbances.

Vestibular disorders arising from central origin have been already confirmed in other diseases (4849); it is reasonable that SARS-CoV-2 spreading in the vestibular pathways may be responsible of equilibrium disorders observed in COVID-19 patients.

Limits of the Study

This study presents several limitations. First, the sample size (204 patients) is small. Second, the quality rating of the studies is not always satisfactory; in fact, there are several case reports and the cross-sectional studies have uncontrolled designs or provide insufficient details on the control groups. Third, in some studies the hearing deterioration could be already present before SARS-CoV-2 infection. Lastly, some of these studies described “self-reported symptoms” without an objective assessment of the hearing.

Conclusions

Hearing loss, despite rarely, might be present in COVID-19 patients. Auditory evaluation, although with all preventive measures to prevent contagion for healthcare providers, should be performed, especially if hearing disturbance are self-reported. The early recognition of these non-specific symptoms, which might be an early sign of brain inflammation, could help in preventing the spread of the infection to other areas of the brain.

SARS-CoV-2 vaccine-associated-tinnitus: A review

Authors: Syed HassanAhmedaSummaiyyaWaseemaTaha GulShaikhaNashwa AbdulQadiraSarush AhmedSiddiquiaIrfanUllahbAbdulWarisbZohaibYousafc

Annals of Medicine and Surgery Volume 75, March 2022, 103293

Abstract

The global vaccination drive against severe acute respiratory syndrome coronavirus-2 is being pursued at a historic pace. Unexpected adverse effects have been reported following vaccination, including thrombotic thrombocytopeniamyocarditis, amongst others. More recently, some cases of tinnitus are reported post-vaccination. According to the Vaccine Adverse Events Reporting System (VAERS), 12,247 cases of coronavirus post-vaccination tinnitus have been reported till September 14, 2021. To the best of our knowledge, this is the first review evaluating any otologic manifestation following vaccine administration and aims to evaluate the potential pathophysiologyclinical approach, and treatment. Although the incidence is infrequent, there is a need to understand the precise mechanisms and treatment for vaccine-associated-tinnitus.

1. Introduction

The SARS-CoV-2 virus has infected approximately 225 million people globally, resulting in 4.6 million deaths [1]. It commonly manifests as fever, dry cough, shortness of breath, fatigue, and myalgias. However, it can also lead to severe complications like pneumonia, leukopenia, kidney failure, myocardial involvement, and central nervous system (CNS) disorders [2].

Vaccinations are arguably the most effective preventive tool against SARS-CoV-2. In August 2020, Russia became the first country to register Sputnik V, a coronavirus vaccine based on human adenovirus vectors rAd26 and rAd5 developed by the Gamaleya national center of epidemiology and microbiology. However, this vaccine was approved without phase III trials, raising concerns over its safety [3].

The currently available vaccines underwent clinical trials and were approved after demonstrating an acceptable safety profile and efficacy [4]. To date, 5.5 billion vaccine doses have been administered [1]. The adverse effects of vaccines are mostly mild and transient, commonly including pain at the injection site, pyrexia, headache, myalgias, fatigue, chills [5] and dermatologic manifestations like Pityriasis Rosea [6]. However, severe complications like anaphylaxis [7], vaccine-induced immune thrombotic thrombocytopenia [8], myocarditis [9] have also been reported. The adverse effects of vaccine are markedly outweighed by their beneficial effects, in decreasing hospital admissions and deaths due to the SARS-CoV-2 [10,11].

Investigations of the otologic manifestations of the SARS-CoV-2 suggest the incidence of tinnitus, hearing loss, sensorineural hearing loss (SNHL), otalgia, amongst others. However, only association with tinnitus and hearing loss were statistically significant [12]. More recently, cases of tinnitus presented following both vector-based and mRNA SARS-CoV-2 vaccines [13,14]. According to the Vaccine Adverse Event Reporting System (VAERS), 12,247 cases of tinnitus post-coronavirus vaccination have been reported [15].

Tinnitus is an otologic symptom characterized by a conscious perception of sound without an external auditory stimulus. The prevalence varies from one population subset to another [16]. The study by Jong Kim et al., which employed data from the Korean National Health and Nutrition Examination survey, reported tinnitus prevalence to be 20.7% among adults, i.e., 20- to 98-year-old [17]. The National Health and Nutritional Examination survey data indicated a prevalence of 16.5% among the overall population and 6.6% among Asian Americans [18]. Along with varying prevalence, it has also been associated with a wide range of risk factors including male gender, hearing impairment, ear infections, stress, unemployment, military services, dyslipidemiaosteoarthritisrheumatoid arthritis, asthma, depression, thyroid disease, noise exposure, history of head injury and numerous others [17,19].

Herein, we review the association between SARS-CoV-2 vaccines and tinnitus. This review aims to evaluate the potential pathophysiologyclinical approach to diagnosis and management of post-vaccination tinnitus.

2. Literature search, data extraction, and results

Two independent authors (SHA, TGS) conducted a thorough literature search over PubMed, Cochrane Library, and Google Scholar from inception till September 12, 2021, without any language restriction. To achieve comprehensive results, search string comprised of keywords, “SARS-CoV-2 Vaccine”, “Coronavirus Vaccine,” “Corona Vaccine,” “COVID-19 Vaccine”, “Tinnitus,” “Ear Ringing,” “Otologic Manifestations,” and separated by BOOLEAN operators “OR” and “AND.” All relevant case reports, case series, cohort studies, editorials, and correspondences were reviewed. Grey literature and bibliographies of the relevant articles were also screened. Results of the literature search are summarized in Fig. 1. The work has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria [20].

Fig. 1

Ultimately, two studies [13,14] (case report and case series) were retrieved for inclusion in the review. The studies comprised data from four patients (three males and one female) with a mean age of 41.8 ± 12.6 years. The following figure (Fig. 2) demonstrates the geographical locations where these cases were reported. Out of the four reported cases, three presented in Italy, while one was reported from Taiwan. Along with these findings, future research may enable us to predict the gender, age groups, and geographical locations that may leave certain individuals more susceptible to COVID-19 vaccine-associated tinnitus than others.

Fig. 2

Following studies selection, two independent authors (SW, NAQ) retrieved all the relevant data comprising of author’s name, patient’s age, and sex, past medical history, vaccine administered, time from dose administration till the onset of symptoms, presenting complaint, laboratory findings, treatment interventions, and outcome into a table. All significant findings are summarized in Table 1. Any discrepancies were resolved by discussion with a third reviewer (SS).

Table 1. A tabulation of the outcomes of literature review.

AuthorAge
Sex
Past Medical HistoryVaccine AdministeredTime from Vaccination to Onset of symptomsPresenting ComplaintInvestigationsTreatmentOutcome
Tao-Tseng et al. [14]37 y/o MaleGlaucoma is treated with latanoprost and brimonidine eye dropsChAdOx1 nCoV-19 AstraZeneca (1st dose)5 hIntermittent, high pitch, right ear tinnitus, high fever with chills and myalgias. It progressed to continuous high pitch and intermittent low pitch tinnitus.THI = 28 (5 h post vaccination)
THI = 46 (after visiting emergency)
Audiometry test on 1st May revealed normal PTA and short SiSi
THI (post-treatment) = 0
Single-dose of 10 mg IV dexamethasone and 3 × 5 mg oral prednisone daily for 3 days.Recovered on day 4
Parrino et al. [13]37 y/o FemaleGlaucoma, undifferentiated connective tissue disease, and transient tinnitus due to acute otitis media 20 years previouslyBNT162b2 mRNA-vaccine Pfizer (1st dose)7 hRight ear tinnitus, short-term dizziness, pain at the injection site.Otoscopy investigation was normal.
PTA revealed normal bilateral hearing with slight asymmetry on the right ear
THI = 90/100
Psychoacoustic Measures of Tinnitus = 20 dB pure tone at 10,000 Hz
THI (post-treatment) = 78/100
30 mg Deflazacort daily given orally for first 5 days followed by 15mg/daily dose for next 5 days.Recovering
Parrino et al. [13]63 y/o MaleBilateral symmetrical mild high frequencies SNHL, chronic gastritis, extrinsic asthma, and reactive depression for which he had undergone psychotherapyBNT162b2 mRNA-vaccine Pfizer (1st dose)20 hLeft tinnitus associated with hyperacusis and dysacusis and local pain at the injection siteOtoscopy examination was normal.
PTA revealed slight threshold worsening on the left ear
Psychoacoustic Measures of Tinnitus = white noise of 25 dB intensity
THI = 76/100
THI (after 7 days) = 36/100
Corticosteroid therapy was proposed, but the patient refused.Recovering
Parrino et al. [13]30 y/o MaleHashimoto thyroiditisBNT162b2 mRNA-vaccine Pfizer (2nd dose)6 daysLeft tinnitus, hyperacusis, dysacusis. Reported fever, nausea, and local pain after dose administration that was treated with 1 × 1000 mg acetaminophenOtoscopy was normal
PTA showed normal bilateral hearing.
THI = 78/100
THI (post-treatment) = 6/100
10 days course of oral prednisone at 50 mg/day for first 4 days followed by 25 mg/day for the next 3 days and 12.5 mg/day for the last 3 days.Recovered

THI: Tinnitus Handicap Inventory, PTA: Pure Tone Average, SiSi: Short increment Sensitivity index, SNLH: sensorineural hearing loss.

3. COVID-19 vaccines and their characteristics

Most of the current COVID-19 vaccines use the genetic code of spike protein to stimulate a protective immune reaction against coronavirus. The viral vector vaccines (AstraZeneca, sputnik, Janssen) incorporate spike protein gene into adenovirus DNA, which induces spike protein formation and hence antibodies, conferring protection against the virus. Conversely, mRNA vaccines (Pfizer, Moderna) deliver messenger RNA for spike protein into the host cells, stimulating a protective response [21]. Another category of COVID-19 vaccines (Sinopharm, Sinovac) employs a weakened or attenuated virus, capable of replication but not potent enough to cause the disease itself [22].

Moreover, research done after SARS-CoV-1 indicated the protective and long-lasting effect of T-cell immunity. The transfer of T-cells led to a swift viral clearance and disease elimination [23,24] Unlike antibody response, T cell memory can last longer as seen in SARS-CoV-1 when the immunity was even detected 4 years after the infection. Especially, Regulatory T cells play a vital role in resolving the infection, confirmed from the fact that they were found to be risen in COVID-19 patients [25]. Along with them, circulating follicular T helper cells have been seen in individuals with COVID-19. They play a major role in representing antibody response to infection. Hence, despite no vaccine currently offering the T-cell response to COVID-19, there is a room to further investigations.

Listed in Table 2 are some of the most common vaccines currently used to counter the pandemic and their characteristics including mechanism of action, dosage, time between dosages, efficacy, general and serious adverse effects. What is of immense concern is the fact that despite a vast previous knowledge on T-cell immunity, none of the marketed vaccine is using it as a mechanism of their action. Hence, leaving room for further investigations.

Table 2. Table 2: Characteristics of COVID-19 vaccines.

VaccineManufacturer & CountryMechanism of ActionDoses – Time Between DosesEfficacyAdverse EffectsSerious Adverse Effects
BNT162b2BioNTech, Fosun Pharma, Pfizer – America and GermanyRNA vaccine [26,27]Two doses – 3 weeks [26]100% against severe disease as per CDC, 93% against severe disease as per FDA [26]Redness, Swelling, Headache, Muscle pain, Chills, Fever, Nausea, Tiredness [28]Lymphadenopathy, paroxysmal ventricular arrhythmia, syncope, and right leg paresthesia [29], heart inflammation in young adults [26]
mRNA-1273Moderna- U.S. and SwitzerlandRNA vaccine [26]Two doses – 4 weeks [26]>90% [26]Pain, swelling, redness, fever, fatigue, headache, vomiting, arthralgia, myalgia, urticaria [28]Bell’s Palsy, facial swelling [27]
ChAdOx1 nCoV-19/AZD1222AstraZeneca (University of Oxford) – U.K.Viral vector vaccine [27]Two doses −4 to 12 weeks [26]76% (phase III trials) [26]Redness, myalgias, arthralgias, and headache [27]Pulmonary embolism, Thromboembolism [27]
Ad26.COV2.SJohnson & Johnson -U.S.Viral vector vaccine [26]A single dose [26]72% [26]Pain, redness, and swelling at the injection site [27]Rare and Severe blood clots [27]
Ad5-nCoVCansino – ChinaViral vector vaccine [30]A single dose [30]65.7% [30]Fever, redness, and pain [30]Not reported [30]
CoronavacSinovac – ChinaInactivated Virus [31]Two doses – 2 to 4 weeks [32]51% [32]Pain on injection [31]Acute hypersensitivity with the manifestation of urticaria [31]
BBIBP-CorVSinopharm – ChinaInactivated Virus [33]Two doses – 2 to 3 weeks apart, followed by a booster dose in Age group >18 years [33].79% [33]Pain at the vaccination site, fatigue, lethargy, headache, and tenderness [34]
Gam-COVID-Vac/Sputnik VGamaleya Research Institute of Epidemiology and Microbiology – RussiaViral Vector Vaccine [35]2 doses, 3 weeks apart [35]91.6% [35]Mild pain at the injection site, fever, headache, fatigue, and muscle aches [36]

WHO: World Health Organization; CDC: Center for Disease Control and Prevention; FDA: U.S. Food and Drug Administration.

Moreover, all the listed vaccines include the ones currently, accepted in many countries throughout the world. With frequent introduction of numerous vaccines in the market to combat the pandemic, there is a definite need to evaluate their characteristics in comparison and the better ones shall be publicly made available.

4. Pathophysiology

Tinnitus is defined as intermittent or continuous, unilateral or bilateral, pulsatile or non-pulsatile, acute or chronic, and subjective or objective [37,38]. There are several classifications categorizing tinnitus into numerous types, with each type associated with multiple potential etiologies. It can result from a lesion in the auditory pathway. Potential etiologies may include otitis externacerumen impactionotosclerosis, otitis media, cholesteatomavestibular schwannomaMeniere’s diseasecolitisneuritis, and ototoxic drugs [37,38]. The character of tinnitus can vary based on etiology. Furthermore, certain non-otologic conditions like vascular anomalies, myoclonus, and nasopharyngeal carcinoma can also contribute. Despite several cases of tinnitus being reported post-SARS-CoV-2 vaccination, the precise pathophysiology is still not clear.

4.1. Molecular mimicry

Based on the mechanisms behind other COVID-19 vaccine-induced disorders (38, 39) and the phenomenon of molecular mimicry [41], a cross-reactivity between anti-spike SARS-CoV-2 antibodies and otologic antigens is a possibility. The heptapeptide resemblance between coronavirus spike glycoprotein and numerous human proteins further supports molecular mimicry as a potential mechanism behind such vaccine-induced disorders [41]. Several autoimmune conditions, including vaccine-induced thrombotic thrombocytopenia (VITT) [8] and Guillain-Barré syndrome (GBS) [40], have been reported following coronavirus vaccination. Anti-spike antibodies may potentially react with antigens anywhere along the auditory pathway and initiate an inflammatory reaction involving the tympanic membrane, ossicular chain, cochlea, cochlear vessels, organ of Corti, etc. Therefore, understanding the phenomenon of cross-reactivity and molecular mimicry may be helpful in postulating potential treatment behind not only tinnitus but also the rare events of vaccination associated hearing loss and other otologic manifestations [42]. Moreover, serologic investigations may play a role in understanding the underlying mechanism. Specific findings, such as raised anti-platelet factor 4, have been reported in cases of VITT post-COVID-19 vaccination [39].

4.2. Autoimmune reactions

Antibodies can form complexes with one or more antigens leading to a type III hypersensitivity reaction. Deposition of circulating immune complexes and vestibule-cochlear antibodies can play a role in autoimmune inner ear disease [43,44]. Incidence of pre-existing autoimmune conditions like Hashimoto thyroiditis and gastritis in patients, as shown in Table 1, further leaves patients prone to immune dysfunction and thus abnormal immune responses [13]. However, future research should investigate the incidence of post-vaccination tinnitus in individuals with autoimmune diseases with a suitable control as all the currently reported patients were known cases of such conditions. Moreover, several potential genes, including Glial cell Derived Neurotrophic Factor (GDNF), Brain Derived Neurotrophic Factor (BDNF), potassium recycling pathway genes, 5-Hydroxytryptamine Receptor 7 (HTR7), Potassium Voltage Gated Channel Subfamily E Regulatory Subunit 3 (KCNE3), and a few others, have been studied to understand the underlying mechanism. However, the evidence is still insufficient to draw any conclusion [45]. Therefore, genetic predisposition and immunologic pathways may play a role in post-vaccination-tinnitus.

4.3. Past medical history

Literature suggests a relationship between glaucoma and tinnitus, with glaucoma patients having 19% increased odds for tinnitus than in patients without it [46]. The mechanism linking these disorders is ambiguous, but vascular dysregulation may play a significant role in causing both disorders. Nitric oxide (NO) production inhibition is a potential mechanism [46]. NO is a regulator of intraocular pressure (IOP), thus linking defects in the nitric oxide guanylate cyclase (NO-GC) pathway with glaucoma [47]. Furthermore, diminished jugular vein NO levels have been reported in tinnitus patients, leading to the reduced blood supply to the ears [46]. As shown in Table 1, two of the reported cases had pre-existing glaucoma. Therefore, any potential association between vaccines and NO dysregulation should be investigated. Certain COVID-19 vaccines have been associated with vaccine-induced thrombotic thrombocytopenia [8]. Developing thrombus can reduce the blood supply to the ear and increase the probability of developing tinnitus. The existing literature lacks articles investigating associations between vaccines and NO levels. Therefore, the association of vaccines with NO deficiency in genetically susceptible patients should be investigated. Lastly, the association between vaccines and other vascular dysregulations must also be evaluated, as such abnormalities can disrupt laminar blood flow and cause pulsatile tinnitus [48].

4.4. Ototoxicity

Numerous drugs and chemical substances have been reported as ototoxic, causing damage to the auditory pathway and cochlear hair cells. Exposure to such agents, including aminoglycosidesvancomycin, platinum-based anticancer drugsloop diureticsquinine, toluene, styrene, lead, trichloroethylene, and others, may lead to tinnitus, hearing loss, and other otologic manifestations [37,49]. The mechanisms behind ototoxicity are not fully understood but may involve chemical and electrophysiological alterations in the inner ear structures and the eighth cranial nerve. Certain agents, including loop diuretics, incite such symptoms by inhibiting endolymph production from stria vascularis, whereas drugs like aminoglycosides and cisplatin are directly toxic to the hair cells the organ of Corti. Meanwhile, Non-Steroidal Anti-Inflammatory Drugs (NSAID) induce ototoxicity by reducing cochlear blood flow and alterations in the sensory cell functions [50]. Hence, the possibility of one or more vaccine components exerting ototoxic effects cannot be written off and requires attention.

Furthermore, the current literature also proposes certain risk factors associated with drug-induced ototoxicity. For example, age, hypoalbuminemia, and uremia significantly increase the risk of developing NSAIDs induced ototoxicity. Similarly, erythromycin-related ototoxicity is more commonly associated with hepatic and renal failure, increasing age and female gender [50]. Therefore, genetic predispositions and associated conditions may also play a significant role in determining the development of vaccine-induced tinnitus. As shown in Table 1, most of the cases reported till now were transient, which may be accountable to past administration of offending agents as seen in cases of erythromycin, aminoglycosides, vancomycin, and NSAIDs associated ototoxicity, which resolved upon early discontinuation of the inciting agent [50].

4.5. Psychological conditions

Anxiety-related adverse events (AEFI) following vaccination, defined by WHO, “a range of symptoms and signs that may arise around immunization that are related to anxiety and not to the vaccine product, a defect in the quality of the vaccine or an error of the immunization program” [51], have been witnessed in around 25% COVID-19 vaccination cases in India, as reported by Government of India, Ministry of health and family welfare, immunization division [52]. These responses may include vasovagal mediated reactions, hyperventilation mediated reactions, and stress-related psychiatric reactions or disorders [53]. Loharikar et al. [54], in their systematic review, reported common symptoms of it to be dizziness, headache, and fainting with rapid onset after vaccination. There are several speculations on the causative agents behind AEFIs after immunization. Since most of the vaccines are delivered through needles, it may be possible that trypanophobia, affecting at least 10% of the population around the globe [55], may trigger stress, hence leading to a stress-mediated response. Moreover, hearing or witnessing someone else’s sickness can lead to reporting similar symptoms, known as psychogenic illness, as reported by Blaine Ditto et al. [56]. Hence, a possible connection can exist between people’s presumption and social media misinformation, leading to anxiety and possible adverse reaction.

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite the availability of vaccination services” [57], is a complex behavior, and the most common cause of it usually includes perceived risks vs. benefits, religious beliefs, and lack of knowledge [58]. People with vaccine hesitancy may have pre-assumed beliefs. Hence, after getting vaccinated, there is a chance of facing AEFIs, with symptoms constellating stress. Numerous studies have demonstrated anxiety and stress as risk factors for tinnitus [17,19]. In one of the reported cases [13], the patient had a history of reactive depression. Therefore, the incidence of anxiety and stress disorders also need to be explored, with a particular emphasis on vaccine-related anxiety, as a potential cause of tinnitus developing post-vaccination.

4.6. Overview

While several suggested hypotheses exist, the precise mechanism behind vaccine-induced tinnitus remains undetermined, leaving room for future studies. Furthermore, as shown in Table 1, two reported cases had a medical history of otologic conditions involving recovered tinnitus and SNHL. Therefore, the possibility of vaccines aggravating underlying otologic disorders and exacerbating any morphologic damage also needs to be explored. Lastly, the character of tinnitus, including subjective or objective, intermittent or continuous, and pulsatile or non-pulsatile, can also give beneficial insight into understanding the involved sights and underlying mechanisms.

5. Clinical approach and management

To start the treatment regimen, it is crucial to determine a well-established diagnosis for Tinnitus. For this purpose, a well-focused and detailed history and examination are necessary [38]. In case of vaccine-induced tinnitus, vaccine administered, days since dose administered to the onset of symptoms, and any other adverse effects experienced must be further added. Additionally, a particular emphasis must be placed on pre-existing health conditions, specifically autoimmune diseases like Hashimoto thyroiditis, otologic conditions like SNHL, glaucoma, and psychological well-being. All the reported patients presented with a history of one or more of the aforementioned disorders, as shown in Table 1. However, any such association has not yet been established and requires further investigation to be concluded as potential risk factors for vaccine-induced tinnitus. Routine cranial nerve examinationotoscopyWeber’s test, and Rinne test, that are used for tinnitus diagnosis in general [38], may also be used for confirmation of the disorder post-vaccination. Due to the significant association between tinnitus and hearing impairment [59], audiology should be performed as well.

Tinnitus handicap inventory (THI), a reliable and valid questionnaire to evaluate tinnitus-related disability [60], is recommended by the tinnitus research initiative (TRI) [61]. To date, it has been translated into numerous languages and is being used across the globe. In THI, the scores of 0, 2, and 4 are assigned to no, sometimes, and yes, respectively, to answer a subset of questions. The scores can vary from 0 to 100, with higher scores indicating a more significant disability. Based on scores, the patients can be classified into five categories: Scores ranging between (1) 0 to 16 indicate no handicap, (2) 18 to 36 indicate mild handicap, (3) 38 to 56 indicate moderate, (4) 58 to 76 indicate severe handicap and (5) 78 to 100 indicate catastrophic handicap [62]. This scale can be employed to evaluate both the severity of the condition and therapeutic response, as reported in the included studies [13,14].

While the treatment options for non-vaccine-induced tinnitus show a significant degree of variance, corticosteroids were the lead treatment choice for SARS-CoV-2 vaccine-induced tinnitus, as reported in both the included studies [13,14]. Based on the results, Tseng et al. [14] recommend immediate use of steroids for sudden onset tinnitus post-coronavirus vaccination. The reason may lie in their underlying immunosuppressive mechanism. After entering the cell, Corticosteroid forms a steroid-receptor complex in the cytoplasm, which then modifies transcription by incorporating itself into DNA. Hence playing their role in synthesizing or inhibiting certain proteins. A well-known protein synthesized by them is lipocortin, which inhibits Phospholipase A2, ultimately inhibiting arachidonic acid (AA) which leads to hampered Leukotrienes and Prostaglandins production. It also impedes mRNA that plays role in interleukin-1 formation [63] as well as sequestrate CD4+ T-lymphocytes in the reticuloendothelial system, all building up and leading to immunosuppression [64].

Although two out of four patients showed improvement following drug administration, the efficacy of steroid therapy is yet to be investigated in larger populations.

There is also a dire need to perform trials for other pharmacological interventions that can be administered in post-vaccine tinnitus. Numerous non-pharmacological (counseling, tinnitus retraining therapy, sound therapy, auditory perceptual training) as well pharmacological interventions (sodium channel blockers, anti-depressants, anti-convulsant, benzodiazepines, and several others) for treatment of tinnitus have been evaluated [16,65], however, there is insufficient data for tinnitus following vaccination, despite that vaccine-induced tinnitus have also been reported after hepatitis B, rabies, measles and (influenza A virus subtype) H1N1 vaccines, associated to Sensorineural hearing loss (SNHL) [66].

Thereby, deeming high-quality trials evaluating the efficacy of conventional treatment necessary. Lastly, the transient nature also requires special attention, as one of the patients recovered without any medication [13].

6. Adverse effects monitoring

Although the COVID-19 vaccines were approved after rigorous testing and trials, the center for disease control and prevention (CDC) has taken numerous initiatives to ensure a highly intensive safety monitoring program to determine potential adverse effects that may not be reported during clinal trials. Several vaccine safety monitoring systems are being employed, including the VAERS, v-safe, clinical immunization safety assessment (CISA) program, vaccine safety datalink (VSD), and a few others. This wide range of systems allows patients, attendants, and healthcare workers to report any side effects they have been experiencing following SARS-CoV-2 vaccination. CDC and vaccine safety experts evaluate all the reports regularly and assess vaccines safety on their basis [67]. Investigations into reported side effects are conducted to ensure vaccines safety, as was observed following cases of thrombotic thrombocytopenia, which led to a temporary ban on two vaccines and were only lifted once the vaccines demonstrated an acceptable safety profile. With already established benefits and such critical safety monitoring, the COVID-19 global vaccination program must be supported and appreciated for prioritizing public safety. However, such reporting systems may be more useful if there was a way to determine if the reported adverse events were vaccine-induced, exacerbated following vaccination, or due to some underlying pathology.

7. Conclusion

This review scrutinizes the currently available literature and highlights potential pathophysiology and clinical approaches to diagnose and manage vaccine-induced tinnitus. Although the incidence of COVID-19 vaccine-associated tinnitus is rare, there is an overwhelming need to discern the precise pathophysiology and clinical management as a better understanding of adverse events may help in encountering vaccine hesitancy and hence fostering the COVID-19 global vaccination program. Despite the incidence of adverse events, the benefits of the SARS-CoV-2 vaccine in reducing hospitalization and deaths continue to outweigh the rare ramifications.

8. Limitations

This study carries some limitations. Firstly, given the limited number of cases reported, there is an imperative need to overcome the paucity of data and evaluate the impact of different COVID-19 vaccines, type of tinnitus, response to conventional treatment options, and reversible nature of the condition. Secondly, all the patients evaluated reported substantial past medical history and carried a high risk of immune dysregulation; therefore, the role of genetic predisposition and underlying conditions requires special surveillance, which can help redefine vaccine administration criteria to avoid any further cases.

Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatarzohaib.yousaf@gmail.com

References

[1]WHO coronavirus (COVID-19) dashboard | WHO coronavirus (COVID-19) dashboard with vaccination datahttps://covid19.who.int/, Accessed 19th Sep 2021Google Scholar[

2]H. Esakandari, M. Nabi-Afjadi, J. Fakkari-Afjadi, N. Farahmandian, S.M. Miresmaeili, E. BahreiniA comprehensive review of COVID-19 characteristicsBiol. Proced. Online, 22 (1) (2020), 10.1186/S12575-020-00128-2 View PDFGoogle Scholar[

3]B.M. PrüβCurrent state of the first COVID-19 vaccinesVaccines, 9 (1) (2021), pp. 1-12, 10.3390/VACCINES9010030 View PDFView Record in ScopusGoogle Scholar[

4]Z.P. Yan, M. Yang, C.L. LaiCOVID-19 vaccines: a review of the safety and efficacy of current clinical trialsPharmaceuticals, 14 (5) (2021), 10.3390/PH14050406 View PDFGoogle Scholar[

5]A.F. Hernández, D. Calina, K. Poulas, A.O. Docea, A.M. TsatsakisSafety of COVID-19 vaccines administered in the EU: should we be concerned?Toxicol. Rep., 8 (2021), pp. 871-879, 10.1016/J.TOXREP.2021.04.003ArticleDownload PDFView Record in ScopusGoogle Scholar[

6]S.A. Temiz, A. Abdelmaksoud, R. Dursun, K. Durmaz, R. Sadoughifar, A. HasanPityriasis rosea following SARS-CoV-2 vaccination: a case seriesJ. Cosmet. Dermatol., 20 (10) (2021), pp. 3080-3084, 10.1111/JOCD.14372 View PDFView Record in ScopusGoogle Scholar[

7. Greenhawt, E.M. Abrams, M. Shaker, et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE Assessment, and international consensus approachJ. Allergy Clin. Immunol. Pract. (2021), 10.1016/J.JAIP.2021.06.006Published online View PDFGoogle Scholar[

8 S.H. Ahmed, T.G. Shaikh, S. Waseem, N.A. Qadir, Z. Yousaf, I. UllahVaccine-induced thrombotic thrombocytopenia following coronavirus vaccine: a narrative reviewAnn. Med. Surg. (2021), p. 102988, 10.1016/J.AMSU.2021.102988Published online October 30 View PDFGoogle Scholar[

9]B. Singh, P. Kaur, L. Cedeno, et al.COVID-19 mRNA vaccine and myocarditisEur. J. Case Rep. Intern. Med. (2021), 10.12890/2021_002681Published online June 14 View PDFGoogle Scholar[10]S.M. Moghadas, T.N. Vilches, K. Zhang, et al.The impact of vaccination on COVID-19 outbreaks in the United StatesmedRxiv (2020), 

10.1101/2020.11.27.20240051Published online November 30 View PDFGoogle Scholar[

11]H.L. Moline, M. Whitaker, L. Deng, et al.Effectiveness of COVID-19 vaccines in preventing hospitalization among adults aged ≥65 Years — COVID-NET, 13 states, February–April 2021MMWR (Morb. Mortal. Wkly. Rep.), 70 (32) (2021), p. 1088, 10.15585/MMWR.MM7032E3 View PDFView Record in ScopusGoogle Scholar[

12]Z. Jafari, B.E. Kolb, M.H. MohajeraniHearing loss, tinnitus, and dizziness in COVID-19: a systematic review and meta-analysisCan. J. Neurol. Sci. (2021), p. 1, 10.1017/CJN.2021.63Le Journal Canadien Des Sciences Neurologiques. Published online View PDFGoogle Scholar[

13]D. Parrino, A. Frosolini, C. Gallo, R.D. de Siati, G. Spinato, C. de FilippisTinnitus following COVID-19 vaccination: report of three casesInt. J. Audiol. (2021), pp. 1-4, 10.1080/14992027.2021.19319690(0) View PDFGoogle Scholar[

14]P.T. Tseng, T.Y. Chen, Y.S. Sun, Y.W. Chen, J.J. ChenThe reversible tinnitus and cochleopathy followed first-dose AstraZeneca COVID-19 vaccinationQJM: Int. J. Med. (2021), pp. 1-9, 10.1093/qjmed/hcab210Published online View PDFView Record in ScopusGoogle Scholar[

15]The vaccine adverse event reporting system (VAERS) results formhttps://wonder.cdc.gov/controller/datarequest/D8;jsessionid=12CA0722184B2B3F6A88AE4A4AE0, Accessed 19th Sep 2021Google Scholar[

16]B. Langguth, P.M. Kreuzer, T. Kleinjung, D. de RidderTinnitus: causes and clinical managementLancet Neurol., 12 (9) (2013), pp. 920-930, 10.1016/S1474-4422(13)70160-1ArticleDownload PDFView Record in ScopusGoogle Scholar[

17]H.J. Kim, H.J. Lee, S.Y. An, et al.Analysis of the prevalence and associated risk factors of tinnitus in adultsPLoS One, 10 (5) (2015), 10.1371/JOURNAL.PONE.0127578 View PDFGoogle Scholar[

18]J.S. Choi, A.J. Yu, C.C.J. Voelker, J.K. Doherty, J.S. Oghalai, L.M. FisherPrevalence of tinnitus and associated factors among Asian Americans: results from a national sampleLaryngoscope, 130 (12) (2020), pp. E933-E940, 10.1002/lary.28535 View PDFView Record in ScopusGoogle Scholar

[19]D.M. Nondahl, K.J. Cruickshanks, G.H. Huang, et al.Tinnitus and its risk factors in the Beaver dam offspring studyInt. J. Audiol., 50 (5) (2011), p. 313, 10.3109/14992027.2010.551220 View PDFView Record in ScopusGoogle Scholar[

20]M.J. Page, J.E. McKenzie, P.M. Bossuyt, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviewsInt. J. Surg., 88 (2021), p. 105906, 10.1016/J.IJSU.2021.105906ArticleDownload PDFView Record in ScopusGoogle Scholar[

21]A.J.M. Ligtenberg, H.S. BrandLigtenberg AJM, Brand HS. Wat zijn de verschillen tussen diverse vaccins tegen COVID-19? [What are the differences between the various covid-19 vaccines?](epub ahead of print 2021)Ned Tijdschr Tandheelkd., 128 (2021), 10.5177/ntvt.2021.epub.21038Published 2021 Jul 6. doi:10.5177/ntvt.2021.epub.21038 View PDFGoogle Scholar[

22]I. Delrue, D. Verzele, A. Madder, H.J. NauwynckInactivated virus vaccines from chemistry to prophylaxis: merits, risks and challengesExpet Rev. Vaccine, 11 (6) (2014), pp. 695-719, 10.1586/ERV.12.38dx.doi.org/101586/erv1238 View PDFGoogle Scholar[

23]J. Z, J. Z, S. PT cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected miceJ. Virol., 84 (18) (2010), pp. 9318-9325, 10.1128/JVI.01049-10 View PDFGoogle Scholar[

24]R. KamepalliHow immune T-cell augmentation can help prevent COVID-19: a possible nutritional solution using ketogenic lifestyleUniv. Louisville J. Respir. Infect., 4 (1) (2020), p. 7, 10.18297/jri/vol4/iss1/7 View PDFView Record in ScopusGoogle Scholar[

25]M. T, Y. L, R. Z, et al.Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, ChinaImmunology, 160 (3) (2020), pp. 261-268, 10.1111/IMM.13223 View PDFGoogle Scholar[

26]Comparing the COVID-19 vaccines: how are they different? > news > yale medicinehttps://www.yalemedicine.org/news/covid-19-vaccine-comparison, Accessed 23rd Sep 2021Google Scholar[

27]M.T. Mascellino, F Di Timoteo, M. De Angelis, A. OlivaOverview of the main anti-SARS-CoV-2 vaccines: mechanism of action, efficacy and safetyInfect. Drug Resist., 14 (2021), pp. 3459-3476, 10.2147/IDR.S315727 View PDFView Record in ScopusGoogle Scholar[

28]COVID-19 Vaccines: Comparison of Biological, Pharmacological Characteristics and Adverse Effects of Pfizer/BioNTech and Moderna Vaccines.Google Scholar[

29]P. FP, T. SJ, K. N, et al.Safety and efficacy of the BNT162b2 mRNA covid-19 vaccineN. Engl. J. Med., 383 (27) (2020), pp. 2603-2615, 10.1056/NEJMOA2034577 View PDFGoogle Scholar[

30]CanSino vaccine in Pakistan: side effects, efficacy, approval, price, etc – *updated 23 September 2021* – wego bloghttps://blog.wego.com/cansino-vaccine-pakistan/, Accessed 23rd Sep 2021Google Scholar[

31]Y. Z, G. Z, H. P, et al.Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trialLancet Infect. Dis., 21 (2) (2021), pp. 181-192, 10.1016/S1473-3099(20)30843-4 View PDFGoogle Scholar[

32]The Sinovac-CoronaVac COVID-19 vaccine: what you need to knowhttps://www.who.int/news-room/feature-stories/detail/the-sinovac-covid-19-vaccine-what-you-need-to-know?gclid=CjwKCAjwy7CKBhBMEiwA0Eb7aihNZUJbAujxMi25FEPTAggpbDVF0lqcZqT9i4kCEngjY4LqxhezbBoCYDwQAvD_BwE, Accessed 23rd Sep 2021Google Scholar[

33]The Sinopharm COVID-19 vaccine: what you need to knowhttps://www.who.int/news-room/feature-stories/detail/the-sinopharm-covid-19-vaccine-what-you-need-to-know, Accessed 23rd Sep 2021Google Scholar

[34]B.Q. Saeed, R. AlShahrabi, S.S. Alhaj, Z.M. Alkokhardi, A.O. AdreesSide effects and perceptions following Sinopharm COVID-19 vaccinationInt. J. Infect. Dis., 111 (2021), pp. 219-226, 10.1016/J.IJID.2021.08.013ArticleDownload PDFView Record in ScopusGoogle Scholar[

35]I. Jones, P. Roy, V. SputnikCOVID-19 vaccine candidate appears safe and effectiveLancet, 397 (2021), p. 642, 10.1016/S0140-6736(21)00191-410275ArticleDownload PDFView Record in ScopusGoogle Scholar[

36]Pagotto V, Ferloni A, Soriano MM, et al. ACTIVE MONITORING OF EARLY SAFETY OF SPUTNIK V VACCINE IN BUENOS AIRES, ARGENTINA.Google Scholar[

37]C.B. Coelho, R. Santos, K.F. Campara, R. TylerClassification of tinnitus: multiple causes with the same nameOtolaryngol. Clin., 53 (4) (2020), pp. 515-529, 10.1016/j.otc.2020.03.015ArticleDownload PDFView Record in ScopusGoogle Scholar[

38]A.A. Esmaili, J. RentonA review of tinnitusAust. J. Gen. Pract., 47 (4) (2018), pp. 205-208, 10.31128/AJGP-12-17-4420 View PDFView Record in ScopusGoogle Scholar[

39]P. Rzymski, B. Perek, R. FlisiakThrombotic thrombocytopenia after covid-19 vaccination: in search of the underlying mechanismVaccines, 9 (6) (2021), pp. 1-12, 10.3390/vaccines9060559 View PDFView Record in ScopusGoogle Scholar[

40]T. Hasan, M. Khan, F. Khan, G. HamzaCase of Guillain-Barré syndrome following COVID-19 vaccineBMJ Case Rep., 14 (6) (2021), 10.1136/BCR-2021-243629 View PDFGoogle Scholar[

41]D. Kanduc, Y. ShoenfeldMolecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccineImmunol. Res., 68 (5) (2020), pp. 310-313, 10.1007/S12026-020-09152-62020 View PDFView Record in ScopusGoogle Scholar[

42]E.J. Formeister, W. Chien, Y. Agrawal, J.P. Carey, C.M. Stewart, D.Q. SunPreliminary analysis of association between COVID-19 vaccination and sudden hearing loss using US centers for disease control and prevention vaccine adverse events reporting system dataJAMA Otolaryngol Head Neck Surg., 147 (7) (2021), pp. 674-676, 10.1001/JAMAOTO.2021.0869 View PDFView Record in ScopusGoogle Scholar[

43]O. Shamriz, Y. Tal, M. GrossAutoimmune inner ear disease: immune biomarkers, audiovestibular aspects, and therapeutic modalities of cogan’s syndromeJ. Immunol. Res. (2018), 10.1155/2018/14986402018 View PDFGoogle Scholar[

44]A. Ciorba, V. Corazzi, C. Bianchini, et al.Autoimmune inner ear disease (AIED): a diagnostic challengeInt. J. Immunopathol. Pharmacol., 32 (2018), 10.1177/2058738418808680 View PDFGoogle Scholar[

45]S.A. JA LEHeritability and genetics contribution to tinnitusOtolaryngol. Clin., 53 (4) (2020), pp. 501-513, 10.1016/J.OTC.2020.03.003 View PDFGoogle Scholar[

46]A.R. Loiselle, A. Neustaeter, E. de Kleine, P. van Dijk, N.M. JansoniusAssociations between tinnitus and glaucoma suggest a common mechanism: a clinical and population-based studyHear. Res., 386 (2020), p. 107862, 10.1016/J.HEARES.2019.107862ArticleDownload PDFView Record in ScopusGoogle Scholar[

47]L.K. Wareham, E.S. Buys, R.M. SappingtonThe nitric oxide-guanylate cyclase pathway and glaucomaNitric Oxide : Biol. Chem., 77 (2018), p. 75, 10.1016/J.NIOX.2018.04.010ArticleDownload PDFView Record in ScopusGoogle Scholar[

48]E. Hofmann, R. Behr, T. Neumann-Haefelin, K. SchwagerPulsatile tinnitus: imaging and differential diagnosisDtsch. Ärztebl. Int., 110 (26) (2013), p. 451, 10.3238/ARZTEBL.2013.0451 View PDFView Record in ScopusGoogle Scholar[

49]E. NiesOtotoxic substances at the workplace: a brief updateArh. Hig. Rad. Toksikol., 63 (2) (2012), pp. 147-152, 10.2478/10004-1254-63-2012-2199 View PDFView Record in ScopusGoogle Scholar[

50]H. S, L. P, J. BD, M. F, M. GDrug-induced tinnitus and other hearing disordersDrug Saf., 14 (3) (1996), pp. 198-212, 10.2165/00002018-199614030-00006 View PDFGoogle Scholar[

51]Module 3 – immunization anxiety-related reactions – WHO vaccine safety basicshttps://vaccine-safety-training.org/immunization-anxiety-related-reactions.html, Accessed 27th Sep 2021Google Scholar[

52]Z-16025/05/2012 Imm P/F Government of India Ministry of Health & Family Welfare Immunization Division Date : 12 Th July , 2021 Nirman Bhawan , New Delhi Causality Assessment Results of 88 Reported Serious Adverse Events Following Immunization (2021)(AEFI. Published online)Google Scholar[

53]G. MS, M. NE, M. CM, et al.Immunization stress-related response – redefining immunization anxiety-related reaction as an adverse event following immunizationVaccine, 38 (14) (2020), pp. 3015-3020, 10.1016/J.VACCINE.2020.02.046 View PDFGoogle Scholar

[54]L. A, S. TA, M. NE, et al.Anxiety-related adverse events following immunization (AEFI): a systematic review of published clusters of illnessVaccine, 36 (2) (2018), pp. 299-305, 10.1016/J.VACCINE.2017.11.017 View PDFGoogle Scholar[

55]C.J. Sokolowski, J.A. Giovannitti, S.G. BoynesNeedle phobia: etiology, adverse consequences, and patient managementDent. Clin., 54 (4) (2010), pp. 731-744, 10.1016/J.CDEN.2010.06.012ArticleDownload PDFView Record in ScopusGoogle Scholar[

56]N.B. B D, S.B. C HSocial contagion of vasovagal reactions in the blood collection clinic: a possible example of mass psychogenic illnessHealth Psychol. : Off. J. Div. Health Psychol. Am. Psychol. Assoc., 33 (7) (2014), pp. 639-645, 10.1037/HEA0000053 View PDFGoogle Scholar

[57]M. NEVaccine hesitancy: definition, scope and determinantsVaccine, 33 (34) (2015), pp. 4161-4164, 10.1016/J.VACCINE.2015.04.036 View PDFGoogle Scholar[

58]E. K, H.J. LThe benefit of the doubt or doubts over benefits? A systematic literature review of perceived risks of vaccines in European populationsVaccine, 35 (37) (2017), pp. 4840-4850, 10.1016/J.VACCINE.2017.07.061 View PDFGoogle Scholar[

59]B.C. Oosterloo, P.H. Croll, Rjb Jong, M.K. Ikram, A. GoedegeburePrevalence of tinnitus in an aging population and its relation to age and hearing lossOtolaryngology-Head Neck Surg. (Tokyo), 164 (4) (2021), p. 859, 10.1177/0194599820957296 View PDFView Record in ScopusGoogle Scholar[

60]C.W. Newman, G.P. Jacobson, J.B. SpitzerDevelopment of the tinnitus handicap inventoryArch. Otolaryngol. Head Neck Surg., 122 (2) (1996), pp. 143-148, 10.1001/ARCHOTOL.1996.01890140029007  View PDFView Record in ScopusGoogle Scholar[

61]B. Langguth, R. Goodey, A. Azevedo, et al.Consensus for tinnitus patient assessment and treatment outcome measurement: tinnitus Research Initiative meeting, RegensburgProg. Brain Res., 166 (July 2006), pp. 525-536, 10.1016/S0079-6123(07)66050-62007 View PDFGoogle Scholar[

62]A. McCombe, D. Baguley, R. Coles, L. McKenna, C. McKinney, P. Windle-TaylorGuidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999Clin. Otolaryngol. Allied Sci., 26 (5) (2001), pp. 388-393, 10.1046/J.1365-2273.2001.00490.X View PDFView Record in ScopusGoogle Scholar[

63]Topical corticosteroids: mechanisms of action – PubMedhttps://pubmed.ncbi.nlm.nih.gov/2533778/, Accessed 30th Dec 2021Google Scholar[

64]N.R. Barshes, S.E. Goodpastor, J.A. GossPharmacologic immunosuppressionFront. Biosci. : J. Vis. Literacy, 9 (2004), pp. 411-420, 10.2741/1249 View PDFView Record in ScopusGoogle Scholar[

65]D.J. Hoare, V.L. Kowalkowski, S. Kang, D.A. HallSystematic review and meta-analyses of randomized controlled trials examining tinnitus managementLaryngoscope, 121 (7) (2011), pp. 1555-1564, 10.1002/LARY.21825 View PDFView Record in ScopusGoogle Scholar[

66]S. Okhovat, R. Fox, J. Magill, A. NarulaSudden onset unilateral sensorineural hearing loss after rabies vaccinationBMJ Case Rep., 2015 (2015), 10.1136/BCR-2015-211977 View PDFGoogle Scholar[

67]CDC Monitors Health Reports Submitted after COVID-19 Vaccination to Ensure Continued Safety COVID-19 Vaccines Are Part of the Most Intensive Vaccine Safety Monitoring Effort in U . S . History (2019), p. 323652Published onlineGoogle Scholar