Hearing Damage Caused by Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a multisystem disease associated with episodes of acute illness and progressive organ damage, leading to impairment of several organs. It is characterized by vaso-occlusive processes resulting from local hypoxia, increased number of sickled erythrocytes, and dissemination of occlusion to adjacent tissues. SCD has a chronic inflammatory mechanism that affects several organs and systems, including the auditory system. Hearing loss resulting from SCD includes conductive hearing loss, sensorineural hearing loss, in the central auditory system, in addition to otoneurological symptoms. These findings occur in both the adult and pediatric populations. At the end of this chapter, it is expected that the reader will be able to identify the main damages in the auditory system resulting from sickle cell disease, understand the pathophysiology of the damage generated in hearing, as well as understand the main care needed to monitor the hearing health of this population.

1. Introduction

Sickle cell disease (SCD) is characterized by vaso-occlusive processes resulting from local hypoxia, increased number of sickled erythrocytes, and spread of occlusion to adjacent tissues [1]. SCD has a chronic inflammatory mechanism that affects several organs and systems, including the audit system [2]. Hearing losses resulting from SCD include conductive hearing loss [3, 4, 5], sensorineural hearing loss (SNHL), analyzed by conventional pure tone audiometry (PTA), in addition, otoneurological symptoms such as tinnitus and dizziness (vertigo) occur [6, 7], and damage to the central auditory system [8, 9, 10]. Studies exclusively analyzing the sensory structure of hearing through otoacoustic emissions (OAEs) were also carried out [10, 11, 12, 13, 14]. However, there are reports in the literature that disorders in the auditory system are associated with cognitive deficits and learning difficulties [15, 16].

The PTA determines the subject’s minimum sensitivity auditory analyzing frequency and intensity. Sensory alterations are detected by electrophysiological auditory tests – OAE and neural alterations (auditory nerve and brainstem) by ABR test [17].

The knowledge about hearing damage in SCD contribute to health promotion, and measures can be adopted, as well as the institution of treatments, respecting their individuality, to improve the quality of life.

2. Hearing impairments in sickle cell disease

2.1 Pathophysiology applied to hearing loss in sickle cell disease

Hearing damage in SCD possibly has several pathophysiological mechanisms. Conductive hearing loss resulting from middle ear disorders may be caused by upper airway infections [4]. Adenoid hypertrophy may contribute to otitis media with effusion mechanically due to Eustachian tube obstruction, or functioning as a reservoir for otitis media-causing bacteria [18]. Children with SCD are predisposed to adenoid hypertrophy as a response to their functional asplenia, predisposing infections caused by streptococcus pneumoniae and hemophilus influenzae [19]. The prevalence of adenotonsillar hypertrophy in children with SCD was reported to be 55.3% compared to 30–37.6% in children without the disease [20]. Few data are available on the risk and consequences of otitis media in children with SCD. Taipale et al. [5], analyzing a cohort of 61 children with SCD, found 3% of children with acute otitis media, no cases of chronic otitis media, and only 2% with otitis media with effusion. MacDonald et al [21], in the United States, detected 19 cases of otitis media with effusion in a cohort of 84 children. These data are similar to the healthy population. Stuart and Smith, in 2019, state in their study that although they did not collect the etiology of conductive losses, it can be assumed that they were most caused by otitis media [22].

The physiopathology of SNHL in SCD has not been understood. The known hypothesis refers to the reduction of blood circulation in the auditory system due to the deformed shape of the blood cells, resulting in hypoxia in the structures of the auditory system [23, 24, 25]. Histopathological study of the temporal bone of a child SNHL and SCD demonstrated conglomerate of sickled erythrocytes in the circulation of the structures of the auditory system (cochlear stria vascularis) and reduction in the number of outer hair cells compatible with hypoxia [26].

The SNHL in SCD apparently affects high frequencies, which can be explained due to the high consumption of the oxygen of the stria vascularis [27]. Lago et al. [2] demonstrated reduced flow-mediated dilation, with ultrasonographic imaging of the brachial artery, in patients with SCD-homozygous (HbSS) – sickle cell anemia (SCA) with SNHL de displaying the role of vascular endothelium dysfunction in vaso-occlusion in SCD associated with SNHL.

2.2 Characteristics and prevalence of hearing damage associated with sickle cell disease

The hearing loss in SCD presents great variation among different studies. Conductive hearing loss occurs in about 27.5% of children and adolescents [4]. A retrospective study analyzes the prevalence of hearing loss in audiometric data of 128 children and adolescents with SCA. The occurrence of hearing loss ranged from 28.8% to 50.8%, according to the method used (i.e. individual vs. ear-specific; any elevated threshold vs. a three-frequency pure tone average). There are more occurrences of conductive hearing loss than SNHL [22].

The prevalence of SNHL in SCD varies from 3.8% [4] to 66% [28] including adults and children and different genotypes (homozygous (HbSS), heterozygous (HBSC) and, thalassemias). This difference may be linked to factors such as genotype, age group, geographic region, socioeconomic aspects, level of sequelae related to the disease, treatments used, and the cutoff point adopted in the evaluation to identify hearing point adopted. A systematic review and meta-analysis study including 12 studies and a total of 636 SCD patients and 360 controls identified 26.3% of SNHL in adults with SCD [29], including different genotypes. Another systematic review, including 14 studies, with 884 homozygous participants aged between 4 and 56 years, found a prevalence of 20.5%.

As to the characteristics of SNHL in SCD patients, the SNHL can occur in both sexes, in one or both ears and, the severity is predominance in the mild range. Apparently, it initially affects effect higher frequencies (4–8 kHz) followed by the low frequencies (0.25–0.5 kHz). The basal portion is metabolically active, and the structures are the main receptors of acoustic energy from the external environment, and it becomes more sensitive to variations and/or deprivation of oxygen or glucose. Changes in other frequencies suggest that the damage is diffuse in the cochlea [30]. Based on the hypothesis of circulatory changes in the auditory system in SCD, variations in SNHL characteristics could be explained by the duration, distribution, and size of the ischemic process in the circulation of the inner ear [4].

Studies demonstrated that SNHL in SCD patients could occur in different age groups (children, adolescents, and young adults). Most of the studies included samples with a wide age range, which led to inaccurate results regarding prevalence by age group. Studies that included only children and adolescents demonstrated high occurrence [2, 22, 31]. Studies with a broad age range showed a greater prevalence over 30 years of age [8, 32, 33]. And, other two studies [6, 34] described a trend toward worsening with increasing age, suggesting that SNHL is progressive in SCD patients. It might be expected that as patients with SCD grow older, and they will experience repeated crises and show an increased incidence of SNHL.

The characteristics of the SNHL are shown in Table 1.

Study (Author, year, and country)	Number of patients (Sex); Genotype	Age (years)	Hearing loss	Rate of SNHL	Laterality, severity
Al-Dabbous et al. (1996); Saudi Arabia [35]	100 (42F/58M); HbSS	5–40	≥ 25 dB at one or more frequencies	19 (19%)	52.6% unilateral; Severity: 10.5% mild; 63.5% moderate; and 26.3% severe range
Al-Muhaimeed et al. (2000); Saudi Arabia [33]	50 (22F/28M); HbSS	4–45	> 20 dB at two or more frequencies	18 (36%)	72% unilateral; Severity: 73.9% mild; 17.4% moderate; and 8.7% severe
Piltcher et al. (2000); Brazil [6]	28 (15M/13F); HbSS	6–55	> 20 dB at two or more frequencies	6 (21.4%)	Tendency to be bilateral; Severity: NR
Onakoya et al. (2002); Nigeria [28]	167(96F/73M); HbSS	15–56	> 25 dB at one or more frequencies	110(66%)	62% bilateral; Severity: 58% mild
Mgbor and Emodi (2004); Nigeria [27]	52 (36M/16 F); HbSS	6–19	> 25 dB at one or more frequencies	7 (13.4%)	100% unilateral; Severity: 100% mild
Aderibigbe et al. (2005); Nigeria [34]	46(21M/25F); HbSS	16–48	> 25 dB (mean of frequencies 0.5, 1, 2, and 4 kHz)	4 (4.3%)	100% unilateral; Severity: 100% mild
Jovanovic-Batman and Hedreville (2006); Guadeloupe (France) [8]	79(36M/43F); HbSS; HbSC	16–50	> 20 dB at two or more frequencies in one or both ears	36(45.56%)	NR laterality; Severity: 100% mild
Alabi et al. (2008); Nigeria [4]	80 (45M/35F); HbSS	4–15	> 25 dB at one or more frequencies	3 (3.8%)	100% unilateral; Severity: 100% mild
Samperi et al. (2005); Italy [36]	73 Sex: NR; 23 HbSS; 50S-β-thalassemia	7–54	> 25 dB at one or more frequencies	24% (S-β-thalassemia); 30% (HbSS)	71,42% unilateral; Severity: 100% mild
Onakoya et al. (2010); Nigeria[32]	43 HbSC	15–65	> 25 dB at one or more frequencies	12 (27.9%)	Severity: mild
Al Jabr (2016); Saudi Arabia [37]	40HbSC, HbSS	20–45	>25 dB at one or more frequencies	9 (22.5%)	6 (15%) bilateral; Severity: mild
Lago et al. (2018); Brazil[2]	52HbSS (27M/25F)	6–18	> 20 dB at one or more frequencies	15 (28.8%)	(86.66%) unilateral; Severity: 100% mild
Olajuyin et al. (2018); Nigeria [31]	81; Sex: NR	5–17	>25 dB (mean value of frequencies of 0.5, 1, 2 kHz)	23 (28.3%)	Severity: majority mild
Bois et al. (2018); France [3]	61	4–19	>20 dB at the mean value of frequencies of 0.5, 1, and 2 kHz	2 (3.27%)	100% unilateral; Severity: moderate
Sarac et al. (2018); Turkey [38]	45; (20M/25F)	18–45	> 25 dB at the mean value of frequencies of 0.5, 1, and 2 kHz	2 (4.4%)	NR
Towerman et al. (2018); United States [39]	60; (*did not discriminate sex in the HbSS Group)	>22	≥ 25 dB at the mean value of frequencies of 0.5, 1, 2, and 4 kHz	3 (5%)	100% unilateral; Severity: 100%moderate
Stuart and Smith (2019); United States [22]	128	3-14	*Variable	3.1% to 17.1% depending on the calculation method employed	Unilateral or bilateral; Severity: 60.0% slight; 5.7% mild; 28.6% moderate; 1.4% severe; and 4.3% profound
Bomfim et al. (2022); Brazil [16]	31 25HbSS 6HbSC; (16M;14F)	8–17	>20 dB at one or more frequency	25.8%	Severity: 100% severity mild

Table 1.

Prevalence and characteristics of sensorineural hearing loss in sickle cell disease.

kHz, kilohertz; dB, decibel; HL, hearing loss; M, male; F, female; HbSS, hemoglobin SS; HbSC, hemoglobin SC; NR, Not reported.

In principle, variables such as the treatment used, and even the model of these studies, may interfere in this relationship, since observational cross-sectional studies do not allow identification of the moment of SNHL installation of hemoglobin and fetal hemoglobin levels. Although SNHL may go unnoticed, there are records of patients who developed a severe/profound degree, requiring intervention with electronic devices such as a cochlear implant to restore hearing [40]. The pediatric population presented, in most studies, the severity of mild/moderate hearing loss, which is often not perceptible for the discernment of the children themselves.

Case studies demonstrate sickle cell crisis directly correlating with sudden and sometimes permanent unilateral or bilateral SNHL presentation [25, 41, 42]. While suffering in the midst of an acute pain crisis, one of these patients also experienced debilitating vestibular dysfunction [42].

Rissatto-Lago et al [7] describe a high occurrence of otoneurological symptoms (vertigo and/or tinnitus) in the pediatric population with SCA 46.4 % and concluded that the presence of sickle cells in vascularization in the labyrinthine artery is capable of compromising the vascularization of the structures responsible for body balance, such as the semicircular canals.

Considering the physiopathology and sensitivity of the inner ear, hidden damage can be present and not yet been detected in PTA. The OAE are sounds of cochlear origin, which can be recorded by a microphone fitted into the ear canal. They are caused by the motion of the cochlea’s sensory hair cells as they energetically respond to auditory stimulation.

The OAE test is the fast, noninvasive method to identify subclinical alterations in the cochlea. The transient otoacoustic emissions (TOAEs) responses are the strongest, and therefore, the easiest to detect in the primary auditory frequency band of 1–4 kHz, triggered by broad-spectrum acoustic stimulus as whole and detected in subjects. The distortion product otoacoustic emissions (DPOAEs) responses that are generated by the nonlinear interaction of two pure tones presented simultaneously valuates specific parts of the cochlea and varies from 0.5 to 8 kHz, which are the frequencies in subjects with normal hearing or mild hearing loss detected [43, 44].

Differences in the OAE amplitudes were noted in four of the six studies, with an increase in amplitude being identified in the group with SCA [11, 12, 13, 14]. The main studies and characteristics of the OAE are shown in Table 2.

Study	Participants Fri; Age (years)	Results
Downs et al. (2000); United States	20 (11M/9F); 6–13	DPOAE amplitudes significantly larger for the SCA group; lower amplitude for the lower frequencies
Walker et al. (2004); United States	12 (5M/7F); 6–14	DPOAE amplitudes were significantly larger for the SCA group; reduced amplitude for lower frequencies
Stuart et al. (2012); United States	30; Group I: 15 treated HDU (9M/6F); Group II: 15 non-treated HDUs (6M/9F)	DPOAE amplitudes were significantly larger in the SCA group not treated with HDU in comparison with the SCA group treated with HDU and the healthy controls; lower amplitude for the lower frequencies
Stuart and Preast (2012); United States	13 (5M/7F) 5–17	TOAE amplitudes were significantly larger for the SCA group. There was no difference in the mean to inhibit evaluating effects of the MOC system (effects suppression) between the groups with SCA and HC.
Kegele et al. (2015); Ghana	35 (Fri NR); 6 months–10 years	There was no difference relative to the presence and amplitude of TOAEs in the comparison between the SCA group and HC
Lake et al. (2018); Brazil	37 (20M/17F); 6–18	There was no statistically significant difference in the DPOAE amplitudes between the SCA and healthy controls groups. No difference in the absolute level of inhibition effects of the MOC between SCA and HC.

Table 2.

Studies with sickle cell disease (homozygous) using the tests of transient and distortion product otoacoustic emissions (n = 6).

F, female sex; M, male sex; DPOAE, distortion product otoacoustic emissions; HDU, hydroxyurea; SCA, sickle cell anemia; TOAE, transient otoacoustic emissions.

The increase in OAE amplitude in SCD suggests early changes in cochlear micromechanics, which may progress to the appearance of SNHL. The increase in amplitude may not be attributed to ear and functional differences in the outer values in the mean evaluated in tympanometry [12]. One hypothesis for the increase in OAE amplitude in SCD would be due to aberrant median olivocochlear neural function; however, this hypothesis was found contrary in a study, which no differences in the mean suppression of TOAE between the groups suppress SCD and healthy participants, indicating normal function of the medial or olivocochlear system [14]. This normality of the medial olivocochlear system was also observed in the study by Rissatto-Lago et al. [10], who identified similar DPOAE amplitudes in participants with SCD and hearing thresholds within normal limits when compared to healthy controls.

The association between increased OAE amplitude in participants with SCD who did not receive hydroxyurea (HU) compared to those treated with HU is evidence for the possibility of premature changes in the cochlear micromechanics of the inflammatory process of SCA. As HU is a drug that reduces the inflammatory process in SCA by reducing the adhesion of erythrocytes and leukocytes to the vascular endothelium, it reduces myelosuppression and vasodilation through the release of nitric oxide [45]. It is possible that the return of OAE amplitudes to a normal level reflects a reduction in the mechanism of the undetermined cause of the increase in OAE amplitude.

The iron chelator deferoxamine, administered parenterally, or deferasirox orally are ototoxic drugs and may cause permanent or transient hearing deficits depending on the dosage and time of exposure to the medication. These ototoxic effects culminate in changes in the cochlea and a reduction in the number of outer hair cells [35].

Damage to the central auditory pathways must be considered, including subclinical damage such as hidden damage to the auditory system. Increased contralateral acoustic reflexes were found in homozygous SCD children and adolescents, with hearing thresholds within normal limits. According to the authors, considering that alterations in the brainstem or efferent system can affect the level of the acoustic reflex in the presence of integrity of the afferent pathway, and the hypothesis of possible retrocochlear alterations (brain stem) is raised. This study auditory brainstem response (ABR) mean latencies of waves III and V and the mean interpeak latencies I–III and IV are significantly higher in the SCD patients, compared to the healthy group [10].

A study in France found changes in the ABR in 25.35% of patients with SCD compared to healthy controls due to an increase in interpeak latencies (III–V), and men were the most affected by this alteration [8]. In another study, Husain et al (2011) reported that 51% of patients with SCD had altered ABR results suggesting damage to a portion of the brainstem (retrocochlear alteration) [9].

P300 is an auditory cognitive evoked potential involved in attention, discrimination, and memory. It is an indicator of cortical processing, speed, and delay in patients with cognitive deterioration [46]. Children with SCD had a longer P300 latency compared to the control group; however, none of the SCD morbidity markers were related to P300 [15]. However, it is still controversial, as another study, including children and adolescents with SCD, found similar P300 responses between patients with SCD and controls [47]. Similar results were found by Rissatto-Lago et al [10], in which children and adolescents with clinically stable SCD had similar P300 latencies with healthy controls.

2.3 Conduct and clinical applicability

Damage to the auditory system in patients with SCD, including the pediatric population, seems quite evident, making it clear that risk detection for hearing disorders should focus on young people, in order to accurately detect subclinical changes that can progress to sensory impairments. SNHL hearing impairments already installed in a very young population is a very relevant fact and requires particular attention from specialists who deal with these patients, considering that, in addition to influencing quality of life, good hearing is crucial for learning and school performance, which can also be harmed by this factor, and a periodic hearing assessment is indicated.

Thus, patients who underwent hearing assessment at birth (neonatal hearing screening) with positive results should be audiologically monitored. Audiological procedures, such as OAE exams, can be ordered at any age, assessing sensory integrity. Patients using ototoxic medications, for example, iron chelator deferoxamine or deferasirox, should be monitored more carefully and in a short period of time.

Hearing assessment, including behavioral procedures such as pure tone audiometry and immitanciometry, should be requested at the beginning of literacy, even for participants without auditory signs or symptoms, since studies have shown that the presence of mild impairments may be associated with school difficulties. And when possible, an evaluation with ABR should be performed to monitor the central auditory pathway in order to detect damage that may manifest with advancing age.

3. Conclusions

There is a higher prevalence of SNHL in patients with SCD compared to the general population. This is likely due to the pathophysiology of the disease and the hematologic effects on the labyrinthine microvasculature. The otorhinolaryngologist must be aware of the otological manifestations of SCD such as SNHL and request periodic assessment of the auditory function of patients with SCD.

Acknowledgments

The author would like to thank professors Ana Marice Teixera Ladeia and Cristina Salles for the teachings and contributions in the works that resulted in the construction of this chapter.

Conflict of interest

The author declares no conflict of interest.