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Should EHDI Programs Be Concerned about Cytomegalovirus
(CMV)?
Karen B. Fowler, DrPH
Department of Pediatrics
University of Alabama at Birmingham
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.
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?
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)
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
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
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
Symptoms of congenital CMV infection
petechiae
hyperbilirubinemia (jaundice)
hepatosplenomegaly (enlarged spleen or liver)
thrombocytopenia
seizures
intracranial calcifications
microcephaly (< 5%tile)
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
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.
Sequelae of congenital CMV infection
Sensorineural hearing loss 19%
Mental retardation (IQ < 70) 19%
Retinitis 6%
Cerebral Palsy 4%
Neurologic problems/Seizures 6%
Based on UAB data
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
Characteristics of Populations at Increased Risk for Congenital CMV Infections
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%.
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.
0102030405060708090
100
0.24 0.4 0.6 1.2 1.4 1.7 2 2.1 2.2
Rate of Congenital CMV Infection (%)
Mat
erna
l Ser
opre
vale
nce
(%)
Similar maternal and socio-demographic factors have been associated with delivering an infant with congenital CMV infection in studies of different populations
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 Young maternal age
Black race
Unmarried
Birmingham, AL, 1993 27,045 Young maternal age
Black race
Lower SES
Iowa City, IA, 1994 7,229 Young maternal age
Unmarried
San Luis Potosi, Mexico, 2003 599 Young maternal age
No previous pregnancies
Residence in rural area
Rates of Congenital CMV Infection
Population & Year N Congenital CMV Infection (%)
England, 1978 6,051 0.2
Denmark, 1979 3,060 0.4
Canada, Ontario, 1980 15,212 0.4
England, 1983 14,200 0.3
Sweden, 1985 16,474 0.5
USA, Texas, 1988 3,899 0.4
USA, Alabama, 1993 13,061 0.6
USA, Iowa, 1994 7,229 0.5
Italy, 1997 1,045 0.6
Italy, 1998 1,268 0.5
Caucasian (origin in any of the original people of Europe, the Middle East or North Africa)
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
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 (%)
Ivory Coast, 1978 2,032 1.4
USA, Texas, 1980 337 0.9
Gambia, 1991 178 14.0
USA, Alabama, 1993 13,978 1.4
USA, Alabama, 2000* 18,996 1.3
African or African American (origins in any of the black racial groups of Africa)
*Fowler, unpublished data
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
Asian (origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent)
*S Broor, personal communication
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
Incidence of Congenital CMV Infection
by Racial/Ethnic Categories
Prevalence of Congenital CMV Infection by Maternal Age for Newborns Screened at UAB
Hospital (n=46,095) & a Private Hospital (n=9,892)
0
5
10
15
20
25
< 20 years 20-24 years 25-29 years > 29 years
UABPrivate
Fowler, et. al. JID1993 & Fowler, et. al. submitted
Maternal Age at Delivery
Per
100
0 bi
rths
Prevalence of Congenital CMV Infection Teen Mothers
Screened at UAB Hospital, 1980 - 2000
05
10152025303540
< 16 years 16-17 years 18-19 years > 29 years
Maternal Age at Delivery
Per
100
0 bi
rths
Fowler, unpublished data
African American
Caucasian
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
Congenital CMV Infection & Sensorineural Hearing Loss (SNHL)
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. 1974 & Dahle, et al. 1974Hanshaw, et al. 1976Stagno, et al. 1977
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
Population Based Longitudinal Studies
Hamilton, Canada 3 Sx 1 (33) N Y NSaigal, et. al. 1982 38 ASx 6 (16)
Malmö, Sweden 9 Sx 2 (22) N N NAhlfors, et. al. 1984 34 ASx 2 (6)
London, England 3 Sx 1 (33) Y N NPreece, et. al. 1984 47 ASx 4 (8)
Symptoms
N
SNHL
N (%)
Progressive Loss
Delayed Onset
Loss
Fluctuating
Loss
Population Based Longitudinal Studies
Cleveland, US 17 ASx 4 (23) N N YKumar, et. al. 1984
Houston, US 17 Sx 11 (65) Y N YWilliamson, et al. 1982 59 ASx 9 (15)Williamson, et al. 1992
Birmingham, US 209 Sx 85 (41) Y Y Y Dahle, et al. 2000 651 ASx 48 (7)
Sapporo, Japan 17 ASx 2 (12) N N Y Numazaki, et al. 2004
Symptoms
N
SNHL
N (%)
Progressive Loss
Delayed Onset
Loss
Fluctuating
Loss
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
In the 1990s & 2000s, multiple studies have further characterized HL due to congenital CMV infection
UAB Cohort-the largest cohort to dateCharacteristics of CMV related HL
UAB Longitudinal Study of HL
Total Number of Children 651 209
SNHL 48 (7.4%) 85 (40.7%)
Unilateral 25 (52.1%) 28 (32.9%)
Bilateral 23 (47.9%) 57 (67.1%)
High-Frequency Only 18 (37.5%) 11 (12.9%)(4000-8000 Hz)
Asymptomatic Symptomatic
Dahle, et. al., 2000
UAB Longitudinal Study of HL
Total Number of Children 651 209
Degree of Loss % %
Mild (21-45 dB HL) 17.0 11.8
Moderate (46-70 dB HL) 14.9 13.4
Severe (71-90 dB HL) 17.0 30.7
Profound (> 90 dB HL) 51.1 44.1
Asymptomatic Symptomatic
Dahle, et. al., 2000
UAB Longitudinal Study of HL
Total Number of Children 651 209
Delayed Onset Loss 18 (37.5%) 23 (27.1%)
Median age (range) of Delayed Onset 44 mo (24-182) 33 mo (6-197)
Asymptomatic Symptomatic
Dahle, et. al., 2000
UAB Longitudinal Study of HL
Total Number of Children 651 209
Progressive Loss 26 (54.2%) 46 (54.1%)
Median age (range) of First Progression 51 mo (3-186) 26 mo (2-209)
Fluctuating Loss 26 (54.1%) 25 (29.4%)
Improvement of Loss 23 (47.9%) 18 (21.2%)
Asymptomatic Symptomatic
Dahle, et. al., 2000
Timing of HL due to CMV
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 months 10.8% 7.6%
60 months 12.4% 7.6%
72 months 15.4% 8.3%
Age of Child SNHL > 20 dB SNHL > 30 dB
Fowler, et. al., 1999
Cumulative incidence of SNHL in 388 children with congenital CMV infection
< 1 month 16.5% 2.9%
3 months 22.8% 4.0%
72 months 36.4% 11.3%
Age of ChildSymptomatic
n=53
Asymptomatic
n=335
Fowler, et. al., 1999
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
Possible Other factor Contributing to HL due to CMV
Boppana, et al. 2005
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
Viral Burden in Infancy & HL in Asymptomatic Infants
Mean duration of follow-up, mos 39.3 ± 23.9 33.5 ± 17.6
Median number of hearing evals 7 (2-14) 6 (2-13)
Mean amount of CMV in urine 1.6 x 105 ± 2.1 x 105 2.9 x 104 ± 7.8 x 104
(pfu/ml ± SD)*
Mean PB blood virus burden 8.7 x 105 ± 1.6 x 106 1.1 x 104 ± 1.5 x 104
(ge/ml ± SD)*
Hearing Loss
N=4
Normal Hearing
N=54
Boppana, et al. 2005
*p < 0.05
Impact of Universal Newborn Screening on the Detection of HL due to CMV
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 1985-1998
SNHL in infants with congenital CMV infection according to results of risk criteria based neonatal
auditory screening, 1985-1998
Audiology
Newborn Hearing N Follow-up SNHL
Failed 15 15 8 (53.3)
Inconclusive 3 3 1 (33.3)
Passed 55 50 4 (8.0)
Not Tested 321 287 38 (13.2)Hicks, et al., 1993Fowler, unpublished data
SNHL in infants with congenital CMV infection since universal newborn hearing screening, 1998-2002
Audiology
Newborn Hearing N Follow-up SNHL
Failed 8 8 3 (37.5)
Passed 34 32 4 (11.8)
Not Tested 42 42 5 (11.9)
Fowler, unpublished data
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% 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
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?
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
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)
What is the contribution of CMV in Newborn & Early Childhood Hearing Loss?
NIH/NIDCD Contract
The Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as
Adjunct to Hearing in the Newborn
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
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
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
University Hospital & Cooper Green HospitalBirmingham, AL
University of Mississippi Medical CenterJackson, MS
Carolinas Medical CenterCharlotte, NC
Saint Peters University HospitalNew Brunswick, NJ
Good Samaritan HospitalCincinnati, OH
Magee Women’s HospitalPittsburgh, PA
Parkland Memorial HospitalDallas, TX
Selected Hospital Populations
38% Caucasian, Non Hispanic
29% African American
33% Caucasian, Hispanic
Selected Hospital Populations
What should EHDI programs know about CMV?
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.
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
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
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
< 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
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
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