Audio-Vestibular Side Effects of Drugs and Vaccines in Treatment of COVID-19

Abstract

Due to the pandemic of COVID-19, a few new drugs and vaccines were officially approved by the EMA (European Medical Agency) and FDA (Food and Drug Administration) for prevention and treatment of SARS-CoV-2. The aim of this study is to analyze and highlight their potential audio-vestibular side effects as an ototoxic adverse reaction. The chapter was written by the review of the available literature in the scientific databases such as PubMed, ResearchGate, Scopus, and ScienceDirect, and in summaries of product characteristics as an official source of information. There were 39 publications and 15 summaries of product characteristics (as other sources of data), which were also used in this analysis. Adverse events could be permanent or disappear over time. Following treatment for COVID-19, the most frequent adverse audio-vestibular reactions reported in clinical trials and publications in the area of audiology and otorhinolaryngology were dizziness, blurry vision with dizziness, nasopharyngitis, dysgeusia, and tinnitus. As far as vaccines are concerned, dizziness as an ototoxic effect was uncommon and occurs only in hypersensitive people who experience anaphylactic shock. However, there is still a need to monitor ototoxic side effects because of potential interactions with other ototoxic drugs.

1. Introduction

The main aim of this chapter is to draw attention to the pharmacological treatments (medications and vaccines) for COVID-19 and the side effect. The number of patients who were treated and vaccinated against COVID-19 is very high. It is very important due to the fact that during clinical trials when the number of participants is limited, it is not always possible to detect every single adverse reaction of drug. Additionally, the participants in clinical trials are included after meeting the specific inclusion criteria. After approval of the drug, the treated population is more different (e.g., extensive or poor metabolizers). The potential audio-vestibular side effect as an ototoxic adverse effect was analyzed in relation to drugs that were currently approved by the EMA (European Medical Agency) and FDA (Food and Drug Administration) for the treatment of COVID-19. Some of the drugs and vaccines for the treatment of COVID-19 are new, and sometimes it is hard to predict every side effect. The number of patients in the 1, 2, and 3 phases of clinical trials is limited. As a result, some side effects may be observed during the IV phase (post-market surveillance). The detection risk and adverse events in this phase are possible due to the real-world usage of each drug. Adverse reactions are classified by the World Health Organization (WHO), and the probability of the occurrence of side effect is defined as follows: (1) very common (≥ 1/10), (2) common (≥ 1/100 to < 1/10), (3) uncommon (≥ 1/1000 to < 1/100), (4) rare (≥ 1/10000 to < 1/1000), (5) very rare (<1/10000), and the last, not known, which means that the frequency cannot be estimated from the available data.

The audio-vestibular side effects of drugs are classified as ototoxic side effects. Tinnitus, vertigo, and dizziness are examples of audio-vestibular side effects that should be considered during treatment for COVID-19. However, drugs and vaccines in the treatment of COVID-19 may cause the side effects in the area of the audio-vestibular area, the SARS-CoV-2 may itself manifest in the similar way. Similarly, COVID-19 disease may be linked to such audio-vestibular disorders as hearing loss, vertigo, dizziness, and/or tinnitus. There are a few hypotheses that are postulated. First is neuritis or cochleitis caused by the viral involvement of the vestibulocochlear nerve or inner ear. Second is vascular disorders, which may affect semicircular canals and cochlea by ischemia. The next purpose may be because of the production of the proinflammatory cytokines or microvascular injuries in the region of the peripheral and central nervous system that may be caused by the endothelial dysfunction. The last purpose may be connected with the accidental after cross-reaction of antibodies or T-cells damage to the inner ear [1]. Otorhinolaryngologists, neurologists, audiological specialists, and general practitioners should be aware of this. Tinnitus may manifest as sensorineural hearing loss (SNHL) or may be a consequence of central alterations caused by drugs. Vestibular side effects may manifest as loss of balance and dizziness, instability, unsteadiness, and difficulties in maintaining an upright posture [2, 3]. In many cases, it is difficult to find out if the source of the clinical symptoms is drug or the transition of the disease of COVID-19.

2. Material and methods

The analysis of the audio-vestibular adverse reactions of the treatment of COVID-19 was based on the identification of the relevant literature searching and the summaries of product characteristics of the drugs, which were officially approved by Food and Drug Administration (FDA) and European Medical Agency (EMA). From the analysis of adverse reactions of treatments and based on Evidence-Based Medicine (EBM), those drugs were eliminated from the analysis: chloroquine and hydroxychloroquine, favipiravir, lopinavir/ritonavir, amantadine, oseltamivir, azithromycin, and ivermectin. All of these drugs, even if at the beginning of the pandemic of COVID-19, were administered to patients and now are no longer recommended for treatment of COVID-19 due to a lack of clinical data, publications, and recommendation. The number and the type of drugs that are used at the same time in the treatment of COVID-19 depend on many different factors, such as: the severity of the disease, comorbidities, or other drugs that may interact with anti-COVID-19 drugs (e.g., PF-07321332/ritonavir). The terms of searching were as follows: SARS-CoV-2, COVID-19, audio-vestibular side effects, dizziness, ototoxicity, dexamethasone, anakinra, molnupiravir, tocilizumab, casirivimab and imdevimab, bamlanivimab and etesevimab, remdesivir, PF-07321332 and ritonavir, tixagevimab and cilgavimab, sotrovimab, and COVID-19 vaccines. The criteria of analyzed and inclusion were: (1) language (English), (2) type of studies (double-blinded, randomized), (3) the number of participants in the study. During the analysis of the adverse reactions, it is important to prove correlation between the presence of clinical symptoms with the exact drug or vaccine.

3. The results

To this moment, EMA has authorized 10 treatments against COVID-19, which were authorized: (1) tixagevimab and cilgavimab (2) casirivimab and imdevimab, (3) sotrovimab (4) regdanvimab, (5) tocilizumab, (6) PF-07321332 and ritonavir, (7) remdesivir, (8) anakinra, (9) molnupiravir, and (10) dexamethasone. FDA additionally approved bamlanivimab and etesevimab in the treatment of COVID-19. Most frequently reported adverse reactions following COVID-19 treatment in terms of the audio-vestibular disorders were dizziness, blurry vision with dizziness, nasopharyngitis, dysgeusia, and tinnitus [4]. All medications in the treatment of COVID-19 may be classified into one of the three groups: monoclonal antibodies, anti-viral drugs, and immunosuppressive agents.

Tixagevimab and cilgavimab are both recombinant human IgG1κ monoclonal antibodies, and the mechanism of action against SARS-CoV-2 is based on them binding to non-overlapping regions of receptor binding domain (RBD) of spike proteins. In total, 4220 subjects were enrolled in two clinical studies (PROVENT and STORM CHASER), where safety and efficiency were examined. In the area of audio-vestibular disorders, no side effects have so far been identified [5, 6]. Casirivimab and imdevimab are human immunoglobulin G1 (IgG1) antibodies that reduce endogenous immunoglobulin G levels by up to 79% [7, 8]. The effectiveness of the combination of these monoclonal antibodies was assessed on the results of a clinical trial of 799 adult participants with mild to moderate symptoms of COVID-19. For patients at high risk of developing severe disease, those treated with monoclonal antibodies had a reduced risk (3% versus 9%) of hospitalization or an emergency room visit within 28 days of starting treatment [9, 10, 11, 12]. Sotrovimab is another monoclonal antibody (IgG1κ) with indication of treatment COVID-19 in adult and adolescents (above 12 years and weighing more than 40 kg), without requirement of supplemental oxygen but with the risk of progressing to severe phase of disease. The adverse reactions that were reported after administration of sotrovimab during phase II/III randomized, double-blind, and placebo-controlled clinical trial for treatment of COVID-19 in 1057 non-hospitalized, non-vaccinated adult patients (COMET-ICE clinical trial) include: hypersensitivity reactions (rash, bronchospasm), infusion-related reactions, and anaphylaxis, and dyspnea, but none of these can be classified as audio-vestibular disorders. The frequency of reported adverse reactions was classified as rare or uncommon. The adjusted relative risk reduction in hospitalization or death at 29 days of observation was 79% [13, 14].

Bamlanivimab is a recombinant, fully neutralizing human IgG monoclonal antibody. The mechanism of action based on the targeting RBD (receptor binding domain) of the spearhead protein. The information about the possible ototoxic effects of bamlanivimab is still limited, but dizziness may occur during and after of treatment with bamlanivimab according to the result of the clinical study BLAZE-1 (3.2% of patients reported an adverse event of dizziness) [15, 16, 17, 18]. The combination of different monoclonal antibodies (tocilizumab and sarilumab – IL-6 receptor antagonists) in the clinical trials has been assessed in 803 adult patients: 353 patients in the “tocilizumab group,” 48 patients in the sarilumab group and 402 patients, who were enrolled to the control group [19, 20]. Dizziness, as a type of ototoxicity side effect, is classified as common after treatment of tocilizumab [21, 22]. For sarilumab, according to the clinical trials and according to data, nasopharyngitis was reported as a common side effect [19, 23, 24].

Molnupiravir is an oral prodrug and treatment for COVID-19. Molnupiravir is a nucleotide analogue, which works by inhibiting the viral replication of the SARS-CoV-2 by causing viral mutagenesis [25]. The indication for molnupiravir is treatment of COVID-19 from mild to moderate in adult patients (COVID-19 positive patients) and those of them who are in the population of patients who are at the high risk of progressing the disease to severe phase. Molnupiravir is administered twice a day at the dose of 800 mg for 5 days. The effectiveness and safety were assessed in phase 3, double-blinded clinical trial (acronym MOVe-OUT) with 1411 non-hospitalized subjects, randomly divided into two subgroups: N = 710 (subjects that are treated with molnupiravir and N = 701 subjects as a control group (placebo group). During clinical trials, serious adverse reactions occurred in 7% in the first subgroup and in 10% of those patients from the placebo group. In the area of audio-vestibular disorders, dizziness was mostly reported and occurs in 1% of patients from both groups [25, 26]. The second oral anti-COVID-19 drug is the combination of co-packaged tablets with two active substances ritonavir and PF-07321332. PF-07321332 is a SARS-CoV-2 main protease (Mpro) inhibitor, and ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor [27]. The efficacy and safety of this drug were assessed in the randomized and placebo-controlled, phase 2/3 of the clinical trial (C4671005 EPIC-HR) with 2224 adult patients who suffer form COVID-19. Enrolled patients were then divided into two subgroups: the first one with 1109 patients and the second one with 1115 subjects. In total, 6% of all patients reported dysgeusia, and the most common side reactions were: hypertension, myalgia, and diarrhea [27].

Anakinra has been authorized for treatment of many diseases such as rheumatoid arthritis for adult patients, autoinflammatory periodic fever syndromes, and for treatment of Cryopyrin-Associated Periodic Syndromes. The mechanism of action of anakinra is based on neutralization of the biologic activity of interleukins (IL-1α and IL-1β) by inhibiting the binding to the receptor IL-1RI. The efficacy and safety of anakinra in the treatment of COVID-19 were assessed during randomized, placebo-controlled clinical trial with the acronym SAVE-MORE. In total, 405 patients were enrolled to this study. Side effects in the area of the otorhinolaryngology and audio-vestibular disorders were not [28, 29].

Dexamethasone has an anti-inflammatory effect and is therefore mainly used as an adjunct in the treatment of viral pneumonia. Due to its higher potency, it is suspected that this drug might prove effective in treating patients with SARS-CoV-2 [30, 31, 32]. Dexamethasone in the treatment of COVID-19 is responsible downgrading IDO1 (indoleamine 2,3-dioxygenase) and AhR (aryl hydrocarbon receptors) genes and as a result, reducing inflammation. After entering the human body, SARS-CoV-2 activates receptor AhR (aryl hydrocarbon receptors) after entering their target cells through a mechanism independent of IDO1. SAAS (systemic AhR activation syndrome) is the result of the upregulation of the series effectors that are depended on the AhR [30, 33, 34]. The strong recommendation for administration of dexamethasone in severe-ill patients is to prevent or reduce a systemic inflammatory response, which may lead to the multiorgan dysfunction and damage of the lung [35]. The European Medical Agency (EMA) approved dexamethasone for the treatment of COVID-19 patients undergoing mechanical or aerobic ventilation [36]. Side effects in the area of otorhinolaryngology may cause blurry vision with dizziness [30, 35].

Remdesivir, which is an adenosine nucleotide prodrug, was one of the first drugs approved for the treatment of COVID-19. It is metabolized in the human organism into the remdesivir triphosphate and impacts on the replication of the viral RNA. The safety and efficacy were evaluated during NIAID ACTT-1 Study with 1063 participants. None of the audio-vestibular adverse reactions were reported [37].

3.1 COVID-19 vaccines

Until then, there are five vaccines approved by European Medical Agency: (1) Comirnaty (marketing authorization holder: BioNTech and Pfizer), (2) Nuvaxovid (marketing authorization holder: Novavax), (3) Spikevax (marketing authorization holder: Moderna), (4) Vaxzevria (marketing authorization holder: AstraZeneca), and (5) Jcovden (marketing authorization holder: Janssen). According to the data presented by EMA in safety report of COVID-19 vaccines, 870 million doses of vaccines have been given to citizens in the area of European Union (UE) and European Economic Area (EEA), and there is no information about the new audio-vestibular adverse reactions. The vast majority of all side effects are mild and short-lived [38]. Clinical trials show that systemic and local reactions may occur as a result of vaccination. According to the clinical data and what patients most frequently report are pain at the injection site and less frequently redness or swelling at the site, headache and fatigue, and fever. After official authorization of COVID-19 vaccines by European Medical Agency (EMA) and Food and Drug Administration (FDA), the continuation of monitoring and analysis of further side effects is obligation of pharmaceutical companies and safety authorities. Some of the drugs and vaccines for the treatment of COVID-19 are new, and sometimes it is hard to predict every side effect. The number of patients in the 1, 2, and 3 phases of clinical trials is limited. As a result, some side effects may be observed during the IV phase (post-market surveillance). The detection risk and adverse events in this phase are possible due to the real-world usage of each drug. Some authors highlight that there may be relationship between occurrence of tinnitus and SSNHL (Sudden Sensorineural Hearing Loss) after vaccination, but it needs further clinical studies and observation as the relationship has been described as indirect [39, 40, 41].

According to the summary of product characteristics, Comirnaty in one dose contains 30 μg of COVID-19 mRNA embedded in lipid nanoparticles. The efficacy and safety ratio of this vaccine was evaluated in participants enrolled in two clinical studies that included 21,744 participants who had received at least one dose of the vaccine. The most frequent side effects in participants that were reported are: (1) pain at the injection site (>80%), (2) fatigue (>60%), (3) headache (> 50%), (4) myalgia and chills (>30%), (5) arthralgia (>20 %), (6) pyrexia, and (7) swelling at the injection site (>10 %). The side effects were classified as mild to moderate and usually resolved within a few days after vaccination. Dizziness as an audio-vestibular side effect occurred only in hypersensitive people as part of anaphylactic shock, and its frequency is unknown (it cannot be estimated from available data) [42].

Moderna COVID-19 vaccine in one dose contains 100 μg of COVID-19 messenger RNA embedded in SM-102 lipid nanoparticles. The effectiveness and safety profile was evaluated in a randomized, placebo-controlled phase 3 clinical trial in 30,351 participants who received at least one dose of the vaccine. The most frequent reported adverse reactions in participants were similar as in all other vaccines: (1) pain at the injection site (92%), (2) fatigue (70%), (3) headache (64.7%), (3) myalgia (61.5%), (4) arthralgia (46.4%), (5) chills (45.4%), (6) nausea/vomiting (23%), (7) axillary swelling/tenderness (19.8%), (8) fever (15.5%), (9) swelling at the injection site (14.7%), and (10) redness (10%). The side effects were defined between mild to moderate and not long-lasting (usually side effects resolved in the period within a few days after injection). Dizziness as an ototoxic effect may occurred only in hypersensitive people as part of anaphylactic shock, and its frequency is unknown (cannot be estimated from the available data) [43].

One dose of vaccine consists of 0.5 mL (brand name: Vaxzevria. The efficacy and safety were assessed in four clinical trials with number of participants: 23,745. The most frequently reported adverse reactions were: (1) injection site tenderness (>60%); (2) injection site pain, (3) headache, (4) fatigue (>50%); (5) myalgia, (6) malaise (>40%); (7) pyrexia, (8) chills (>30%), (9) arthralgia, and (10) nausea (>20%). In the area of otorhinolaryngology, dizziness as an ototoxic side effect may occur only in people who are hypersensitive for the ingredients of vaccine as a part of anaphylactic shock. The frequency of the reaction is unknown [44, 45, 46, 47, 48].

Janssen vaccine is an adenovirus vaccine against COVID-19 disease, and one dose (0.5 mL) contains adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein* (Ad26.COV2-S, not less than 8.92 log10 infectious units). The safety of Janssen COVID-19 vaccine has been evaluated in an ongoing Phase 3 study (COV3001) in which a total of 21,895 adults aged 18 years and older received a single-dose vaccination. The most common systemic adverse reactions were: (1) headache (38.9%), (2) fatigue (38.2%), (3) myalgia (33.2%), and (4) nausea (14.2%). Pyrexia (body temperature ≥ 38.0°C) was observed in 9% of participants. The most important side effects in the audiology and otorhinolaryngology field reported in the clinical trials were dizziness (of uncommon frequency) and tinnitus (rare).

Nuvaxovid is a recombinant, adjuvanted vaccine against COVID-19, and one dose (0.5 mL) contains 5 μg of the SARS-CoV-2 spike protein and is adjuvanted with Matrix-M. The safety profile was evaluated from five clinical trials involving 49,950 adult participants. The adverse reactions were mild to moderate and included (1) site tenderness (75%), (2) injection site pain (62%), (3) fatigue (53%), (4) myalgia (51%), (5) headache (50%), (6) malaise (41%), (7) arthralgia (24%), (8) nausea, and (9) vomiting (15%). The duration of adverse reactions was a few days. No adverse reactions important from an otorhinolaryngological or audiological point of view were reported. Dizziness as an ototoxic effect occurred only in hypersensitive people as part of anaphylactic shock and as an adverse reaction with uncommon frequency [49].

4. Discussion and conclusion

At the beginning of pandemic of COVID-19 and due to the lack of specific treatment ototoxicity as a side effect was reported after treatment included chloroquine and hydroxychloroquine. By analyzing new, COVID-19 therapies, including those already approved by the regulatory authorities (EMA and FDA), we will be able to gain knowledge about new disease treatment protocols and their possible side effects, including those related to the hearing organ. The earlier we can implement monitoring measures the better. Patients with renal impairment, children under 3 years of age, people over 65 years of age, pregnant women, and patients who have been treated with ototoxic drugs or who will be administered an ototoxic drug for more than 14 days are at higher risk of presence of side effects [41, 50, 51]. Tinnitus, dizziness, vertigo are the most frequently reported side effects in the area of the audio-vestibular disorders during the treatment of COVID-19. This is important not only for specialist such as otorhinolaryngologists, audiologists, but also for neurologists and general practitioners. As far as tinnitus is concerned, this disorder may manifest as sensorineural hearing loss (SNHL). Loss of balance, dizziness, instability, difficulties in maintaining an upright posture, and unsteadiness are classified as vestibular side effects.

In 2021, the FDA and EMA approved monoclonal antibodies and oral drugs for treatment of COVID-19. The SARS-CoV-2 itself may cause similar audio-vestibular disorders. Many of the drugs approved by the EMA and FDA are new, and as a result not every side effect is known. Dizziness, blurry vision with dizziness, and tinnitus are the most frequently reported adverse reactions during and after treatment of the COVID-19. Additionally, nasopharyngitis and dysgeusia have been reported. While vaccines are concerned, dizziness as an ototoxic effect may occur only in hypersensitive people as a result of anaphylactic shock (a rare adverse reaction). The ototoxicity (hearing loss) of the drugs described in this chapter does not have such severe symptoms as some drugs used in the treatment of COVID-19 in 2020 (in particular, hydroxychloroquine). The continuous monitoring of possible ototoxic side effects may arise from interactions with other ototoxic drugs. Finally, the SARS-CoV-2 itself may cause similar audio-vestibular disorders as the drugs for treatment of COVID-19.