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Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)? Karen B. Fowler, DrPH Department of Pediatrics University of Alabama at Birmingham.

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Presentation on theme: "Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)? Karen B. Fowler, DrPH Department of Pediatrics University of Alabama at Birmingham."— Presentation transcript:

1 Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)? Karen B. Fowler, DrPH Department of Pediatrics University of Alabama at Birmingham

2 Faculty 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 presentation This presentation will not include discussion of pharmaceuticals or devices that have not been approved by the FDA.

3 Brief Review of Congenital CMV Infection Congenital CMV Infection & Sensorineural Hearing Loss (SNHL) Characteristics of Populations at Increased Risk for Congenital CMV Infections NIDCD Study What should EHDI programs know about CMV?

4 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)

5 Human CMV may be transmitted through either direct or indirect person-to-person contact Sources of Virus: urinesemen tearsblood oropharyngeal secretions cervical & vaginal secretions

6 Human 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

7 Diagnosis of Congenital CMV Infection Within the first 2 weeks of life Saliva or urine Virus isolation (culture) or identification (immunofluorescence test-DEAFF) of virus Clinical evidence alone will not identify most congenital CMV infections

8 Symptoms of congenital CMV infection petechiae hyperbilirubinemia (jaundice) hepatosplenomegaly (enlarged spleen or liver) thrombocytopenia seizures intracranial calcifications microcephaly (< 5%tile)

9 90% of the infants with congenital CMV infection will have no clinical evidence (symptoms) of infection during the newborn period Only 10% of the infants with congenital CMV infection will have clinical evidence or symptoms of infection during the newborn period

10 The 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.

11 Sequelae of congenital CMV infection Sensorineural hearing loss19% Mental retardation (IQ < 70)19% Retinitis 6% Cerebral Palsy 4% Neurologic problems/Seizures 6% Based on UAB data

12 CMV is a common virus although not easily spread person to person Diagnosis needs to be made in the first 2 weeks of life Clinical observation of infection in the newborn period identifies < 5% of all infants with congenital CMV infection Long term sequelae may occur following infection with sensorineural hearing loss being the most common Summary Review of Congenital CMV infection

13 Characteristics of Populations at Increased Risk for Congenital CMV Infections

14 Congenital 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%.

15 The incidence of congenital CMV infection varies: by geography the underlying CMV seroprevalence in the maternal population The incidence of congenital CMV infection is higher in populations where the underlying CMV seroprevalence or pre- existing immunity is higher in the mothers.

16 Rate of Congenital CMV Infection (%) Maternal Seroprevalence (%)

17 Similar maternal and socio-demographic factors have been associated with delivering an infant with congenital CMV infection in studies of different populations

18 Population & DateNRisk Factors Hamilton, Canada, ,212Young maternal age No previous pregnancies < 12 years education Unmarried London, England, 19868,026Young maternal age Black race Unmarried Birmingham, AL, ,045Young maternal age Black race Lower SES Iowa City, IA, 19947,229Young maternal age Unmarried San Luis Potosi, Mexico, Young maternal age No previous pregnancies Residence in rural area

19 Rates of Congenital CMV Infection

20 Population & YearNCongenital CMV Infection (%) England, 19786, Denmark, 19793, Canada, Ontario, , England, , Sweden, , USA, Texas, 19883, USA, Alabama, , USA, Iowa, 19947, Italy, 19971, Italy, 19981, Caucasian (origin in any of the original people of Europe, the Middle East or North Africa)

21 Population & YearNCongenital CMV Infection (%) USA, Texas, Chile, Chile, Brazil, Mexico, Central/South America (Hispanic-Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race)

22 Population & YearNCongenital CMV Infection (%) Ivory Coast, 19782, USA, Texas, Gambia, USA, Alabama, , USA, Alabama, 2000*18, African or African American (origins in any of the black racial groups of Africa) *Fowler, unpublished data

23 Population & YearNCongenital CMV Infection (%) Japan, 19832, Japan, 19901, Korea, Taiwan, 19961, India, 2003* Asian (origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent) *S Broor, personal communication

24 Racial Category*NCongenital CMV Infection % (95% CI) Caucasian81, (0.4 – 0.5) Hispanic2, (1.1 – 2.2) African/African American35, (1.3 – 1.5) Asian5, (0.6 – 1.1) *Fowler, meta analysis, unpublished Incidence of Congenital CMV Infection by Racial/Ethnic Categories

25 Prevalence of Congenital CMV Infection by Maternal Age for Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892) Fowler, et. al. JID1993 & Fowler, et. al. submitted Maternal Age at Delivery Per 1000 births

26 Prevalence of Congenital CMV Infection Teen Mothers Screened at UAB Hospital, Maternal Age at Delivery Per 1000 births Fowler, unpublished data African American Caucasian

27 Congenital CMV infection will be more common in populations with high (> 70%) maternal CMV seroprevalances African Americans and Hispanic delivery populations will have higher rates of congenital CMV infection than primarily Caucasian and Asian delivery populations Delivery populations with large numbers of teens will have the highest rates of congenital CMV infection Summary Review of Congenital CMV Infection Rates

28 Congenital CMV Infection & Sensorineural Hearing Loss (SNHL)

29 CMV Infection & Hearing Loss 1960s-CID or Symptomatic CMV Infection & HL was first reported. Medearis, 1964 McCracken, et al s-Inapparent or Asymptomatic CMV Infection & HL was first reported Reynolds, et al & Dahle, et al Hanshaw, et al Stagno, et al. 1977

30 CMV Infection & Hearing Loss 1970s & 1980s-Progression and Delayed Onset Hearing Loss were first described Dahle, et al Pass, et al Williamson, et al. 1982

31 Population Based Longitudinal Studies Hamilton, Canada3 Sx 1 (33) NY N Saigal, et. al ASx 6 (16) Malmö, Sweden9 Sx 2 (22) NN N Ahlfors, et. al ASx 2 (6) London, England3 Sx 1 (33) YN N Preece, et. al ASx 4 (8) Symptoms N SNHL N (%) Progressive Loss Delayed Onset Loss Fluctuating Loss

32 Population Based Longitudinal Studies Cleveland, US 17 ASx 4 (23) NN Y Kumar, et. al Houston, US 17 Sx 11 (65) YN Y Williamson, et al ASx 9 (15) Williamson, et al Birmingham, US 209 Sx 85 (41) YY Y Dahle, et al ASx 48 (7) Sapporo, Japan 17 ASx 2 (12) NN Y Numazaki, et al Symptoms N SNHL N (%) Progressive Loss Delayed Onset Loss Fluctuating Loss

33 Summarizing from these studies: 22 – 65% Symptomatic children will have hearing loss 6-23% Asymptomatic children will have hearing loss Sensorineural hearing loss following congenital CMV infection may be present at birth or delayed Progression (audiometric threshold > 10 dB deterioration) and fluctuation of hearing loss may occur in children with SNHL due to congenital CMV infection

34 In the 1990s & 2000s, multiple studies have further characterized HL due to congenital CMV infection UAB Cohort-the largest cohort to date Characteristics of CMV related HL

35 UAB Longitudinal Study of HL Total Number of Children SNHL48 (7.4%)85 (40.7%) Unilateral25 (52.1%)28 (32.9%) Bilateral23 (47.9%)57 (67.1%) High-Frequency Only18 (37.5%)11 (12.9%) ( Hz) AsymptomaticSymptomatic Dahle, et. al., 2000

36 UAB Longitudinal Study of HL Total Number of Children Degree of Loss % % Mild (21-45 dB HL) Moderate (46-70 dB HL) Severe (71-90 dB HL) Profound (> 90 dB HL) AsymptomaticSymptomatic Dahle, et. al., 2000

37 UAB Longitudinal Study of HL Total Number of Children Delayed Onset Loss18 (37.5%)23 (27.1%) Median age (range) of Delayed Onset44 mo (24-182)33 mo (6-197) AsymptomaticSymptomatic Dahle, et. al., 2000

38 UAB Longitudinal Study of HL Total Number of Children Progressive Loss26 (54.2%)46 (54.1%) Median age (range) of First Progression51 mo (3-186)26 mo (2-209) Fluctuating Loss26 (54.1%)25 (29.4%) Improvement of Loss23 (47.9%)18 (21.2%) AsymptomaticSymptomatic Dahle, et. al., 2000

39 Timing of HL due to CMV

40 Cumulative incidence of SNHL in 388 children with congenital CMV infection < 1 month 5.2%3.9% 3 months 6.5%5.3% 12 months 8.4%6.8% 24 months 9.9%7.2% 36 months10.8%7.6% 60 months12.4%7.6% 72 months15.4%8.3% Age of ChildSNHL > 20 dBSNHL > 30 dB Fowler, et. al., 1999

41 Cumulative incidence of SNHL in 388 children with congenital CMV infection < 1 month16.5%2.9% 3 months22.8%4.0% 72 months36.4%11.3% Age of Child Symptomatic n=53 Asymptomatic n=335 Fowler, et. al., 1999

42 Possible Other factor Contributing to HL due to CMV Rivera, et al Disseminated infection at birth with or without CNS involvement is associated with HL in symptomatic infants Maternal and perinatal factors do not predict hearing loss in children with asymptomatic congenital CMV infection Fowler, unpublished data

43 Possible Other factor Contributing to HL due to CMV Boppana, et al 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 SNHL

44 Viral Burden in Infancy & HL in Asymptomatic Infants Mean duration of follow-up, mos 39.3 ± ± 17.6 Median number of hearing evals 7 (2-14) 6 (2-13) Mean amount of CMV in urine 1.6 x 10 5 ± 2.1 x x 10 4 ± 7.8 x 10 4 (pfu/ml ± SD)* Mean PB blood virus burden 8.7 x 10 5 ± 1.6 x x 10 4 ± 1.5 x 10 4 (ge/ml ± SD)* Hearing Loss N=4 Normal Hearing N=54 Boppana, et al *p < 0.05

45 Impact of Universal Newborn Screening on the Detection of HL due to CMV

46 Risk criteria based neonatal auditory screening was not successful in identifying HL due to congenital CMV infection Only 17.6% of children with SNHL due to congenital CMV infection were identified by risk criteria based neonatal auditory screening at UAB between

47 SNHL in infants with congenital CMV infection according to results of risk criteria based neonatal auditory screening, Audiology Newborn HearingN Follow-up SNHL Failed (53.3) Inconclusive (33.3) Passed (8.0) Not Tested (13.2) Hicks, et al., 1993 Fowler, unpublished data

48 SNHL in infants with congenital CMV infection since universal newborn hearing screening, Audiology Newborn HearingN Follow-up SNHL Failed (37.5) Passed (11.8) Not Tested (11.9) Fowler, unpublished data

49 Overall, 3/12 (25%) of the children with SNHL due to congenital CMV infection were identified in the newborn period by universal screening 3/5 not tested had documented delayed onset loss 7/12 (58%) of children with SNHL had delayed onset loss 3/5 (60%) of children with SNHL at birth were identified by universal screening

50 ~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 Summary Review of SNHL due to CMV

51 Although 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?

52 Only one report from Sweden has estimated the relative contribution of congenital CMV infection to bilateral profound SNHL in a newborn population 10/12,000 (0.08%) children with profound HL, 4 were due to congenital CMV infection, 4 due to hereditary or syndromic causes & 2 with uncertain/unknown etiology Harris et al. 1984

53 Other 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)

54 What is the contribution of CMV in Newborn & Early Childhood Hearing Loss?

55 NIH/NIDCD Contract The Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as Adjunct to Hearing in the Newborn

56 Define the long-term audiologic/otologic outcome in children with congenital CMV infection Determine the clinical validity and utility of CMV screening: in the detection of hearing impairment in the newborn in the prediction of hearing impairment with onset during infancy or in the early years of life Objectives

57 Screen at least 100,000 newborns for CMV infection who currently undergo newborn hearing screening Audiometric follow-up of all CMV positive infants Compare the accuracy of two diagnostic methods for CMV screening Project Design

58 Evaluate Real-Time PCR/Dried Blood Spots Compare rapid saliva cell culture method Develop alternative methods if necessary Long term storage/repository of DBS Assay Development & Validation

59 University Hospital & Cooper Green Hospital Birmingham, AL University of Mississippi Medical Center Jackson, MS Carolinas Medical Center Charlotte, NC Saint Peters University Hospital New Brunswick, NJ Good Samaritan Hospital Cincinnati, OH Magee Womens Hospital Pittsburgh, PA Parkland Memorial Hospital Dallas, TX Selected Hospital Populations

60 38% Caucasian, Non Hispanic 29% African American 33% Caucasian, Hispanic Selected Hospital Populations

61 What should EHDI programs know about CMV?

62 CMV 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.

63 CMV is often overlooked as a significant factor in childhood hearing impairment Systematic review of the literature for the etiology of bilateral SNHL in children 43 studies were included: 37 retrospective studies 3 prospective studies 3 population studies 7 studies (1 prospective, 6 retrospective) had a start date after 1990 Morzaria, et al. 2004

64 CMV 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% Unknown 29.2% Genetic non-syndromic 12% 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 syndromes Morzaria, et al. 2004

65 CMV 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

66 < 5% of infected newborns have clinically recognized disease at birth After the newborn period, congenital CMV infection cannot be reliably determined Variation of onset and progression of hearing loss following congenital CMV infection CMV is often overlooked as a significant factor in childhood hearing impairment

67 32,000 (0.8%) infants are born each year in the US with congenital CMV infection 3.9% will have HL at birth Assume universal hearing screening 1,248 children with congenital CMV infection & HL will be identified before hospital discharge 0.31 per 1000 children 1,408 children with congenital CMV infection born each year will develop hearing loss later 0.35 per 1000 children

68 3 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 CMV 1,408 children with congenital CMV infection born each year will develop hearing loss later


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