CMV: perinatal management of infected neonates

ccmv Epidemiology The prevalence of ccmv in developed countries is 04 0 0.4 0.8% In the UK, symptomatic congenital infection was estimated to be 3/1000 in the 1970s 80s (Epidemiol Community Health 1986;40(3):205 9; CID 2013;56(9):1232 9) the current burden of disease in the UK is unknown

T. Shah et al.

ccmv the imaging i Cranial ultrasound is a good predictor of outcomes in symptomatic ti newborns with cerebral abnormalities and is a useful initial imaging modality in newborns with suspected ccmv (Ancora et al., 2007). However, MRI may be better. MRI findings in symptomatic newborns: white matter involvement is variable, difficult to evaluate and not clearlyrelatedrelated to clinical outcome although cortical malformations, ventriculomegaly and hippocampal dysplasia are predictors of a poor neurological outcome (Manara et al., 2011) MRI may provide important information on the extent of CNS disease, including polymicrogyria, hippocampal p dysplasia and cerebellar dysplasia (L. S. de Vries et al., 2004) In one study, MRI added additional information (temporal lobe injury, white matter abnormalities, cortical malformation) to that of cranial ultrasound in 8 of 40 ccmv cases (Capretti et al., 2014)

ccmv Treatment Any baby with a diagnosis of ccmv should be considered for treatment Evidence of benefit from RCTs is only available for treatment started in the first month of life, in infants over 32 weeks gestation Treatment is with IV GCV or oralvgv 2 RCTs only 6 weeks of IV GCV had a positive effect on neurological outcome in infants with CNS involvement & reduced drisk of progression or development of hearing loss at 12 months of age (Kimberlin J Pediatr 2003) 6 weeks vs 6 months VGV in symptomatic ccmv disease +/ CNS involvement: 6 m improved audiological and neurodevelopmental outcomes at 2 years of age; improvement in language and receptive communication scales (Kimberlin NEJM 2015)

Change in hearing birth to 12 months Kimberlin NEJM 2015 (best ears) Kimberlin J Pediatr 2003

Change in hearing birth to 12 months Kimberlin NEJM 2015 (best ears) At 24 months, the 6m group vs 6w group, had better neurodevelopmental scores (BSID3): language composite component (P = 0.004) 004) receptive communication scale (P = 0.003) Kimberlin J Pediatr 2003

Research priorities ccmv 1. Which babies need treatment? RCT s have shown the benefit of treating babies with CNS involvement. The data dt on treatment t tof bbi babies with less severe disease remain limited. 2. Is there benefit of treatment starting beyond the neonatal period? (or in prems<32 weeks?) Valgan toddler (prem PK) 3. Could there be earlier testing for CMV within routine pathways? Pilot data in the UK have shown that it is feasible and acceptable to parents to test for ccmv in newborns who do not pass their initial newborn hearing screen (ArchDisChildFetalNeonatalEd 2014;99(3): 230 6; EurJPediatr 2015) Larger multi regional studies inc. costeffectiveness are warranted.

Research priorities ccmv 4. Is treatment t twith oral valganciclovircomparable l i to intravenous ganciclovir? no head dto head dti trials of intravenous vs oral treatment. t t 5. What is the best way to monitor treatment response? monitoring blood viral load is often conducted but urine may be more relevant given the high levels and prolonged virus excretion in urine. Our understanding of ccmv is still limited and there is an urgent need to combine information on a central database, since individual centres will have only small numbers of patients. Congenital CMV Initiative (ECCI) website: www.ecci.nhs.uk

Treatment of CCMV is there any benefit for treatment after the SNHL can be delayed neonatal period? Majority of SNHL in first 4 years of life (Dahle, 2000) CMV excretion is prolonged (Noyola, PIDJ 2000) T t t h i d d i Treatment when ongoing damage and virus excretion is rational but not addressed in a RCT

Characteristics of CMV related hearing loss 2/3 with CMV hearing loss are Asymptomatic at birth Any type or severity Progressive in 50% Delayed onset in 50% Dhl Dahle 2000, Fowler J Pd1999 Ped Fowler J Ped 1997, Williamson 1992 (Pass, Herpes, 2005)

Hearing loss mostly occurs over the first 4 years of life AGE SYMPTOMATIC ASYMPTOMATIC Birth 1 month 43.5% 25.5% 3 months 55.3% 31.4% 6 months 67.2% 43.1% 2 years 82.4% 47.1% 3 years 88.2% 58.8% 4 years 89.4% 72.5% 6 years 95.3% 86.6% 7 15 years 100% 100% Dhl Dahle, J AA Aud, 2000

Noyola, PIDJ 2000 Median 3.9 years (range 5mo 9.8) years Mean 4.3 (SD 2.3) years

Toddler valgan (DMID 11 0069) Can 6 wks oral valganciclovir stabilise hearing in children older than 1 month (to 4y)? Placebo controlled ll study Oral valganciclovir 6 weeks vs placebo Primary outcome 6 month audiology Secondary outcomes viral load (blood, urine, saliva) Safety & tolerability Tertiary outcomes Pharmacokinetics Dr Sue Luck, Prof fmike Sharland, Prof fpaul lgiffith Griffiths

Postnatal CMV innocent bystander or hidden problem? acquisition/transmission: perinatally/postnatally from the birth canal, maternal breastmilk milk, or other body fluids (saliva) the clinical use of maternal milk for VLBW is increasing because of its established health benefits newborns, esp. of low birth weight or extreme prematurity, are immunocompromised serious morbidity in prems following CMV acquisition is increasingly reported

Postnatal CMV innocent bystander or hidden problem? CMV transmission via breast milk first identified in the late 1960s Using PCR, Vochem et al: 96% of seropositive women had detectable CMV DNA (Pediatr Infect Dis J 1998;17:53 8) 8)

Postnatal CMV innocent tbystander or hidden problem?

Postnatal CMV innocent bystander or hidden problem? CLINICAL SIGNS in term infants, infection nearly always asymptomatic in prems many signs are attributed to pcmv.... pneumonitis, cholestasis, hepatosplenomegaly, lymphadenopathy,enteritis, enteritis, aseptic meningitis, sepsis like syndrome, neutropenia, thrombocytopenia.,

Postnatal CMV innocent bystander or hidden problem? LONG TERM SEQUELAE ccmv: neurodevelopmental impairment & sensorineural hearing loss What is potential for long term damage in neonates with pcmv infection, especially ill prems who are at a similar stage neurodevelopmentally to fetuses acquiring CMV in utero?.data are limited on long term follow up No SN deafness described

Postnatal CMV innocent bystander or hidden problem? LONG TERM SEQUELAE IN ADOLESCENTS born 23 32 weeks, infected at 36 190 days; symptomatic and asymptomatic infections

Postnatal CMV innocent bystander or hidden problem? TREATMENT Evidence in postnatal CMV is sparse and based on case reports: suggest benefit for GCV in neonatal hepatitis and cholestasis and gastrointestinal manifestations but also studies with spontaneous resolution or no obvious GCV benefit

Postnatal CMV innocent bystander or hidden problem? RESEARCH: There islittleconsensus.. Should breast milk be routinely pasteurised / frozen to prevent p CMV disease? BUT exposure to fresh mother's milk reduces the risk of other morbidities associated with NDI, including NEC, late onset sepsis, retinopathy of prematurity and other late benefits AAP 2012 policy statement: The value of routinely feeding [fresh] human milk from [CMV] seropositive mothers to preterm infants outweighs the risks of clinical disease, especially because no long term neurodevelopmental abnormalities have been reported. Does postnatal CMV causes long term sequelae?..if yes, can signs or severity at time of infection predict NDI? Could routine screening of babies with CMV VL identify a threshold for symptomatic disease; can this threshold then be used to selectively treat to prevent symptomatic infection? Does treatment with GCV/ValGCV offer benefit in pcmv disease?

Strengthening gperinatal infection management A wide range of infections can cause significant morbidity in pregnancy and the newborn period nearly every acute NHS Trust has a midwifery lead for HIV, with regular multidisciplinary team meetings between obstetric and paediatrics Services for other perinatal infections are less well developed. Information sharing between different teams may be inconsistent One approach is to build on the success of HIV and broaden this approach to include other infections. An integrated Perinatal Infection Service, bringing together primary care providers, clinical commissioning groups, midwives, obstetricians, neonatologists, paediatricians and microbiologists & virologists would allow a joined up approach to management, improved monitoring of outcomes for all infections, continuous quality improvement and make a valuable contribution to the evidence base.

CMV controversies

Reducing Acquisition of CMV through antenatal Education: A feasibility study to assess an educational intervention to prevent cytomegalovirus infection in pregnancy (RACE FIT) Attitudes of UK pregnant women to CMV awareness of CMV in UK adults; only 10% indicated knowledge about CMV, in agreement with US data. after reading information about CMV, 91% of women agreed that pregnant women should ldbe given preventive information and 75% agreed it was easy to prevent Phase 1: Development of an educational intervention (a film) to increase the awareness of CMV and encourage the adoption of risk reduction behaviours among at risk pregnant women. Phase 2: Evaluation of the feasibility of a future full scale RCT of the educational intervention in the NHS

Postnatal CMV innocent bystander or hidden problem? All surviving infants <1500 g born in one centre: June 1995 June 2000, with postnatal CMV infection acquired at up to 3 months of corrected age; controlled matched pairs design 50 eligible children, 42 (84%) tested. Mean 6.6 y no difference in the prevalence of cerebral palsy pcmv infants had significantly lower results in the simultaneous processing scale (p=0.029). Results for the sequential and achievement scales slightly reduced only (p>0.05) Arch Dis Child Fetal Neonatal Ed 2013;98:F430 F433

CMV Information: Lack of awareness Information offered to women of child bearing age, g,pregnant women, maternity health care workers Screening: Antenatal screening: Israel & 8 European countries Newborn screening Which newborns? Symptomatic? Failed hearing test? Which test? Who to perform the screening? Who would train the screeners? Is the screening acceptable to parents? Diagnosis: What is considered d severe? How useful is viral load testing? What is a high VL? Abnormal imaging / well baby how do we react? Treat as CNS disease? How predictive is thrombocytopenia?

Change in hearing birth to 6 months Kimberlin NEJM 2015 (best ear) Kimberlin J Pediatr 2003

ccmv Neonatal PK: 16mg/kg/dose of VGC bd = 6mg/kg/dose GCV, in infants 32 weeks GA (JInfectDis 2008;197:836 45) PK/PD study of GCV for infants <32 weeks underway (ClinicalTrials.gov Identifier: NCT01602614) Treatment is a balance of benefit versus risk and counselling families is critical Neutropenia can be anticipated in 50% treated with GCV, 20% VGC may require treatment interruption and rarely G CSF) Thrombocytopenia and hepatotoxicity in up to 30% of patients and risks of long term intravenous accessneed to be considered for treatment with IV ganciclovir. Long term toxicity, including potential effects on malignancy risk and fertility, is not known.