Infection

Symptomatic CCMV is defined as positive CMV in any

secretions within the first three weeks of life with clinical

manifestations of intra-uterine infection involving central

nervous system (CNS) or lymphoreticular system (1).

Neonate with life-threatening infection

Mortality rate for CCMV ranges between 5% and 10%.

CMV can cause pneumonitis, oesophagitis, colitis and

severe thrombocytopenia requiring repeated platelet transfusions

(10,15). Individual case reports have shown that infected neonates could benefit clinically and virologically

from treatment with ganciclovir.

Recommendation: Grade D: Neonates with life-threatening

infection should be considered for immediate treatment.

Neonate with central nervous system involvement

Infected neonates have CNS involvement if there is evidence

of one of the following findings: isolated microcephaly,

symmetric intrauterine growth restriction, abnormal

CNS examination, abnormal cranial US⁄CT⁄ MRI, abnormal

ophthalmology or hearing screen. Four level 1 (25–28)

and two level 2 (10,21) studies have shown that prospects

for normal development are poor, as >90% of surviving

infants develop significant CNS sequelae, perceptual defects

or both within the first 2 years of life.

One level 1 (26) and two level 2 (10,21) studies have

shown that microcephaly has 100% specificity and positive

predictive value for prediction of mental retardation (IQ <

70) and ⁄ or major motor deficits. Absence of microcephaly

is a sensitive marker for normal cognitive function.

Normal neuroimaging at birth in symptomatic CCMV

predicts a good long-term neurologic outcome (10,21,25–

28). Intracranial lesions on neuroimaging are associated

with severe intellectual impairment in >80% of cases (27).

The most common findings are intracranial calcifications

(21). MRI provides important additional information, especially

with regard to associated polymicrogyria, hippocampal

dysplasia and cerebellar hypoplasia (24,29).

Calcifications are better seen using US or CT. One level 1

study (21) has demonstrated a good correlation between

cerebral US abnormalities and prediction of outcome in

symptomatic CCMV infants. CT has been mainly recommended

in the literature, but a combination of ultrasound

and ⁄ or MRI might be a useful alternative.

Chorioretinitis can cause sight-threatening infection and

hence warrants prompt treatment. Anecdotal reports during

the CASG study suggest clinical improvement after treatment

(20). In two level 1 studies (30,31) nearly 60% of the

patients with retinitis had complete normal ophthalmological

assessment after treatment.

Sensori-neural hearing loss is the most frequent neurological

disability caused by CCMV. It can be both early-onset

and late-onset. The deafness caused can be severe enough

to require hearing aids and rehabilitation. Various studies

have tried to identify the predictors for hearing loss, i.e.

presence of petechiae, thrombocytopenia, intra-uterine

growth restriction, microcephaly, abnormalities on cranial

imaging. SNHL is defined as unequivocally failed or >30 dB

hearing loss on two or more audiologic tests suitable for

newborns and middle ear disease ruled out with normal

bone conduction or use of hearing aids in one or both ears

(10,32).

Two level 1 studies (30,33) have shown that treatment

with ganciclovir improved neurodevelopmental outcome in

24%, improved or stabilized hearing impairment in 84%

and improved visual acuity in 70% of the cases. A phase III

non-blinded controlled trial of ganciclovir for CCMV

reported that treated infants experienced a greater increase

in median head circumference from baseline to 6 weeks

evaluation although the long-term follow-up data were not

available (33).

Recommendation: Grade A: Neonates with CNS involvement

should be treated.

Neonate with disseminated CCMV infection and high viral

load or petechiae or thrombocytopenia

Disseminated CCMV infection at birth is defined as presence

of asymmetric IUGR, hepatosplenomegaly, hepatitis,

anaemia and conjugated hyperbilirubinaemia (10,20,25,26);

40–50% of neonates will show evidence of disseminated

infection at birth. Three level 1 (19,22,34) and two level 2

(12,13) studies have shown that the quantum of CMV copies

in the blood correlates with neurological outcome irrespective

of whether children are considered symptomatic or

asymptomatic at birth. Four level 1 studies (13,22,26,27)

have demonstrated that a high viral load in early infancy

expressed by a high amount of virus in the urine is highly

predictive of audiologic impairment. Greater than 70% of

symptomatic (with or without CNS symptoms) infants with

viruria of >5 · 104 pfu ⁄mL will have poor neurodevelopmental

outcome when compared with only 4% with viruria

of <3.5 · 103 pfu ⁄mL (27). In an animal model for human

CMV infection, the number of detected DNA copies of

CMV by PCR was compared with an established semi-quantitative

plaque assay (35). It was concluded that 1 plaqueforming

unit (pfu) is the equivalent of 1500 viral genome

(35). In a study presented as abstract at the ESPID meeting

2009 in Belgium the average viral load in the urine in symptomatic

infants was 1 · 107.5 copies ⁄mL (17). In a group of

four symptomatic patients from our unit the urinary viral

load was 5.6 · 107 copies ⁄mL (unpublished data). One level

2 study (36) has shown that congenitally infected newborns

have higher urinary CMV viral load (1 · 106.3 copies ⁄ mL)

when compared with post-natally acquired CMV infants.

Studies summarized in an article (37) have shown to

decrease the viral load after commencing treatment which

may lead to better hearing outcome and cognitive profile.

Two level 1 (22,26) and one level 2 (10) studies have

demonstrated that presence of petechiae and thrombocytopenia

with or without disseminated infection are associated

with an increased likelihood of SNHL and adverse neurodevelopmental

outcome. Moreover, petechiae or thrombocytopenia

and IUGR alone correlate well with development

of hearing loss.

Recommendation: Grade B: At this point in time, a treatment

cut-off has not been established as a result of the differences