CMV (Cytomegalovirus)

Congenital

Congenital – Neonates

Commonest congenital infection in developed world – 0.3% of births. Assoc with STIs, breast feeding and childcare. About 40% of pregnant women seronegative. Primary maternal CMV transmits in 40%, of which 10% symptomatic. Symptomatic babies have 30% mortality, and 90% morbidity. Even asymptomatic babies have 5-15% long term sequlae esp deafness. Virus is found in all body fluids so spread by close contact. Survives in fomites for several hours, but no apparent increase in risk in health care environments cf nurseries. Transmission usually occurs during primary infection, but possible in maternal reactivation (but disease is less aggressive) – an important issue if a vaccine is ever considered. Gestation at time of infection not very important (cf toxo, rubella, etc!).

CMV positive mothers nearly all secrete CMV DNA in breast milk, even if other body fluids are negative! Main cause of postnatally acquired CMV – usually asymptomatic in term babies but can be severe in preterms. See Prevention, below.

Causes anaemia, thrombocytopaenia, petechiae, hepatosplenomegaly, pneumonitis. Can cause a sepsis-like syndrome. Also chorioretinitis, enteritis (even NEC type picture), conjugated jaundice, and/or aseptic meningitis. Later, abnormal teeth, deafness (about 12% of all cases, can be progressive but sometimes improves, major economic impact), cerebral palsy. CNS involvement can lead to abnormal tone and (rarely) seizures. Whether postnatal infection can also cause late effects is uncertain.(Pediatr 2003;143:16-25, PMID 12915819 )

Investigations

CT to look for intracranial calcifications (more sensitive than USS), opthalmology. Urine/blood PCR, culture of urine and surface swabs. IgG will usually be maternal, as usual; IgM is only 70% sensitive and sometimes gives false positives (in adults, can persist or reappear during reactivation). The presence of low/moderate avidity anti-CMV antibody indicates primary infection, and persists for about 20 weeks.

USS is vaguely prognostic: (n=57) at least 1 sequela developed in all neonates with symptoms who had abnormal US results, whereas none of the neonates with symptoms who had normal US results had long-term sequelae. Unusual to get asymptomatic babies with abnormal scans. In the population without symptoms, sensorineural hearing loss developed in 3 of 37 (8.1%) neonates with normal US results, so NPV isn’t great. (J Pediatrics Volume 150, Issue 2 , February 2007, Pages 157-161)

Guthrie PCR testing has been looked at, but sensitivity only about 70% cf urine.

Treatment

Ganciclovir gives mixed results, many studies have been uncontrolled and small. Not curative: appears that viruria always returns. Drug is carcinogenic, mutagenic, causes infertility, needs central line, 6/52 course, causes neutropenia in 63% so line infection is a big problem. For sepsis-like syndrome, treatment with Ganciclovir is worthwhile until oral valganciclovir can be tolerated. For less severe infections, the risk:benefit balance of treatment is less clear. Kimberlin RCT (n=100) chose patients with:

  • microcephaly
  • deafness
  • intracranial calcification
  • chorioretinitis
  • or abnormal CSF

Patients received 12mg/kg/d of Ganciclovir for 6 weeks. At 1 year, just 26% of untreated controls had normal hearing in their best ear. 50% of the ganciclovir group had improved hearing or maintained normal hearing cf 26% of controls (not significant). 21% of the ganciclovir group had deterioration cf 68% of controls (p=0.002). Interim results at 6 months were similar. These figures are for hearing in the best ear.

In conclusion, in a fairly small study, ganciclovir appears to help prevent hearing deterioration for at least a year, and may also help recovery of hearing impairment. The number needed to treat (NNT) is 1.91 to prevent 1 case of hearing deterioration at 6/12, and 3.66 at 1 year. There are, however, some problems with Kimberlin’s trial.

  • The intervention requires a central line, and ganciclovir causes neutropenia. Grade 3 or 4 neutropenia was seen in 64% of treated patients, although this led to discontinuation of treatment in only 4 out of the 29 patients on ganciclovir.
  • 3 patients had catheter infections.
  • There were 3 deaths in the ganciclovir group and 6 in the control group. None of the deaths was considered to be related to therapy.
  • It should also be noted that there was an extremely high drop out rate (58%) due to a combination of factors including difficulties with transport, and access to BSER testing. This drop out rate could potentially lead to confounding.
  • There was little evidence of other benefit to treatment. There was no difference in resolution of hepatosplenomegaly or retinitis. There was better weight gain and head growth at 6 weeks but this was not sustained at 1 year. A subsequent conference abstract looked at developmental delay using the Denver developmental evaluation and found significantly less delay at 12 months but neither this study nor any other longer term neurological outcome data appear to have been published, perhaps surprisingly.(Oliver et al, Pediatric Academic Societies 2006)

Valganciclovir

Valganciclovir is a prodrug of ganciclovir. It is an oral preparation. Pharmacokinetic studies have found that a dose of 16mg/kg produces a similar AUC12 (area under the concentration-time curve over a 12 hour period) to that obtained with ganciclovir. Neutropenia was still seen but was less common, perhaps because of the dosing strategy and drug level monitoring.

It is an attractive alternative to ganciclovir but there is currently no evidence to show any long term benefit. A current UK placebo controlled study aims to compare 6 weeks and 6 months of valganciclovir (16mg/kg). A randomized comparison with ganciclovir has not been attempted, perhaps due to fears of a high drop out rate.

How to counsel parents

Given the limited evidence and the complex nature of the interventions, a full discussion should be had with the parents and a treatment plan drawn up with their explicit consent.

Issues to consider are:

  • How severe is the infection? Microcephaly, petechiae, IUGR, cranial USS abnormalities are all indicators of a poor outcome. Viral load predicts asymptomatic babies at high risk of deafness.(Arch Dis Child 2008 PMID 18039747) This may increase the perceived need for intervention, or alternatively make intervention seem more hopeless.
  • How do the parents feel about the potential for deafness or other disability? Deafness is not inevitable, and may not be the most significant issue for that child. Different individuals have differing attitudes about the seriousness of potential disabilities.
  • Can parents accept an experimental treatment? Neither ganciclovir or valganciclovir are used routinely, and the evidence in their favour is limited. At the same time there is no long term safety data.
  • If treatment is considered, does the lack of evidence for valganciclovir compensate for its ease of use and better side effect profile? An initial course of ganciclovir followed by valganciclovir is another option, particularly if access or side effects are problematic.

Prevention

Postnatal infection is known to occur, ie initial screening of the baby is negative, but blood PCR turns positive after 10 days, or urine after 3 weeks of age. Breast feeding is the most likely mechanism, given that blood products for transfusions are generally CMV negative or leucodepleted. CMV can be found in the breast milk of most seropositive mothers, even though it does not appear in maternal urine/blood, so it appears to be local reactivation in the breast! There also appear to be factors in the milk that inhibit CMV (hence virolactia is not the same as DNAlactia!).

The rate of postnatal infection varies widely between studies (6-55%), as does the rate of symptomatic infection (0-75%). (Hamprecht K, J Clin Virol 2008;41:198�205.) The mean age at seroconversion is 77 days; appears to be related to maternal IgG level, and whether virus can actually be cultured from milk or not.(PIDJ 2004 PMID 15361725) In term babies postnatal infection is rarely symptomatic, but in preterm babies a spectrum of disease is seen, with some developing a sepsis syndrome, others just transient neutropenia, thrombocytopenia, and cholestasis. The severity appears to relate to gestation and birth weight (inversely related, with the highest risk in birthweights below 1000g and gestation below 30 weeks).(Maschmann J, Clin Infect Dis 2001;33:1998�2003). Evidence to date does not support any long term sequelae of postnatal infection, in term or preterm babies. Luck S, Arch Dis Child 2009;94:F58-F64 PMID 18838466 Freeze-thawing and pasteurization are quite effective at eliminating CMV from breast milk (Holder pasteurization, ie for 30 min at 62.5�C, is probably more effective) and the UK association for milk banking (UKAMB) recommends a sequence of alternate freezing and pasteurization – but immunological qualities of breast milk are affected, and cases of severe infection have still been described.(Hamprecht K, J Clin Virol 2008;41:198�205.)

Whether the breastmilk of all seropositive mothers should be treated before being given to preterm babies is unclear. Austria and France currently support pasteurization. If risk factors for symptomatic infection could be identified, then a selective policy might be the best way forward.

Prevention in utero has been tried. IVIG should theoretically work if sufficient seropositives in donating population but a RCT of its use preventively did not show significant benefit. CMV hyperimmune globulin has been given to Italian women with CMV in amnio, only 1 of 31 had an infant with symptomatic CMV at birth, as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Appears to be safe, and also to prevent disease in women with primary infection. Not strictly an RCT, and surprisingly high rate of CMV disease in primary infection. N Engl J Med. 2005 Sep 29;353(13):1350-62

See Euro Cong CMV initiative, who have a register of cases and are looking at whether viral load will help predict which babies do badly.