Impact of COVID-19 Medication (Favipiravir and Hydroxychloroquine) on High Frequency Hearing

Abstract

During the initial phase of the COVID-19 pandemic, there was ongoing investigation into potentially effective treatments. Antiviral medications such as Favipiravir and Hydroxychloroquine were employed to treat COVID-19 infections. However, limited studies have examined the adverse effects of these medications on hearing, particularly at extended high frequencies. This study included 10 subjects who had received medications like Azithromycin, a combination of Favipiravir and Hydroxychloroquine, and Hydroxychloroquine alone as part of their COVID-19 treatment. These subjects had previously undergone extended high-frequency audiometry testing (from 8 to 20 kHz) as part of another project conducted by the same department before contracting COVID-19. Post-COVID-19 extended high-frequency audiometry was performed 1 month after the patients received a negative RT-PCR report. The results were then compared using a Paired t-test. A significant shift in the thresholds of high frequencies above 8–20 kHz is found in subjects who had received Favipiravir and Hydroxychloroquine medications. We observed a significant impact of COVID-19 medications on high-frequency hearing, which tends to go unnoticed in regular pure-tone audiometry evaluations. Therefore, our study emphasizes the need for regular follow-ups, including detailed audiological assessments that incorporate extended high-frequency testing, at least once every 3 months for patients who have taken medications for COVID-19 treatment.

Introduction

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus [1]. The primary mode of transmission is through the inhalation of infected air and contact with respiratory droplets from infected individuals. COVID-19 symptoms vary from person to person, with the most common ones identified by WHO being fever, cough, fatigue, and loss of smell. The majority of infected individuals experience mild to moderate illness and recover without hospitalization.

Viruses, including the one responsible for COVID-19, are subject to continuous mutations, leading to the emergence of new variants with distinct characteristics [2]. Some of these variants spread more easily or become resistant to treatments and vaccines. As a result, the symptoms associated with infections caused by different variants can differ. WHO has identified two major variants of COVID-19: Delta (B.1.617.2), first identified in India, and Omicron (B.1.1.529), first identified in South Africa. The medical treatment for these variants relies on FDA-authorized monoclonal antibody treatments, determined by the patient's symptoms and the severity of the infection.

During the second wave of COVID-19, while effective treatments were still under investigation, antiviral drugs like Favipiravir and Hydroxychloroquine were utilized to combat the spread of the virus. Favipiravir was shown to promote viral clearance within seven days and clinical improvement within 14 days, suggesting its potential for treating COVID-19, particularly in patients with mild-to-moderate illness [3]. However, research on the efficacy, safety, and side effects of Favipiravir for COVID-19 patients remains limited.

Similarly, in the early stages of the second wave of COVID-19 in 2020, India approved the use of Hydroxychloroquine (HCQ), an antimalarial drug, as a potential treatment for COVID-19. HCQ was used for the prophylaxis of asymptomatic healthcare workers treating suspected or confirmed COVID-19 cases, as well as asymptomatic household contacts of confirmed patients in India [4].

Ototoxicity during COVID-19

According to Andrea Ciorba et al. (2020) [5], several drugs proposed for the treatment of COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and antiviral drugs like remdesivir, favipiravir, and lopinavir, may have potential ototoxic side effects. Common ototoxic side effects of these drugs include sensorineural hearing loss, tinnitus, and persistent or reversible balance issues. In most cases, ototoxic effects develop after prolonged use of these medications over weeks or months. The exact mechanisms that mediate inner ear hair cell damage, as well as the etiology of ototoxicity, remain unknown in many cases. Another challenge is the difficulty of monitoring hearing threshold shifts while maintaining social distancing during the pandemic [6].

Subsequent studies have suggested that hydroxychloroquine is ineffective in treating COVID-19 and carries a high risk of fatal heart arrhythmias [7], consistent with the findings proposed by Sherief Abd-Elsalam et al. in 2020 [8].

Currently, few studies have examined the post-COVID-19 effects on pure-tone thresholds, especially at extended high frequencies. A comparative study by Osman Durgut et al. in 2021 [9] found no significant difference in pre- and post-COVID-19 hearing levels across frequencies from 250 Hz to 8 kHz. A similar outcome was reported in another study by Kerem Kökoğlu et al. in 2021 [10], which compared pure-tone thresholds between 125 and 8000 Hz before and after COVID-19.

Most research on the effects of medications used for COVID-19 on hearing levels has been limited to frequencies from 250 Hz to 8000 kHz, even though drugs like Chloroquine, Hydroxychloroquine, and Favipiravir are ototoxic drugs that primarily affect higher frequencies (above 6000 Hz–20 kHz). Given this, the focus of this study was to understand the effects of medications like Hydroxychloroquine and Favipiravir, used in COVID-19 treatment, on hearing thresholds, especially at higher frequencies between 8 and 20 kHz.

Methodology

The study was conducted at the Department of Audiology, MAA Institute of Speech and Hearing, India. A total of 10 subjects participated in the study. Extended high-frequency pure-tone audiometry tests were conducted in a soundproof room using a clinical audiometer (Maico MA 42 – Dual channel digital audiometer) and Sennheiser HDA 2000 Circumaural earphones. Air-conduction hearing thresholds were measured at 8 kHz, 9 kHz, 10 kHz, 12.5 kHz, 14 kHz, 16 kHz, 18 kHz, and 20 kHz for both the right and left ears separately, using the Modified Hughson–Westlake method, and plotted on a high-frequency audiogram. The high-frequency pure-tone average (PTA) was calculated by averaging the three poorest thresholds between 8 and 20 kHz. All subjects included in the study had pre-recorded high-frequency hearing thresholds collected 1 year before as part of another study conducted in the same department. These pre-recorded extended high-frequency hearing thresholds between 8 and 20 kHz were compared with the post-COVID-19 thresholds for all subjects (Table 1).

Table 1.

Demonstrates the demographic details of the participants

Age range	20–45 years
Gender	06 males and 04 females
Co – Morbid conditions	Nill

All subjects had been diagnosed with COVID-19 and had taken medications for the condition. None of them had been hospitalized due to severe or critical COVID-19. Exclusion criteria included complaints of hearing loss both before and after COVID-19 infections, a history of ear disease or surgery, and symptoms such as tinnitus, otalgia, and ear discharge before COVID-19 infection.

Name, age, gender, medications received for COVID-19 treatment, and the duration of medication taken were noted as part of data collection. Post-COVID-19 extended high-frequency audiometry was conducted 1 month after the patients received a negative RT-PCR report following their treatment (Table 2).

Table 2.

Demonstrates the details of the medications used by the participants

Participants	Medications used during COVID– 19 infection	Duration of the medication	Mode of medication taken
Participants 1 and 2	Azithromycin along with Vitamin supplements	7–10 days	Orally
Participants 3–7	Favipiravir and Hydroxychloroquine along with vitamin supplements	7–10 days	Orally
Participants 8–10	Hydroxychloroquine along with vitamin supplements	7–10 days	Orally

Results

The data normality of n = 20 ears was tested using the Shapiro–Wilk and Kolmogorov normality tests, and it was found to be normally distributed. Inferential statistics, specifically a Paired t-test, were employed to determine if there was a statistically significant difference between the groups before and after taking medications for COVID-19 infections. Tabular evidence is provided in Table 3

Table 3.

Mean Threshold values with paired t-test analysis of pre and post COVID-19 groups (n = 20 ears)

Timeline	Medications used	8 kHz		9 kHz		10 kHz		12.5 kHz		14 kHz		16 kHz		18 kHz		20 kHz		Paired test analysis
		Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	t	p
Pre-Covid-19	No Medication group	9.5	5.7	8.4	2.8	11.5	5.2	10.5	4.5	15.5	4.27	26	7.63	19	5.27	15	2.24	0.74	= 0.89
Post-Covid-19	Azithromycin	11	2.0	11.25	2.5	13.75	3.5	7.5	2.0	15	6.24	10	3.76	10	5.0	5.0	0.32	7.64	= 0.024
	Favipiravir & HCQ	16	4.2	20	2.4	26	3.2	26	5.4	44.75	3.2	44.5	2.62	30	3.5	10	5	9.26	< 0.001
	HCQ	10.50	2.35	18	4.08	23	2.76	31.5	6.23	38	4.02	40	4.36	NR	NR	NR	NR	9.2	< 0.001

Table 3 shows that the P-value of the Paired t-test analysis indicates a significant post-COVID-19 threshold shift in subjects who had received Favipiravir and Hydroxychloroquine medications as part of their treatment for COVID-19 infections, whereas there was no significant threshold shift seen in subjects who had received Azithromycin medications.

Figure 1 demonstrates that, when compared to the pre-recorded extended high-frequency hearing thresholds, significant threshold shifts were observed at all frequencies from 9 to 20 kHz for the subjects who had received Favipiravir and Hydroxychloroquine medications. A very significant threshold shift of more than 15 dB HL was seen in frequencies above 12.5 kHz for the same group of subjects, with the maximum threshold shift ranging from 15 to 45 dB HL. Most of the subjects who had received only Hydroxychloroquine medications showed ‘No Response’ at 18 kHz and 20 kHz, even when pure tones were presented at the maximum audiometric limits.

Fig. 1.

Effect of Post COVID—19 medications (Azithromycin, Favipiravir and Hydroxychloroquine) on hearing thresholds at Extended high frequencies

For the subjects who had received Azithromycin medications, threshold shifts of only 5–10 dB HL were observed across 8–20 kHz, which is considered negligible.

Discussion

During the early stages of the COVID-19 pandemic, antiviral and antimalarial drugs like Favipiravir and Hydroxychloroquine were employed to control the spread of the virus and treat infected patients. However, very few studies have explored the risk factors of these medications, such as ototoxicity and heart failures.

Subsequently, in 2021, WHO declared that they do not recommend Hydroxychloroquine for preventing COVID-19 due to its higher rate of side effects, including heart failures. Nevertheless, hydroxychloroquine and chloroquine are considered safe for use in patients with autoimmune diseases or malaria (but not for COVID-19) [1]. Recent studies have also identified the ototoxic side effects of other drugs proposed for COVID-19 treatment, such as chloroquine, hydroxychloroquine, and favipiravir.

This study was conducted to assess the impact of COVID-19 medications, specifically Hydroxychloroquine, Favipiravir, and Azithromycin, on extended high frequencies ranging from 8000 to 20,000 Hz. Extended high-frequency (EHF) audiometry has the potential to detect early changes in auditory function more effectively than conventional frequency audiometry and is the most sensitive measure for identifying ototoxic damage [11]. While obtaining baseline EHF audiometry is optimal for monitoring ototoxicity, it is often challenging in clinical settings. Thus, high-quality reference data for extended high-frequency hearing thresholds, as in this study, is essential. This study identified a significant shift in thresholds at extended higher frequencies for subjects who had received Hydroxychloroquine and Favipiravir drugs for the treatment of COVID-19 infection by comparing these thresholds with the pre-recorded reference thresholds.

The clinical implications of hearing loss in the extended high-frequency range are not fully understood, but there is increasing evidence that these frequencies are relevant for functional hearing and are important for skills such as speech localization and speech perception in noisy environments [12]. Significant hearing loss at extended high frequencies, as observed in this study, can impact speech frequencies over time. In most cases, hearing loss at higher frequencies is known to be irreversible, further highlighting the severity of the effect of COVID-19 medications on extended high frequencies.

Additionally, aging negatively affects hearing ability at extended high frequencies even in healthy individuals. According to Mingming Wang et al. (2021) [13], hearing thresholds at these frequencies deteriorate with age and with rising frequencies, while the upper frequency limit decreases with aging.Even though none of the participants in this study reported decreased hearing sensitivity, the clinical implications of extended high-frequency audiometry, especially for tracking the adverse effects of ototoxic drugs, emphasize the importance of early identification of hearing loss at these high-frequency regions. This, in turn, facilitates the implementation of rehabilitation measures when necessary.

The present study involved patients who had received only Hydroxychloroquine, Favipiravir, and Azithromycin drugs to treat COVID-19. The effects of other medications used for the same purpose also need evaluation. Furthermore, the results of this study highlight the importance of comprehensive audiological evaluations, including electrophysiological tests to identify the retrocochlear effects of these medications, as there are very few studies available in this area.

Conclusion

We found a significant impact of COVID-19 medications on high-frequency hearing, which tends to be overlooked in regular pure-tone audiometry evaluations. The adverse effects of these medications on speech frequencies over time have yet to be determined. Therefore, our study underscores the importance of regular follow-ups, including comprehensive audiological assessments that incorporate EHF audiometry, at least once every 3 months for patients who have taken medications for COVID-19 treatment.

Funding

None.

Code Availability

Not applicable.

Declarations

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in the study including, involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.