key: cord-0866561-khbzw28z authors: Britto, Diana Babini Lapa de Albuquerque; Rocha, Mônyka Ferreira Borges; Silva, Jéssica Dayane da; Pinheiro, Natália dos Santos; Silva, Lidiane Kelvin da; Advíncula, Karina Paes title: Auditive and Vestibular Changes Related to the Use of Hydroxychlorochine and Chlorochine: An Integrative Review date: 2021-03-29 journal: Int Arch Otorhinolaryngol DOI: 10.1055/s-0040-1722292 sha: fc0d700a68ff3f9756e5ac2870ae4963540a66f0 doc_id: 866561 cord_uid: khbzw28z Introduction The use of hydroxychloroquine and chloroquine is formally indicated in cases of chronic autoimmune diseases. However, the use of these medications has already been associated with possible transitory or definitive alterations in hearing function and/or vestibular function in humans, when administrated in the short and long terms. Objective To describe, through a literature analysis, the functional vestibular and/or hearing alterations, caused by the use of hydroxychloroquine and chloroquine in youths and adults. Data Synthesis In total, 2,481 studies were identified in the initial search: out of these 32 were selected for a full-text reading, and 9 were selected after the exclusion of those which did not meet the eligibility criteria. Of these, four articles pointed to the presence of vestibular and auditory-associated alterations, three indicated only auditory pathologies, and two, vestibular disorders. Regarding the auditory alterations, tinnitus was the most frequent symptom, and bilateral sensorineural hearing loss was described in most studies, varying in degree from mild to severe. As for the vestibular alterations, vertigo was the most reported symptom. Conclusion Knowledge of the auditory and vestibular effects after the use of these substances can help in the decision regarding the best treatment, enabling the consideration of other available therapies for patients at risk of suffering those alterations, reducing the risk of auditory and vestibular disorders. Introduction The use of hydroxychloroquine and chloroquine is formally indicated in cases of chronic autoimmune diseases. However, the use of these medications has already been associated with possible transitory or definitive alterations in hearing function and/or vestibular function in humans, when administrated in the short and long terms. Objective To describe, through a literature analysis, the functional vestibular and/or hearing alterations, caused by the use of hydroxychloroquine and chloroquine in youths and adults. Data Synthesis In total, 2,481 studies were identified in the initial search: out of these 32 were selected for a full-text reading, and 9 were selected after the exclusion of those which did not meet the eligibility criteria. Of these, four articles pointed to the presence of vestibular and auditory-associated alterations, three indicated only auditory pathologies, and two, vestibular disorders. Regarding the auditory alterations, tinnitus was the most frequent symptom, and bilateral sensorineural hearing loss was described in most studies, varying in degree from mild to severe. As for the vestibular alterations, vertigo was the most reported symptom. Conclusion Knowledge of the auditory and vestibular effects after the use of these substances can help in the decision regarding the best treatment, enabling the consideration of other available therapies for patients at risk of suffering those alterations, reducing the risk of auditory and vestibular disorders. Introduction In December 2019, an increasing number of cases of acute respiratory disease in the province of Wuhan, China, was being related to a new β-coronavirus, temporarily named 2019-nCoV. 1 On February 11th, 2020, the World Health Organization (WHO) officially named the pathogen SARS-CoV-2 and the infectious disease caused by it, COVID-19. 2 In the following month, the entity recognized the occurrence of the infection with great geographic distribution, and declared a state of pandemic. 3 Brazil is one of the countries with community transmission of COVID-19, presenting 438.238 cases and 26.754 deaths by the disease confirmed until May 30th, 2020. 4 The most common symptoms of COVID-19 are fever, fatigue, and dry cough, and some patients can present myalgia, runny nose, sore throat, and diarrhea, those being normally considered light symptoms. However, some patients can develop more serious symptoms, such as dyspnea and severe acute respiratory syndrome (SARS), with the need for intensive therapy and the use of mechanical ventilation; in these cases, the disease may be fatal. 5, 6 COVID-19 infects people of all ages; some cases are asymptomatic, and the factors that determine the clinical manifestation of the disease are still unknown. Yet, shreds of evidence until now suggest that elderly people or those with underlying medical issues are under higher risk of developing the severe symptoms of the pathology. 3 Considering the rapid advance of the disease, and the development of quick diagnostic tests with good accuracy, researchers have also been able to test therapeutic options to the treatment and prevention of this disease and its complications. Thus, based on preliminary studies, Chinese and South Korean health authorities have recommended the off-label use of hydroxychloroquine (HQ) and chloroquine (CQ) in cases of COVID-19 to prevent or treat one of the most severe symptoms of the disease: acute respiratory infection. [7] [8] [9] The use of HQ and CQ is formally indicated in cases of chronic autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, photosensitive diseases, and malaria; despite the absence of recommendations from the Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, Anvisa, in Portuguese), the off-label use of these drugs to treat COVID-19 has already spread in Brazil and worldwide. 10 Antiviral drugs are being urgently administrated to COVID-19 patients, such as favipiravir, remdesivir, CQ, HQ, lopinavir, ritonavir and interferon PEGylated with ribavirin. 11 However, the drugs considered to have a high potential in the treatment of COVID-19 are CQ and HQ. 12 Chloroquine and HQ have different chemical structures, but belong to the same aromatic 4-aminoquinoline group, and are fully absorbed in the gastrointestinal tract. These substances achieve peak plasmatic concentrations in 2 to 8 hours; they are slowly eliminated by the kidneys (in 3 to 6 months), and can accumulate in the liver, spleen, lungs, kidneys, eyes, skin, adrenal glands and the pituitary gland, and they remain in the body for years after the discontinuation of its use. 13 Despite being cited as a potentially promissing antiviral drug for the treatment of COVID-19, 11,12 CQ and HQ, known as antimalarial drugs, have been associated with possible transitory or definite alterations in the auditory and/or vestibular functions in humans, when administered in the short or long terms. 14 Pioneer studies on the use of these drugs on humans report that such substances have a selective affinity to melanincarrying cells, which are also found in the inner ear; therefore, these cells can suffer from alterations in their function. 15 It is presumed that these temporary and/or permanent auditory alterations and vestibular dysfunctions are caused by the toxicity of those substances. The limited knowledge on these side effects makes the review of the matter necessary. Thus, the present integrative review has the objective of describing auditory and/or vestibular functional alterations related to the short-or long-term use of HQ and CQ in patients aged between 18 and 55 years. Between March and April, 2020, we conducted a search on the following databases: PubMed; Web of Science; Scientific Electronic Library Online (SciELO); Latin American and Caribbean Health Sciences Literature (LILACS); Scopus; Science Direct; and the Cochrane Library. As for the gray literature, we consulted the following databases: OpenGrey; DissOnline; and OAlster, without restrictions regarding language or publishing date. The search was conducted using the following Medical Subject Headings (MeSH): hydroxychloroquine AND hearing OR hearing loss OR hearing disease; chloroquine AND hearing OR hearing loss OR hearing disease; hydroxychloroquine AND vestibular diseases OR labyrinth diseases; and chloroquine AND vestibular diseases OR labyrinth diseases. Following the inclusion criteria, two independent reviewers initially selected the articles through a review of the titles and abstracts; the studies that seemed to fill the inclusion criteria had their full texts read, and the following data was extracted from them: title, authors, publishing date, country, design and objective of the study, sample size and age range, drugs used, duration of the therapy, auditory and vestibular alterations, conclusions, and evidence level. Discrepancies related to the selection and extraction of data were discussed between the reviewers at the end of each step to reach a consensus, and, in the absence of agreement, a third reviewer was consulted. The data was compiled in tables for systematization. The inclusion criteria were as follows: studies with human patients with ages ranging between 18 and 55 years, who had used CQ and/or HQ, and were subjected to any type of auditory exam and/or self-report questionnaire related to the auditory and vestibular functions, with hypotheses or evidence of pathophysiology of compromised hearing associated with the use of these drugs. We excluded literature reviews, book chapters, and studies with individuals with previous auditory and/or vestibular functional alterations. In the initial search, 2,481 studies were identified,, and 32 of them had their full texts read; then, 9 were selected after the exclusion of those which did not meet the eligibility criteria. The other 23 articles were excluded because: they were literature reviews (8) ; the auditory and/or vestibular alterations were associated with the base disease and not the drugs used (5); they were studies involving animals (3); the sample was out of the age range defined by the present review (5); they described preexisting auditory and/or vestibular alterations (1); and they made use of another kind of medication (1) . The included studies were: 6 case studies (level of evidence: 5), 15-20 1 non-randomized clinical trial (level of evidence: 3), 21 1 case-control study (level of evidence: 4), 22 and 1 cross-sectional observational study (level of evidence: 4) (►Fig. 1). 23, 24 A flowchart of the process of selection of articles is presented in ►Fig. 1. The selected studies were published between 1975 and 2018 in Europde, 17, 19, 23 South America, 16 North America, 20, 22 Asia, 15, 18 and Africa. 21 The age of the patients ranged from 18 to 57 years, and they had diseases like rheumatoid arthritis, [18] [19] [20] 22 Sjogren syndrome, 19 and human immunodeficiency virus (HIV) (►Table 1). 18, 22 ►Table 2 presents the data extracted from the results and conclusion of the studies selected for the present review, and three of them had as targets individuals medicated with CQ, 15, 21, 22 five, with HQ, [16] [17] [18] [19] 23 and one described a patient to whom both drugs were administered. 20 The oral doses administrated were of 400 mg/day in all of the studies that presented this information, and only one study involved intravenous administration. 21 In total, four articles reported an association of vestibular and auditory alterations, 17, 19, 22 three indicated only hearing pathologies, 16, 18, 23 and two, vestibular disorders. 20, 21 The results of the auditory exams were described in eight studies, 15-18,20-23 and a vestibular evaluation was only performed in three of them (►Table 2). 15, 17, 22 Report of imbalance. One patient needed to continue with the treatment and presented constant disorientation, with repeated attacks of acute vertigo, slightly reduced labyrinthic excitability, and greater hearing impairment. They found that the long-term use of chloroquine generated changes in the brainstem auditory-evoked potential in 13 of the 74 patients. ►Table 3 presents a summary of the auditory and vestibular alterations described in the selected studies; tinnitus 15, 16, 19, 22, 23 was the most commonly described symptom, and many studies [15] [16] [17] 23 reported mild to severe bilateral sensorineural hearing loss (HL). As for the vestibular alterations, positional or non-positional vertigo, 15, 19, 20, 22 was the most reported symptom (►Table 3). To have a greater understanding of the different audiological and vestibular findings after the ingestion of the two medications in the studies herein analyzed, the following two sections describe their findings. Hydroxychloroquine is used to treat different pathologies. In the included studies, it was possible to observe its oral administration in patients with lupus systemic erythematosus, 16,17 rheumatoid arthritis, 15, 18, 19 and human immunodeficiency virus. 18 In these surveys, the authors associate changes in the cochlear-vestibular system with the use of HQ, excluding the relationship with the underlying disease by verifying negative results for antiphospholipid antibodies, 16 the association of the medication with these changes using the Naranjo scale, 17,18 the onset of symptoms through drug ingestion, 19 and complaints other than the clinical manifestation of the studied pathology. 15, 17 The authors pointed out that signs and symptoms of auditory and vestibular disorders appear with the shortterm exposure, either in the period of days 19 or months. 15, 16, 18 Only one of the studies indicated the onset of complaints after years of ingestion of HQ. 17 It is not possible to generalize the symptoms found after using the drug, since few individuals are investigated and different clinical manifestations are reported in the studies. The audiological complaints reported by the patients were tinnitus 15, 16 and bilateral HL, 15,16 which may appear suddenly 17 or progressively slow. 18 None of the studies show results of vestibular exams, but vestibular syndrome 17 and the presence of nausea and vertigo worsened by head movement, in addition to the observation of nystagmoid eye movements in lateral view. 19 As for the audiological evaluations, there is a predominance of bilateral sensorineural HL, 15, 16, 18 ranging from mild to profound, in addition to an indication of a reduction in speech recognition thresholds. 18 Among the articles that demonstrate hearing complaints, only one did not perform audiological tests. 17 The drug therapy was discontinued in all studies. Only one patient remained on prednisolone, 18 which was used in combination with HQ, and another one 17 was treated with 3 doses of 1,000 mg of intravenous methylprednisolone. The researches showed the remission of the auditory and vestibular symptoms after the discontinuation of the HQ, 15, 19 and two of them showed only improvements in the audiograms, with the patients remaining with mild HL 17, 18 and changes in speech intelligibility. 18 However, even after four months without the use of the medication, the patient with speech intelligibility 18 remained with HL and tinnitus. 16 After remission of the auditory and vestibular symptoms, two patients from different studies 17, 19 were once again submitted to HQ therapy. In one of the studies, 19 the drug was reintroduced days after the disappearance of the vestibular manifestations, and the patient reported the reappearance of headache and vertigo 48 hours after ingestion; the medication was discontinued again, therapy with prednisolone was started, and the symptoms disappeared after 36 hours, and did not recur in the following twelve months. In the other study, 17 the medication was also reintroduced, and the patient once again had peripheral vestibular syndrome, and was diagnosed with neuritis. Four months after the last interruption, the individual had no vestibular symptoms; however, bilateral HL was identified at a frequency of 1 KHz. The ototoxicity of HQ is a serious complication that interferes with the quality of life and functional activities of individuals, 16 and it may appear in a short time and with low doses in the treatment of different pathologies. 16, 18 Despite the possibility of changing to corticosteroid therapy, 18 interruption of the drug does not always lead to the disappearance of symptoms. 17 Although cases of HQ ototoxicity are rare, 16,17 the authors of the analyzed studies point out the need for prescribers to know about possible side effects and report the risks to the patients before starting the therapy. 16, 17 They also highlight the need to periodically evaluate these patients, especially those who have been using the drug for prolonged periods of time, observing the appearance of any signs or symptoms. 16 In studies that aimed to report the side effects of CQ, the use of the drug was investigated in healthy individuals, 20 and in individuals with malaria, 21,22 rheumatoid arthritis, 22,23 lupus erythematosus, 22, 23 and Sjogren syndrome. 22 The authors point out that auditory and vestibular symptoms can appear immediately or in the short term, such as one hour after taking the drug, 20,21 one day, or even one month after using it. 22 The most commonly reported hearing symptoms were tinnitus [21] [22] [23] and HL, [21] [22] [23] and the vestibular symptoms were vertigo and/or dizziness 20-23 and imbalance. 23 The type of administration was related to the onset of adverse effects in three studies, in which all individuals who received a dose by intravenous infusion reported adverse effects, 20 while in cases of oral administration, some had symptoms, 21,23 and others did not have objective side effects. 20 Regarding the findings of the audiological tests, no changes were described in the external ear canal and tympanic membrane 20-23 referring to normal tympanometries and middle ear pressure. 21 A decrease in stapedial reflexes was recorded at 125 dB for the frequency of 500 Hz in both ears. 21 In the evaluation of pure-tone audiometry, the absence of thresholds was observed in all frequencies in the left ear, and, in the right ear, their presence was only observed in the frequencies of 500 Hz, 750 Hz and 2,000 Hz, but with a maximum intensity of 100 dB, characterizing deep sensorineural HL in both ears. 21 Besides, significant variations in high-frequency thresholds were found after the administration of CQ. 20 In the evaluation of the brainstem auditory-evoked potential (BAEP), changes were described around the eighth month of treatment in 13 patients with rheumatoid arthritis, characterized by increased latencies in waves III and V and in interpeaks I-III and III-V, with the possibility of alterations in the fifth wave being interpreted as a sign of primary changes in the basal part of the cochlea. 23 Only one study 21 described vestibular assessment tests, showing the absence of spontaneous or positional nystagmus, negative fistula test, and Kobrac caloric test with cold water without response in both ears. Regarding the remission and persistence of the auditory and vestibular alterations, vertigo 21 and imbalance 23 gradually decreased after the discontinuation of CQ, and were described as transient episodes, but they may become irreversible with the continuous use of the medication. 22 The persistence and irreversibility of the alterations were more described for the symptoms of tinnitus and HL, 21, 22 with remissions of these changes observed in a period of 12 to 16 months after the interruption of the treatment. 23 The onset of irreversible bilateral sensorineural deafness was also reported after a few days of using the drug, 22 as well as the immediate onset after the first dose. 21, 22 In patients with rheumatoid arthritis who required prolonged therapy with CQ for pain control, progressive deterioration of hearing was observed, with a change in the latency of wave I of the BAEP associated with an increase in the auditory threshold and a decrease in the speech discrimination score, with no additional deterioration of the hearing thresholds or vestibular function after two years of follow-up. 23 Some studies 20,21 agree that the involvement of CQ with cells that carry melanin found in the tissues of the inner ear may be responsible for the adverse effects on individuals, and that this tissue affinity is extensive and variable. Although some authors confirm the ototoxicity caused by high and prolonged doses of CQ, it may result in irreversible HL and reversible damage if the medication is stopped 21, 23 some studies reported that the results did not enable the determination of the real incidence of the medication-related ototoxicity, 22 and that the threshold changes observed in the high-frequency audiometry did not reveal conclusive signs of ototoxicity, but may indicate a subtle effect of CQ on hearing. 20 Thus, although CQ is a drug with unusual pharmacokinetic properties, 20 there is a consensus among the studies that interrupting the CQ treatment may favor the reversal of auditory and vestibular alterations caused by its use, [21] [22] [23] and that individuals who need to continue the treatment have risks of progression, which can generate permanent HL. 23 Moreover, they suggest that therapists inform the risks at the beginning of the treatment, and that monitoring of the auditory pathway should be performed. 22 Considering the variability of the ototoxic effects and the time of manifestation of these alterations shown in the present study, new researches must be performed to expand the knowledge of the impact of HQ and CQ in the auditory and vestibular systems. The data available in the present review showed evidences of auditory and vestibular alterations associated with the use of QC and HQ in humans, with the most reported symptoms being sensorineural HL, tinnitus, and vertigo for both medications. Such manifestations were reported in the short and long terms after treatment with both substances, and, with the discontinuation of their use, the symptoms ceased or reversed. The knowledge of these auditory and vestibular effects after the use of these substances can help in the decision regarding the best treatment, so that other available therapies can be considered in the case of patients who are already at risk of suffering these alterations, reducing the probability of hearing disorders and vestibular disorders. Thus, considering the widespread use of these drugs in the recent COVID-19 pandemic, the present review endorses the importance of further research on the adverse effects related to auditory and/or vestibular functions with the use of HQ and CQ, as a support in the treatment of COVID-19. In addition, the need to alert the patients about the risks inherent to the use of these medications before the treatment and the importance of conducting audiological monitoring during the ingestion of these components are emphasized. Financial support by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brazil (CAPES) -Finance Code 001. Word Health Organization. 2020Novel Coronavirus (2019-nCoV) Situation report -1 /2021 © 2021. Fundação Otorrinolaringologia. 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