- Email: [email protected]
Sensorineural Hearing Loss in Primary Antibody Deficiency Disorders
Sensorineural Hearing Loss in Primary Antibody Deficiency Disorders MARCO BERLUCCHI, MD,* ANNAROSA SORESINA, MD,* LUCA O. REDAELLI DE ZINIS, MD, LUISA VALETTI, MD, ROBERTA VALOTTI, MD, VASSILIOS LOUGARIS, MD, ANTONELLA MEINI, MD, DARIA SALSI, MD, PIERO NICOLAI, MD, AND ALESSANDRO PLEBANI, MD
To evaluate the hearing function in patients affected by primary antibody deficiency disorders. Forty-seven patients, 25 of whom were affected by X-linked agammaglobulinemia and 22 of whom were affected by common variable immunodeficiency were evaluated with audiologic tests that included pure tone audiometry, acoustic immittance assessment and auditory brainstem-evoked response. Eighteen patients (38%), 7 with X-linked agammaglobulinemia and 11 with common variable immunodeficiency, showed sensorineural hearing loss, bilateral in 12 and unilateral in 6. Our data underline the high frequency of hearing loss in patients with antibody deficiency and suggest that a systematic audiologic evaluation should be part of the clinical care of these patients. (J Pediatr 2008;153:293-6)
ncreased susceptibility to pyogenic encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae is the most frequent clinical manifestation of primary immunodeficiency disorders characterized by a prevalent defect of the humoral compartment.1-5 X-linked agammaglobulinemia (XLA) or autosomal recessive agammaglobulinemia (AAR) and common variable immunodeficiency (CVID) represent the most clinically relevant forms of antibody deficiency; hypogammaglobulinema is caused by an early arrest of B-lymphocyte differentiation in both XLA and AAR6 and by a B-lymphocyte functional defect in CVID.7 Recurrent acute otitis media (AOM), sinusitis, bronchitis, and pneumonia are the most frequent clinical manifestations of these immune disorders,1-4 with str. pneumoniae and H influenzae being the most frequent pathogens. In patients who are antibody deficient, recurrence of infections of the lower respiratory tract can be considered 1 of the major factors contributing to the development of chronic lung disease.2,8 Recurrent AOM is another clinical problem in these patients. In a survey of 29 patients with XLA, recurrent AOM was recorded in 26.9 These clinical observations suggest that hearing loss caused by recurrent otitis media might be a relatively frequent complication in patients with antibody deficiency. However, in contrast with the many clinical reports on lung complications in patients with antibody deficiency,2-5,8 no consistent data are available on the incidence of hearing loss in a large cohort of such patients. In this study, we addressed this issue by evaluating the hearing function in 25 patients affected by XLA and in 22 patients affected by CVID.
I
METHODS Twenty five patients with XLA, all with mutations of the BTK gene, and 22 patients with CVID who were observed at the Department of Pediatrics of the University of Brescia from March 2004 to September 2005 were included in this study. The diagnosis of CVID and XLA was based on the Pan American Group for Immunodeficiency (PAGID)/European Society for Immunodeficiencies (ESID) criteria.10 Patients’ clinical and immunologic data at diagnosis are reported in Tables I and II. The patients’ median current age is 15 years (range, 2-38 years) and 25 years (range, 9-47 years) for the XLA group and the CVID group, respectively. The median age at diagnosis was 3 years (range, 0-8 years) for patients with XLA and 14.5 years (range, 1-38 years) for patients with CVID, whereas the median age at onset of symptoms was 12 months and 33 months for patients with XLA and CVID, respectively. Recurrent respiratory tract infections were the most frequent clinical manifestation at diagnosis and also during follow-up. However, a precise quantification of the number of infections, including AOM, was at times lacking because the patients were seen in AAR AOM CVID IVIG
Autosomal recessive agammaglobulinemia Acute otitis media Common variable immunodeficiency Immunoglobulin substitution therapy by intravenous route
SNHL XLA
Sensorineural hearing loss X-linked agammaglobulinemia
From the Department of Pediatric Otorhinolaringology, Spedali Civili, Brescia, Italy (M.B.); Department of Pediatrics (A.S., R.V., V.L., A.M., A.P.), Department of Otorhinolaringology (L.d.Z., D.S., P.N.), University of Brescia, Brescia, Italy. *M.B. and A.S. contributed equally to this work. Supported in part by the contribution of the Fondazione C. Golgi, Brescia, the Associazione Immunodeficienze Primitive, and by the grant PRIN 2006 to A.P. Submitted for publication Nov 30, 2007; last revision received Feb 6, 2008; accepted Mar 11, 2008. Reprint requests: Prof Alessandro Plebani, Head of Pediatrics Clinic, University of Brescia, Spedali Civili, 25123 Brescia, Italy. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.03.008
293
Table I. Immunological features of the patients with X-linked agammaglobulinemia at diagnosis Ig serum levels (mg/dL)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Age at diagnosis (years)
Age at the time of the study (years)
IgG
IgA
IgM
B-lymphocyte counts (%)
BTK mutation
1 5 7 3 8 0 3 6 3 4 2 1 1 2 2 5 1 1 3 4 3 1 2 3 4
20 26 27 10 38 2 6 34 18 14 10 10 10 9 13 15 3 2 24 26 10 6 12 22 10
161 330 360 32 120 385 70 190 108 12 200 240 280 412 462 355 40 89 102 163 334 10 50 59 41
6.5 0 6.5 50 0 0 0 6.5 6.5 5.9 6 6 6 15 54 29 4 0 6.5 13 6.5 4.9 4 0 0
10 0 6.5 17 5 0 0 19 38 11 25 9 9 7 44 20 15 0 6 14 26 4.9 10 0 24
1 1 2 0 0 2 0 0 2 0 0 0 0 0 2 1 0 0 1 0 0 0 0 3 0
K19X G594E G594E splicing defect G594R R288W W147X Q328X L175FSX193 R255X E90FSX120 L512P L512P Del R288W R288W splicing defect R641H R133FSX175 splicing defect G612X Y461X K185FSX193 M509X C154G
different centers and by different consultants, before being followed regularly by a single center. No history of congenital infections was recorded. Since diagnosis, all patients have been treated with immunoglobulin substitution therapy by intravenous route (IVIG) at a dosage of 400 to 600 mg/kg/month, with a median duration of therapy of 11.9 and 10.8 years and a median duration of follow-up of 12 and 10 years for patients with XLA and CVID, respectively. All patients underwent otoscopy and audiologic tests including pure tone audiometry. Air and bone conduction thresholds for both ears were determined in a sound isolation booth with a 5 dB step and appropriate masking with narrow band noise of the opposite ear with the plateau method. Bone threshold variability for the audiometer used in subjects with normal hearing with and without narrow band masking was within 10 dB, and a test-retest variability was within 5 dB. An impairment ⬎20 dB of bone threshold for at least 1 frequency was considered a sensorineural hearing loss (SNHL). Acoustic immittance assessment and auditory brainstem-evoked responses were performed to confirm the SNHL and to differentiate cochlear from retro-cochlear hearing loss. When a suspicion of retro-cochlear hearing loss was still present after auditory brainstem-evoked response or when auditory brainstem-evoked responses were not possible because of severe hearing loss, magnetic resonance imaging of the ear and brain was also performed. 294
Berlucchi et al
The same audiologic tests were performed on a cohort of 46 age-matched healthy subjects (median age, 17.5 years; range, 5-46 years), which included 7 female and 39 male subjects. Comparison of the audiologic tests’ results in the 2 groups was performed by the 2 test.
RESULTS The results of patients’ hearing evaluation are summarized in Table III. Eighteen patients (38%), 7 with XLA (28%) and 11 with CVID (50%), showed SNHL, bilateral in 12 patients (4 with XLA and 8 with CVID) and unilateral in 6 patients (3 with XLA and 3 with CVID). The mean audiometric threshold of sensorineural hearing loss was 31.6 db. All cases were high frequencies hearing loss, except for 2 patients with severe SNHL who presented a flat configuration and 1 patient who presented a rising configuration (low frequency SNHL) In addition, otoscopy did not reveal either acute or chronic otitis media in our patients. The median age at diagnosis was significantly higher in patients with XLA and SNHL than patients with XLA without SNHL (4 years; range, 2-8 years; versus 2 years; range, 3 months-6 years; P ⫽ .0226); however, the median age at diagnosis did not differ significantly in patients with CVID who had SNHL and in patients with CVID who did not have SNHL, although a trend of older age was present in patients with SNHL (17 years; range, 1-38 years; versus 12 years, 1-27 years; P ⫽ .179). The Journal of Pediatrics • August 2008
Table II. Immunological features of the patients with common variable immunodeficiency at diagnosis Ig serum levels (mg/dl)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sex
Age at diagnosis (years)
age at the time of the study(yr)
IgG
IgA
IgM
B-lymphocyte counts (%)
M M F M F M M M M M M M F F F F F M M M M M
15 6 21 17 21 4 14 1 16 1 4 12 27 23 31 21 10 1 24 13 9 38
19 25 26 40 32 18 27 10 19 12 10 13 34 31 41 21 26 9 42 29 23 47
290 239 334 46 408 319 190 208 316 234 330 0 495 110 179 91 399 282 150 160 225 150
4 46 26 12 4 11 10 8 14 9 26 20 9 0 0 7 11 1 5 14 25 6.5
60 18 20 8 17 43 31 35 49 29 10 40 7 0 0 33 104 9 3 14 33 12
24 10 21 3 4 6 5 5 10 3 23 13 5 3 3 5 4 20 12 7 3 3
Ig, Immunoglobulin; M, male; F, female.
Table III. Hearing loss in patients with X-linked agammaglobulinemia, patients with common variable immunodeficiency, and control group
Immunodeficient subjects Patients with XLA Median age at diagnosis (range) Patients with CVID Median age at diagnosis (range) Control group
Sensorineural hearing loss N (%)
Normal bone conduction N (%)
Number of patients
18 (38%) 7 (28%) 4 years (2-8 years) 11 (50%) 17 years (1-38 years) 4 (9%)
29 (62%) 18 (72%) 2 years (0-6 years) 11 (50%) 12 years (1-27 years) 42 (91%)
47 25
Of the 18 patients with SNHL, documented epidsodes of recurrent AOM from infancy was recorded in 13 patients (4 with XLA and 9 with CVID), noise exposure was recorded in 5 patients, and central or peripheral nervous system involvement was recorded in 4 patients with XLA (2 with meningoencephalitis, 1 with Arnold-Chiari anomaly, and 1 with vaccine associated poliomyelitis). During follow-up at our center, the frequency of AOM episodes, before the audiologic tests were performed, was not significantly different between the patients who were antibody deficient with sensorineural defect and patients without sensorineural defect. Although some patients had a history of taking aminoglycoside antibiotics, there was no correlation with SNHL. In the control cohort group, unilateral SNHL was observed in only 4 patients (9%), all of whom had noise exposure as a risk factor. Sensorineural Hearing Loss in Primary Antibody Deficiency Disorders
22 46
The SNHL documented with pure tone audiometry was confirmed with acoustic immittance assessement. Auditory brainstem-evoked responses performed in all patients who were antibody deficient and in the control subjects with SNHL revealed cochlear hearing loss in all patients who were antibody deficient except 2 patients (1 patient who had meningitis and 1 patient who had echovirus encephalitis), in whom a retro-cochlear pattern of hearing loss was documented. Magnetic resonance imaging of the ear and the auditory pathways was normal in both, ruling out an acoustic nerve disorder.
DISCUSSION Recurrent upper and lower respiratory tract infections, substained by pyogenic encapsulated bacteria, is the major clinical problem in patients with primary antibody deficiency. 295
This is likely to result from the lack of the antibody-mediated opsonic activity that plays an important role in the clearance of encapsulated pathogens. Immunoglobulin substitution therapy is the treatment of choice in antibody deficiencies. However, respiratory tract infections also occur during immunoglobulin substitution therapy, although to a lesser degree, likely as a result of the inability of administered immunoglobulin to reach the mucosal surfaces. This can partially explain why chronic lung disease is still the major long-term complication in these patients.1-5,8 It is well recognized that recurrent AOM is the most frequent infection of the upper respiratory tract in patients who are antibody deficient.2,9 However, systematic data on the frequency of hearing loss as complication of this type of infection are lacking. In this study of a large cohort of patients with antibody deficiencies, we have shown that SNHL is frequent, having been observed in 18 of 47 patients (7 with XLA and 11 with CVID), bilateral in 12 patients and unilateral in 6 patients. Several factors can contribute to the development of SNHL. Noise exposure may contribute to SNHL; however, even in the hypothetical case, it accounted only for a small number of patients. Recurrent AOM, a relatively frequent clinical finding in pediatric patients, is another possible cause. A causal role of recurrent AOM in SNHL in otherwise immunocompetent subjects is still a matter of debate.11-13 In the control group included in this study, the frequency of AOM reflected that observed in healthy individuals. SNHL could be attributed to recurrent AOM, to the use of antibiotics that might damage the 8 cranial nerves, or both. For XLA, patients with SNHL received a diagnosis at a significantly older age compared with patients without hearing loss, and 13 of 18 patients with SNHL had history of recurrent AOM from infancy. However, 3 of 7 patients with XLA and SNHL had no history of recurrent AOM, suggesting that other causes may be important. In patients with XLA, infections other than AOM, such as enteroviral or cytomegalovirus infections have been reported to affect hearing.14 In our cohort of patients, 2 patients with XLA had meningoencephalitis (caused by echovirus in 1 patient), and 1 patient with XLA had vaccine-associated poliomyelitis; 2 of these 3 patients sustained recurrent AOM also. Sensorineuronal deafness in XLA may have a genetic basis, as demonstrated in a few patients with XLA with deletion of the BTK gene involving stretches of DNA downstream of the 3’ end of exon 19, including the deafness-dystonia protein gene.15 The patients with XLA included in our study had no deletions encompassing DNA regions outside of the BTK gene, suggesting that involvement of deafness-dystonia protein gene is very unlikely. As for patients with CVID, 9 of the 11 with SNHL had a history of recurrent AOM; however, we cannot rule out the
296
Berlucchi et al
possibility of yet unidentified genetic defects causing CVID, which might affect cells other than those of the immune system. A large proportion of patients with adenosine-deaminase deficiency have bilateral SNHL, suggesting a systemic manifestation of adenosine-deaminase deficiency rather than the result of ear infections.16 Whatever the reason for SNHL in patients who are antibody deficient, our data indicate a significant frequency of deafness and suggest the necessity for systematic complete audiologic evaluations at diagnosis and during follow-up. It is important to identify hearing defects in children, because even mild defects can have detrimental effects on communication and learning. In addition, a better definition of the role of otitis media on the development of SNHL, by means of multicenter studies, may help to formulate better therapeutic strategies. We would like to thank the patients and their families for their collaboration during this study.
REFERENCES 1. Winkelstein JA, Marino MC, Lederman HM, Sullivan K, Burks AW, Conley ME. Cunningham-Rundles C, Ochs HD, X-linked agammaglobulinemia. Report on a United States registry of 201 patients. Medicine 2001;85:193-202. 2. Plebani A, Soresina AR, Rondelli R, Amato G, Azzari C, Cardinale F, et al. Clinical, immunological and molecular analysis of a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 2002;104: 221-30. 3. Dukes RJ, Rosenow EC, Heremans PE. Pulmonary manifestations of hypogammaglobulinemia. Thorax 1978;33:603-7. 4. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency:clinical and immunological features of 248 patients. Clin Immunol 1999;92:34-48. 5. Quinti I, Soresina AR, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol 2007;27:308-16. 6. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev 2005;203:216-34. 7. Castigli E, Geha RS. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol 2006;117:740-6. 8. Quartier P, Debrè M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999;134:589-96. 9. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr 2002;141:566-71. 10. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Clin Immunol 1999;93:190-7. 11. Paparella MM, Brady DR. Sensorineural hearing loss in chronic otitis media and mastoiditis. Trans Am Acad Ophthal Otolaryngol 1970;74:108-15. 12. Noordzij JP, Dodson E, Ruth A. Chronic otitis media and sensorineural hearing loss: is there a clinically significant relation? Am J Otol 1995;16:420-3. 13. Redaelli de Zinis LO, Campovecchi C, Parrinello G, Antonelli AR. Predisposing factors for inner ear hearing loss association with chronic otitis media. Int J Audiol 2005;44:593-8. 14. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia:an analysis of 96 patients. Medicine 1985;64:145-56. 15. Richter R, Conley ME, Rohrer J, Myers LA, Zahradka K, Kelecic J, et al. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatr Allergy Immunol 2001;12:107-11. 16. Albuquerque W, Gaspar HB. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency. J Pediatr 2004;144:278-80.
The Journal of Pediatrics • August 2008
To evaluate the hearing function in patients affected by primary antibody deficiency disorders. Forty-seven patients, 25 of whom were affected by X-linked agammaglobulinemia and 22 of whom were affected by common variable immunodeficiency were evaluated with audiologic tests that included pure tone audiometry, acoustic immittance assessment and auditory brainstem-evoked response. Eighteen patients (38%), 7 with X-linked agammaglobulinemia and 11 with common variable immunodeficiency, showed sensorineural hearing loss, bilateral in 12 and unilateral in 6. Our data underline the high frequency of hearing loss in patients with antibody deficiency and suggest that a systematic audiologic evaluation should be part of the clinical care of these patients. (J Pediatr 2008;153:293-6)
ncreased susceptibility to pyogenic encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae is the most frequent clinical manifestation of primary immunodeficiency disorders characterized by a prevalent defect of the humoral compartment.1-5 X-linked agammaglobulinemia (XLA) or autosomal recessive agammaglobulinemia (AAR) and common variable immunodeficiency (CVID) represent the most clinically relevant forms of antibody deficiency; hypogammaglobulinema is caused by an early arrest of B-lymphocyte differentiation in both XLA and AAR6 and by a B-lymphocyte functional defect in CVID.7 Recurrent acute otitis media (AOM), sinusitis, bronchitis, and pneumonia are the most frequent clinical manifestations of these immune disorders,1-4 with str. pneumoniae and H influenzae being the most frequent pathogens. In patients who are antibody deficient, recurrence of infections of the lower respiratory tract can be considered 1 of the major factors contributing to the development of chronic lung disease.2,8 Recurrent AOM is another clinical problem in these patients. In a survey of 29 patients with XLA, recurrent AOM was recorded in 26.9 These clinical observations suggest that hearing loss caused by recurrent otitis media might be a relatively frequent complication in patients with antibody deficiency. However, in contrast with the many clinical reports on lung complications in patients with antibody deficiency,2-5,8 no consistent data are available on the incidence of hearing loss in a large cohort of such patients. In this study, we addressed this issue by evaluating the hearing function in 25 patients affected by XLA and in 22 patients affected by CVID.
I
METHODS Twenty five patients with XLA, all with mutations of the BTK gene, and 22 patients with CVID who were observed at the Department of Pediatrics of the University of Brescia from March 2004 to September 2005 were included in this study. The diagnosis of CVID and XLA was based on the Pan American Group for Immunodeficiency (PAGID)/European Society for Immunodeficiencies (ESID) criteria.10 Patients’ clinical and immunologic data at diagnosis are reported in Tables I and II. The patients’ median current age is 15 years (range, 2-38 years) and 25 years (range, 9-47 years) for the XLA group and the CVID group, respectively. The median age at diagnosis was 3 years (range, 0-8 years) for patients with XLA and 14.5 years (range, 1-38 years) for patients with CVID, whereas the median age at onset of symptoms was 12 months and 33 months for patients with XLA and CVID, respectively. Recurrent respiratory tract infections were the most frequent clinical manifestation at diagnosis and also during follow-up. However, a precise quantification of the number of infections, including AOM, was at times lacking because the patients were seen in AAR AOM CVID IVIG
Autosomal recessive agammaglobulinemia Acute otitis media Common variable immunodeficiency Immunoglobulin substitution therapy by intravenous route
SNHL XLA
Sensorineural hearing loss X-linked agammaglobulinemia
From the Department of Pediatric Otorhinolaringology, Spedali Civili, Brescia, Italy (M.B.); Department of Pediatrics (A.S., R.V., V.L., A.M., A.P.), Department of Otorhinolaringology (L.d.Z., D.S., P.N.), University of Brescia, Brescia, Italy. *M.B. and A.S. contributed equally to this work. Supported in part by the contribution of the Fondazione C. Golgi, Brescia, the Associazione Immunodeficienze Primitive, and by the grant PRIN 2006 to A.P. Submitted for publication Nov 30, 2007; last revision received Feb 6, 2008; accepted Mar 11, 2008. Reprint requests: Prof Alessandro Plebani, Head of Pediatrics Clinic, University of Brescia, Spedali Civili, 25123 Brescia, Italy. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.03.008
293
Table I. Immunological features of the patients with X-linked agammaglobulinemia at diagnosis Ig serum levels (mg/dL)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Age at diagnosis (years)
Age at the time of the study (years)
IgG
IgA
IgM
B-lymphocyte counts (%)
BTK mutation
1 5 7 3 8 0 3 6 3 4 2 1 1 2 2 5 1 1 3 4 3 1 2 3 4
20 26 27 10 38 2 6 34 18 14 10 10 10 9 13 15 3 2 24 26 10 6 12 22 10
161 330 360 32 120 385 70 190 108 12 200 240 280 412 462 355 40 89 102 163 334 10 50 59 41
6.5 0 6.5 50 0 0 0 6.5 6.5 5.9 6 6 6 15 54 29 4 0 6.5 13 6.5 4.9 4 0 0
10 0 6.5 17 5 0 0 19 38 11 25 9 9 7 44 20 15 0 6 14 26 4.9 10 0 24
1 1 2 0 0 2 0 0 2 0 0 0 0 0 2 1 0 0 1 0 0 0 0 3 0
K19X G594E G594E splicing defect G594R R288W W147X Q328X L175FSX193 R255X E90FSX120 L512P L512P Del R288W R288W splicing defect R641H R133FSX175 splicing defect G612X Y461X K185FSX193 M509X C154G
different centers and by different consultants, before being followed regularly by a single center. No history of congenital infections was recorded. Since diagnosis, all patients have been treated with immunoglobulin substitution therapy by intravenous route (IVIG) at a dosage of 400 to 600 mg/kg/month, with a median duration of therapy of 11.9 and 10.8 years and a median duration of follow-up of 12 and 10 years for patients with XLA and CVID, respectively. All patients underwent otoscopy and audiologic tests including pure tone audiometry. Air and bone conduction thresholds for both ears were determined in a sound isolation booth with a 5 dB step and appropriate masking with narrow band noise of the opposite ear with the plateau method. Bone threshold variability for the audiometer used in subjects with normal hearing with and without narrow band masking was within 10 dB, and a test-retest variability was within 5 dB. An impairment ⬎20 dB of bone threshold for at least 1 frequency was considered a sensorineural hearing loss (SNHL). Acoustic immittance assessment and auditory brainstem-evoked responses were performed to confirm the SNHL and to differentiate cochlear from retro-cochlear hearing loss. When a suspicion of retro-cochlear hearing loss was still present after auditory brainstem-evoked response or when auditory brainstem-evoked responses were not possible because of severe hearing loss, magnetic resonance imaging of the ear and brain was also performed. 294
Berlucchi et al
The same audiologic tests were performed on a cohort of 46 age-matched healthy subjects (median age, 17.5 years; range, 5-46 years), which included 7 female and 39 male subjects. Comparison of the audiologic tests’ results in the 2 groups was performed by the 2 test.
RESULTS The results of patients’ hearing evaluation are summarized in Table III. Eighteen patients (38%), 7 with XLA (28%) and 11 with CVID (50%), showed SNHL, bilateral in 12 patients (4 with XLA and 8 with CVID) and unilateral in 6 patients (3 with XLA and 3 with CVID). The mean audiometric threshold of sensorineural hearing loss was 31.6 db. All cases were high frequencies hearing loss, except for 2 patients with severe SNHL who presented a flat configuration and 1 patient who presented a rising configuration (low frequency SNHL) In addition, otoscopy did not reveal either acute or chronic otitis media in our patients. The median age at diagnosis was significantly higher in patients with XLA and SNHL than patients with XLA without SNHL (4 years; range, 2-8 years; versus 2 years; range, 3 months-6 years; P ⫽ .0226); however, the median age at diagnosis did not differ significantly in patients with CVID who had SNHL and in patients with CVID who did not have SNHL, although a trend of older age was present in patients with SNHL (17 years; range, 1-38 years; versus 12 years, 1-27 years; P ⫽ .179). The Journal of Pediatrics • August 2008
Table II. Immunological features of the patients with common variable immunodeficiency at diagnosis Ig serum levels (mg/dl)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sex
Age at diagnosis (years)
age at the time of the study(yr)
IgG
IgA
IgM
B-lymphocyte counts (%)
M M F M F M M M M M M M F F F F F M M M M M
15 6 21 17 21 4 14 1 16 1 4 12 27 23 31 21 10 1 24 13 9 38
19 25 26 40 32 18 27 10 19 12 10 13 34 31 41 21 26 9 42 29 23 47
290 239 334 46 408 319 190 208 316 234 330 0 495 110 179 91 399 282 150 160 225 150
4 46 26 12 4 11 10 8 14 9 26 20 9 0 0 7 11 1 5 14 25 6.5
60 18 20 8 17 43 31 35 49 29 10 40 7 0 0 33 104 9 3 14 33 12
24 10 21 3 4 6 5 5 10 3 23 13 5 3 3 5 4 20 12 7 3 3
Ig, Immunoglobulin; M, male; F, female.
Table III. Hearing loss in patients with X-linked agammaglobulinemia, patients with common variable immunodeficiency, and control group
Immunodeficient subjects Patients with XLA Median age at diagnosis (range) Patients with CVID Median age at diagnosis (range) Control group
Sensorineural hearing loss N (%)
Normal bone conduction N (%)
Number of patients
18 (38%) 7 (28%) 4 years (2-8 years) 11 (50%) 17 years (1-38 years) 4 (9%)
29 (62%) 18 (72%) 2 years (0-6 years) 11 (50%) 12 years (1-27 years) 42 (91%)
47 25
Of the 18 patients with SNHL, documented epidsodes of recurrent AOM from infancy was recorded in 13 patients (4 with XLA and 9 with CVID), noise exposure was recorded in 5 patients, and central or peripheral nervous system involvement was recorded in 4 patients with XLA (2 with meningoencephalitis, 1 with Arnold-Chiari anomaly, and 1 with vaccine associated poliomyelitis). During follow-up at our center, the frequency of AOM episodes, before the audiologic tests were performed, was not significantly different between the patients who were antibody deficient with sensorineural defect and patients without sensorineural defect. Although some patients had a history of taking aminoglycoside antibiotics, there was no correlation with SNHL. In the control cohort group, unilateral SNHL was observed in only 4 patients (9%), all of whom had noise exposure as a risk factor. Sensorineural Hearing Loss in Primary Antibody Deficiency Disorders
22 46
The SNHL documented with pure tone audiometry was confirmed with acoustic immittance assessement. Auditory brainstem-evoked responses performed in all patients who were antibody deficient and in the control subjects with SNHL revealed cochlear hearing loss in all patients who were antibody deficient except 2 patients (1 patient who had meningitis and 1 patient who had echovirus encephalitis), in whom a retro-cochlear pattern of hearing loss was documented. Magnetic resonance imaging of the ear and the auditory pathways was normal in both, ruling out an acoustic nerve disorder.
DISCUSSION Recurrent upper and lower respiratory tract infections, substained by pyogenic encapsulated bacteria, is the major clinical problem in patients with primary antibody deficiency. 295
This is likely to result from the lack of the antibody-mediated opsonic activity that plays an important role in the clearance of encapsulated pathogens. Immunoglobulin substitution therapy is the treatment of choice in antibody deficiencies. However, respiratory tract infections also occur during immunoglobulin substitution therapy, although to a lesser degree, likely as a result of the inability of administered immunoglobulin to reach the mucosal surfaces. This can partially explain why chronic lung disease is still the major long-term complication in these patients.1-5,8 It is well recognized that recurrent AOM is the most frequent infection of the upper respiratory tract in patients who are antibody deficient.2,9 However, systematic data on the frequency of hearing loss as complication of this type of infection are lacking. In this study of a large cohort of patients with antibody deficiencies, we have shown that SNHL is frequent, having been observed in 18 of 47 patients (7 with XLA and 11 with CVID), bilateral in 12 patients and unilateral in 6 patients. Several factors can contribute to the development of SNHL. Noise exposure may contribute to SNHL; however, even in the hypothetical case, it accounted only for a small number of patients. Recurrent AOM, a relatively frequent clinical finding in pediatric patients, is another possible cause. A causal role of recurrent AOM in SNHL in otherwise immunocompetent subjects is still a matter of debate.11-13 In the control group included in this study, the frequency of AOM reflected that observed in healthy individuals. SNHL could be attributed to recurrent AOM, to the use of antibiotics that might damage the 8 cranial nerves, or both. For XLA, patients with SNHL received a diagnosis at a significantly older age compared with patients without hearing loss, and 13 of 18 patients with SNHL had history of recurrent AOM from infancy. However, 3 of 7 patients with XLA and SNHL had no history of recurrent AOM, suggesting that other causes may be important. In patients with XLA, infections other than AOM, such as enteroviral or cytomegalovirus infections have been reported to affect hearing.14 In our cohort of patients, 2 patients with XLA had meningoencephalitis (caused by echovirus in 1 patient), and 1 patient with XLA had vaccine-associated poliomyelitis; 2 of these 3 patients sustained recurrent AOM also. Sensorineuronal deafness in XLA may have a genetic basis, as demonstrated in a few patients with XLA with deletion of the BTK gene involving stretches of DNA downstream of the 3’ end of exon 19, including the deafness-dystonia protein gene.15 The patients with XLA included in our study had no deletions encompassing DNA regions outside of the BTK gene, suggesting that involvement of deafness-dystonia protein gene is very unlikely. As for patients with CVID, 9 of the 11 with SNHL had a history of recurrent AOM; however, we cannot rule out the
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possibility of yet unidentified genetic defects causing CVID, which might affect cells other than those of the immune system. A large proportion of patients with adenosine-deaminase deficiency have bilateral SNHL, suggesting a systemic manifestation of adenosine-deaminase deficiency rather than the result of ear infections.16 Whatever the reason for SNHL in patients who are antibody deficient, our data indicate a significant frequency of deafness and suggest the necessity for systematic complete audiologic evaluations at diagnosis and during follow-up. It is important to identify hearing defects in children, because even mild defects can have detrimental effects on communication and learning. In addition, a better definition of the role of otitis media on the development of SNHL, by means of multicenter studies, may help to formulate better therapeutic strategies. We would like to thank the patients and their families for their collaboration during this study.
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The Journal of Pediatrics • August 2008