Congenital CMV infection

Siriporn phongjitsiri,MDPediatric Infectious Division

Queen Sirikit National Institute of Child HealthJuly 27,2007

Congenital CMV infection Congenital CMV infection

• Approximately 0.15–2% of live births

• Leading cause of sensorineural deafness

• Major cause of mental retardation, cerebral palsy

• Approximately 10% death in symptomatic newborns

• Lifelong habilitation for impaired survivors

• Fetus: Via placenta from the mother• Human milk• Blood transfusion, organ transplantation• Children and adults: Mainly via bodily

fluids (esp. urine, saliva)

How is CMV transmitted?

• Duration of viral shedding following primary infection:

• 2-3 weeks for adults

• Months to years for young children

• Therefore, CMV is most often transmitted by young children

Who transmits CMV?

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

Infected mother viraemia infection of placenta trophoblasts

Infection of fetalendothelial cells

Viralreplication intarget organs

(kidney)

Fetal viruria

Virus inamniotic fluid

Infection ofthe oropharynx

Fetal viraemia

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%)

MATERNAL CMV INFECTION DURING PREGNANCY • Primary maternal infection leads to fetal

infection in 30-50% of cases--10-15% of these have overt clinical disease

• Secondary maternal infection less likely to lead to fetal infection (1-2% ) but can do so and may lead to severe disease (Boppana et al, NEJM 2001, 344: 1366)

Rates of primary CMV infection during pregnancyRates of primary CMV infection during pregnancy

Study (Location) Rate as % of Rate as % of % cong CMV,Pregnancies Seronegatives primary mat

inf

Stern 1.1 4.1 45(London)

Grant (Scotland) 0.29 0.71 38

Stagno (USA, 0.57 1.4 47mid-income)

Ahlfors (Sweden) 0.32 1.4 43

Griffiths (London) 0.30 0.86 20

Symptomatic Congenital CMV Infection

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

Boppana et al . (1999 ) Pediatrics 104:55

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 neurological sequelae

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

Sequelae of Congenital CMV Infections

• Cranial CT is a good predictor of sequelae in neonates with congenital CMV infection

• Most common abnormality is intracerebral calcification (typically periventricular)

• Boppana et al (Pediatrics 99:409, 1997) reported that 90% of neonates with abnormal CT scan developed at least 1 sequelae

• Only 1/17 neonates with normal CT had IQ < 70

SEQUELAE OF SYMPTOMATIC CONGENITAL CMV INFECTION

• Seizures• Chorioretinitis• Periventricular calcifications• Sensorineural hearing loss• motor deficits

CHORIORETINITIS

Congenital CMV

Congenital CMV

CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE

• Primary maternal infection• Symptomatic congenital CMV

infection• 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% 7–15%

Mental retardation 45% 2–10%

Cerebral palsy 35% <1%

Chorioretinitis 15% 1–2%

Diagnosis of Congenital CMV 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 infection

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

• PCR may be useful in selected cases

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

• Antibody avidity testing can increase accuracy of detection of primary infection

• No test for immune mothers who will transmit

Advanced CMV diagnosisAdvanced CMV diagnosis

IgM confirmation by Western blot

Determination of the IgG avidity index

Isolation of the virus from urine, saliva and blood

A confirmatory test for CMV-IgMA confirmatory test for CMV-IgM

New immunoblot

1) Contains both structural and nonstructural proteins

2) Reactivity to vp 150 can be confirmed with recpUL32

3) Agrees with consensus of different ELISAs

4) Is easy to standardize

5) Is easy to interpret

rp150

rp52

rp130

CKS

rp38

Purifiednativeviral

proteins

Recombinantproteins

Vp28

Vp65Vp82

Vp150

Weeks after beginning of symptoms

Avi

dity

inde

x (%

)

70

0

60

50

40

30

20

10

05 10 15 20 25 30 35

Congenital CMV infectionsCongenital CMV infections

Low IgG avidity is linked to primary infection

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

N eg ative ,n o fu rth er tes tin g

P os it ive =p rim ary in fec tion

Tes t fo r Ig M A n tib od y

P os it ive

Ig G P os it ive =S erocon vers ion

N eg ative ,n o fu rth er tes ts

R etes t la te r

N eg ative

Tes t fo r Ig G an tib od ya t firs t p ren a ta l vis it

Refer for prenatal diagnosis

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

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

Possible intervention

• Counsel regarding prevention (seroneg mother)

• Use prenatal diagnosis, abort infected fetus

• Use antivirals to prevent or treat fetal infection

Problems

• No proven means to prevent maternal infection

• ~75% infected fetuses will be normal

• No available antiviral treatment for prenatal use

Case Report: “Oral ganciclovirfor 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

Antiviral Therapy for Congenital CMV Infection?

• 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)

• Hearing Improvement was more likely in the GCV treated group at 6 and 12 mos (OR 4.31, 4.03)

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

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

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

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 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

• Patients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks

• 19 % of participants had neutropenia requiring dose modification

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

• 3 patients 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)

• 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 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 routinely because of insufficient efficacy data”

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

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 !!

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

How do we communicate this message?

The End