Congenital Cytomegalovirus and Hearing Loss

Congenital Cytomegalovirus and Hearing Loss Dr Simone Walter SpR Audiological Medicine St George’s Hospital Simone.walter@stgeorges.nhs.uk Simone.walter@nhs.net 1 CMV-Related SNHL • • • • • • • • • Burden of Disease Diagnosis Pathogenesis Predictive factors Characteristics Management Prevention and Treatment Research Summary Cytomegalovirus 2 CMV Definitions • Congenital CMV CMV infection before birth, diagnosed on testing body fluids/tissue samples taken prior to Day 21 May cause SNHL • Perinatal CMV CMV infection acquired perinatally i.e acquired during or after birth (up to Day 28) Does not cause SNHL 3 Burden of Disease in the UK • 1 in 200 births • Major cause of neurodisability • SNHL is the commonest sequel • • • • Proportion of Childhood SNHL due to CMV: Retrospective studies: 3% Das 1996 But Prospective studies: 12% Peckham 1987 75% not attributed to congenital CMV 4 Incidence of significant SNHL due to Congenital CMV Copied from Pass 2005 Study Peckham 1987 Harris 1984 Location London Sweden Rate/1000 live births 0.2 0.32 Hicks 1993 USA 0.6 ‘108 children in England and Wales each year’ Peckham1987 5 Why the discrepancy between retrospective and prospective studies? Congenital CMV 10% Symptomatic 50% SNHL 90% Asymptomatic 7-15% SNHL 6 Diagnosis of CMV-Related SNHL is difficult ‘Asymptomatic’ at birth Samples need to be taken before Day 21 Presentation is too late Negative IgG: exclude CMV Positive serology: congenital or perinatal/acquired Clues: Hx of IUGR, rash at birth, motor delay, neurological deficit, microcephaly, white matter lesions brain MRI • But SNHL may be the only finding Arav-Boger 2002, Griffiths 2005, Lee 2005 7 • • • • • • Differential diagnosis of isolated SNHL in a healthy child Symptomatic 1/3 Unknown: CMV ? Genetic Asymptomatic 2/3 What proportion of these children have SNHL due to CMV? How can we find out? 8 Retrospective Diagnosis on Dried Blood Spots (Guthrie cards) • Quantitative Polymerase Chain Reaction (PCR) for CMV DNA • Sensitivity: 75% of confirmed cases 85% of those destined to develop disease (BPSU) • Parental consent Shibata 1994, Barbi 2000, guidelines:http://www.ich.ucl.ac.uk/newborn/resources/policies.htm 9 Diagnosis by Polymerase Chain Reaction (PCR) for CMV DNA • Barbi 2003 • 130 Guthrie cards: unexplained SNHL • Positive for • 10% diagnosed age 0-2m • 34.2% diagnosed in early childhood • 42.7% with SNHL>70dB • 20-30% of SNHL due to CMV • • • • Also: White matter lesions Cerebral palsy Developmental delay • Blood, Urine, Amniotic fluid, Perilymph at Cochlear Implant van der Knaap 2004, Suigura 2004 10 Pathogenesis • Intracellular pathogen • Cell damage and death • T cell response • Inflammation • ‘CMV Immune escape mechanisms’ • Reactivation Large CMV infected cells in the Organ of Corti, Photograph courtesy of Professor Leslie Michaels 11 Pathogenesis: Unanswered Questions • ‘Host susceptibility’ • Genetic factors • Effect of timing of infection • Mechanism of delayed onset and progression • Site of lesion 12 Possible Predictive Factors • Disseminated disease • IUGR, petechiae, hepatosplenomegaly Rivera 2002 • Increased Viral Load: Boppana 2005 13 Characteristics • • • • Any configuration on PTA Progressive-50% Fluctuates-30% High Frequency 20-30% Dahle 2000, Williamson 1992 Dahle 1979, Fowler 1997 14 Onset • Delayed Onset in up to 50% • Mostly pre-lingual • Over half will be missed by NHSP • Also missed by risk-based screening Fowler 1999, Hicks 1993 15 Cumulative Incidence • Symptomatic Group: Most occur by age 2y • Asymptomatic Group: Most occur by age 6y Fowler 1999 16 CMV and the Vestibular System • Vestibular abnormalities in 6/11 • Hypofunction/arreflexia • Unilateral/bilateral • May be independent of SNHL • 3 cases ‘Delayed endolymphatic hydrops’ • Motor delay Pappas 1983 Huygen 1996 17 Management • Risk of late-onset SNHL and of progression • Unilaterals: Risk to other ear • Regular review till age 6y • Early ref for CI • Vision CMV Association: • Motor delay http://mysite.freeserve.com/CMVsupport • Precautions congenitalcmv.association@ntlworld.com 18 Primary Prevention of CMV-related SNHL • • • • Vaccines are currently in trial… Women of child bearing age Adolescents Patients awaiting solid organ transplantation 19 Secondary Prevention of CMV-Related SNHL • • • • Antenatal screening Prenatal diagnosis Counselling Intravenous CMV hyperimmune globulin? • Antiviral Rx in pregnancy? 20 Treatment of Congenital CMV to prevent SNHL • Ganciclovir preserves hearing in symptomatic neonates with CNS involvement Kimberlin 2003 • Offered to neonates with symptomatic congenital CMV with CNS involvement Ganciclovir is IV 21 Problems with Ganciclovir • IV (via longline) • Neutropenia • Limited period of treatment • Long term safety (and efficacy)? Valganciclovir is oral 22 National Study of Symptomatic Congenital CMV (BPSU) • • • • Incidence/disease burden/treatment Feb 2001-March 2003 54 confirmed and 26 possible cases In 11/51 cases maternal infection diagnosed prenatally – U/S or flu illness • 50% had CNS signs – 8 given GCV • 5 infants died 23 CMV in Hearing Impaired Children (CHIC) Study • What is the relationship between the CMV viral load on DBS and hearing thresholds? 140 120 100 Average 80 hearing thresholds 60 dBHL 40 20 0 0 10000 20000 30000 40000 50000 60000 ? Copies of CMV DNA/semicircle 24 Future studies • MRCT of Valganciclovir (Outcome: hearing) • Pilot screen +/- NHSP • Pathogenesis • Predictive factors • Site of lesion testing • CAPD • Role of OAEs • CMV and the Vestibular System Valganciclovir 25 Neonatal Screening for Congenital CMV • Aim: to allow early identification of sequelae including SNHL • Follow up those ‘at risk’ • Early amplification, rehabilitation (and possibly treatment) • Practicalities • Cost-benefit? Barbi 2006, Nance 2006, Pass 2005 26 Summary: CMV-related SNHL… • • • • • • Accounts for 12-40% SNHL May be the only feature of cCMV Will be missed by the NHSP in 50% Often progresses Can now be diagnosed by Guthrie PCR May be prevented by antiviral therapies and/or vaccine in the future… 27 What can we do? • Consider CMV in children with unexplained SNHL (including unilateral SNHL) • Try to exclude CMV • Consider Guthrie testing when CMV urine or serology positive • Monitor any children known to have congenital CMV for SNHL till age 6y at least • Ophthalmological and Vestibular assessment • Inform families about the CMV Association Thank you very much for listening 28 Acknowledgements • • • • • • • • • • • • Dr Mike Sharland, Supervisor, and Chief Investigator Professor Paul Griffiths, Virologist RFH Dr Ewa Raglan, Supervisor Claire Atkinson, Virologist RFH Dr Philip Rice, Virologist SGH Jan Poloniecki, Statistician, SGH Dr Deirdre Lucas, Local Principal Investigator , RNTNEH Dr Tracey Davis, Local Principal Investigator, Northampton Gen Hospital Mr Kevin Gibbin, Local Principal Investigator, Queen’s Medical Centre Dr Jeff Baron and Julia Rider, Regional Infant Screening Service, ESH All participating families,Consultants, SpRs, and clinic/lab staff Keri Stephenson, Congenital CMV Association SGH=St Georges Hospital RFH=Royal Free Hospital ESH=St Helier Hospital RNTNEH=Royal National Throat Nose and Ear Hospital 29 Congenital CMV information for families • Congenital CMV Association Carmen Burton, 32 Grosvenor Street Derby DE24 8AU, Tel 01332-365-528 congenitalcmv.association@ntlworld.com http://mysite.freeserve.com/CMVsupport • http://www.astdhpphe.org/infect/cytomegalo.html 30 References Das VK. 1996 Aetiology of bilateral sensorineural hearing impairment in children: a 10 year study. Arch Dis Child. Jan;74(1):8-12 Peckham CS 1987, Stark O, Dudgeon JA, Martin JA, Hawkins G. Congenital cytomegalovirus infection: a cause of sensorineural hearing loss. Arch Dis Child. Dec;62(12):1233-7 Harris S 1984, Ahlfors K, Ivarsson S, Lernmark B, Svanberg L. Congenital cytomegalovirus infection and sensorineural hearing loss. Ear Hear. Nov-Dec;5(6):352-5 Hicks T 1993, Fowler K, Richardson M, Dahle A, Adams L, Pass R Congenital cytomegalovirus infection and neonatal auditory screening. J Pediatr. Nov;123(5):779-82. Arav-boger 2002 Pass RF Diagnosis and Management of Cytomegalovirus infection in the Newborn Paediatric annals Nov;31,11 pg719-25 31 References Griffiths PD 2005 Walter S Cytomegalovirus Curr Opin Infect Dis. Jun; 18(3): 241-5 Lee DJ 2005, Lustig L, Sampson M, Chinnici J, Niparko JK. Effects of cytomegalovirus (CMV) related deafness on pediatric cochlear implant outcomes.Otolaryngol Head Neck Surg Dec;133(6):900-5. Shibata M 1994, Takano H, Hironaka T, Hirai K. Detection of human cytomegalovirus DNA in dried newborn blood filter paper. J Virol Methods. Feb;46(2):279-85 Barbi M 2000, Binda S, Primache V, Caroppo S, Dido P, Guidotti P, Corbetta C, Melotti D. Cytomegalovirus DNA detection in Guthrie cards: a powerful tool for diagnosing congenital infection. J Clin Virol. Sep 1;17(3):159-65. Barbi M 2003, Binda S, Caroppo S, Ambrosetti U, Corbetta C, Sergi P A wider role for congenital cytomegalovirus infection in sensorineural hearing loss. Pediatr Infect Dis J. Jan;22(1):39-42. 32 References Dahle AJ (2000) Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF Longitudinal Investigation of Hearing Disorders in Children with Congenital CMV. Journal of American Audiology; 11: 283-290 Fowler KB (1997) McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr; 130(4): 624630 Fowler KB (1999) Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed? J Pediatr; 135(1): 60-64. Bradford RD (2005) Cloud G, Lakeman AD, Boppana S, Kimberlin DW,Jacobs R et al. Detection of cytomegalovirus (CMV) DNA by polymerase chain reaction is associated with hearing loss in newborns with symptomatic congenital CMV infection involving the central nervous system. J Infect Dis; 191(2): 227-233. 33 References Boppana S (2005) Congenital CMV infection: Association between virus burden in infancy and hearing loss Journal of Pediatrics June p817-823 Rivera LB (2002) Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics; 110(4): 762-767. Kimberlin DW (2003) Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr; 143(1): 1625. 34 References McCollister FP 1996, Simpson LC, Dahle AJ, Pass RF, Fowler KB, Amos CS, Boll TJ.Hearing loss and congenital symptomatic cytomegalovirus infection: a case report of multidisciplinary longitudinal assessment and intervention. J Am Acad Audiol. 1996 Apr;7(2):57-62. Barbi M 2006 Binda S, Caroppo S, Primache V Neonatal screening for congenital cytomegalovirus infection and hearing loss. J Clin Virol. Feb; 35(2): 206-9. Epub 2005 Dec 27. J Nance WE 2006 Lim BG, Dodson KM Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss. Clin Virol. Feb;35(2):221-5. Epub 2005 Dec 27. 35 Cumulative % of SNHL according to Age Age 0-1 mo 3 mo 6mo 2 yrs 3 yrs 4 yrs 6 yrs 7-15yrs Asymptomatic % 25 31 43 47 59 73 87 100 Symptomatic % 43 55 67 82 88 89 95 100 36 Dahle 2000 Degree of SNHL Asymptomatic % Symptomatic % Mild (21-45dBHL) 17 Mod (46-70dBHl) Sev (71-90dBHL) Prof (>90dBHL) 15 17 51 12 13 31 44 37 Dahle 2000 860 children with Congenital CMV Asymptomatic Total no. SNHL Unilateral Bilateral High Freq only Delayed onset Symptomatic 209 85 (40.7%) 33% 67% 12.9% 27% 33 mo (6-197) 651 48 (7.4%) 52% 48% 37.5% 37.5% Median Age of delayed 44 mo (24-182) onset Prog SNHL Fluctuating loss 54% 54% 54% 29% 38 Dahle 2000 Cochlear Implant in Congenital CMV • High risk of progression and some risk to vision • Additional difficulties • Speech and language disorders • Central auditory • Learning disorders • Developmental delay Careful counselling tailored towards the individual child. Benefit is seen in many. Lee 2005, Ramirez Inscoe 2004 39 Vision in Congenital CMV • • • • • • Symptomatic 22% mod/sev VI: Optic atrophy 37% Macular scars 13% Cortical VI 50% Strabismus 29% • • • • Asymptomatic 1% mild unilateral VI Macular scar 1.2% strabismus Coats 2000 40 Information required to find the correct Guthrie card… • • • • • • • Mother’s address at the time of birth Mother’s name All previous names for the baby DOB Birthweight Name of hospital if inpatient at Day 5-7 Signed Informed consent 41