Cytomegalovirus in Neonates

David K. Hong, MDPediatrics/Infectious Diseases &

Immunology/AllergyStanford University Medical SchoolSanta Clara Valley Medical Center

Objectives

1. Describe the clinical features of congenital infection with CMV2. Review current treatment options for congenital CMV infections3. Discuss the unique features of CMV infections in premature infants

Cytomegalovirus

Beta herpesvirus - dsDNACo-evolved with humansLargest virus to infect humans – 230 proteins

CMV infection is not cleared. Chronic infection leads to intermittent viral shedding

1956 – Margaret Smith isolated virus from human salivary gland1965 – 1st recognized CMV disease in a healthy adult (Br Med J. 1965;1099:102)

CMV - Pathology

• Cell enlargement with intranuclear inclusions– “Cytomegalic inclusion

disease”

• Cytomegalia in viscera and parotid glands.– “salivary gland virus”

Margaret Smith. Proc Soc Exp Biol Med 1956, 92:424

Thomas Weller named virus Cytomegalovirus

Historical Interest

Virologic and Clinical Observations on Cytomegalic Inclusion Disease. Thomas Weller and JB Hanshaw. NEJM 1962

Clinical Manifestations of acute CMV infectionImmunocompetent Individuals

Primary CMV infection in immunocompetent children and adults is usually asymptomatic

Clinical features of acute infection overlap with EBV

Mononucleosis syndrome – more common in EBV-fever, lymphadenopathy, lymphocytosis-Mean duration of fever is 2 weeks

Sore throat with enlarged exudate-covered tonsils – more common in EBV

Low level elevation of liver transaminases common (>90%)

CMV infection is very CommonPrevalence of CMV by Age Group and Ethnic Group

Bates SL et al, CID 2010 vol. 50 (11) pp. 1439-1447

Mexican American females

Mexican American males

Non-Hispanic white females

Non-Hispanic white males

Stagno S et al, Clin Obstet Gynecol. 1982 Sep;25(3):563-76

CMV is the most common congenital infection

Stanford/El Camino Hospital/SCVMC – 0.6%

Stagno S et al, N Engl J Med 1982; 306:945-9

Multiple studies have shown maternal acquisition of CMV leads to fetal infection from 33—75%

Disease rates may be as high as 50% if infection occurs during first half of pregnancy

10% 90%

Disease manifestations – Congenital CMV

Symptomatic at birth

Symptomatic at birth

10%

Newborn infected with CMVNewborn infected with CMV

Congenital CMV

AsymptomaticAsymptomatic

90%

90% 10%

Progressive hearing lossProgressive hearing lossNo symptomsNo symptoms

DeathDeath

5-10%

Sensorineural hearing loss

Sensorineural hearing loss IQ < 70IQ < 70 Microcephaly,

seizures, paralysisMicrocephaly,

seizures, paralysis

~3% with bilateral hearing loss

SurvivalSurvival

50%

~33% with bilateral hearing loss

55% 52%

IQ < 70, Microcephaly, seizures, paralysis

IQ < 70, Microcephaly, seizures, paralysis

3%

Clinical abnormalities in symptomatic congenital CMV

Boppana SB et al, Pediatr Infect Dis J. 1992 Feb;11(2):93-9

Laboratory abnormalities in symptomatic congenital CMV

Boppana SB et al, Pediatr Infect Dis J. 1992 Feb;11(2):93-9

Symptomatic Congenital CMV

• 10% die

• 45% - 90% will have CNS sequelae

• Sequelae – Sensorineural hearing loss– Developmental & cognitive

deficits – Chorioretinitis

Congenital CMV Risk Factors• Caring for preschool children in the year before delivery• Onset of sexual activity <2yrs before delivery• Sexually transmitted diseases during pregnancy• Household size > 3 people• Maternal age < 25• Seroconversion between children and delivery of subsequent

child within 2 years• HIV infection• Pre-term delivery• Lower socioeconomic status• Black race

Fowler KB, Pass RF Pediatrics (2006) 118:e286; Fowler KB, Stagno S, Pass RF. Clin Infect Dis 2004; 38:1035–1037; Kenneson A, Cannon MJ. Rev Med Virol 2007; 17:253–276.

Diagnosis of Congenital CMV

• Virus should be isolated within the first 2-3 weeks of life

• Isolation of CMV after this time may represent acquisition at birth or post-natally

• Options for isolation of virus include viral culture or PCR from saliva or urine

• CMV IgM lacks adequate sensitivity or specificity compared with culture or PCR

Stagno S et al, N Engl J Med 1982; 306:945-9

CMV-infect infants shed virus in their urine for many months

CMV viral testing• Conventional viral culture can take 2-4 weeks

to isolate CMV• CMV shell vial – identification can occur in 24-

48 hours• CMV PCR in urine is available at LPCH

Specimen is centrifuged onto cover slip covered with fibroblasts to accelerate virus entry

CMV is detected with fluorescent antibodies against early CMV proteins

How many CMV urine tests are needed?

Viral culture POS NEG Shell POS 13 1 14 Sensitivity = 1 NEG 0 753 753 Specificity = .999 13 754 PPV = 0.923 NPV = 1

Viral culture POS NEG Shell POS 16 1 17 Sensitivity = 1 NEG 0 1220 1220 Specificity = 0.999 16 1221 PPV = 0.941 NPV = 1

Viral culture POS NEG Shell POS 20 1 21 Sensitivity = 1 NEG 0 1530 1530 Specificity = 0.999 20 1531 PPV = 0.952 NPV = 1

1st test

2nd test

3rd test

Two CMV urine tests are adequate to screen for CMV infection

Courtesy N. Srinivas, LPCH

Treatment of Congenital CMV

• Antiviral against CMV is available– Ganciclovir - IV

• Which patients do you treat?• How long do you treat?• How do you know if it worked?

J Pediatr 2003; 143:16-25

- Enrolled 100 patients with symptomatic CMV disease involving the CNS- Patients received 6 weeks of IV ganciclovir- Patients were followed for 1 year and had hearing evaluations at 6 months and 1 year- Found less hearing loss at 6 months and possibly less hearing loss at 1 year

Kimberlin DW. J Pediatr 2003, 143:16;

Ganciclovir therapy appears to be beneficial

• After 6 weeks of IV ganciclovir…

– At 6 months, 84% (21/25) improved or maintained hearing status

• 59% (10/17) controls

– At 12 months, 21% (5/24) worse hearing• 68% (13/19) controls

Kimberlin DW. J Pediatr 2003, 143:16;

Major caveats…• 100 subjects enrolled; 42 with full follow-up for

analysis• 63% (29/46) grade 3 or 4 neutropenia

– Dosage modifications 14/29 patients– GCSF in 2 patients– Gram negative sepsis in 1 patient

• What about mildly symptomatic or asymptomatic patients?

• How do you know 6 weeks is enough?– CMV can be detected in inner ear fluid

(perilymph/endolymph) in patients getting cochlear implants

1. Virus in the urine increases after treatment

2. Viral load in blood increases after treatment

3. CMV genome detected in perilymph

3 Reasons for Prolonged Ganciclovir Therapy

Whitley RJ, et al. JID 1997, 175:1080; KImberlin DW, et al. JID, 2008, Mar 15; Bauer PW, et al. Laryngoscope 2005, 115:223Sugiura S, et al. J mEd Virol 2003, 69:72

Valganciclovir is a form of ganciclovir that can be given orallyDosing information is now available for infants

J Infect Dis (2008) 197:836-45

CASG 112

CASG 112

CASG 112

Symptomatic at birth

Symptomatic at birth

10%

Newborn infected with CMVNewborn infected with CMV

Congenital CMV

AsymptomaticAsymptomatic

90%

90% 10%

Progressive hearing lossProgressive hearing lossNo symptomsNo symptoms

DeathDeath

5-10%

Sensorineural hearing loss

Sensorineural hearing loss IQ < 70IQ < 70 Microcephaly,

seizures, paralysisMicrocephaly,

seizures, paralysis

~3% with bilateral hearing loss

SurvivalSurvival

50%

~33% with bilateral hearing loss

55% 52%

IQ < 70, Microcephaly, seizures, paralysis

IQ < 70, Microcephaly, seizures, paralysis

3%

Asymptomatic congenital CMV

• 90% of infants infected with CMV have no symptoms

• 5-10% will progress to sensorineural hearing loss• We do not know…

– Which infants will have progressive hearing loss.– If ganciclovir treatment would prevent hearing loss– If treatment is helpful, how long would you need to

treat?

• Routine screening of newborns and treatment of newborns is NOT recommended at this time

Can anti-CMV immunoglobulin prevent severe congenital infection?

Nigro G et al, N Engl J Med 2005 vol. 353 (13) pp. 1350-1362

Congenital CMV disease

1 (3%) 7 (50%) 6 (16%) 19 (40%)

Prospective, double-blind, placebo-controlled randomized controlled trial evaluating the effectiveness of CMV hyperimmune globulin (Cytogam) at preventing congenital CMV infection in babies born to moms with primary CMV infection during the first half of pregnancy

Inclusion Criteria:-Primary CMV infection in a mother prior to :

- 24wks gestational age - Singleton pregnancy

Intervention:-Cytogam – 100mg/kg – how many doses?

Primary outcome measures:-fetal loss (spontaneous or termination)-confirmed fetal CMV infection from amniocentesis-neonatal congenital CMV infection diagnosed by urine or saliva collected by 3 weeks of age that is positive for CMV by culture (the intent will be to obtain in the first two days of life)

A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV) - NCT01376778

CMV Vaccine?

The ideal vaccine would:-induce high levels of CMV neutralizing antibodies-Would be targeted at women of child-bearing age-Would have to induce immunity better than natural immunity

- recent phase 2 trial showed 50% vaccine efficacy at preventing CMV infection in CMV-seronegative women over 42 months

- 1 infant had congenital CMV in vaccine group (1%), while 3 infants had congenital CMV in placebo group (3%) – more women became pregnant in the placebo group

CMV glycoprotein B vaccine with MF59

Pass RF et al, N Engl J Med (2009) 360:1191

Acquired CMV infection in premature infants

Perinatal infections can be acquired from exposure to virus in maternal genital secretions, breast milk, or transfusion

Incubation period is 4-12 weeks

Most infections are asymptomatic with no long-term sequelae

Premature infants (750-1500g) at greater risk of symptomatic postnatal CMV infection-CMV from maternal source led to hepatosplenomegaly, neutropenia, lymphocytosis, thrombocytopenia. Longer oxygen requirementYeager AS et al, J Pediatr (1983)102:918

Transfusion associated CMV occurred in 13.5% of 74 infants of seronegative mothers who were exposed to blood donors with CMV

Severe or fatal CMV disease in infants born to seronegative mothers who received CMV+ blood – all were 1200g or less (<28 wks)Yeager AS et al, J Pediatr (1981)98:281-287

What about CMV acquisition via breastmilk in ELBW and VLBW babies?

CMV is shed intermittently in breast milk

Rates of symptomatic infection in VLBW and ELBW infants from breast-milk associated infections range from 0.6 – 18%

Symptoms are variable – asymptomatic infection to severe sepsis

Lower birthweight infants and younger infants were more likely to be infected with CMV

Some data suggests that administering anti-CMV immunoglobulin prophylaxis can decrease symptomatic disease from CMV acquisition

Maschmann J et al, Clin Infect Dis (2001) 33:1998; Hamele M et al, PIDJ (2010) 29:84; Capretti MG et al, J Pediatr (2009) 154:842