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
Characteristics of Populations at Increased Risk for Congenital CMV Infections
Congenital CMV Infection & Sensorineural Hearing Loss (SNHL)
NIDCD Study
What 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)

5. Human CMV may be transmitted through either direct or indirect person-to-person contact
Sources of Virus:
urine semen
tears blood
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
Clinical evidence alone will not identify most congenital CMV infections
Diagnosis of Congenital CMV Infection
Saliva or urine
Within the first 2 weeks of life
Virus isolation (culture) or identification (immunofluorescence test-DEAFF) of virus

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 loss 19%
Mental retardation (IQ < 70) 19%
Retinitis %
Cerebral Palsy %
Neurologic problems/Seizures 6%
Based on UAB data

12. Review of Congenital CMV infection
Summary
Review of Congenital CMV infection
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

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

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 & Date N
Risk Factors
Hamilton, Canada, 1980
15,212
Young maternal age
No previous pregnancies
< 12 years education
Unmarried
London, England, 1986
8,026
Black race
Birmingham, AL, 1993
27,045
Lower SES
Iowa City, IA, 1994
7,229
San Luis Potosi, Mexico, 2003
599
Residence in rural area

19. Rates of Congenital CMV Infection

20. Congenital CMV Infection (%)
Caucasian (origin in any of the original people of Europe, the Middle East or North Africa)
Population & Year N
Congenital CMV Infection (%)
England, 1978
6,051
0.2
Denmark, 1979
3,060
0.4
Canada, Ontario, 1980
15,212
England, 1983
14,200
0.3
Sweden, 1985
16,474
0.5
USA, Texas, 1988
3,899
USA, Alabama, 1993
13,061
0.6
USA, Iowa, 1994
7,229
Italy, 1997
1,045
Italy, 1998
1,268

21. Congenital CMV Infection (%)
Central/South America (Hispanic-Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race)
Population & Year N
Congenital CMV Infection (%)
USA, Texas, 1980
132
1.5
Chile, 1982
197
1.7
Chile, 1996
689
1.8
Brazil, 2001
452
2.0
Mexico, 2003
599
0.9

22. Congenital CMV Infection (%)
African or African American (origins in any of the black racial groups of Africa)
Population & Year N
Congenital CMV Infection (%)
Ivory Coast, 1978
2,032
1.4
USA, Texas, 1980
337
0.9
Gambia, 1991
178
14.0
USA, Alabama, 1993
13,978
USA, Alabama, 2000*
18,996
1.3
*Fowler, unpublished data

23. Congenital CMV Infection (%)
Asian (origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent)
Population & Year N
Congenital CMV Infection (%)
Japan, 1983
2,070
0.5
Japan, 1990
1,824
0.4
Korea, 1992
514
1.2
Taiwan, 1996
1,000
1.8
India, 2003*
500
1.4
*S Broor, personal communication

24. Incidence of Congenital CMV Infection by Racial/Ethnic Categories
Racial Category* N
Congenital CMV Infection
% (95% CI)
Caucasian
81,499
0.4 (0.4 – 0.5)
Hispanic
2,069
1.5 (1.1 – 2.2)
African/African American
35,521
1.4 (1.3 – 1.5)
Asian
5,908
0.8 (0.6 – 1.1)
*Fowler, meta analysis, unpublished

25. Maternal 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 births
Maternal Age at Delivery
Fowler, et. al. JID1993 & Fowler, et. al. submitted

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

27. Review of Congenital CMV Infection Rates
Summary
Review of Congenital CMV Infection Rates
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

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. 1969
1970s-Inapparent or Asymptomatic CMV Infection & HL was first reported
Reynolds, et al & Dahle, et al. 1974
Hanshaw, et al. 1976
Stagno, et al. 1977

30. CMV Infection & Hearing Loss
1970s & 1980s-Progression and Delayed Onset Hearing Loss were first described
Dahle, et al. 1979
Pass, et al. 1980
Williamson, et al. 1982

31. Population Based Longitudinal Studies
Delayed Onset
Loss
Symptoms N
SNHL
N (%)
Progressive Loss
Fluctuating
Loss
Hamilton, Canada 3 Sx 1 (33) N Y N
Saigal, et. al ASx (16)
Malmö, Sweden 9 Sx 2 (22) N N N
Ahlfors, et. al ASx (6)
London, England 3 Sx 1 (33) Y N N
Preece, et. al ASx (8)

32. Population Based Longitudinal Studies
Delayed Onset
Loss
Symptoms N
SNHL
N (%)
Progressive Loss
Fluctuating
Loss
Cleveland, US ASx 4 (23) N N Y
Kumar, et. al. 1984
Houston, US Sx (65) Y N Y
Williamson, et al ASx (15)
Williamson, et al. 1992
Birmingham, US Sx (41) Y Y Y
Dahle, et al ASx (7)
Sapporo, Japan ASx (12) N N Y
Numazaki, et al. 2004

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. UAB Cohort-the largest cohort to date
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
Asymptomatic
Symptomatic
Total Number of Children
SNHL (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

36. UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
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)
Dahle, et. al., 2000

37. UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
Total Number of Children
Delayed 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

38. UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
Total Number of Children
Progressive 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

39. Timing of HL due to CMV

40. Cumulative incidence of SNHL in 388 children with congenital CMV infection
Age of Child
SNHL > 20 dB
SNHL > 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

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

42. Possible Other factor Contributing to HL due to CMV
Rivera, et al. 2002
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
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
Boppana, et al. 2005

44. Viral Burden in Infancy & HL in Asymptomatic Infants
Hearing Loss
N=4
Normal Hearing
N=54
Mean duration of follow-up, mos ± ± 17.6
Median 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 < 0.05
Boppana, et al. 2005

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

48. Newborn Hearing N Follow-up SNHL
SNHL in infants with congenital CMV infection since universal newborn hearing screening,
Audiology
Newborn Hearing N 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. Review of SNHL due to CMV
Summary
Review 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

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. 10/12,000 (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 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. Objectives
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

57. Project Design
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

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

59. Selected Hospital Populations
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 Women’s Hospital
Pittsburgh, PA
Parkland Memorial Hospital
Dallas, TX

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

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. CMV is often overlooked as a significant factor in childhood hearing impairment
< 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

67. Assume universal hearing screening
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