Congenital CMV infection the first years of life. Jacob Amir 2017

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1 Congenital CMV infection the first years of life Jacob Amir 2017

2 Congenital CMV infection - introduction Is the most common cause of non-hereditary hearing loss. Is the most frequent viral cause of mental retardation in developed countries. In approximately 1:750 live birth infants, permanent disabilities occur,loriv )2007 dem ver :CS drallod(

3 Congenital CMV Epidemiology Congenital infection occurs in approximately 1% of live births. Most cases are subclinical. In the USA, out of approximately 44,000 infants annually - 4,400 have S & S of cong. CMV. In Israel, the calculated numbers of infants will be 1,700 per year.

4 Natural history of primary maternal infection with CMV Periconceptional- fetal infection 5-20% First trimester- fetal infection 35% infants sequellae 25-30% Second trimester- fetal infection 40% infants sequellae 20% Third trimester- fetal infection 50% infants sequellae < 5%

5 Natural history of infant with congenital CMV (primary maternal infection) Asymptomatic infant- 15% late onset hearing loss Mild symptomatic- SNHL %, neurodevelopmental disorders % Moderate symptomatic-snhl - 70% neurodevelopmental disorders-40-70% Sever symptomatic SNHL- 70%, vision disorder- 10%, neurodevelopmental disorders->95%

6 The outcome of infants born to mother with primary maternal CMV infection fetal infection 100- cases symplomatic infection 15 - cases asymptomatic infection 85 - cases develop sequelae 14 - cases develop sequelae 13 - cases Remington & Klein- textbook 2011

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8 Congenital CMV Infection

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10 Non primary congenital CMV infection Attribution of congenital cytomegalovirus infection to primary versus non-primary maternal infection. Wang G, Zhang X, Bialek S, et al. Clin Inf Dis 2011;52: The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model. de Vries JJ, van Zwet EW, Dekker FW, et al. Rev Med Virol 2013;23:241 9.

11 Infants screening Generalized screening Targeted screening

12 In Israel, screening for CMV infection is not recommended by the ministry of health However, screening is frequently performed before or during the first trimester of pregnancy Amniocentesis is performed in mothers with a primary infection in order to detect fetal infection.

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14 2011

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16 To evaluate the outcome of infants born to mothers with positive amniotic fluid for CMV after primary infection in the first and second trimester. Short- and intermediate term followup of these infants.

17 The diagnosis of primary CMV infection: 1. Seroconversion of IgG from negative to positive during pregnancy; 2. Low IgG with low avidity in the presence of specific IgM and a significant rise in IgG and avidity at a later date 3. Clinical symptoms (fever >10 days, rash, weakness, elevated liver enzymes, thrombocytopenia) in the presence of positive specific IgM and increased titers of IgG with low avidity.

18 Amniocentesis to detect fetal CMV is performed after 21 completed weeks of gestation and at least 7 weeks after the assumed date of infection. Fetal CMV infection is diagnosed when the virus is detected in the amniotic fluid by both PCR and rapid shell vial culture.

19 Fetal brain US Fetal brain MRI Normal fetal brain imaging

20 Funduscopy Ultrasonography (brain US) Blood tests, CBC, liver and kidney function. Brainstem evoked response audiometry (BERA) during the first 2 weeks of life and again every 3-6 months through age 2 years. behavioral hearing tests are performed from age 2 to 5 years. Tympanometry is performed in patients with an abnormal BERA test and suspected conduction problems. If middle ear dysfunction is found, BERA is repeated after a few weeks, and only the bone-conduction results are used.

21 Full physical examination and neurological and developmental assessments are performed in the neonatal period, and every 3-6 months thereafter. Bayley Scales of Infant and Toddler Development, 3 rd Edition (Bayley-III) was administered to a subgroup of the patients at age 1-3 years by a clinical psychologist

22 IV ganciclovir 5mg/kg twice a day for 6 weeks followed by oral valganciclovir, 17mg/kg/dose in 2 daily doses for another 6 weeks and then 1 daily dose for 9 months. ( ) Valganciclovir 17mg/kg/dose (Amir J, Eur J Pediatr in 2,2010( daily doses for 12 weeks followed by 1 daily dose for 9 months. ( )

23 Between January 2007 and January 2013, 101 infants (>1Y) with known primary maternal CMV infection in our clinic. 3 cases were lost to follow-up All infants were diagnosed by positive amniotic fluid confirmed by positive urine culture after birth. 98 are seen routinely in our clinic

24 Number of cases

25 Primary CMV infection in all First trimester - 52 cases Second trimester - 46 cases Amniocentesis performed-mean 27.5±4.8 wks. range wks.

26 Full term infants 92 Preterm infants 6 (34-36 weeks) Birth weight mean 3094 ± 494 grams A.G.A 94 infants (96%) S.F.D 4 infants (1900, 2300, 2460,2490 Gr )

27 Table 1 Postnatal signs and symptoms in infants with congenital CMV infection (n=98), by trimester of infection Signs and symptoms 1 st trimester 2 nd trimester n=52 (%) n=46 (%) P Abnormal brain ultrasound* 25 (48.1) 21 (45.7) Small head circumference 4 (7.7) 2 (4.4) Thrombocytopenia 3 (5.6) 1 (2.2) Elevated liver enzymes 2 (3.9) 2 (4.4) Chorioretinitis 1 (1.9) 0 (0) Splenomegaly 9 (17.3) 9 (19.6) SNHL (ears) 16 (15.4) 9 (9.8) SNHL, sensorineural hearing loss

28 Signs & symptoms 1 st trimester N=52 (%) 2 nd trimester N=46 (%) P Abnormal brain US 25 (48.1) 21 (45.7) Small head circumference. 4 (7.7) 2 (4.4) Thrombocytopenia 3 (5.6) 1 (2.2) Elevated liver enzymes 2 (3.9) 2 (4.4) Chorioretinitis 1 (1.9) 0 (0) Splenomegaly 9 (17.3) 9 (19.6) SNHL* (ears) 16 (15.4) 9 (9.8) SNHL-sensorineural hearing loss *

29 Signs and symptoms 1 st trimester 2 nd trimester n=52 (%) n=46 (%) P Abnormal brain ultrasound* 25 (48.1) 21 (45.7) Small head circumference 4 (7.7) 2 (4.4) Thrombocytopenia 3 (5.6) 1 (2.2) Elevated liver enzymes 2 (3.9) 2 (4.4) Chorioretinitis 1 (1.9) 0 (0) Splenomegaly 9 (17.3) 9 (19.6) SNHL (ears) 16 (15.4) 9 (9.8) SNHL, sensorineural hearing loss

30 Brain imaging ultrasound Hearing loss Chorioretinitis Microcephaly

31 Calcifications Ventricular dilatation Periventricular hyperechoisity Periventricular pseudocyst Lenticulostriated vasculopathy (LSV (

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33 Normal brain US -52 infants (53%) Abnormal brain US 46 infants (47%) LSV 44/46 (95.7%) Periventricular hyperechoisity 1 Calcifications (small) -1

34 Hearing Number of ears % Normal Mild hearing loss Moderate hearing loss Sever hearing loss Hearing loss in 12.8%

35 52 infants were treated in the first mo -53% An additional 5 infants started treatment for late onset SNHL (total 58.2%) 20 patient started IV ganciclovir 37 patient only oral valganciclovir

36 Follow-up

37 The mean duration of follow-up was 35.1±16.1 months Infants infected during the first trimester were followed for significantly less time than those infected during the second trimester (29.7±14.2 versus 41.0±15.6 months, P<0.001).

38 Hearing level (SNHL) Normal (<25dB) Mild (25-44 db) Moderate (45-69 db) Sever ( 70 db) Initial study 171 (87.2) 13 (6.6) 9 (4.6) 3 (1.5) Last study 186 (94.9) 4 (2.0) 2 (1.0) 4 (2.0) Hearing loss in 5.1%

39 Table 2 Initial and last assessments of hearing levels in 98 infants (196 ears) with congenital CMV infection by trimester of infection* Initial study Last study 1 st trimester 2 nd P 1 st trimester 2 nd P Normal 88 (84.6) 83 (90.2) (91.4) 91 (98.9) Mild SNHL 6 (5.8) 7 (7.6) 3(2.9) 1(1.1) Moderate SNHL 7 (6.7) 2 (2.2) 2 (1.9) 0 (0.0) Severe SNHL 3 (2.9) 0 (0.0) 4(3.9) 0 (0.0) *Mean duration of follow-up, 35.1±16.1 months. SNHL, sensorineural hearing loss

40 Hearing Number of cases % Normal Mild hearing loss 0 0 Moderate hearing loss 0 0 Sever hearing loss 2** 2 ** Cochlear implantation

41 All 98 children were attending regular educational institutions. 5 were in first or second grade, 40 in kindergarten, and 53 in day-care centers. Two children experienced mild motor delays (started independent walking at 18 and 19 months).

42 The BSID was administered by a trained psychologist 27 infants age months were studied The mean mental developmental index (MDI) was ±10.3 (range ).

43 The patient with chorioretinitis had normal vision with a small retinal scar.

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45 מה הסיבות שהתוצאות בארץ שונות כל כך מהידוע בספרות?

46 Primary CMV infection-prenatal selection CMV serology screening TOP in pregnant women with positive amniotic fluid and abnormal fetal imaging

47 Post natal factors High rate of early treatment with valganciclovir

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49 Hearing loss and LSV Solitary LSV No Therapy Group - 1 Solitary LSV Therapy group - 2 LSV + SNHL Therapy Group - 3 Asymptomatic Group - 4 Number of Cases Number (%) Hearing loss 11 (84.6%) 0 5 (9.6%) P Values 1-2 P< P= P<0.001

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54 Conclusion In children with late-onset hearing loss due to congenital CMV infection, treatment with ganciclovir/valganciclovir beyond the neonatal period appears to be beneficial in preventing further deterioration and inducing improvement. Controlled studies are needed to verify this observation.

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59 בסיכום הפרוגנוזה של ילדים עם CMV מולד והדמיה תוך רחמית תקינה היא טובה מאד עם מעט מאוד נזקים לטווח ארוך בילדים שנולדו לאימהות שלא היו במעקב במהלך ההיריון, הפרוגנוזה תלויה במידת הנזק. אם הנזק התוך רחמי היה קל או בינוני, טיפול מוקדם ישפר חלק גדול מהם. אלה שנולדו עם נזק קשה, השפעת הטיפול קטנה, אולי רק תשפר שמיעה.

60 סיכום האתגרים לעתיד איתור תינוקות עם הדבקה לא ראשונית מסוג הדבקה חוזרת טיפול בזמן ההיריון למניעת הדבקת העובר CMV ל חיסון

61 THANK YOU