Original Article

International Journal of Audiology 2004; 43:438–441

Effects of interferon-�2b on hearing

Efectos del interferón-�2b en la audición

Irfan Kaygusuz*Türkkan Öztürk Kaygusuz†

Ahmet Öztürk*Süleyman Sırrı Kiliç†

Turgut Karlidag*Erol Keles*Sinasi Yalçin*

*Department of Otorhinolaryngology,†Department of Infectious Diseasesand Clinical Microbiology, MedicalFaculty, Fırat University, Elazıg,Turkey

Key WordsInterferonHearing lossAudiometry

AbstractThe aim of the present study was to investigate the effectsof interferon-a2b treatment on hearing in patients withchronic active hepatitis B. Twenty-six patients with chronicactive hepatitis B were enrolled in the study, and pure-tone audiometry was performed to determine hearingthresholds of the patients before and at the end of6 months of interferon-a2b treatment. There was no sig-nificant change in hearing thresholds of patients aftertreatment with interferon-a2b ( p �0.05). The results ofthe present study indicate that interferon-a2b therapydoes not have any negative effect on hearing thresholdsof patients with chronic active hepatitis B. There is a needfor further studies involving larger numbers of patients toallow conclusions to be drawn regarding the safety of thistherapy with respect to hearing.

SumarioExisten algunas publicaciones que reportan pérdida audi-tiva sensorineural en pacientes tratados con interferón.El objetivo del presente estudio fue investigar los efectosdel tratamiento con interferón-a2b en la audición depacientes con hepatitis B crónica activa. Se incluyeron enel estudio veintiséis pacientes con esa enfermedad y serealizó audiometría tonal para determinar sus umbralesauditivos antes y al final de tratamiento con interferón-a2b. No hubo cambios significativos en los umbralesauditivos después del tratamiento con interferón-a2b( p > 0.05). Los resultados del presente estudio indicanque la terapia con interferón-a2b no tiene efectos nega-tivos en los umbrales auditivos de pacientes con hepatitisB crónica activa. Existe la necesidad de más estudios enlos que se involucre a un mayor número de pacientes, quepermitan obtener conclusiones relacionadas con la seguri-dad de esta terapia en relación con la audición.

Irfan KaygusuzFırat Üniversitesi, Tıp Merkezi KBB Klinigi,23200 Elazig, TurkeyE-mail: kaygusuz_67@yahoo.com

Received:August 23, 2002Accepted:September 15, 2003

Interferons (IFNs) are widely used in the treatment of acute andchronic viral illnesses and certain autoimmune and neoplasticdiseases (Akyol et al, 2001). IFN acts as a direct antiviral agentby regulating the functions of many cells of the immune system.It is a pleotropic molecule with a variety of biological actions,including antiviral activity, regulation of cell growth, and modu-lation of cellular immunity (Cadoni et al, 1998; Kanda et al,1995).

The common side-effects associated with IFN therapy includea flu-like syndrome, and hematologic, infectious, autoimmune,ophthalmic, intestinal and psychiatric problems, but auditorycomplications of IFN-a administration are rare (Okanoue et al,1996; Chung & Older, 1997; Dusheiko, 1997; Kanda et al, 1994).Kanda et al (1994, 1995) and Cadoni et al (1998) reportedsudden hearing loss during IFN therapy. However, very littleattention has been paid to the influence of IFN therapy on audi-tory sensitivity. To investigate the impact of long-term IFNtherapy on hearing, Kanda et al (1994) prospectively assessedthe auditory function of 49 patients who were receiving IFN-a2a and noted sudden sensorineural hearing loss in three indi-viduals. They reported hearing impairment (hearing loss, tinnitus,or both) in 45% of the patients and audiometry-documentedsensorineural hearing loss in 37% of those, which developed inthe late stages of treatment and resolved in all patients within7–14 days of discontinuation of IFN therapy.

The aim of the present study was to assess the effects ofinterferon-a2b therapy on hearing in patients with chronicactive hepatitis B (CAH-B).

Materials and methods

This study was performed at Fırat Medical Center ENT Clinic ofFırat University, between January 2001 and June 2002. The pro-tocol of this study was approved by the local Ethics Committee.

This study included 26 patients (17 males, nine females) withCAH-B who were treated with IFN-a2b (Intron A; ScheringPlough Corporation, Kenilworth, NJ, USA) at the InfectiousDiseases and Clinical Microbiology Department of the samehealth center. Subjects with any hearing problem, a history ofany disorder causing hearing loss, the presence of other systemicdiseases (diabetes mellitus, hypertension, kidney failure, etc.), ahistory of ototoxic agent use, trauma to the head, or a history ofhearing loss in their relatives, were excluded from the study. Allindividuals were examined by an otolaryngologist and had asystemic examination. Those who were found to have a hearingproblem were also excluded from the study.

Hearing thresholds of all patients were evaluated before andafter 6 months of IFN-a2b therapy. In order to determinethe hearing thresholds at 250, 500, 1000, 2000, 4000, 6000 and8000 Hz, the ascending method of Hughson and Westlake wasemployed (Yantis, 1994). Audiologic tests were carried out instandard acoustically controlled rooms (Industrial AcousticsCompany) using Interacoustics Clinical Computer AudiometerModel AC5 (Denmark).

All patients received 10 million units/day of IFN-a2b everyother day (3 days/week). The treatment continued for 6 months,and at the end of therapy the hearing thresholds of patients were

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Effects of interferon-�2b on hearing

re-evaluated. Hearing loss was defined as a decrease in thresholdsensitivity of 20 dB or greater at one or more test frequencies rel-ative to the baseline measurement.

Statistical analysisStatistical analysis was carried out by using SPSS for Windowsversion 10.0. The paired Student’s t-test was used for comparingthe threshold values before and after the therapy. A p-value�0.05 was considered to be statistically significant.

Results

The mean age of the patients was 30.1 �9.7 (range 15–57) years.The mean hearing threshold levels at speaking frequencies(500–2000 Hz) were determined to be 7.4 �4.3 dB for the rightear and 8.4 �4.5 dB for the left ear before therapy, and 7.6 � 4.6 dB and 8.6 �4.8 dB, respectively, after therapy. Theclinical status and hearing status of the patients are shown inTable 1. Hearing threshold levels in the right and left ears ofpatients at frequencies between 250 and 8000 Hz before andafter therapy are given in Figures 1 and 2, respectively. There was

no statistically significant difference between hearing thresholdlevels at all frequencies tested before and after therapy( p �0.05). During IFN-a2b therapy, fever (96.2%), myalgia(88.5%), arthralgia (73.0%) and other side-effects were experi-enced (Table 2). In four patients, the fever lasted for 2 weeks.Therapy was completed without reduction of the dose in all buttwo patients. In patients 6 and 11, IFN-a2b was discontinuedbecause of the progression of subjective tinnitus. Tinnitusoccurred on the 35th day of therapy in patient 6, and on the47th day in patient 11. The tinnitus disappeared in these twopatients within 10–14 days after discontinuation of IFN-a2b.

Discussion

There are three types of IFN, namely leukocyte-derived IFN-a,fibroblast-derived IFN-b, and T-lymphocyte-derived IFN-g.IFN-a is known to have antitumor effects in cases of chronicmyelogenous leukemia, melanoma, renal cell carcinoma, non-Hodgkin’s lymphoma, and multiple myeloma (Akyol et al, 2001;Conlon et al, 1990).

Hepatitis infections have been associated with a plethora ofimmune and autoimmune disturbances (Hadziyannis, 1997). Infact, with the increasing long-term use of IFN in chronic hepati-tis C, numerous autoimmune problems, including thyroid dis-ease (Okanoue et al, 1996; Lisker-Melman et al, 1992), type 1diabetes mellitus (Okanoue et al, 1996; Fabris et al, 1992), andothers (Hadziyannis, 1997), have been recognized. The majorside-effects encountered during IFN-a therapy include chills,fever, myalgia, arthralgia, fatigue, mild and reversible bone mar-row suppression, nausea, vomiting, and diarrhea (Okanoue etal, 1996; Quesada et al, 1986). Our patients had side-effects sim-ilar to those previously reported, and the most common side-effects were fever (96.2%), myalgia (88.5%) and arthralgia(73.0%). In our study, fever, myalgia, arthralgia, headache, nau-sea and vomiting were seen at the initial stage of IFN-a2b ther-apy, but these side-effects gradually disappeared during thecourse of therapy. In the later stages of therapy, side-effects suchas leukopenia, thrombocytopenia, fatigue, lack of appetite,sleeplessness, loss of hair, weight loss, tinnitus and psychologicaldisturbances were observed.

The reported rapid improvement in auditory function after thediscontinuation of IFN might suggest microvascular pathogenesis,which has been reported in retinal vascular complications associ-ated with IFN-a therapy (Guyer et al, 1993). IFN is reported toinhibit the motility of capillary endothelial cells (Brouty-Boye &Zetter, 1980). Thrombocytopenia induced by IFN therapy mighthave caused microvascular damage in the inner ear. However,Kanda et al (1995) failed to demonstrate any association betweenthrombocytopenia and hearing impairment during IFN therapy.Autoimmunity remains another possible mechanism mediatingthe side-effects associated with IFN therapy. IFN can induce orenhance autoimmune diseases (Schattner, 1988), and auto-immunity is believed to be one of the major etiologies of idio-pathic sudden hearing loss (Cole & Jahrsdoerfer, 1988).Thrombocytopenia was seen in 30.8% of our patients duringtreatment. Two patients with tinnitus also had thrombocytopenia.

Sudden hearing impairment during IFN therapy was previ-ously observed by Kanda et al (1995), who conducted a prospec-tive study to assess auditory function in 73 patients receiving IFN.They observed hearing impairment in 17 of 35 patients treated

Table 1. Demographic features, clinical features and some audio-metric findings for patients before and after IFN-a2b therapy

Speech frequency average HTL (500–2000 Hz) (dB)

PatientTinnitus BT AT

no. Age Sex BT AT L R L R

1 19 F � � 7 3 8 32 20 M � � 8 5 8 53 16 M � � 7 8 7 84 28 M � � 7 7 7 85 34 M � � 7 7 7 66 33 M � � 10 15 10 157 25 M � � 5 7 5 78 15 F � � 8 8 8 89 38 M � � 10 10 10 10

10 35 M � � 7 3 8 311 50 M � � 23 20 25 2012 24 M � � 5 7 5 713 37 F � � 5 5 5 514 30 M � � 10 7 10 815 29 M � � 5 3 5 316 16 M � � 5 3 5 317 25 F � � 5 3 5 318 28 F � � 5 5 5 519 32 F � � 8 7 8 720 57 F � � 7 8 7 821 30 F � � 13 13 15 1522 24 M � � 5 3 5 323 31 M � � 5 5 5 624 36 M � � 20 15 20 1525 38 M � � 12 12 12 1226 34 F � � 10 5 10 5

AT, after therapy; BT, before therapy; L, left; R, right; HTL, hearing thresholdlevel.

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with IFN-b (including hearing loss in 13 patients), and in 15 of 38patients treated with IFN-a. They reported that the hearing lossand tinnitus disappeared in all patients within 7–14 days after dis-continuation of IFN. It has also been reported that hearing lossand tinnitus were observed during IFN-a2b therapy, especiallyduring the 2–4 months of therapy, and recovered within 7–14 daysafter the end of treatment (Kanda et al, 1995; Cadoni et al, 1998).In our patients, the time of onset of tinnitus was comparable withthat reported in the literature. In these patients, tinnitus disap-peared within 10–14 days after cessation of therapy. However, wedid not detect hearing loss in any patient after IFN therapy; thismay be due to the small number of patients involved.

Several different mechanisms have been suggested, such asmicrovascular damage. Cadoni et al (1998) reported suddenhearing loss in an individual with hepatitis C who received

5 million units/day of IFN-a by the intramuscular route andconcluded that this effect was due to microvascular damagecaused by IFN. In the present study, as seen in Figures 1 and 2,no significant difference in hearing status was observed beforeand after treatment in either ear of the patients ( p �0.05).

Akyol et al (2001) investigated the effect of IFN-a2a on themouse cochlea. They reported a significant difference in hearingstatus before and after treatment. They suggested that vac-uolization in fibroblasts of the spiral limbus and epithelial cellsof the lateral wall and atrophy of the spiral limbus and spiralprominence were among the histopathologic signs of ototoxicity.The observed vacuolization in these cell populations is a sign ofearly and reversible damage. It is possible that IFN ototoxicitycauses reversible biochemical and metabolic changes in thecochlea, rather than morphologic abnormalities.

Figure 2. Mean values and standard deviations for air conduction hearing thresholds for left ears before and after IFN-a2b therapy.

Figure 1. Mean values and standard deviations for air conduction hearing thresholds for right ears before and after IFN-a2b therapy.

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As reported in the literature, 5–10 million units/day of IFN-a2b is used for CAH-B treatment, and the development of hearingloss is associated with cumulative dosage (Kanda et al, 1995;Cadoni et al, 1998). The dose of IFN-a2b (10 million units/day)that we used for CAH-B treatment is consistent with those inthe literature. In our patients, some side-effects of IFN-a2boccurred, but hearing loss did not.

In conclusion, there was no hearing loss in patients treatedwith IFN-a2b for CAH-B. This finding may be related to thesmall number of patients. However, in previous studies it hasbeen documented that the use of IFN might cause hearing loss.Further studies with larger populations are needed to determinethe ototoxic effects of IFN.

References

Akyol, M.U., Sarac, S., Akyol, G., Atac, A., Poyraz, A., et al. 2001.Investigation of the ototoxic effects of interferon a2A on the mousecochlea. Otolaryngol Head Neck Surg, 124, 107–110.

Brouty-Boye, D. & Zetter, B.R. 1980. Inhibition of cell motility by inter-feron. Science, 208, 516–518.

Cadoni, G., Marinelli, L., De Santis, A., Romito, A., Manna, R., et al.1998. Sudden hearing loss in a patient hepatitis C virus (HCV) posi-tive on therapy with alpha-interferon: a possible autoimmune-microvascular pathogenesis. J Laryngol Otol, 112, 962–963.

Chung, A. & Older, S.A. 1997. Interferon-alpha associated arthritis.J Rheumatol, 24, 1844 –1845.

Cole, R.R. & Jahrsdoerfer, R.A. 1988. Sudden hearing loss: an update.Am J Otol, 9, 211–215.

Conlon, K.C., Urba, W.J., Smith, J.W. 2nd, Steis, R.G., Longo, D.L.,et al. 1990. Exacerbation of symptoms of autoimmune disease inpatients receiving alpha-interferon therapy. Cancer, 65, 2237–2242.

Dusheiko, G. 1997. Side effects of alpha interferon in chronic hepatitis C.Hepatology, 26, 112–121.

Fabris, P., Betterle, C., Floreani, A., Greggio, N.A., de Lazzari, F., et al.1992. Development of type 1 diabetes mellitus during interferon alfatherapy for chronic HCV hepatitis. Lancet, 340, 548.

Guyer, D.R., Tiedeman, J., Yannuzzi, L.A., Slakter, J.S., Parke, D., et al.1993. Interferon-associated retinopathy. Arch Ophthalmol, 111,350–356.

Hadziyannis, S.J. 1997. The spectrum of extrahepatic manifestations inhepatitis C virus infection. J Viral Hepatol, 4, 9–28.

Kanda, Y., Shigeno, K., Kinoshita, N., Nakao, K., Yano, M., et al.1994. Sudden hearing loss associated with interferon. Lancet, 343,1134–1135.

Kanda, Y., Shigeno, K., Matsuo, H., Yano, M., Yamada, N., et al. 1995.Interferon-induced sudden hearing loss. Audiology, 34, 98–102.

Lisker-Melman, M., Di Bisceglie, A.M., Usala, S.J., Weintraub, B.,Murray, L.M., et al. 1992. Development of thyroid disease duringtherapy of chronic viral hepatitis with interferon alfa. Gastroentero-logy, 102, 2155–2160.

Okanoue, T., Sakamoto, S., Itoh, Y., Minami, M., Yasui, K., et al. 1996.Side effects of high-dose interferon therapy for chronic hepatitis C.J Hepatol, 24, 283–291.

Quesada, J.R., Talpaz, M., Rios, A., Kurzrock, R. & Gutterman, J.U.1986. Clinical toxicity of interferons in cancer patients: a review.J Clin Oncol, 4, 234–243.

Schattner, A. 1988. Interferon and autoimmunity. Am J Med Sci, 295:532–544.

Yantis, P.A. 1994. Puretone air-conduction thresholds testing. In: J. Katz(ed.) Handbook of Clinical Audiology. Baltimore: Williams & Wilkins,pp. 97–108.

Table 2. The side-effects experienced by patients during IFN-a2btherapy

No. of cases Frequency Side-effects (n526) (%)

Fever 25 96.2Myalgia 23 88.5Arthralgia 19 73.1Weakness 18 69.2Lack of appetite 15 57.7Leukopenia 15 57.7Loss of weight 13 50.0Headache 12 46.2Loss of hair 11 42.3Psychological disturbances 11 42.3Fatigue 8 30.8Thrombocytopenia 8 30.8Anxiety 8 30.8Indifference 7 26.9Nausea 4 15.4Vomiting 4 15.4Sleeplessness 3 11.5Tinnitus 2 7.7Chill 2 7.7Diarrhea 1 3.8

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