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

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)


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)


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


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



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





Delayed Onset Loss 18 (37.5%) 23 (27.1%)

Median age (range) of Delayed Onset 44 mo (24-182) 33 mo (6-197)





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%)



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


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)


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.


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


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



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.


< 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


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

Documents

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