C M V a n d t h e N e o n a t e D r M e g P r a d o N e o n a t o l o g i s t D i r e c t o r, N I C U, S t F r a n c i s M e d i c a l C e n t e r

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1 C M V a n d t h e N e o n a t e D r M e g P r a d o N e o n a t o l o g i s t D i r e c t o r, N I C U, S t F r a n c i s M e d i c a l C e n t e r

2 C M V S e r o - P r e v a l e n c e ( I g G p o s i t i v i t y )

3 T h e N a t i o n a l H e a l t h a n d N u t r i t i o n E x a m i n a t i o n S u r v e y s,

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7 C y t o m e g a l i c I n c l u s i o n D i s e a s e ( C I D ) most severe form of congenital CMV almost always occurs in women with primary disease during pregnancy IUGR hepatosplenomegaly hematologic abnormalities (thrombocytopenia) petechiae purpura

8 C y t o m e g a l i c I n c l u s i o n D i s e a s e Microcephaly ventriculomegaly cerebral atrophy chorioretinitis sensorineural hearing loss intracranial calcifications predictive of cognitive, audiology deficits and poor neurodevelopment prognosis

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13 A s y m p t o m a t i c C o n g e n i t a l C M V most infants with congenital CMV born to women with existing immunity to CMV they appear well at birth may have subtle growth restriction major consequence is hearing loss: unilateral or bilateral, 15% of affected infants may not be detected by hearing screen at birth may develop months or years after birth

14 A c q u i r e d C M V I n f e c t i o n

15 A c q u i r e d C M V i n f e c t i o n acquired CMV infection occurs postnatally generally asymptomatic (term, well) may be symptomatic (preterm, immunocompromised) exposure to infected vaginal secretions or via breastfeeding CMV acquired by term babies via breastfeeding regarded as a form of natural immunization

16 A c q u i r e d C M V i n f e c t i o n disease due to postnatal exposure (breastfeeding or breast milk) generally limited to preterm/low birth weight infants lymphadenopathy, hepatitis, pneumonitis can be severe/life-threatening considerable morbidity need more longterm data on preterm infants who acquire CMV perinatally from breast milk blood transfusions no longer considered significant source of infection postnatally

17 A c q u i r e d C M V i n f e c t i o n recent study in JPeds, April 2015 by Brecht et al 42 adolescents born very preterm 19 with and 23 without postnatal CMV infection compared to 24 typically developing adolescents who were born term and healthy cognitively and visuoperceptively, adolescents born very preterm scored significantly lower than term controls furthermore, adolescents born very preterm with postnatal CMV infection scored significantly lower than those born very preterm without postnatal CMV infection

18 A c q u i r e d C M V i n f e c t i o n very important study!!! though small cohort, results show that adolescents born very preterm who are infected with CMV postnatally suffer significantly more cognitive deficits than adolescents born very preterm who are not infected with CMV postnatally if confirmed, these results stress the importance of strong efforts for prevention in this group of babies must direct our efforts at reducing transmission to these most vulnerable infants via breast milk

19 Long- t e r m H e a l t h C o n s e q u e n c e s atherosclerosis immunosenescence increased risk of malignancy (oncomodulation) need further study may indicate potential justification for universal vaccination of both sexes against CMV

20 P r e v e n t i v e S t r a t e g i e s

21 P r e v e n t i o n d u r i n g p r e g n a n c y needs to be directed toward seronegative women at risk of primary infection or women with primary disease routine prenatal CMV screening during pregnancy not universally recommended due to lack of proven effective intervention to prevent CMV transmission poor reliability of IgM assays (may be present during primary or reactivation, false positives) IgM only present in 30% of women with a primary infection IgG avidity testing significantly improves ability to identify primary infection (1997, Lazzarotto et al, Clin Diagn Lab Immunol)

22 P r e v e n t i o n d u r i n g p r e g n a n c y CMV-specific hyperimmune globulin (HIG) in primary infection recent RCT in 124 pregnant women with documented primary infection (2014, Revello et al, NEJM) CMV-HIG group: 30% delivered infants with congenital CMV compared to 44% in the placebo group Not statistically significant but encouraging 2 ongoing large RCTs will hopefully provide definitive evidence for this treatment modality (2015, Bialis et al, NeoReviews)

23 P r e v e n t i o n d u r i n g p r e g n a n c y live-attenuated vaccines have failed to protect seronegative women with children attending daycare (1998, Adler et al, J Infect Dis) CMV subunit/adjuvant vaccines may appear to be more effective, multiple in development (2009, Pass et al, NEJM) risk factors: lower SES, history of STDs (HPV), very young maternal age (<15) child care workers/young children at home proper hygiene and behavioral practices

24 G o t m i l k?

25 P r e v e n t i o n o f p o s t n a t a l C M V f r o m b r e a s t m i l k investigators in Germany and Japan, using CMV DNA PCR viral shedding in breast milk of CMV-seropositive women is very high (70-90%) viral shedding is seen as early as 2-3 wks post-delivery, peaks by 3-6 weeks and usually ends around 8-10 weeks pasteurization: destroys virus but also destroys important nutritional/immunologic factors freezing at -20 overnight reduced infectivity by 90%, after 72 hours, by 99% and >7 days no virus detected the plot thickens: still mrna present after freezing

26 T r e a t m e n t o f p o s t n a t a l C M V

27 T r e a t m e n t o f p o s t n a t a l C M V The Collaborative Antiviral Study Group (2003, Kimberlin et al, JPeds) looked at infants with congenital CMV and CNS-involvement 6 weeks IV ganciclovir clear improvement in hearing outcome in infants who received ganciclovir neutropenia in 2/3 treated infants long-term IV therapy challenging as many infants did not need 6 weeks of hospitalization

28 T r e a t m e n t o f p o s t n a t a l C M V same group found similar pharmacokinetics and plasma levels using the oral pro-drug, valganciclovir more practical solution 6 months of oral valganciclovir versus 6 weeks has been shown to improve hearing and developmental outcomes for CMV-infected children more work: not treating babies who are asymptomatic at birth?treatment for preterm and very preterm infants