Congenital CMV

Anna Marie Teena C. Mendiola, M.D.NICU Rotation

February 5, 2009

Cytomegalovirus infection ubiquitous virus most CMV infections are asymptomatic

and cause mild diseaseand cause mild disease cause serious disease in newborns and

immunocompromised children

Cytomegalovirus Infection Herpesvirus family Epstein-Barr virus (EBV); herpes simplex viruses

(HSV)-1 and 2; varicella-zoster virus (VZV); and human herpesviruses (HHV)-6, -7, and -8. human herpesviruses (HHV)-6, -7, and -8.

all share properties, including a genome of double-stranded linear DNA, a virus capsid of icosahedral symmetry, and a viral envelope

share the biological properties of latency and reactivation, which cause recurrent infections in the host.

Cytomegalovirus Infection developing countries- most children are

infected by 3 years of age developed countries, such as the United developed countries, such as the United

States or United Kingdom, as many as 60 to 80 percent of the population will be infected with CMV by adulthood

Fetus: Via placenta from the mother (congenital infection)

Human milk, via contact with maternal cervicovaginal secretions during delivery (perinatal infection)

How is CMV transmitted?

(perinatal infection) Blood transfusion, organ transplantation Children and adults: Mainly via bodily fluids

(esp. urine, saliva) Sexual transmission

CMV INFECTION IN THE NEONATE: IMPORTANCE OF CONGENITAL CMV INFECTION

Most common congenital infection Approximately 1 % (0.2 2.5 % ) of live births 90% asymptomatic at birth (15% with progressive 90% asymptomatic at birth (15% with progressive

hearing loss 10% symptomatic at birth (2/3 will have neurologic

involvement) Leading cause of sensorineural hearing loss in

children Major cause of mental retardation, cerebral palsy

Congenital CMV infectionCongenital CMV infection

Approximately 10% death in symptomatic newborns

Lifelong habilitation for impaired survivors Leading infectious cause of brain damage in US

children

PRIMARY MATERNAL CMV INFECTION DURING PREGNANCY

95% clinically inapparent

35% transmitted to fetus

No clear relationship between gestational age and transmission

Fetal damage more likely in first 26 weeks, (32%) than later (15%)

HIGH RISK FOR PRIMARY MATERNAL AND CONGENITAL CMV INFECTION

Teen mothers

Exposure to young children: day-care workers day-care workers mothers

Sexual activity

Transmission of CMV through the placenta barrier and infection of the fetus

Transmission of CMV through the placenta barrier and infection of the fetus

Infected mother viraemia infection of placenta trophoblasts

Infection of fetalVirus in

Infection ofthe oropharynx

Infection of fetalendothelial cells

Viralreplication intarget organs

(kidney)

Fetal viruria

Virus inamniotic fluid

Fetal viraemia

Symptomatic Congenital CMV Infection

Jaundice (67%) Petechiae (76%) Hepatosplenomegaly (60%) Hepatosplenomegaly (60%) Microcephaly (53%) Chorioretinitis (20%) Seizure (7%) Fatal outcome (10%)

Boppana et al. (1999) Pediatrics 104:55

Infant born with congenital CMV infection

Skin has typical petechial and purpuric lesions. Periorbital echymoses and subconjuctival hemorrhages also are seen and were most likely caused by infant's severe thrombocytopenia (platelet count 2000/cu mm).

Congenital CMV

Blueberry muffin lesions

Petechial rash

Sequelae of Congenital CMV Infections

Neurological sequelae are the most common, and most severe: >90% of newborns with symptomatic congenital

CMV infection have visual, audiologic and/or other CMV infection have visual, audiologic and/or other neurological sequelae

- 5-17% of newborns with asymptomatic congenital CMV infection develop neurological sequelae (esp. hearing loss)

Congenital CMV InfectionAbnormalities in the brain Perventricular leukomalacia & cystic abnormalities Periventricular calcifications (linear or punctate) Ventriculomegaly Vasculitis Neuronal migration abnormalities hydranencephaly

shows classic linear periventricular calcifications, as well as cortical atrophy.

Congenital CMV

Congenital CMV

Congenital CMV InfectionOcular Abnormalities Chorioretinitis (posterior uveitis) Retinal scars Retinal scars Optic atrophy Central vision loss

CHORIORETINITIS

Congenital CMV infectionSensorineural hearing loss > 2/3 of newborns with symptomatic

infectioninfection Progressive : severe to profound hearing

loss Patients may be cognitively normal or may

experience cognitive delays depending upon degree of brain involvement in utero

Congenital CMV InfectionLaboratory Abnormalities : Thrombocytopenia Hemolytic anemia Hemolytic anemia Elevated transaminases Elevated direct & indirect serum bilirubin

CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE

Primary maternal infection Symptomatic congenital CMV infection Presence of neonatal neurological Presence of neonatal neurological

abnormalities Abnormal head CT scan Chorioretinitis in the newborn

CLINICAL IMPACT OF CONGENITAL CMV INFECTION

Frequency of sequelae Symptomatic (7%) Asymptomatic (93%)

Infant death 10% 0

Hearing loss 60% 715%Hearing loss 60% 715%

Mental retardation 45% 210%Cerebral palsy 35%

Diagnosis of CongenitalCMV Infections

Isolation of CMV from urine or other body fluid (CSF, blood, saliva) in the first 21 days of life is considered proof of congenital infectioninfection

Infants often have very high titers of virus and culture (+) within 1-3 days of incubation

Diagnosis of CongenitalCMV Infections

Serologic tests are unreliable; IgM tests currently available have both false positive and false negative results

PCR may be useful in selected cases PCR may be useful in selected cases> more expensive , less available ,often

less reliable

Detection: screening for maternalCMV infectionDetection: screening for maternalCMV infection

CMV IgG antibody sensitive and specific screen for past infection

CMV IgM antibody variable sensitivity and specificity CMV IgM antibody variable sensitivity and specificity Antibody avidity testing can increase accuracy of detection

of primary infection No test for immune mothers who will transmit

Evaluation of mothers at risk of transmitting CMV to the fetusEvaluation of mothers at risk of transmitting CMV to the fetus

Positive Negative

Test for IgG antibodyat first prenatal visit

Negative,no further testing

Positive =primary infection

Test for IgM Antibody

IgG Positive =Seroconversion

Negative,no further tests

Retest later

Refer for prenatal diagnosis

Intervention: using results of maternal screening to prevent congenital CMV diseaseIntervention: using results of maternal screening to prevent congenital CMV disease

Possible intervention Counsel regarding prevention

(seroneg mother) Use prenatal diagnosis, abort

Problems No proven means to

prevent maternal infection Use prenatal diagnosis, abort

infected fetus Use antivirals to prevent or

treat fetal infection

~75% infected fetuses will be normal

No available antiviral treatment for prenatal use

SCREENING FOR CONGENITAL CMV INFECTION

Rationale early detection of hearing loss and identification of children at risk

Specimens urine or saliva Serology costly and less accurate than virus detection Technical virus easily and reliably detected by: Technical virus easily and reliably detected by:

urine culture urine PCR mouth swab culture

Antiviral Therapy for Congenital CMV Congenital CMV

Infection?

Treatment

Treatment of asymptomatic CMV congenital and acquired infection in the normal host is not recommendednormal host is not recommended

No clinical trials to document efficacy

Treatment among neonates with congenital & acquired infection

controversialWho are likely to benefit with ganciclovir ?? Viral sepsis like syndrome Viral sepsis like syndrome Pneumonitis or severe refractile

thrombocytopenia Sight threatening retinitis

Treatment among neonates with congenital & acquired infection

Newborns that may benefit long term form of antiviral therapy

Sensorineural hearing loss microcephaly

Case Report: Oral ganciclovir for the treatment of intrauterine cytomegalovirus infection

Nulligravid cmv seronegative pt. received renal allograft from seropositive donor

Pt. became pregnant 3 months following acute CMV infection

AF CMV DNA+(80 copies) at 21 wks. Oral CGV administered at 22 wks. AF CMV DNA-at 26 weeks (8 copies) Vigorous female delivered at birth Newborn urine and blood CMV DNA- Normal development @ 3 years of age

Puliyandaet al. (2005)Transplant Infectious Disease 7:71-7

100 Neonates enrolled to receive 6 weeks of IV ganciclovir (6 mg/kg/dose q 12 hours)

No significant difference in mortality (6% GCV, 12% untreated)

Phase lll randomized trial of ganciclovir for symptomatic congenital CMV infections involving the CNS

Hearing Improvement was more likely in the GCV treated group at 6 and 12 mos (OR 4.31, 4.03) : prevents hearing deterioration at 6 months and possibly beyond

29/46 (63%) GCV recipients experienced neutropenia, compared with 9/43 (21%) untreated control patients

Kimberlin et al, J. Pediatrics,143:17,2003

USE OF GANCICLOVIR IN SYMPTOMATIC CONGENITAL CMV INFECTION

12 newborns treated for 2 weeks with 5 mg/kg/day or 7.5 mg/kg/day + 3 months of 10 mg/day 3x/week

Higher, but not lower dose, cleared viruria Abnormal liver and haematologic function appeared to Abnormal liver and haematologic function appeared to

clear faster with higher dose Although outcome appeared better with higher dose,

CNS sequelae appeared in both groups

from Nigro et al, J Pediatr 1994; 124: 318

A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION

47 patients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks

19 % of participants had neutropenia requiring dose modificationmodification

12 mg/kg reduced viral shedding; shedding returned when drug was discontinued

3 patients(16%) had improved hearing at 6 months; 25 had abnormal hearing

from Whitley et al, J Infect Dis, 1997; 175: 1080

Antiviral Therapy for Congenital CMV Infection?

Ganciclovir has been shown to be effective therapy for certain CMV infections in immunocompromised hosts (e.g., retinitis or enterocolitis in HIV-infected patients)patients)

Neonatal experience with ganciclovir is limited, the toxicity of the drug is considerable (e.g., platelets, neutrophils), and oral bioavailability unreliable

Ganciclovir Therapy for Congenital CMV? 2006

A six week course of IV ganciclovir may reduce the rate of long-term hearing loss in neonates with symptomatic CMV infection

However, this regimen is associated with significant toxicity, long-term followup data are lacking, and the toxicity, long-term followup data are lacking, and the optimal duration of therapy (if any) is unknown

Potential benefits of antiviral therapy for asymptomatically infected neonates may be greater

Antiviral Therapy for Congenital CMV? 2006

Current role for IV ganciclovir uncertain: therapy may be considered for patients with symptomatic congenital CMV disease involving the CNS (Kimberlin et al, 2003)

2006 Red Book says that it is not recommended 2006 Red Book says that it is not recommended routinely because of insufficient efficacy data

?? Treatment of neonates with worsening retinitis or hepatitis, severe pneumonia, or persistent severe thrombocytopenia ?? Duration of therapy ??

USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION

Pro- Antiviral effect Might prevent death or

improve newborn disease No other options

Con- Most damage done prior to

birth Limited antiviral effect Potential reproductive toxicity No other options Potential reproductive toxicity Potential rebound retinitis or

other disease Lack of evidence of efficacy

Prevention of CMV Infections?

A vaccine to prevent CMV infections is desperately needed

Trials of candidate vaccines are underway CMV Vaccine development a Level One

priority !!

INVESTIGATIONAL CMV VACCINES, 1997

Vaccine Composition Manufacturer

Towne Live virus Merck/Microbiological Associates

CMVgB Recomb gB/MF59 Chiron Vaccines

ALVAC-CMVgB Viral vector/recomb gB Pasteur-Merieux Connaught

Chimeric CMV Live virus, Avironrecomb Towne/Toledo

POTENTIAL GOAL OF CMV VACCINE PROGRAMME

Prevent maternal primary infection

Reduce rate of congenital Reduce rate of congenital infections

Reduce rate of disease

from Whitley et al, J Infect Dis, 1997; 175: 1080

How is congenital CMV prevented?

Many different ways toprevent CMV

Our approach:

Hygiene, especially handwashing

Education about CMV and how to prevent it through hygiene

Thank you