Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)?

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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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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.

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• 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?

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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

• 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

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Symptoms of congenital CMV infection petechiae
hyperbilirubinemia (jaundice) hepatosplenomegaly
(enlarged spleen or liver) thrombocytopenia seizur
es intracranial calcifications microcephaly (lt
5tile)
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, lt 5 of infants with CMV
infection are identified.
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Sequelae of congenital CMV infection Sensorineura
l hearing loss 19 Mental retardation (IQ lt
70) 19 Retinitis 6 Cerebral Palsy
4 Neurologic problems/Seizures 6
Based on UAB data
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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 lt 5 of all infants with
  congenital CMV infection
• Long term sequelae may occur following infection
  with sensorineural hearing loss being the most
  common

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Characteristics of Populations at Increased Risk
for Congenital CMV Infections
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• 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.

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• 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.

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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 N Risk Factors
Hamilton, Canada, 1980 Hamilton, Canada, 1980 15,212 Young maternal age No previous pregnancies lt 12 years education Unmarried
London, England, 1986 London, England, 1986 8,026 Young maternal age Black race Unmarried
Birmingham, AL, 1993 Birmingham, AL, 1993 27,045 Young maternal age Black race Lower SES
Iowa City, IA, 1994 Iowa City, IA, 1994 7,229 Young maternal age Unmarried
San Luis Potosi, Mexico, 2003 San Luis Potosi, Mexico, 2003 599 Young maternal age No previous pregnancies Residence in rural area
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Rates of Congenital CMV Infection
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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 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
21
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
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 1.4
USA, Alabama, 2000 18,996 1.3
Fowler, unpublished data
23
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
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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
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Prevalence of Congenital CMV Infection by
Maternal Age for Newborns Screened at UAB
Hospital (n46,095) a Private Hospital (n9,892)
Per 1000 births
Maternal Age at Delivery
Fowler, et. al. JID1993 Fowler, et. al.
submitted
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Prevalence of Congenital CMV Infection Teen
MothersScreened at UAB Hospital, 1980 - 2000
African American
Caucasian
Per 1000 births
Maternal Age at Delivery
Fowler, unpublished data
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Summary Review of Congenital CMV Infection Rates

• Congenital CMV infection will be more common in
  populations with high (gt 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

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Congenital CMV Infection Sensorineural Hearing
Loss (SNHL)
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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. 1974 Hanshaw, et al. 1976 Stagno,
et al. 1977
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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
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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. 1982 38 ASx
6 (16) Malmö, Sweden 9 Sx 2 (22)
N N N Ahlfors, et. al. 1984 34 ASx
2 (6) London, England 3 Sx 1 (33)
Y N N Preece, et. al. 1984 47
ASx 4 (8)
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Population Based Longitudinal Studies
Delayed Onset Loss
Symptoms N
SNHL N ()
Progressive Loss
Fluctuating Loss
Cleveland, US 17 ASx 4 (23)
N N Y Kumar, et. al. 1984 Houston, US
17 Sx 11 (65) Y N
Y Williamson, 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
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• 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 gt 10 dB
  deterioration) and fluctuation of hearing loss
  may occur in children with SNHL due to congenital
  CMV infection

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• 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

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UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
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)
Dahle, et. al., 2000
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UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
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 (gt
90 dB HL) 51.1 44.1
Dahle, et. al., 2000
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UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
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)
Dahle, et. al., 2000
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UAB Longitudinal Study of HL
Asymptomatic
Symptomatic
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)
Dahle, et. al., 2000
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Timing of HL due to CMV
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Cumulative incidence of SNHL in 388 children
with congenital CMV infection
Age of Child
SNHL gt 20 dB
SNHL gt 30 dB
lt 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
Fowler, et. al., 1999
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Cumulative incidence of SNHL in 388 children
with congenital CMV infection
Symptomatic n53
Asymptomatic n335
Age of Child
lt 1 month 16.5 2.9 3 months 22.8 4.0 7
2 months 36.4 11.3
Fowler, et. al., 1999
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Possible Other factor Contributing to HL due to
CMV
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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
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Viral Burden in Infancy HL in Asymptomatic
Infants
Hearing Loss N4
Normal Hearing N54
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)
p lt 0.05
Boppana, et al. 2005
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Impact of Universal Newborn Screening on the
Detection of HL due to CMV
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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
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SNHL in infants with congenital CMV infection
according to results of risk criteria based
neonatal auditory screening, 1985-1998 Audiol
ogy 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., 1993 Fowler, unpublished data
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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
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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
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

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• 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?

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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
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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)
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What is the contribution of CMV in Newborn
Early Childhood Hearing Loss?
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NIH/NIDCD Contract The Natural History of
CMV-Related Hearing Loss and the Feasibility of
CMV Screening as Adjunct to Hearing in the Newborn
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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

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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
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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

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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 Womens
Hospital Pittsburgh, PA Parkland Memorial
Hospital Dallas, TX
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Selected Hospital Populations
38 Caucasian, Non Hispanic 29 African
American 33 Caucasian, Hispanic
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What should EHDI programs know about CMV?
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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

• lt 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

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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
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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