Congenital CMV

infection
Infectious and Tropical Pediatric Division
Department of Child Health
Medical Faculty, University of Sumatera Utara
Congenital CMV infection

Approximately 0.152% 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
How is CMV transmitted?

Fetus: Via placenta from the mother

Human milk
Blood transfusion, organ
transplantation
Children and adults: Mainly via bodily
fluids (esp. urine, saliva)
Transmission of CMV through the placenta
barrier and infection of the fetus

Infected mother viraemia infection of placenta trophoblasts

Infection of
the oropharynx

Infection of fetal
Virus in
endothelial cells
amniotic fluid

Fetal viraemia
Fetal viruria
Viral
replication in
target organs
(kidney)
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 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 47
mid-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% 12%
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 maternal
CMV 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 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-IgM
New immunoblot

1) Contains both structural Vp150 Purified

and nonstructural proteins Vp82 native
Vp65 viral
2) Reactivity to vp 150 can Vp28 proteins

be confirmed with
recpUL32 rp150

rp52 Recombinant
3) Agrees with consensus of rp130 proteins
different ELISAs
rp38
4) Is easy to standardize
5) Is easy to interpret CKS
Congenital CMV infections
Low IgG avidity is linked to primary
infection
70

60
Avidity index (%)

50

40

30

20

10

0
0 5 10 15 20 25 30 35
Weeks after beginning of symptoms
Evaluation of mothers at risk of
transmitting CMV to the fetus

T e s t fo r I g G a n t ib o d y
a t fir s t p r e n a t a l v is it

P o s it iv e N e g a t iv e

T e s t fo r I g M A n t ib o d y R e t e s t la t e r

N e g a t iv e , P o s it iv e = I g G P o s it iv e = N e g a t iv e ,
n o fu r t h e r t e s t in g p r im a r y in fe c t io n S e r o c o n v e r s io n n o fu r t h e r t e s t s

Refer for prenatal diagnosis

Intervention: using results of maternal
screening to prevent congenital CMV
disease
Possible intervention Problems
Counsel regarding No proven means to
prevention (seroneg prevent maternal
mother) infection
Use prenatal diagnosis,
~75% infected fetuses
abort infected fetus
will be normal
Use antivirals to prevent
or treat fetal infection No available antiviral
treatment for prenatal
use
Antiviral Therapy
for
Congenital CMV
Infection?
Phase lll randomized trial of ganciclovir for
symptomatic congenital CMV infections
involving the CNS

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

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 to
prevent CMV

Our approach:

Hygiene, especially
handwashing

Education about CMV

and how to prevent it
through hygiene
How do we communicate
this message?
The End