Chloroquine and COVID-19: Should We Care about Ototoxicity?

Update Articles Special Article COVID-19 Chloroquine and COVID-19: Should We Care about Ototoxicity? Eduardo Machado Rossi Monteiro1  http://orcid.org/0000-0002-9082-3232 Maria Fernanda Lima Nascimento1  http://orcid.org/0000-0001-7215-3549 Thayanne Rachel Cangussu Brito1  http://orcid.org/0000-0003-4874-6904 Marcos Correia Lima1  http://orcid.org/0000-0002-6398-2019 Laura Rodrigues Sefair1  http://orcid.org/0000-0002-0165-6162 Maisa Mendes Pedrosa1  http://orcid.org/0000-0002-9070-6247 1Department of Otorhinolaryngology, Hospital Felício Rocho, Belo Horizonte, MG, Brazil Abstract Introduction Severe acute respiratory syndrome coronavirus 2 was first described in December 2019 in China leading to a Public Health Emergency of International Concern. It was named by the World Health Organization as Coronavirus Disease 2019 (COVID-19), and it garnered unprecedented attention from public health researchers around the world, and studies analyzing chloroquine and hydroxychloroquine as a possible therapy have arisen in the last 2 months. Objective To review the literature and describe updated facts about the ototoxicity of chloroquine and hydroxychloroquine, an important side effect that can be present in patients with COVID-19 treated with these drugs. Data Synthesis The most typical treatment regimen is 5 days of hydroxychloroquine at daily doses of 400 to 600 mg. There is no randomized clinical trial that can prove so far the efficacy of this medication, and few studies have evaluated adverse events potentially linked to their use in patients with COVID-19. While there is no concrete evidence on the incidence of ototoxicity using chloroquine in the short term, we need to consider that, as a pandemic disease, millions of patients with COVID-19 may receive this treatment, and ototoxicity can be a possible adverse event. Conclusion Despite the urgent global situation caused by the COVID-19, the risk of irreversible hearing loss may outweigh the unproven benefit of using hydroxychloroquine or chloroquine, especially in patients with mild forms of COVID-19, who may be cured with supportive treatment. The potential hearing loss that can be caused by these medications may advise against their use in COVID-19 patients. Keywords ototoxicity; hearing loss; COVID-19; hydroxychloroquine; chloroquine Introduction On December 31st, 2019, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was identified in Wuhan, China. It was responsible for an outbreak of a severe acute respiratory syndrome that led to a Public Health Emergency of International Concern (PHEIC), and the World Health Organization (WHO) named it Coronavirus Disease 2019 (COVID-19). It is considered the third zoonotic human coronavirus of the century, since there were cases of SARS-CoV in 2002 in China and cases of Middle East Respiratory Syndrome (MERS-CoV) in 2012 in Saudi Arabia, and it was declared a pandemic by the WHO on March 11th, 2020.1,2 Since the emergency of COVID-19, many studies have been published trying to clarify some clinical questions, such as route of transmission, risk factors, natural course, outcomes, and treatment options. One of the medications that has been used in many hospitals to manage these patients is chloroquine, a 4-aminoquinoline drug currently used to treat malaria, rheumatoid arthritis, and systemic erythematosus lupus, reported as a potential broad-spectrum antiviral drug. Hydroxychloroquine has also been used, due to its clinical safety profile being better than chloroquine, which allows higher daily doses with fewer drug interactions.3 In his review, Juurlink (2020) has evidenced that the most typical regimen is 5 days of hydroxychloroquine at daily doses of 400 to 600 mg, which was corroborated by Mehra et al (2020), and its doses did not exceed 600 mg daily for 5 to 10 days.4,5 On May 20th, 2020, the Brazilian Department of Health expanded the use of hydroxychloroquine or chloroquine associated with azithromycin during 5 days for patients with mild symptoms of the disease.6 However, on the same day, the Brazilian Society of Infectious Diseases pronounced themselves against the routine use of these drugs, since until this date there are no randomized clinical trials with a control group that confirm the effectiveness of these medications in the treatment of patients diagnosed with COVID-19. According to them, these medications should only be used for scientific purposes and in a clinical trial.7 The most common adverse events related to the use of chloroquine and hydroxychloroquine are cardiotoxicity and retinal toxicity. However, an important side effect that is not commonly discussed is the potential ototoxicity of these medications, which is already known and has been studied for several years. Many reports have described sensorineural hearing loss after prolonged therapy with chloroquine, but there are also studies that described cochleovestibular ototoxicity with both acute and chronic use of chloroquine and hydroxychloroquine. These drugs accumulate and fix selectively in melanocytes of cochlear sensory hair cells, resulting in variable injuries that can be irreparable.3,8 There are reports about children with systemic lupus erythematosus who developed ototoxicity soon after the therapy with hydroxychloroquine was initiated.9 There are also cases reported in the literature, since 1968, of hearing loss in newborns of mothers who had malaria and used chloroquine during pregnancy.10,11 Therefore, the present paper aims to review the literature and describe updated facts about the ototoxicity of chloroquine and hydroxychloroquine, an important side effect that can be present in patients with COVID-19 treated with these drugs. Review of a Particular Subject A bibliographic search was performed in the PubMed and Scientific Electronic Library Online (Scielo) databases for papers published up to May 21st, 2020 using the terms coronavirus or COVID-19 in combination with hydroxychloroquine or chloroquine; and using ototoxicity in combination with hydroxychloroquine or chloroquine. There were no published studies regarding ototoxicity and COVID-19 and chloroquine or hydroxychloroquine. Moreover, we also consulted the web pages of organizations such as World Health Organization, the Brazilian Department of Health, and theBrazilian Academy of Otorhinolaryngology and Head and Neck Surgery. Discussion The SARS-Cov-2 is a betacoronavirus that uses the angiotensin-converting enzyme 2 receptor for cell entry. The main mode of transmission is person-to-person, especially via respiratory droplets that can be dispersed in the air for up to two meters and stay viable in surfaces for a variable amount of time. Thus, the virus is released not only when an infected person sneezes or talks, but also when a person touches an infected surface and then touches the eyes, nose (...truncated)