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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.

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Should ehdi programs be concerned about cytomegalovirus cmv

Should EHDI Programs Be Concerned about Cytomegalovirus (CMV)?

Karen B. Fowler, DrPH

Department of Pediatrics

University of Alabama at Birmingham


Faculty disclosure information

Faculty Disclosure Information (CMV)?

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.


Should ehdi programs be concerned about cytomegalovirus cmv

  • 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?


Should ehdi programs be concerned about cytomegalovirus 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)


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

Symptoms of congenital CMV infection CMV infections

petechiae

hyperbilirubinemia (jaundice)

hepatosplenomegaly (enlarged spleen or liver)

thrombocytopenia

seizures

intracranial calcifications

microcephaly (< 5%tile)


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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.


Should ehdi programs be concerned about cytomegalovirus cmv

Sequelae of congenital CMV infection infants screened for congenital CMV infection where the investigators have reviewed their medical records for specific symptoms and categorized them accordingly.

Sensorineural hearing loss 19%

Mental retardation (IQ < 70) 19%

Retinitis 6%

Cerebral Palsy 4%

Neurologic problems/Seizures 6%

Based on UAB data


Should ehdi programs be concerned about cytomegalovirus cmv

Summary infants screened for congenital CMV infection where the investigators have reviewed their medical records for specific symptoms and categorized them accordingly.

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



Should ehdi programs be concerned about cytomegalovirus cmv

  • Incidence estimates of congenital CMV infection range from 0.2% – 2.2%.

  • US estimates of congenital CMV infection range from 0.5% – 1.0%.


Should ehdi programs be concerned about cytomegalovirus cmv

  • The incidence of congenital CMV infection varies: infection in humans

    • 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.


Should ehdi programs be concerned about cytomegalovirus cmv

Maternal Seroprevalence (%) infection in humans

Rate of Congenital CMV Infection (%)


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

Rates of Congenital CMV Infection associated with delivering an infant with congenital CMV infection in studies of different populations


Should ehdi programs be concerned about cytomegalovirus cmv

Caucasian associated with delivering an infant with congenital CMV infection in studies of different populations (origin in any of the original people of Europe, the Middle East or North Africa)


Should ehdi programs be concerned about cytomegalovirus cmv

Central/South America associated with delivering an infant with congenital CMV infection in studies of different populations (Hispanic-Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race)


Should ehdi programs be concerned about cytomegalovirus cmv

African or African American associated with delivering an infant with congenital CMV infection in studies of different populations (origins in any of the black racial groups of Africa)

*Fowler, unpublished data


Should ehdi programs be concerned about cytomegalovirus cmv

Asian associated with delivering an infant with congenital CMV infection in studies of different populations (origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent)

*S Broor, personal communication


Should ehdi programs be concerned about cytomegalovirus cmv

Incidence of Congenital CMV Infection associated with delivering an infant with congenital CMV infection in studies of different populations

by Racial/Ethnic Categories

*Fowler, meta analysis, unpublished


Should ehdi programs be concerned about cytomegalovirus cmv
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


Prevalence of congenital cmv infection teen mothers screened at uab hospital 1980 2000
Prevalence of Congenital CMV Infection Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892) Teen MothersScreened at UAB Hospital, 1980 - 2000

African American

Caucasian

Per 1000 births

Maternal Age at Delivery

Fowler, unpublished data


Should ehdi programs be concerned about cytomegalovirus cmv

Summary Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

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


Should ehdi programs be concerned about cytomegalovirus cmv

Congenital CMV Infection & Sensorineural Hearing Loss (SNHL) Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)


Should ehdi programs be concerned about cytomegalovirus cmv

CMV Infection & Hearing Loss Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

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


Should ehdi programs be concerned about cytomegalovirus cmv

CMV Infection & Hearing Loss Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

1970s & 1980s-Progression and Delayed Onset Hearing Loss were first described

Dahle, et al. 1979

Pass, et al. 1980

Williamson, et al. 1982


Should ehdi programs be concerned about cytomegalovirus cmv

Population Based Longitudinal Studies Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

Delayed Onset

Loss

Symptoms

N

SNHL

N (%)

Progressive Loss

Fluctuating

Loss

Hamilton, Canada 3 Sx 1 (33) N Y N

Saigal, et. al. 198238 ASx 6 (16)

Malmö, Sweden 9 Sx 2 (22) N N N

Ahlfors, et. al. 198434 ASx 2 (6)

London, England 3 Sx 1 (33) Y N N

Preece, et. al. 198447 ASx 4 (8)


Should ehdi programs be concerned about cytomegalovirus cmv

Population Based Longitudinal Studies Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

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. 2000651 ASx 48 (7)

Sapporo, Japan 17 ASx 2 (12) N N Y

Numazaki, et al. 2004


Should ehdi programs be concerned about cytomegalovirus cmv

  • Summarizing from these studies: Newborns Screened at UAB Hospital (n=46,095) & a Private Hospital (n=9,892)

  • 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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

UAB Longitudinal Study of HL characterized HL due to congenital CMV infection

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


Should ehdi programs be concerned about cytomegalovirus cmv

UAB Longitudinal Study of HL characterized HL due to congenital CMV infection

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 (> 90 dB HL) 51.1 44.1

Dahle, et. al., 2000


Should ehdi programs be concerned about cytomegalovirus cmv

UAB Longitudinal Study of HL characterized HL due to congenital CMV infection

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


Should ehdi programs be concerned about cytomegalovirus cmv

UAB Longitudinal Study of HL characterized HL due to congenital CMV infection

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


Should ehdi programs be concerned about cytomegalovirus cmv

Timing of HL due to CMV characterized HL due to congenital CMV infection


Should ehdi programs be concerned about cytomegalovirus cmv

Cumulative incidence of SNHL in 388 children with congenital CMV infection

Age of Child

SNHL > 20 dB

SNHL > 30 dB

< 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


Should ehdi programs be concerned about cytomegalovirus cmv

Cumulative incidence of SNHL in 388 children with congenital CMV infection

Symptomatic

n=53

Asymptomatic

n=335

Age of Child

< 1 month 16.5% 2.9%

3 months 22.8% 4.0%

72 months 36.4% 11.3%

Fowler, et. al., 1999


Should ehdi programs be concerned about cytomegalovirus cmv

Disseminated infection at birth with or without CNS involvement is associated with HL in symptomatic infants

Rivera, et al. 2002

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


Should ehdi programs be concerned about cytomegalovirus cmv

Possible Other factor Contributing to HL due to CMV involvement is associated with HL in symptomatic infants

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


Should ehdi programs be concerned about cytomegalovirus cmv

Viral Burden in Infancy & HL in Asymptomatic Infants involvement is associated with HL in symptomatic infants

Hearing Loss

N=4

Normal Hearing

N=54

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 < 0.05

Boppana, et al. 2005



Should ehdi programs be concerned about cytomegalovirus 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


Should ehdi programs be concerned about cytomegalovirus cmv

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., 1993

Fowler, unpublished data


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

Summary congenital CMV infection were identified in the newborn period by universal screening

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


Should ehdi programs be concerned about cytomegalovirus 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?


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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)



Should ehdi programs be concerned about cytomegalovirus cmv

NIH/NIDCD Contract Hearing Loss?

The Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as Adjunct to Hearing in the Newborn


Should ehdi programs be concerned about cytomegalovirus cmv

Objectives Hearing Loss?

  • 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


Should ehdi programs be concerned about cytomegalovirus cmv

Project Design Hearing Loss?

  • 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


Should ehdi programs be concerned about cytomegalovirus cmv

Assay Development & Validation Hearing Loss?

  • Evaluate Real-Time PCR/Dried Blood Spots

  • Compare rapid saliva cell culture method

  • Develop alternative methods if necessary

  • Long term storage/repository of DBS


Should ehdi programs be concerned about cytomegalovirus cmv

Selected Hospital Populations Hearing Loss?

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


Should ehdi programs be concerned about cytomegalovirus cmv

Selected Hospital Populations Hearing Loss?

38% Caucasian, Non Hispanic

29% African American

33% Caucasian, Hispanic



Should ehdi programs be concerned about cytomegalovirus 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.


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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


Should ehdi programs be concerned about cytomegalovirus cmv

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

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