Presentation on theme: "Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)?"— Presentation transcript:
1Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)? Karen B. Fowler, DrPHDepartment of PediatricsUniversity of Alabama at Birmingham
2Faculty Disclosure Information In the last 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentationThis presentation will not include discussion of pharmaceuticals or devices that have not been approved by the FDA.
3Brief Review of Congenital CMV Infection Characteristics of Populations at Increased Risk for Congenital CMV InfectionsCongenital CMV Infection & Sensorineural Hearing Loss (SNHL)NIDCD StudyWhat should EHDI programs know about CMV?
4(Congenital CMV Infection) Cytomegalovirus (CMV) is a herpesvirus that may be transmitted from mother to fetus anytime during gestation and may or may not cause any apparent damage to the fetus(Congenital CMV Infection)
5Human CMV may be transmitted through either direct or indirect person-to-person contact Sources of Virus:urine sementears bloodoropharyngeal secretionscervical & vaginal secretions
6Human CMV may be transmitted through either direct or indirect person-to-person contact CMV is not very contagious and the spread of virus requires close or intimate contact with infected secretions
7Diagnosis of Congenital CMV Infection Clinical evidence alone will not identify most congenital CMV infectionsDiagnosis of Congenital CMV InfectionSaliva or urineWithin the first 2 weeks of lifeVirus isolation (culture) or identification (immunofluorescence test-DEAFF) of virus
8Symptoms of congenital CMV infection petechiaehyperbilirubinemia (jaundice)hepatosplenomegaly (enlarged spleen or liver)thrombocytopeniaseizuresintracranial calcificationsmicrocephaly (< 5%tile)
990% of the infants with congenital CMV infection will have no clinical evidence (symptoms) of infection during the newborn periodOnly 10% of the infants with congenital CMV infection will have clinical evidence or symptoms of infection during the newborn period
10The expected 10% symptomatic estimate is based on studies of infants screened for congenital CMV infection where the investigators have reviewed their medical records for specific symptoms and categorized them accordingly.However, in our data about 2/3 of infants we classified as symptomatic were not identified by the medical staff while in the hospital as having CMV infection.This suggests unless routine CMV screening takes place, < 5% of infants with CMV infection are identified.
11Sequelae of congenital CMV infection Sensorineural hearing loss 19%Mental retardation (IQ < 70) 19%Retinitis %Cerebral Palsy %Neurologic problems/Seizures 6%Based on UAB data
12Review of Congenital CMV infection SummaryReview of Congenital CMV infectionCMV is a common virus although not easily spread person to personDiagnosis needs to be made in the first 2 weeks of lifeClinical observation of infection in the newborn period identifies < 5% of all infants with congenital CMV infectionLong term sequelae may occur following infection with sensorineural hearing loss being the most common
13Characteristics of Populations at Increased Risk for Congenital CMV Infections
14Congenital CMV Infection is the most common intrauterine infection in humans Incidence estimates of congenital CMV infection range from 0.2% – 2.2%.US estimates of congenital CMV infection range from 0.5% – 1.0%.
15The incidence of congenital CMV infection varies: by geographythe underlying CMV seroprevalence in the maternal populationThe incidence of congenital CMV infection is higher in populations where the underlying CMV seroprevalence or pre-existing immunity is higher in the mothers.
16Maternal Seroprevalence (%) Rate of Congenital CMV Infection (%)
17Similar maternal and socio-demographic factors have been associated with delivering an infant with congenital CMV infection in studies of different populations
18Population & DateNRisk FactorsHamilton, Canada, 198015,212Young maternal ageNo previous pregnancies< 12 years educationUnmarriedLondon, England, 19868,026Black raceBirmingham, AL, 199327,045Lower SESIowa City, IA, 19947,229San Luis Potosi, Mexico, 2003599Residence in rural area
20Congenital CMV Infection (%) Caucasian (origin in any of the original people of Europe, the Middle East or North Africa)Population & YearNCongenital CMV Infection (%)England, 19786,0510.2Denmark, 19793,0600.4Canada, Ontario, 198015,212England, 198314,2000.3Sweden, 198516,4740.5USA, Texas, 19883,899USA, Alabama, 199313,0610.6USA, Iowa, 19947,229Italy, 19971,045Italy, 19981,268
21Congenital CMV Infection (%) Central/South America (Hispanic-Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race)Population & YearNCongenital CMV Infection (%)USA, Texas, 19801321.5Chile, 19821971.7Chile, 19966891.8Brazil, 20014522.0Mexico, 20035990.9
22Congenital CMV Infection (%) African or African American (origins in any of the black racial groups of Africa)Population & YearNCongenital CMV Infection (%)Ivory Coast, 19782,0321.4USA, Texas, 19803370.9Gambia, 199117814.0USA, Alabama, 199313,978USA, Alabama, 2000*18,9961.3*Fowler, unpublished data
23Congenital CMV Infection (%) Asian (origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent)Population & YearNCongenital CMV Infection (%)Japan, 19832,0700.5Japan, 19901,8240.4Korea, 19925141.2Taiwan, 19961,0001.8India, 2003*5001.4*S Broor, personal communication
24Incidence of Congenital CMV Infection by Racial/Ethnic Categories Racial Category*NCongenital CMV Infection% (95% CI)Caucasian81,4990.4 (0.4 – 0.5)Hispanic2,0691.5 (1.1 – 2.2)African/African American35,5211.4 (1.3 – 1.5)Asian5,9080.8 (0.6 – 1.1)*Fowler, meta analysis, unpublished
25Maternal Age at Delivery Prevalence of Congenital CMV Infection by Maternal Age for Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)Per 1000 birthsMaternal Age at DeliveryFowler, et. al. JID1993 & Fowler, et. al. submitted
26Maternal Age at Delivery Prevalence of Congenital CMV Infection Teen Mothers Screened at UAB Hospital,African AmericanCaucasianPer 1000 birthsMaternal Age at DeliveryFowler, unpublished data
27Review of Congenital CMV Infection Rates SummaryReview of Congenital CMV Infection RatesCongenital CMV infection will be more common in populations with high (> 70%) maternal CMV seroprevalancesAfrican Americans and Hispanic delivery populations will have higher rates of congenital CMV infection than primarily Caucasian and Asian delivery populationsDelivery populations with large numbers of teens will have the highest rates of congenital CMV infection
28Congenital CMV Infection & Sensorineural Hearing Loss (SNHL)
29CMV Infection & Hearing Loss 1960s-CID or Symptomatic CMV Infection & HL was first reported.Medearis, 1964McCracken, et al. 19691970s-Inapparent or Asymptomatic CMV Infection & HL was first reportedReynolds, et al & Dahle, et al. 1974Hanshaw, et al. 1976Stagno, et al. 1977
30CMV Infection & Hearing Loss 1970s & 1980s-Progression and Delayed Onset Hearing Loss were first describedDahle, et al. 1979Pass, et al. 1980Williamson, et al. 1982
31Population Based Longitudinal Studies Delayed OnsetLossSymptomsNSNHLN (%)Progressive LossFluctuatingLossHamilton, Canada 3 Sx 1 (33) N Y NSaigal, et. al ASx (16)Malmö, Sweden 9 Sx 2 (22) N N NAhlfors, et. al ASx (6)London, England 3 Sx 1 (33) Y N NPreece, et. al ASx (8)
32Population Based Longitudinal Studies Delayed OnsetLossSymptomsNSNHLN (%)Progressive LossFluctuatingLossCleveland, US ASx 4 (23) N N YKumar, et. al. 1984Houston, US Sx (65) Y N YWilliamson, et al ASx (15)Williamson, et al. 1992Birmingham, US Sx (41) Y Y YDahle, et al ASx (7)Sapporo, Japan ASx (12) N N YNumazaki, et al. 2004
33Summarizing from these studies: 22 – 65% Symptomatic children will have hearing loss6-23% Asymptomatic children will have hearing lossSensorineural hearing loss following congenital CMV infection may be present at birth or delayedProgression (audiometric threshold > 10 dB deterioration) and fluctuation of hearing loss may occur in children with SNHL due to congenital CMV infection
34UAB Cohort-the largest cohort to date In the 1990s & 2000s, multiple studies have further characterized HL due to congenital CMV infectionUAB Cohort-the largest cohort to dateCharacteristics of CMV related HL
35UAB Longitudinal Study of HL AsymptomaticSymptomaticTotal Number of ChildrenSNHL (7.4%) 85 (40.7%)Unilateral (52.1%) 28 (32.9%)Bilateral (47.9%) 57 (67.1%)High-Frequency Only 18 (37.5%) 11 (12.9%)( Hz)Dahle, et. al., 2000
36UAB Longitudinal Study of HL AsymptomaticSymptomaticTotal Number of ChildrenDegree of Loss % %Mild (21-45 dB HL)Moderate (46-70 dB HL)Severe (71-90 dB HL)Profound (> 90 dB HL)Dahle, et. al., 2000
37UAB Longitudinal Study of HL AsymptomaticSymptomaticTotal Number of ChildrenDelayed Onset Loss 18 (37.5%) 23 (27.1%)Median age (range) of Delayed Onset 44 mo (24-182) 33 mo (6-197)Dahle, et. al., 2000
38UAB Longitudinal Study of HL AsymptomaticSymptomaticTotal Number of ChildrenProgressive Loss (54.2%) 46 (54.1%)Median age (range) of First Progression 51 mo (3-186) 26 mo (2-209)Fluctuating Loss (54.1%) 25 (29.4%)Improvement of Loss 23 (47.9%) 18 (21.2%)Dahle, et. al., 2000
40Cumulative incidence of SNHL in 388 children with congenital CMV infection Age of ChildSNHL > 20 dBSNHL > 30 dB< 1 month % 3.9%3 months % 5.3%12 months % 6.8%24 months % 7.2%36 months % 7.6%60 months % 7.6%72 months % 8.3%Fowler, et. al., 1999
41Cumulative incidence of SNHL in 388 children with congenital CMV infection Symptomaticn=53Asymptomaticn=335Age of Child< 1 month % 2.9%3 months % 4.0%72 months % 11.3%Fowler, et. al., 1999
42Possible Other factor Contributing to HL due to CMV Rivera, et al. 2002Disseminated infection at birth with or without CNS involvement is associated with HL in symptomatic infantsMaternal and perinatal factors do not predict hearing loss in children with asymptomatic congenital CMV infectionFowler, unpublished data
43Possible Other factor Contributing to HL due to CMV Children with asymptomatic congenital CMV infection with higher amounts of infectious CMV in their urine and CMV DNA in their blood during early infancy are more likely to have SNHLBoppana, et al. 2005
44Viral Burden in Infancy & HL in Asymptomatic Infants Hearing LossN=4Normal HearingN=54Mean duration of follow-up, mos ± ± 17.6Median number of hearing evals (2-14) (2-13)Mean amount of CMV in urine x 105 ± 2.1 x x 104 ± 7.8 x 104(pfu/ml ± SD)*Mean PB blood virus burden x 105 ± 1.6 x x 104 ± 1.5 x 104(ge/ml ± SD)**p < 0.05Boppana, et al. 2005
45Impact of Universal Newborn Screening on the Detection of HL due to CMV
46Risk criteria based neonatal auditory screening was not successful in identifying HL due to congenital CMV infectionOnly 17.6% of children with SNHL due to congenital CMV infection were identified by risk criteria based neonatal auditory screening at UAB between
47Newborn Hearing N Follow-up SNHL SNHL in infants with congenital CMV infection according to results of risk criteria based neonatal auditory screening,AudiologyNewborn Hearing N Follow-up SNHLFailed (53.3)Inconclusive (33.3)Passed (8.0)Not Tested (13.2)Hicks, et al., 1993Fowler, unpublished data
48Newborn Hearing N Follow-up SNHL SNHL in infants with congenital CMV infection since universal newborn hearing screening,AudiologyNewborn Hearing N Follow-up SNHLFailed (37.5)Passed (11.8)Not Tested (11.9)Fowler, unpublished data
49Overall, 3/12 (25%) of the children with SNHL due to congenital CMV infection were identified in the newborn period by universal screening3/5 not tested had documented delayed onset loss7/12 (58%) of children with SNHL had delayed onset loss3/5 (60%) of children with SNHL at birth were identified by universal screening
50Review of SNHL due to CMV SummaryReview of SNHL due to CMV~50% of the loss is bilateral~ 65% is severe to profound loss~50% of the loss is progressive~50% to 60% is delayed onset (occurring in the first years of life)Fluctuating and high frequency loss also occur
51Although SNHL due to CMV infection has been documented since the 1960s, it has been difficult to determine the relative contribution of CMV to childhood HL.What is the contribution of CMV in Newborn & Early Childhood Hearing Loss?
5210/12,000 (0.08%) children with profound HL, Only one report from Sweden has estimated the relative contribution of congenital CMV infection to bilateral profound SNHL in a newborn population10/12,000 (0.08%) children with profound HL,4 were due to congenital CMV infection,4 due to hereditary or syndromic causes &2 with uncertain/unknown etiologyHarris et al. 1984
53Other Studies have Retrospectively Assessed the Role of CMV in Newborn Hearing Loss In London, 13.2% of the children with unknown cause of hearing loss were found to be shedding CMV. This was nearly twice the rate found in other children with HL of known causes and in children without loss. (Peckham, et al. 1987)Using data from follow-up of CMV infants, 14 cases of congenital CMV infection with hearing loss were identified out of 12,371 neonates screened for CMV for a HL rate of 1.1 per 1000 live births. (Fowler, et al., 1995)Retrospectively using dried blood spots collected at birth, this study found that 24.7% of children with SNHL, without other genetic causes, likely had hearing loss due to congenital CMV infection. (Barbi, et al. 2003)
54What is the contribution of CMV in Newborn & Early Childhood Hearing Loss?
55NIH/NIDCD ContractThe Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as Adjunct to Hearing in the Newborn
56ObjectivesDefine the long-term audiologic/otologic outcome in children with congenital CMV infectionDetermine the clinical validity and utility of CMV screening:in the detection of hearing impairment in the newbornin the prediction of hearing impairment with onset during infancy or in the early years of life
57Project DesignScreen at least 100,000 newborns for CMV infection who currently undergo newborn hearing screeningAudiometric follow-up of all CMV positive infantsCompare the accuracy of two diagnostic methods for CMV screening
58Assay Development & Validation Evaluate Real-Time PCR/Dried Blood SpotsCompare rapid saliva cell culture methodDevelop alternative methods if necessaryLong term storage/repository of DBS
59Selected Hospital Populations University Hospital & Cooper Green HospitalBirmingham, ALUniversity of Mississippi Medical CenterJackson, MSCarolinas Medical CenterCharlotte, NCSaint Peters University HospitalNew Brunswick, NJGood Samaritan HospitalCincinnati, OHMagee Women’s HospitalPittsburgh, PAParkland Memorial HospitalDallas, TX
62CMV is often overlooked as a significant factor in childhood hearing impairment WHY?First, if you go to the scientific literature on the etiology of hearing loss you rarely find any mention of congenital CMV infection.
63CMV is often overlooked as a significant factor in childhood hearing impairment Systematic review of the literature for the etiology of bilateral SNHL in children43 studies were included:37 retrospective studies3 prospective studies3 population studies7 studies (1 prospective, 6 retrospective) had a start date after 1990Morzaria, et al. 2004
64CMV is often overlooked as a significant factor in childhood hearing impairment Systematic review of the etiology of bilateral SNHL in children found the etiologies were:37.7% Unknown29.2% Genetic non-syndromic12% Prenatal Causes (rubella, CMV, measles, alcohol, drugs)9.6% Perinatal (kernicterus, asyphyxia, prematurity, NICU stay, drugs)8.2% Postnatal (meningitis, trauma, chemotherapy, ECMO, measles)3.2% Genetic syndromesMorzaria, et al. 2004
65CMV is often overlooked as a significant factor in childhood hearing impairment According to the review, CMV as an etiology occurred 0.75% in retrospective studies, and 1.6% in prospective studies, and no information for CMV was available in the population based studies.NONE of the studies, included screening of CMV infection within the newborn period to obtain a true measure of the role of CMV infection in the etiology of childhood hearing loss.Morzaria, et al. 2004
66CMV is often overlooked as a significant factor in childhood hearing impairment < 5% of infected newborns have clinically recognized disease at birthAfter the newborn period, congenital CMV infection cannot be reliably determinedVariation of onset and progression of hearing loss following congenital CMV infection
67Assume universal hearing screening 32,000 (0.8%) infants are born each year in the US with congenital CMV infection3.9% will have HL at birthAssume universal hearing screening1,248 children with congenital CMV infection & HL will be identified before hospital discharge0.31 per 1000 children1,408 children with congenital CMV infection born each year will develop hearing loss later0.35 per 1000 children
683 per 1000 children (12,000) each year in the US will have hearing loss 1,248 children with congenital CMV infection & HL will be identified as newborns~10% (1,248/12,000) will be due to CMV1,408 children with congenital CMV infection born each year will develop hearing loss later