Transcript Congenital Cytomegalovirus

CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Congenital
Cytomegalovirus
Lalith Wijedoru
Lalith Wijedoru is a medical graduate of University College London Medical
School. He completed Senior House Officer training in paediatrics at Sheffield
Children’s Hospital before starting Specialist Registrar posts in Leeds and
subsequently Alder Hey Children’s Hospital, Liverpool. He holds a MSc in
Tropical Paediatrics from the Liverpool School of Tropical Medicine (LSTM), and
a junior clinical lectureship at LSTM.
His academic interests relate to the febrile child in resource limited settings in
Asia. His particular focus relates to the diagnostic difficulty in distinguishing
viral, bacterial and parasitic infections in children, including neonates.
This session looks at cytomegalovirus (CMV) which is the most
common congenital viral infection worldwide. Neonatal clinical
signs, diagnostics, treatment and neurological sequelae in
children will be discussed. Public health measures including
screening and immunisation will also be considered
Edited by Prof Tom Solomon, Dr Agam Jung and Dr Sam Nightingale
Learning Objectives
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
By the end of this session you will be able to:
• Recognise the clinical signs of acute CMV infection in the
newborn
• Define both antenatal and postnatal diagnostic methods for
congenital CMV
• Describe the treatment options for acute CMV infection in
newborns
• List the neurological sequelae of neonatal CMV infection in
children
• Discuss the potential public health measures which could
reduce CMV-associated neuro-disability in children
Introduction
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Congenital infections remain an
important source of neurological
disability for thousands of children
worldwide. Cytomegalovirus (CMV) is
the commonest congenital infection in
the developed world. 1-4% of women
have a primary infection during
pregnancy. Most of them are
asymptomatic.
The majority of congenitally-infected infants appear normal at birth, but
long-term neurological sequelae of psychomotor retardation and/or
hearing loss occur in about 10-15%. Clinical signs of acute CMV infection
in infants include growth retardation, microcephaly, thrombocytopenia,
and jaundice.
Microbiology including serology, biochemical markers and radiology can
be used in both the antenatal and postnatal diagnosis of CMV. The
efficacy and duration of treatment is controversial, with ganciclovir and
valganciclovir demonstrating encouraging trial results.
Prevention strategies of maternal CMV infection including immunisation
and screening. These remain the subject of debate given the current
evidence of both vaccine efficacy and anti-viral treatment.
Congenital Infections and Neurology I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Infections associated with pregnancy may be with or without
foetal consequence. Serious adverse effects include:
• Foetal death
• Stillbirth
• Intrauterine growth retardation
• Congenital malformations
Congenital Infections and Neurology II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
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Symptomatic at birth: Those who are symptomatic at birth generally
have significant long-term neurological sequelae.
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Asymptomatic at birth: Those are asymptomatic at birth may never
manifest evidence of neurological damage, or this may become
clinically evident later in life.
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TORCH(ES) agents: Specific congenitally-acquired infections are often
referred to as the TORCH(ES) agents…
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Toxoplasmosis
Rubella
Cytomegalovirus
Herpes (including varicella zoster and herpes simplex)
HIV
Syphilis
UK public health campaigns for the majority of these infectious agents are
fairly robust. However, the herpes viruses (including CMV) are considered
to be neglected in this context.
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Prevalence: In northern Europe, the overall rate of congential CMV
infection is estimated at 1% of all live births. It is estimated that
between 4000 and 6000 children born each year in the United States
will develop permanent neurological deficits as a result of CMV.
Microbiology
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Cytomegaloviruses (CMV) belong to
the β-herpesviruses sub-family of
herpes viruses. These viruses are
highly species-specific and infect
many animals. Infection is common in
human
populations,
but
rarely
symptomatic in hosts with normal
immune function.
In contrast, it can cause multi-organ disease in immuno-compromised
patients of all ages. Foetuses and neonates with their relative poor
immune function are particularly at risk. Like with other herpes viruses,
primary infection with CMV leads to persistent infection.
CMV can be transmitted from mother to child transplacentally, during
birth, and in the postpartum period.
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Early transplacental transmission during the first trimester is
associated with the greatest neurological damage to the foetus.
The majority of transmission occurs in the third trimester and during
delivery.
Intrapartum transmission of CMV occurs in around 50% of infants born
to mothers shedding CMV from the cervix or vagina.
Up to 70% of sero-positive women shed CMV in breast milk
Epidemiology I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
CMV is found worldwide. In developed countries, the sero-prevalence of
CMV is 40% to 60% in individuals of middle to upper socioeconomic status, and <80% among those of lower socio-economic
status.
Epidemiology II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Congenital infection
Congenital infection can occur as the result of a primary CMV infection,
re-infection with a new strain of CMV, or reactivation of latent infection.
Maternal immunity to CMV
Maternal immunity to CMV provides some protection against vertical
transmission.
Infection in immediate pre-conception period
If a primary CMV infection occurs in the immediate pre-conception
period, the risk of transmission is around 9%.
Infection in 1st, 2nd, 3rd trimester
Primary maternal CMV infection occurring in the first, second, and third
trimester results in congenital infection in approximately 25%, 50% and
75% of foetuses respectively.
Infection after recurrent maternal infection
In contrast, the risk of CMV transmission to the foetus after a recurrent
maternal infection is only 0.15 to 2%.
However, despite the risk reduction preconception immunity affords,
>60% of infants with congenital CMV are born to mothers with prepregnancy CMV immunity.
Epidemiology III - Maternal
Seroprevalence
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Incidence of congenital CMV infection increases with maternal
seroprevalence. The incidence of congenital human CMV infection and
maternal seroprevalance rates from published studies carried out in
North America, Europe, South America and Africa were plotted as shown
opposite.
Note that as the rate of maternal seroprevalence increases, so does the
incidence of congenital CMV infection. This suggests a threshold level of
immunity that would eliminate transmission within human populations
may not be attainable [1].
Adapted from – Britt, W.
2008. “Manifestations of
Human Cytomegalovirus
Infection Proposed
Mechanisms of Acute and
Chronic Disease” in
Current Topics in
Microbiology and Human
Immunology eds. Shenk,
T E & Stinski, M F.
Springer-Verlag, Berlin,
2008.
Clinical Features I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
CMV primarily affects the cerebral ventricles, the ependymal cells, the
organ of Corti, and the neurons of the eighth (vestibulocochlear) cranial
nerve.
90% of congenitally-infected infants are reported to be asymptomatic at
birth.
The remaining symptomatic 10% may demonstrate signs such as
microcephaly, growth restriction and thrombocytopenia. Jaundice,
petechiae, and hepatosplenomegaly are the most common findings.
Other clinical manifestations
include…
• Poly or oligohydramnios
• Prematurity
• Hypotonia
• Poor feeding
• Seizures
• Cerebral ventriculomegaly
• Intracranial periventricular
calcifications
• “Blueberry muffin” spots
• Sensorineural deafness
(10%)
• Mental retardation (10-20%)
Other less frequent findings
include…
• Hydrocephalus
• Pneumonitis
• Haemolytic anaemia
Clinical Features II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
About 10% of infants with symptomatic congenital CMV infection
die during early infancy because of multi-organ disease with
severe hepatic dysfunction, bleeding diatheses, and secondary
bacterial infections. However, infants asymptomatic at birth may
also develop sensorineural hearing loss (7–15%), chorioretinitis
and CNS malformations.
Clinical Features III - Clinical Studies
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
The frequency of various clinical and laboratory findings in 106 neonates
with symptomatic congenital CMV infection is illustrated in the table on
the next slide.
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68% of infants had at least one clinical finding suggestive of
neurological impairment
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Petechiae, jaundice, and hepatosplenomegaly were the most
frequently noted abnormalities, present in approximately 75% of
symptomatic neonates
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Physiological unconjugated jaundice is generally very common in well
neonates, thus identifying a raised conjugated bilirubin fraction in an
otherwise asymptomatic infant is important
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Over half were microcephalic and small for gestational age, and
about a third born prematurely
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About two-thirds of symptomatic infants had clinical neurological
abnormalities such as microcephaly, lethargy/hypotonia, poor suck,
or seizures
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Of the neonates who had ophthalmological
chorioretinitis or optic atrophy was noted in 20%
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Of the babies who had audiological assessments, 50% were found to
have an abnormal hearing screen
assessments,
Clinical Features IV – Clinical Studies
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Adapted from Boppana SB et al. Newborn findings and outcome in
children with symptomatic congenital CMV infection. Pediatr Res 1992.
Clinical Findings and Deficits I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
The risk for neurological sequelae is increased when CMV infection
occurs in the first trimester. The majority of infants with symptomatic
congenital CMV infection at birth have evidence of central nervous
system (CNS) impairment. The outcome and neurological deficits in
38 symptomatic congenital CMV infants are outlined in the table
opposite.
Table adapted from
Kylat RI, Edmond
NK, Ford-Jones
EL. Clinical
findings and
adverse outcomes
in neonates with
symptomatic
congenital
cytomegalovirus
infection. Eur J
Pediatr (2006) 16
5773-778.
Clinical Findings and Deficits II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Ocular manifestations secondary to congenital CMV
include:
- chorioretinitis
- corneal opacities
- anterior polar cataracts
- optic nerve hypoplasia
- optic nerve coloboma
- (and even) anophthalmia
Late onset neurologic symptoms include:
- learning disability
- cerebral palsy
- sensorineural hearing loss (SNHL)
It is important to note that there is an unrecognised burden of
CMV-associated neuro-disability in the paediatric population.
The clinical findings and deficits listed in the table may be
described as an 'unclassified' neurological syndrome in
children with psychomotor retardation, with diagnoses often
made retrospectively.
Sensorineural Hearing Loss
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Of infants with asymptomatic congenital CMV infection at birth, 10% to
15% will go on to develop symptoms, typically manifested as
sensorineural hearing loss (SNHL).
Congenital CMV infection is the most common non-genetic cause of
SNHL in children. In the DECIBEL study, 23% of children with profound
SNHL had congenital CMV infection. Permanent hearing loss occurs in
approximately 14% of children with congenital CMV infection.
SNHL from congenital CMV can present later in childhood. However,
symptomatic infection at birth appears to be much more likely to be
associated with delayed SNHL than asymptomatic infection. Rates of
delayed-onset hearing loss in symptomatic newborns are in the vicinity
of 30- 35%.
Estimates of Long-term Sequelae in Infants
with Congential CMV
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
In a given cohort of 1000 infants with congenital CMV, 170-190
will have permanent sequelae, of whom one out of three is from
the symptomatic group and two out of three are from the
asymptomatic group [2].
17-20% of all infants with
congenital CMV will have
permanent sequelae.
Adapted from Sung H & M R Schleiss. 2010. Update on the current status of
human cytomegalovirus vaccines. Expert Review Vaccines 9 (11), 1303-1314
Diagnosis I - Prenatal Diagnosis
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Studies using ultrasonography,
amniocentesis and fetal blood
sampling have demonstrated
that it is possible to make a
prenatal diagnosis of congenital
CMV infection. The variable
prognosis of CMV infection
limits the value of prenatal
diagnosis.
Although the culture and polymerase chain reaction (PCR) of amniotic
fluid for the detection of CMV or CMV DNA allows for prenatal
identification of the majority of infected infants, the specificity of the PCR
assay is only between 50 and 80%. The sensitivity of amniotic fluid
culture or PCR is lower when the procedure is carried out before 21
weeks of gestation. However, the presence of CMV or CMV DNA in
amniotic fluid and foetal blood samples does not appear to correlate with
symptomatic congenital infection or an adverse long-term outcome in
infected children.
Maternal sero-conversion is another strategy used to demonstrate acute
maternal CMV infection. However, there is a high rate of false positives
and false negatives. Current serological diagnostic methods utilising
CMV-specific IgM require more specific evaluation.
Diagnosis II - Primary Maternal CMV
Infection
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Adapted from Nyholm J L & Schleiss M R. 2010. Prevention of maternal
cytomegalovirus infection current status and future prospects. International Journal
of Women’s Health 2010 225-35
Diagnosis III - Microbiological Diagnosis
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Congenital CMV infection is proven by isolation (culture)
of the virus from body fluids during the first 3 weeks of life.
Urine and saliva are useful for this purpose as neonates shed high levels
of virus. PCR methods can also be used on urine and saliva samples,
although these need further evaluation.
Viraemia is not present in all newborn infants with congenital CMV
infection; therefore detection of virus in peripheral blood should not be
relied upon to diagnose congenital infection. Detection of IgM antibody to
CMV is not as reliable as viral isolation and is not recommended for
diagnosis.
The age of the patient at the time of sample collection for detection
CMV is of some importance. Neonates who acquire CMV during birth
from breast milk shed virus after 3 weeks of age. Thus, detection
CMV in urine or saliva after 3 weeks of age is not unequivocal proof
CMV acquisition in utero.
of
or
of
of
Diagnosis IV - Laboratory Diagnosis
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
The laboratory abnormalities seen in infants with symptomatic congenital
CMV infection include (in decreasing order of frequency):
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Elevated serum aspartate aminotransferase
Conjugated hyperbilirubinemia
Thrombocytopenia – Is noted in the first few days of life in the
majority of CMV-infected infants. This normalizes in most patients by
the third week of life.
Atypical lymphocytosis
Haemolytic anaemia
Elevated cerebrospinal (CSF) fluid protein – CSF protein levels
appear to correlate positively with clinical indicators of CNS damage.
Elevations of serum transaminases and
conjugated bilirubin are present in the
immediate newborn period and peak during
the second week of life. However,
hyperbilirubinemia
and
liver
function
abnormalities often persist beyond the
neonatal period, resolving over a few months.
Invasive procedures such as liver biopsy are
therefore not justified on the basis of
persistent liver function abnormalities.
Diagnosis V – Sero-Diagnosis
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Sero-diagnosis is also used in both
maternal and neonatal CMV. There are
certain parameters which would suggest
evidence of CMV infection.
• Four-fold rise in anti-CMV IgG titres
A four-fold rise in anti-CMV IgG titres would
be suggestive, but this requires serial blood
testing to demonstrate use
• Sero-conversion from negative to positive
Similarly, sero-conversion from negative to positive could be considered.
Pregnant women with an infectious mononucleosis-like illness could be
detected this way with early testing, but this is unlikely to happen in
obstetric practice.
• CMV-specific IgM in cord blood
The diagnosis could also be established by the presence of CMVspecific IgM in cord blood or in the infant’s blood in the first 3 weeks of
life.
This can be detected in only 70% of congenitally-infected infants, as the
titres may rise only late in acute infection.
The diagnosis cannot be confirmed using CMV-specific IgG titre from
cord blood as this may be a reflection of passive placental transmission.
Neuro-imaging I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Imaging findings of congenital CMV infection include intracranial
calcification, ventriculomegaly, white matter disease, neuronal
migrational disorders, lissencephaly and cortical atrophy.
Not all of these findings are seen in every patient, and abnormalities
may range from mild to severe. In fact, unenhanced head CT results
may be normal in as many as 68% of infants with symptomatic
congenital CMV infection that was confirmed at birth. An abnormal CT
scan is a sensitive indicator of poor cognitive outcome in symptomatic
patients.
Intracranial calcification is the most frequently reported imaging finding
of congenital CMV infection, occurring in 34%–70% of patients.
Ventriculomegaly is the second most common and is often associated
with cerebral volume loss.
White matter abnormalities are common in those with congenital CMV
infection, occurring in as many as 22% of patients.
Neuro-imaging II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
The 4 sample images demonstrate ventriculomegaly and scattered
periventricular calcification. These radiological findings are consistent
with intrauterine TORCH infection, such as CMV.
Image by Radswiki.net from Radiopaedia.org
Treatment I
Ganciclovir
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Ganciclovir is a synthetic acyclic nucleotide analog
of guanine which blocks viral DNA synthesis. It has
been used for just under two decades in the
treatment of congenital CMV.
There is only one large randomised controlled
study of the effect of ganciclovir on hearing loss
(Amir et al., 2010). The results showed that 6
weeks
of
intravenous
ganciclovir prevented hearing deterioration at 6
months.
In some infants, there was even an improvement in audiometric
parameters compared to untreated infants, of whom 41% showed
auditory function deterioration.
However, at age 12 months, hearing had deteriorated in 21% of the
treated infants. This suggests that 6 weeks of treatment may not be
sufficient to prevent hearing loss.
Side-effects of ganciclovir therapy are thrombocytopenia, neutropenia,
and gonadal toxicity.
Treatment II
Valganciclovir
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Valganciclovir is another guanine derivative which
is a pro-drug of ganciclovir. It has been used as
CMV prophylaxis in paediatric transplant
recipients.
In some centres in the United States, treatment for
symptomatic infants with congenital CMV has
been
either
intravenous
ganciclovir or valganciclovir.
Given the observations of rebound viraemia and incomplete resolution of
symptoms, clinical trials have been conducted looking at intravenous
ganciclovir followed by long-term oral valganciclovir for the treatment of
infants with symptomatic congenital CMV disease.
Passive immunisation with hyper-immune globulin (CMV HIG) has been
studied for the in utero treatment and prevention of congenital CMV
infection. CMV HIG is a pooled, high-titre immunoglobulin preparation
derived from donors with high levels of CMV antibody. This intervention
is still in early phase trials.
Vaccines I
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
A vaccine for congenital cytomegalovirus (CMV) infection is a public
health priority. Analysis of cost–effectiveness indicates that a vaccine
could have a major impact on the economic burden of paediatric neurodisability caused by congenital CMV.
Like other herpes viruses, CMV has immune evasion genes which
makes it difficult to develop appropriate vaccine targets. The vaccine
table summarises CMV vaccines that have undergone clinical trial
evaluation since 2005. A breakthrough came with the publication of a
Phase II study of a purified, recombinant vaccine based on adjuvant
glycoprotein B. This vaccine demonstrated an efficacy of approximately
50% against acquisition of HMV infection in a clinical trial among young
women [4].
Novel approaches to CMV vaccines include vectored vaccines, DNA
vaccines, bacterial artificial chromosome (BAC)-based vaccines, and
genetically engineered, live attenuated vaccines. These vaccines are in
various stages of pre-clinical and clinical development [2].
Vaccines II
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Vaccine table
Source Sung H & M R Schleiss. 2010. Update on the current status of
human cytomegalovirus vaccines. Expert Review Vaccines 9 (11),
1303–1314.
Key Points
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
• Cytomegalovirus is a herpesvirus, and the commonest
congenitally-transmitted infection in the developed world
• Most infections are asymptomatic in both mothers and
infants,
although
microcephaly,
jaundice,
and
thrombocytopenia are common acute manifestations in the
newborn
• The major long-term neurological sequelae of congenital
CMV are sensorineural hearing loss, ophthalmic deficits, and
general psychomotor retardation
• Isolation of the virus from bodily fluids is the mainstay of CMV
diagnosis. Sero-diagnosis has numerous limitations
• Treatment with intravenous ganciclovir is recommended, with
extended oral treatment with valganciclovir undergoing
clinical trials
• Vaccines for CMV are currently being developed and tested.
Pushes for more robust screening programmes for CMV
remain controversial
Summary
Having completed this session you will now be able to:
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
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Recognise the clinical signs of acute CMV infection in the newborn
Define both antenatal and postnatal diagnostic methods for
congenital CMV
Describe the treatment options for acute CMV infection in newborns
List the neurological sequelae of neonatal CMV infection in children
Discuss the potential public health measures which could reduce
CMV-associated neuro-disability in children
References
1. Britt,
W.
'Manifestations
of
Human
Cytomegalovirus
Infection: Proposed Mechanisms of Acute and Chronic Disease' in
Current Topics in Microbiology and Human Immunology eds. Shenk,
T E & Stinski, M F. Springer-Verlag, Berlin, 2008.Kimberlin et al.,
2003.
2. Sung & Schleiss, 2010.
3. Kimberlin et al., 2003.
4. Pass, Zhang, Evans et al., 2009
5. CDC. View.
6. Neuroimaging of Pediatric Central Nervous System Cytomegalovirus
Infection
Further Reading
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CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
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Nyholm J L & Schleiss M R. Prevention of maternal cytomegalovirus
infection: current status and future prospects. International Journal of
Women's Health 2010;2:25-35
Boppana SB et al. Newborn findings and outcome in children with
symptomatic congenital CMV infection. Pediatric Research. 1992;31:158A
Britt, W. 'Manifestations of Human Cytomegalovirus Infection: Proposed
Mechanisms of Acute and Chronic Disease' in Current Topics in
Microbiology and Human Immunology eds. Shenk, TE & Stinski, MF.
Springer-Verlag, Berlin. 2008
Amir J, Wolf DG, Levy I. Treatment of symptomatic congenital
cytomegalovirus infection with intravenous ganciclovir followed by longterm oral valganciclovir. European Journal of Pediatrics. 2010;169:1061–
1067
Fink KR et al. Neuroimaging of Pediatric Central Nervous
System.Cytomegalovirus Infection. 2010. View
Kimani R W et al. Sensorineural Hearing Loss in a Paediatric Population.
Arch Otolaryngol Head Neck Surg. 2010;136(10): 999-1004
Dollard SC, Schleiss MR, Grosse SD. Public health and laboratory
considerations
regarding
newborn
screening
for
congenital
cytomegalovirus. J Inherit Metab Dis 33 2010;(Suppl 2):S249–S254
Sung H & M R Schleiss. Update on the current status of human
cytomegalovirus vaccines. Expert Review Vaccines. 2010;9(11), 1303–
1314
Self Assessment
Question 1
CONGENITAL
CYTOMEGALOVIRUS
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Learning Objectives
Introduction
Congenital Infections
Microbiology
Epidemiology
Clinical Features
Clinical Findings and
Deficits
Sensorineural
Deafness
Long term Sequelae
Diagnosis
Neuro-Imaging
Treatment
Vaccines
Key Points
Summary
Further reading
Self Assessment
Which one of the following is a common neurological
sequelae of neonatal CMV infection?
A.
B.
C.
D.
Spastic quadriplegia/hemiplegia
Sensorineural hearing loss
Seizures/epilepsy
Visual impairment
To learn more about neurological infectious diseases…
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