CC BY-NC-ND 4.0 · Int Arch Otorhinolaryngol 2022; 26(01): e167-e177
DOI: 10.1055/s-0041-1740986
Systematic Review

The Ototoxicity of Chloroquine and Hydroxychloroquine: A Systematic Review

1   Language and Hearing Sciences at the Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
,
2   Graduate Program in Health Sciences at Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
,
3   Analytical Toxicology and Graduate Program of Health Sciences at Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
,
4   Speech-Language Pathology and Audiology Program at Universidade Federal de Ciências da Saúde de (UFCSPA), Porto Alegre, RS, Brazil
› Author Affiliations

Abstract

Introduction Chloroquine and hydroxychloroquine are antimalarial drugs widely used in the treatment of rheumatic diseases. With the global pandemic caused by the new coronavirus, there was an increase in the prescription of these drugs, which led to a major concern regarding their ototoxic effects.

Objectives The objective of the present study was to assess existing scientific evidence about the toxic effects of chloroquine and hydroxychloroquine on the peripheral and/or central auditory system.

Data Synthesis A systematic literature review was performed by searching the PubMed (Medline), Scopus, Web of Science, LILACS, and SciELO electronic databases, in a search of articles that fullfiled the predefined inclusion and exclusion criteria. The review was conducted in three phases and, in all of them, analyses were performed by two independent researchers. Disagreements were discussed with a third researcher until a consensus was reached. A total of 437 articles were found and 8 were included in this review. Seven of the included studies reported hearing loss in their samples and presented a diagnostic hypothesis of ototoxicity induced by chloroquine or hydroxychloroquine. The most common type of hearing loss was sensorineural, with varying laterality and degrees of severity. The most frequently used audiological test was pure tone audiometry, and only two studies assessed brainstem evoked responses.

Conclusion The scientific evidence compiled in this research showed that chloroquine and hydroxychloroquine have an ototoxic effect in the peripheral auditory system. These drugs can cause cochlear damage, including changes in the stria vascularis and lesions in sensory hair cells.

Final Comments

The present literature review led us to conclude that CQ and HCQ are capable of inducing hearing impairment in their users. The most common finding was sensorineural hearing loss, most likely due to cochlear damage. No differences were found regarding the ototoxic properties of the two drugs. Further studies with greater methodological rigor are needed for the continued clarification of the subject.


Declarations

No funding was received for conducting this study. This study did not involve human or animal subjects. All data generated or analyzed during this study are included in this published article.




Publication History

Received: 21 June 2021

Accepted: 19 September 2021

Article published online:
25 January 2022

© 2022. Fundação Otorrinolaringologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Bernard P. Alterations of auditory evoked potentials during the course of chloroquine treatment. Acta Otolaryngol 1985; 99 (3-4): 387-392
  • 2 Chowdhury MS, Rathod J, Gernsheimer J. A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19. Acad Emerg Med 2020; 27 (06) 493-504
  • 3 Coutinho MB, Duarte I. Hydroxychloroquine ototoxicity in a child with idiopathic pulmonary haemosiderosis. Int J Pediatr Otorhinolaryngol 2002; 62 (01) 53-57
  • 4 Figueiredo MC, Atherino CCCT, Monteiro CV, Levy RA. Antimalarials and Ototoxicity. Rev Bras Reumatol 2004; 44 (03) 212-214
  • 5 Hadi U, Nuwayhid N, Hasbini AS. Chloroquine ototoxicity: an idiosyncratic phenomenon. Otolaryngol Head Neck Surg 1996; 114 (03) 491-493
  • 6 Johansen PB, Gran JT. Ototoxicity due to hydroxychloroquine: report of two cases. Clin Exp Rheumatol 1998; 16 (04) 472-474
  • 7 Patil A, Jerang Y, Mathew J. Hydroxychloroquine-induced auditory toxicity. Indian J Rheumatol 2020; 15 (01) 53-55
  • 8 Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol 1997; 36 (07) 799-805
  • 9 Chen Z, Hu J, Zhang Z. et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv 2020
  • 10 Huang M, Tang T, Pang P. et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol 2020; 12 (04) 322-325
  • 11 Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru 2014; 22 (01) 20
  • 12 Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 2015; 23 (05) 231-269
  • 13 Dwivedi GS, Mehra YN. Ototoxicity of chloroquine phosphate. A case report. J Laryngol Otol 1978; 92 (08) 701-703
  • 14 Seçkin U, Özoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatol Int 2000; 19 (05) 203-204
  • 15 Gustafsson LL, Walker O, Alván G. et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 1983; 15 (04) 471-479
  • 16 Hart CW, Naunton RF. The Ototoxicity of Chloroquine Phosphate. Arch Otolaryngol 1964; 80: 407-412
  • 17 Kokong DD, Bakari A, Ahmad BM. Ototoxicity in Nigeria: why it persists. Ear Nose Throat J 2014; 93 (07) 256-264
  • 18 Mukherjee DK. Chloroquine ototoxicity–a reversible phenomenon?. J Laryngol Otol 1979; 93 (08) 809-815
  • 19 Obiako MN. Chloroquine ototoxicity: an iatrogenic problem. Mater Med Pol 1985; 17 (03) 195-197
  • 20 Toone EC, Hayden GD, Ellman HM. Ototoxicity of chloroquine. [abstract] Arthritis and Rheumatism (N.Y.) 1965; 8 (03) 475-476
  • 21 Chatelet JN, Auffret M, Combret S, Bondon-Guitton E, Lambert M, Gautier S. [Hydroxychloroquine-induced hearing loss: First case of positive rechallenge and analysis of the French pharmacovigilance database]. Rev Med Interne 2017; 38 (05) 340-343
  • 22 Lim SC, Tang SP. Hydroxychloroquine-induced ototoxicity in a child with systemic lupus erythematosus. [letter] Int J Rheum Dis 2011; 14 (01) e1-e2
  • 23 Dencker L, Lindquist NG. Distribution of labeled chloroquine in the inner ear. Arch Otolaryngol 1975; 101 (03) 185-188
  • 24 Lindquist NG, Ullberg S. The melanin affinity of chloroquine and chlorpromazine studied by whole body autoradiography. Acta Pharmacol Toxicol (Copenh) 1972; 2 (Suppl): 2, 1–32
  • 25 Basic Ear and Hearing Care Resource [internet]. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. Accessed Sept 28, 2020
  • 26 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151 (04) 264-269 , W64
  • 27 Malta M, Cardoso LO, Bastos FI, Magnanini MMF, Silva CM. STROBE initiative: guidelines on reporting observational studies. Rev Saude Publica 2010; 44 (03) 559-565
  • 28 Atkins D, Best D, Briss PA. et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328 (7454): 1490-1494
  • 29 Guyatt GH, Norris SL, Schulman S. et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl) 53S-70S
  • 30 Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 2012; 42 (02) 145-153
  • 31 Position Statement and Clinical Practice Guidelines Ototoxicity Monitoring [internet]. American Academy of Audiology; 2009. Accessed Oct 05, 2020 at: https://audiology-web.s3.amazonaws.com/migrated/OtoMonGuidelines.pdf_539974c40999c1.58842217.pdf
  • 32 Cunha EO, Reis AD, Macedo MB, Machado MS, Dallegrave E. Ototoxicity of cypermethrin in Wistar rats. Rev Bras Otorrinolaringol (Engl Ed) 2020; 86 (05) 587-592
  • 33 Andrade KCL, Pinheiro NS, Carnaúba ATL, Menezes PL. Potencial Evocado Auditivo de Tronco Encefálico: Conceitos e Aplicações Clínicas. In: Menezes PL, Andrade KCL, Frizzo ACF, Carnaúba ATL, Lins OG. (org). Tratado de Eletrofisiologia para a Audiologia. São Paulo: Book Toy; 2018: 73-83
  • 34 Scott PMJ, Griffiths MV. A clinical review of ototoxicity. Clin Otolaryngol Allied Sci 1994; 19 (01) 3-8
  • 35 Silveira SCR. Ototoxicidade. In: Piltcher OB, da Costa SS, Maahs GS, Kuhl G. (org) Rotinas em Otorrinolaringologia. Porto Alegre: Artmed; 2015: 90-96
  • 36 Savin C. The blood vessels and pigmentary cells of the inner ear. Ann Otol Rhinol Laryngol 1965; 74 (03) 611-622
  • 37 Fernandes MRN, Soares DBR, Thien CI, Carneiro S. Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus. [letter] An Bras Dermatol 2018; 93 (03) 469-470
  • 38 Brum LFS, Rockenbach L, Bellicanta PL. Farmacocinética I - absorção de drogas. In: Brum LFS. ed. Farmacologia básica. Porto Alegre: SAGAH; 2018: 15-35