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Audiologic and vestibular assessment in children and adolescents with transfusion dependent beta thalassemia major: The era of deferasirox film coated tablet

13:21 22 January in Blog
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Abstract

Background

Hearing impairment has frequently been described in β-thalassemia patients with a significant impact on the patients’ quality of life. Most studies provided evidence of deferoxamine (DFO) dose-related ototoxicity, however, the data is scarce regarding deferasirox (DFX) as a sole iron chelator.

Aim

We aimed to assess the prevalence and risk factors of sensorineural hearing loss (SNHL) and vestibular dysfunction in regularly transfused β-thalassemia patients who had been treated with DFX film coated tablets.

Methods

We conducted a case control study on 57 transfusion dependent β-thalassemia patients with a mean age of 15.3 years who received DFX FCT as monotherapy for at least one consecutive year, and 57 healthy age and sex-matching controls. Comprehensive audiological evaluations using pure tone audiometry (PTA) and transient evoked otoacoustic emission (TEOAE) as well as vestibular evaluation using Video-nystagmography (VNG) were done.

Results

SNHL was identified in 12 patients (21.1 %) using PTA and a statistically significant difference was detected between controls and patients at 6 KHz and 12 KHz frequencies. A higher incidence of SNHL was detected using TEOAE, 22 patients (43.1 %) failed to pass TEOAE, with a statistically significant decrease in the signal at frequencies 1, 4 KHz bilaterally and at frequencies 1.5, 2 KHz in the right ear compared to controls. Canal paresis was detected in 21 (36.8 %) of thalassemic children using bithermal caloric test with significantly more unilateral weakness than control children (P = 0.008). We found no significant correlation between audio-vestibular dysfunction and age, sex, serum ferritin, frequency of blood transfusion and dose of DFX FCT in thalassemic children.

Conclusion

We conclude that the incidence of SNHL and vestibular dysfunction was high among transfusion dependent β-thalassemia patients. Therefore, we recommend performing pre-treatment baseline audio-vestibular assessment and yearly audio-vestibular monitoring to early detect high risk patients and initiate timely management to prevent permanent damage.

Keywords

Audiological
Vestibular
Deferasirox
β-Thalassemia

1. Introduction

Thalassemia is an autosomal recessive inherited disorder in which there is a reduction in production of the normal globin chain which may be manifested by hemolytic anemia and multi-organ involvement [1]. Life expectancy of β-thalassemia patients has remarkably increased due to regular blood transfusions and chelation treatments, however, this allowed for the evolution of comorbidities with a significant impact on the patients’ quality of life [2]. Hearing impairment has frequently been described in β-thalassemia patients and still represents an issue leading to social isolation, depression, and cognitive deficits [[3][4][5]]. Despite several studies, the true mechanism of hearing loss among β-thalassemia patients remains unclear [2]. Also, there are few studies examined chelation-induced ototoxicity in pediatrics. Most studies were conducted on patients receiving deferoxamine (DFO) and provided evidence of dose-related ototoxicity causing sensorineural hearing loss (SNHL) especially in transfusion dependent thalassemia (TDT). However, data is deficient for the other two iron chelatorsdeferasirox (DFX) and deferiprone (DFP), only in few studies, DFX was the sole chelator used, moreover, it wasn’t not clear if the patients were previously treated with DFO [[6][7][8]]. Hence, it is critical to identify the high-risk group of patients who are prone to develop SNHL and its relationship with the use of DFX [7]. DFX was announced as part of customarily accessible chelators in 2009.The new DFX film coated tablet (FCT) formulation was approved based on the clinical trials run for the original DFX formulation [9]. FCT lacks excipients (lactose and sodium sulfate) responsible for gastrointestinal adverse effects, and can be taken with or without a light meal, providing a more appropriate mode of administration [10].

This study was conducted to assess the prevalence of ototoxicity in pediatric β-thalassemia patients who had been treated with DFX FCT for at least one consecutive year, to assess the efficacy of TEOAE as early screening tool of hearing impairment, and to assess vestibular function and correlate ototoxicity with age, serum ferritin levels, frequency of blood transfusion, and dose of chelation therapy.

2. Material and methods

We conducted this case control study at the Audio-Vestibular Medicine Unit, ENT department, Faculty of Medicine, Zagazig University on 57 children with β-thalassemia major from the attendants of pediatric hematology outpatient clinic, Hematology and Oncology Department of Children Hospital – Zagazig University, and 57 healthy age and sex-matching children as a control group throughout the duration from April 2022 to September 2023.

This study was approved by the Institutional Review Board (IRB) of Faculty of Medicine Zagazig University, IRB No. ZU-IRB #9396, and legal guardians signed an informed written consent before enrollment in the study.

We included all children and adolescents with transfusion dependent β-thalassemia major who had been treated with oral DFX FCT at 14–28 mg/kg/day for at least one consecutive year, both sex and 12–18 years’ age. Patients were excluded if they had any otorhinolaryngologic disease, having congenital hearing loss or history of ear surgery, history of neurological disordershead trauma, behavioral and/or genetic syndromes. Also, we excluded patients exposed to other ototoxic medications and those who previously received DFO iron chelator.

Clinical and therapeutic data were extracted from electronic and paper medical records. Data collected included age at diagnosis, frequency of blood transfusion, chelation history, age of onset of chelator use, chelator dosage, and average serum ferritin in the last six months. Full otological history was taken regarding otalgia, otorrhoea, hearing impairment, tinnitus, vertigo and others. Complete physical examination was performed including chest, heart, abdomen and a full neurological examination as well as a full oculomotor and musculoskeletal examination. Also, otological examination was performed to ensure normal tympanic membrane. Basic audio-vestibular evaluation using pure tone audiometry (PTA), speech audiometry, immittancemetry, transient evoked otoacoustic emission (TEOAE) and video-nystagmography (VNG).

Basic audiological evaluation.

  • 1.

    PTA: was performed at frequencies from 0.25 to 8 kHz for air conduction and from 0.5 to 4.0 kHz for bone conduction using two-channel diagnostic audiometer, Amplaid 311.

  • 2.

    Speech audiometry: speech reception threshold (SRT) and word recognition scores (WRS) were examined to confirm the outcomes of pure-tone audiometry. The TDH 39 supra-aural headphones were used to deliver air-conducted stimuli.

  • 3.

    Immittancemetry: Involving tympanometry and contralateral acoustic reflexes at 0.5, 1, 2 and 4 kHz to ensure normal middle ear function by using Immittancemeter, MADSEN, Zodiac 901

  • 4.

    Extended high frequency audiometry: The air conduction stimuli were delivered via HDA 200 circum-aural headphones to assess the extended high-frequency measures, involving 12 kHz for both ears.

  • 5.

    TEOAE: Measured using click stimulus with an intensity of 80 dB peSPL using Intelligent hearing system Smart USB lite. A signal-to-noise (SNR) ratio ≥3 dB in at least 4 of the 5 frequencies 1, 1.5, 2, 3 and 4 kHz is considered as a passed response; a SNR ratio ≥3 dB in 3, 2 or 1 frequencies as a partial passed response and a SNR <3 dB in the five frequencies as a failed response.

  • 6.

    VNG test battery: Recordings were carried out using Ulmar VNG version 0.1. Infrared glasses were placed on the patient’s eye and adjusted to fit him firmly but comfortably. Calibration was performed at the beginning of VNG testing [11]. After calibration acceptance, spontaneous nystagmus, oculomotor, gaze, positional, Dix-Hallpike (positioning), and bithermal caloric tests were assessed

Bithermal Caloric Testing: Caloric test was performed by placing the patient in a supine position with the head elevated to a 30° angle from horizontal. Both ears were subjected to bi-thermal caloric irrigation using cold and warm water irrigation for 30 s at 30 & 44° c respectively. The goggles cover was removed and the patient was asked to fixate on the stationary target directly above for fixation suppression. Unilateral weakness (UW) and directional preponderance (DP) were recorded [12].

Calculation of canal paresis and directional preponderance:

The total caloric response is calculated based on the sum of the peak of the maximum slow phase velocity (SPV) of all four irrigations; warm left (WL), cold left (CL), warm right (WR), and cold right (CR).

Unilateral weakness (UW):UWdouble bond(WR + CR) – (WL + CL)/ WR + CR + WL + CL

UW result was multiplied by 100 to convert to a percentage.

Directional preponderance (DP):DP = (WR + CL) – (WL + CR)/ WR + CR + WL + CL

DP result was multiplied by 100 to convert to a percentage.

Interpretation of caloric testing:

Abnormal bilateral weakness is present if the total caloric response is less than 20° per second [13]. Directional preponderance value > 30 % indicates abnormal asymmetric response. Regarding unilateral weakness, a difference greater than 15 % is indicative of a clinically significant UW in the ear producing the lesser responses [14]. In our study, Caloric test is considered abnormal when unilateral weakness is >20 %.

2.1. Statistical analysis

The collected data were tabulated and analyzed using IBM SPSS Statistics, version 26 (IBM; Armonk, New York, USA). Categorical data were presented as number and percentages while quantitative data were expressed as mean ± standard deviation, median and range. Chi square test (X2) or Fisher’s exact test (FET) were used to analyze categorical variables. Quantitative data were tested for normality using Kolmogorov Smirnova test, assuming normality at P > 0.05. Student “t” test was used to analyze normally distributed variables among 2 independent groups. While non parametric variables were analyzed using Man Whitney U test. Pearson correlation coefficient was used to calculate correlation between two quantitative variables. The accepted level of significance in this work was stated at 0.05 (P ≤ 0.05 was considered significant).

3. Results

This study included 57 children with established diagnosis of β-Thalassemia major (15 males and 42 females with ratio 1:2.8 ratio), mean age 15.3 ± 2.3 years, the median age at diagnosis was 6 months (2–72 months). There were 21 patients underwent splenectomy (36.8 %) and 36 patients were not splenectomized (63.2 %). All patients received regular blood transfusion, 36 (63.2 %) patients received packed RBCs transfusion every 2 weeks while 21(36.8 %) of them received packed RBCs transfusion every 3–4 wks and all were on oral DFX FCT as iron chelating therapy at 14–28 mg/kg/day. The median serum ferritin level was 1897 (700–6567 ng/ml).

In our study, SNHL was detected using PTA and extended high frequency audiometry in 12 patients (21.1 %) from β-thalassemia major group, 6 of them had mild SNHL, 3 patients at 8 KHz, the other 3 at 12 KHz, while the remaining 6 patients had mild to moderate SNHL, 3 of them at 8,12 KHz while the last 3 patients at 4,6,8 and 12 KHz. Moreover, there was a statistically significant difference between control and patients in PTA at 6 and 12 KHz as shown in Table 1. SRT and WRS were examined to confirm the outcomes of pure-tone audiometry and there was no statistically significant difference between control and thalassemic children (P > 0.05).

Table 1. Comparison between β-thalassemia patients and controls regarding Pure tone audiometry (PTA) and extended high frequency audiometry.

PTA (dB) Control mean ± SD Patients mean ± SD P-value
N = 57 N = 57 Empty Cell
250 Hz Right ear 12.37 ± 4.21 13.42 ± 4.73 0.213
Left ear 13.17 ± 3.42 13.16 ± 6.06 0.991
500 Hz Right ear 11.56 ± 3.36 11.58 ± 3.75 0.976
Left ear 12.89 ± 4.19 13.16 ± 4.78 0.749
1 KHz Right ear 14.74 ± 4.85 13.16 ± 5.06 0.092
Left ear 14.47 ± 3.69 13.16 ± 4.15 0.077
2 KHz Right ear 11.58 ± 3.36 12.37 ± 4.21 0.271
Left ear 12.37 ± 3.86 12.38 ± 5.62 0.991
4 KH Right ear 10.79 ± 3.44 12.11 ± 5.21 0.113
Left ear 11.58 ± 3.75 10.26 ± 3.73 0.062
6 KHz Right ear 9.74 ± 3.90 12.47 ± 5.67 0.003
Left ear 8.68 ± 3.27 11.06 ± 5.16 0.004
8 KHz Right ear 13.68 ± 4.23 13.94 ± 5.77 0.784
Left ear 14.47 ± 4.97 13.42 ± 6.27 0.324
12 KHz Right ear 10.79 ± 4.79 13.76 ± 6.92 0.009
Left ear 11.74 ± 4.36 14.21 ± 6.97 0.025

PTA: pure tone audiometry, dB: decibel, KHz: kilohertz.

The TEOAE pass in 33/57 (57.9 %) and failed to pass in 24/57 (42.1 %) thalassemic children bilaterally. Statistically significant difference in TEOAE (represented by SNR) was detected between patient and control groups at frequencies 1, 4 KHz bilaterally and at frequencies 1.5, 2 KHz in right ear. Table 2.

Table 2. Comparison between β-thalassemia patients and controls regarding transient evoked otoacoustic emission (TEOAE).

TEOAE Control Patients P-value
N = 57 N = 57
1 KHz Right ear 10.8 (4.2–17.25) 7.68 (0.76–23.01) 0.025
Left ear 11.32 (2.5–18.56) 8.5 (0.9–17.71) 0.032
1.5 KHz Right ear 11.5 ± 4.1 8.2 ± 3.6 0.000
Left ear 11.98 (1.3–15.79) 12.75 (1.2–19.56) 0.39
2 KHz Right ear 14.5 ± 5.5 12.3 ± 5.6 0.037
Left ear 12.56 (3.46–20.08) 14.86 (2.8–22.32) 0.71
3 KHz Right ear 16.5 (6.1–21.76) 15.21 (0.3–27.76) 0.84
Left ear 15.41(0.8–20.65) 12.25 (1.6–28.1) 0.69
4 KHz Right ear 16.34 (3.1–20.78) 10.22 (0.11–22.3) <0.001
Left ear 15.07 (3.7–19.96) 10.54 (1.5–17.43) 0.006

TEOAE: transient evoked otoacoustic emission, KHz: kilohertz.

Regarding vestibular assessment, caloric test (cold, warm) results were significantly lower in thalassemic children than normal children bilaterally, also thalassemic children had significantly more unilateral weakness than control children (P = 0.008) as shown in Table 3. Caloric test results were normal in 36 (63.2 %) and abnormal in 21 (36.8 %) of thalassemic children.

Table 3. Comparison between β-thalassemia patients and controls regarding bithermal caloric test.

Caloric test Control Patients P-value
n = 57 n = 57 Empty Cell
Cold Right ear 14.7 (6.2–30.6) 10.1(3.2–29.3) 0.037
Left ear 12.9 (7.0–38.0) 11.7 (3.3–30.4) 0.047
Warm Right ear 13.2 (5.9–32.5) 7.8 (2.3–21.3) <0.001
Left ear 14.6 (8.1–39.5) 6.8 (2.3–25.5) <0.001
DP Mean ± SD 8.00 ± 6.49 9.32 ± 12.49 0.480
UW Mean ± SD 7.11 ± 4.51 19.47 ± 15.71 0.000

DP: directional preponderance, UW: unilateral weakness.

There was no correlation between PTA, TEOAE and caloric test results, of both right and left ear, with age, age of diagnosis, serum ferritin concentration, sex, frequency of blood transfusion and dose of chelation therapy in thalassemic children. Table 4Table 5Table 6.

Table 4. Correlations between PTA of right and left ear and different parameters among β-thalassemia patients.

PTA Age (years) Age of Diagnosis (months) Serum
Ferritin (ng/ml)
Sex Frequency of blood transfusion DFX dose
PTA Rt250 r 0.226 0.244 −0.165 0.055 −0.145 −0.186
P 0.352 0.314 0.498 0.824 0.554 0.446
PTA Rt 500 r 0.040 0.068 0.226 0.259 −0.140 −0.115
P 0.872 0.782 0.351 0.285 0.567 0.639
PTA Rt 1000 r 0.290 0.047 0.170 0.019 0.031 0.153
P 0.228 0.850 0.487 0.938 0.898 0.531
PTA Rt 2000 r 0.233 0.347 0.174 0.346 −0.295 −0.037
P 0.337 0.146 0.476 0.147 0.219 0.881
PTA Rt 4000 r 0.346 0.153 −0.173 −0.454 0.055 0.336
P 0.147 0.531 0.480 0.051 0.824 0.159
PTA Rt 6000 r 0.330 0.237 −0.272 −0.144 −0.096 0.216
P 0.167 0.327 0.260 0.557 0.696 0.375
PTA Rt 8000 r 0.445 0.278 −0.224 −0.233 −0.201 0.115
P 0.057 0.250 0.356 0.337 0.409 0.639
PTA Rt 12000 r 0.346 0.394 0.144 0.127 0.415 0.372
P 0.147 0.095 0.557 0.606 0.077 0.117
PTA Lt 250 r 0.191 0.324 0.029 0.219 −0.196 0.226
P 0.432 0.175 0.906 0.368 0.420 0.352
PTA Lt 500 r 0.257 0.237 0.3626 0.277 0.097 −0.112
P 0.288 0.327 0.127 0.250 0.694 0.648
PTA Lt 1000 r 0.440 0.137 0.363 −0.420 0.403 −0.129
P 0.059 0.577 0.127 0.073 0.087 0.600
PTA Lt 2000 r 0.139 0.309 −0.246 −0.069 −0.113 −0.202
P 0.571 0.198 0.310 0.779 0.644 0.406
PTA Lt 4000 r 0.372 0.499 −0.261 0.137 0.214 0.131
P 0.117 0.030 0.280 0.577 0.378 0.592
PTA Lt 6000 r 0.363 0.403 0.011 0.125 0.284 0.050
P 0.127 0.087 0.965 0.609 0.238 0.839
PTA Lt 8000 r 0.277 0.320 0.278 −0.133 0.488 −0.031
P 0.250 0.182 0.249 0.587 0.034 0.900
PTA L 12000 r 0.343 0.394 0.184 0.054 0.407 0.243
P 0.151 0.095 0.452 0.825 0.084 0.315

PTA: pure tone audiometry, DFX: Deferasirox, Rt.: right, Lt: left, r: Pearson Correlation coefficient.

Table 5. Correlations between TEOAE of right and left ear and different parameters among β-thalassemia patients.

TEOAE Age (years) Age of diagnosis (months) Serum
Ferritin (ng/ml)
Sex Frequency of blood transfusion DFX dose
TEOAE_Rt1000 r −0.086 0.338 −0.307 0.271 −0.213 0.071
P 0.727 0.157 0.202 0.262 0.382 0.772
TEOAE_Rt1500 r −0.116 −0.048 −0.067 0.311 0.009 −0.057
P 0.636 0.845 0.786 0.194 0.972 0.816
TEOAE_Rt2000 r −0.320 −0.268 0.174 −0.061 0.209 0.073
P 0.182 0.267 0.477 0.803 0.390 0.766
TEOAE_Rt3000 r −0.077 −0.215 −0.052 −0.357 0.130 −0.178
P 0.754 0.376 0.833 0.134 0.595 0.465
TEOAE_Rt4000 r −0.281 −0.267 −0.178 0.338 −0.357 −0.333
P 0.243 0.269 0.467 0.156 0.134 0.163
TEOAE_Lt1000 r −0.105 0.277 −0.105 −0.122 −0.064 −0.093
P 0.668 0.250 0.670 0.620 0.796 0.705
TEOAE_Lt1500 r −0.212 −0.003 −0.025 −0.297 0.096 0.093
P 0.384 0.991 0.918 0.218 0.695 0.706
TEOAE_Lt2000 r −0.125 0.055 0.022 −0.281 −0.003 −0.088
P 0.610 0.824 0.930 0.243 0.992 0.720
TEOAE_Lt3000 r −0.118 0.143 −0.190 −0.285 −0.155 0.027
P 0.632 0.560 0.435 0.236 0.527 0.912
TEOAE_Lt4000 r −0.440 0.010 0.031 −0.203 −0.165 −0.398
P 0.059 0.968 0.899 0.405 0.499 0.091

TEOAE: transient evoked otoacoustic Emission.

Table 6. Correlations between caloric test and different parameters among β-thalassemia patients.

Caloric test Age (years) Age of Diagnosis (months) Serum
Ferritin (ng/ml)
Sex Frequency of blood transfusion DFX dose
Cold-Right r 0.180 −0.028 0.330 −0.219 0.219 0.139
P-value 0.460 0.908 0.168 0.368 0.367 0.569
Cold-Left r 0.336 0.424 −0.256 0.079 −0.154 0.364
P-value 0.159 0.071 0.290 0.747 0.528 0.125
Warm-Right r 0.391 −0.245 0.301 0.074 0.035 0.076
P-value 0.098 0.312 0.210 0.765 0.887 0.758
Warm-Left r 0.163 0.329 −0.070 0.345 −0.003 0.180
P-value 0.506 0.169 0.775 0.148 0.991 0.460
DP r 0.289 0.083 0.293 −0.352 0.449 −0.316
P-value 0.230 0.737 0.223 0.140 0.054 0.187
UW r 0.303 0.290 0.083 −0.327 0.250 0.085
P-value 0.207 0.228 0.736 0.172 0.301 0.728

DP: directional preponderance, UW: unilateral weakness.

4. Discussion

The current study showed that the prevalence of hearing deficit in our group detected by PTA was found in 12/57 (21.1 %) thalassemic children. On the other hand, 24/57 (42.1 %) of our patients showed a hearing deficit using TEOAE. So, despite the fact that PTA is considered the gold standard to detect hearing loss in clinical practice, TEOAEs can be used as a more sensitive technique for early detection of hearing loss and an accurate tool for assessing cochlear function, especially the outer hair cell function, having the advantages of being objective, rapid, easy to use and non-invasive [2]. A similar finding was reported by Bhardwaj et al. who conducted a study included thirty thalassemic patients undergoing regular chelation therapy with DFO and DFX, they found 7/30 (23 %) patients with hearing deficits using PTA while 14/30 (46 %) were detected using DPOAEs [15]. Styles and Vichinsky followed 28 patients who were chronically chelated using DFO with serial audiograms over a 5-year period and detected a similar prevalence in 8/28 (29 %) patients using PTA, but they did not use DPOAEs as screening test [16]. Chen et al. performed audiologic and ophthalmologic assessments in 30 transfusion-dependent patients receiving DFO, and reported a prevalence of 20 % (6/30) hearing deficit assessed by PTA and 33 % (10/30) by DPOAEs [17]. Chao et al. studied 37 regularly transfused β-thalassemia major patients on DFO and DFP iron chelators, the incidence of hearing impairment detected by PTA was 35.1 % (13/37), Of the 37 patients, 21 received further audiologic assessment, using TEOAE, 7/21 (33.3 %) of them failed to pass the TEOAE [18].

In our study, SNHL was detected more at higher frequencies. This finding is consistent with recent studies which found that high-frequency PTA was highly significant in detecting ototoxicity related threshold changes. Beahan et al. found that high-frequency PTA was reliable in detecting ototoxicity in patients aged 7 years and older [19].

Most studies were conducted on patients receiving DFO, and reported incidence of DFO-related ototoxicity varies widely from 3.8% to 57 % [18,[20][21][22]]. Few studies assessed deferasirox chelator as monotherapy, and to the best of our knowledge, this is the first study to assess the audiological as well as the vestibular function in children and adolescents with transfusion dependent β-thalassemia patients who had been treated with DFX FCT monotherapy after exclusion of patients who previously received DFO iron chelator. We also included a healthy control group to better understand the impact of beta-thalassemia or chelating therapy on the occurrence of hearing deficits. Khan et al. reported a prevalence of 45.45 % sensorineural hearing loss in β-thalassemia major patients at all doses of DFX from 700 to 1800 mg (p < 0.001). It was also revealed that SNHL was found in β-thalassemia major patients at all durations of use, from three to 60 months or more (p < 0.007) [23]. On the other hand, Derin et al. reported that deferasirox and deferiprone were not associated with ototoxicity, however, they reported this finding only in eight patients, a larger series with long term follow up is required to confirm [24]. It is worth to be mentioned that recently, SNHL was reported even among Non-Transfusion-Dependent Thalassemia (NTDT) patients who were not receiving iron chelation therapy, spotlighting the phenomenon of auditory cortex hypoperfusion in thalassemia patients as a cause of SNHL regardless of disease severity and chelation therapy suggesting a more complex pathogenesis of hearing dysfunction [25].

As concerns vestibular function assessment, a high incidence of canal paresis was found in our patients, 36.8 % of them showed abnormal caloric test which is considered an indicator of subclinical vestibulopathy in thalassemic patients. Moreover, caloric test results were significantly lower in thalassemic children than normal children bilaterally, with significantly more unilateral weakness than control children. Chao et al. reported a higher incidence (80 %) of canal paresis [18]. The mechanism of vestibulopathy in thalassemia is still unclear, however, Coffey et al. suggested a theory of having high Erythrone levels, the main erythroid regulator of hepcidin, leads to toxic iron overload and multi-organ abnormalities, they conducted a study on existing mouse models of β-thalassemia, some of these mice exhibited atypical behavior in form of frequent circling and weak righting reflex, which may suggest vestibular dysfunction [26]. On the other hand, we found that the central vestibular functions were preserved in our patients.

More studies are needed for further identification of the incidence of subclinical vestibulopathy in thalassemia and the pathogenic link between thalassemia and audio-vestibular dysfunction.

Our study found no significant correlation between the audio-vestibular impairment with age, sex, age of diagnosis, serum ferritin concentration, frequency of blood transfusion and dose of DFX in thalassemic children. So, we can’t consider any of these parameters as a reliable predictor to the occurrence of ototoxicity. Same findings were reported by Bhardwaj et al. [15]. This is consistent with Derin et al. who found that DFP and DFX were not associated with ototoxic effects in β-thalassemia major patients [24]. Conversely, Khan et al., found a significantly positive correlation between SNHL with dose and duration of DFX [23]. Other studies also reported similar positive correlation [27,28]. On the other hand, a negative correlation between ototoxicity and DFX treatment was reported in a study from Thailand. They included transfusion-dependent thalassemia patients received mono DFX, DFO, or a combination. They reported that there was a rather low incidence of ototoxicity after receiving iron chelators [29].

Regarding serum ferritin level, the relationship with hearing loss is still controversial. Most authors found no significant differences between patients with and without hearing loss [18,24]. Few studies considered low serum ferritin as a risk factor for SNHL [30]. However, two small sample studies suggested that iron overload may be associated with auditory impairment at high frequencies [31].

Indeed, several factors may contribute to this discrepancy between the studies such as, different study design or sample size, the lack of uniform diagnostic criteria of hearing impairment, also, the studies were conducted on patients receiving different iron chelators as well as the difference in other risk factors for hearing impairment.

5. Conclusion

In the current study, the prevalence of SNHL in regularly transfused β-thalassemia major patients was found to be 21.1 % by PTA and 43.1 % using TEOAE highlighting the value of TEOAE as a screening tool to detect early outer hair cell dysfunction. Vestibular dysfunction in form of canal paresis was detected in 36.8 % of the patients. No significant association was observed between audio-vestibular dysfunction and FCT DFX consumption. Future longitudinal studies on larger sample size are recommended to identify the pathogenesis and prevalence of DFX related disorders in β-thalassemia. As the onset of hearing impairment is unpredictable, so, we recommend to perform pre-treatment baseline audiological assessment for newly diagnosed children and regular audio-vestibular monitoring every year to early predict and prevent permanent damage.

5.1. Limitations

Small sample size was the major limitation in our study. The non-use of DPOAE as a hearing assessment tool among the study was a limitation because DPOAE can probe higher frequencies cochlea, which are more sensitive to monitor ototoxic damage compared to TEOAE. Also, the patients were already on DFX therapy so; we didn’t assess the baseline audio-vestibular function.

Disclosure of interest

The authors reported no potential conflict of interests.

Financial support and sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Dalia Helal Galhom: Writing – review & editing, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Rana Mohamed Talaat: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation. Diana Hanna: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Nahla Hassan Gad: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We would like to thank patients and caregivers for their willingness and cooperation to participate in this study.

 

References

 

Diana Hanna

Medical Director

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