mendiola-congenital cmv presentation
DESCRIPTION
citomegalovirusTRANSCRIPT
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Congenital CMV
Anna Marie Teena C. Mendiola, M.D.NICU Rotation
February 5, 2009
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Cytomegalovirus infection ubiquitous virus most CMV infections are asymptomatic
and cause mild diseaseand cause mild disease cause serious disease in newborns and
immunocompromised children
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Cytomegalovirus Infection Herpesvirus family Epstein-Barr virus (EBV); herpes simplex viruses
(HSV)-1 and 2; varicella-zoster virus (VZV); and human herpesviruses (HHV)-6, -7, and -8. human herpesviruses (HHV)-6, -7, and -8.
all share properties, including a genome of double-stranded linear DNA, a virus capsid of icosahedral symmetry, and a viral envelope
share the biological properties of latency and reactivation, which cause recurrent infections in the host.
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Cytomegalovirus Infection developing countries- most children are
infected by 3 years of age developed countries, such as the United developed countries, such as the United
States or United Kingdom, as many as 60 to 80 percent of the population will be infected with CMV by adulthood
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Fetus: Via placenta from the mother (congenital infection)
Human milk, via contact with maternal cervicovaginal secretions during delivery (perinatal infection)
How is CMV transmitted?
(perinatal infection) Blood transfusion, organ transplantation Children and adults: Mainly via bodily fluids
(esp. urine, saliva) Sexual transmission
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CMV INFECTION IN THE NEONATE: IMPORTANCE OF CONGENITAL CMV INFECTION
Most common congenital infection Approximately 1 % (0.2 2.5 % ) of live births 90% asymptomatic at birth (15% with progressive 90% asymptomatic at birth (15% with progressive
hearing loss 10% symptomatic at birth (2/3 will have neurologic
involvement) Leading cause of sensorineural hearing loss in
children Major cause of mental retardation, cerebral palsy
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Congenital CMV infectionCongenital CMV infection
Approximately 10% death in symptomatic newborns
Lifelong habilitation for impaired survivors Leading infectious cause of brain damage in US
children
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PRIMARY MATERNAL CMV INFECTION DURING PREGNANCY
95% clinically inapparent
35% transmitted to fetus
No clear relationship between gestational age and transmission
Fetal damage more likely in first 26 weeks, (32%) than later (15%)
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HIGH RISK FOR PRIMARY MATERNAL AND CONGENITAL CMV INFECTION
Teen mothers
Exposure to young children: day-care workers day-care workers mothers
Sexual activity
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Transmission of CMV through the placenta barrier and infection of the fetus
Transmission of CMV through the placenta barrier and infection of the fetus
Infected mother viraemia infection of placenta trophoblasts
Infection of fetalVirus in
Infection ofthe oropharynx
Infection of fetalendothelial cells
Viralreplication intarget organs
(kidney)
Fetal viruria
Virus inamniotic fluid
Fetal viraemia
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Symptomatic Congenital CMV Infection
Jaundice (67%) Petechiae (76%) Hepatosplenomegaly (60%) Hepatosplenomegaly (60%) Microcephaly (53%) Chorioretinitis (20%) Seizure (7%) Fatal outcome (10%)
Boppana et al. (1999) Pediatrics 104:55
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Infant born with congenital CMV infection
Skin has typical petechial and purpuric lesions. Periorbital echymoses and subconjuctival hemorrhages also are seen and were most likely caused by infant's severe thrombocytopenia (platelet count 2000/cu mm).
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Congenital CMV
Blueberry muffin lesions
Petechial rash
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Sequelae of Congenital CMV Infections
Neurological sequelae are the most common, and most severe: >90% of newborns with symptomatic congenital
CMV infection have visual, audiologic and/or other CMV infection have visual, audiologic and/or other neurological sequelae
- 5-17% of newborns with asymptomatic congenital CMV infection develop neurological sequelae (esp. hearing loss)
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Congenital CMV InfectionAbnormalities in the brain Perventricular leukomalacia & cystic abnormalities Periventricular calcifications (linear or punctate) Ventriculomegaly Vasculitis Neuronal migration abnormalities hydranencephaly
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shows classic linear periventricular calcifications, as well as cortical atrophy.
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Congenital CMV
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Congenital CMV
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Congenital CMV InfectionOcular Abnormalities Chorioretinitis (posterior uveitis) Retinal scars Retinal scars Optic atrophy Central vision loss
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CHORIORETINITIS
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Congenital CMV infectionSensorineural hearing loss > 2/3 of newborns with symptomatic
infectioninfection Progressive : severe to profound hearing
loss Patients may be cognitively normal or may
experience cognitive delays depending upon degree of brain involvement in utero
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Congenital CMV InfectionLaboratory Abnormalities : Thrombocytopenia Hemolytic anemia Hemolytic anemia Elevated transaminases Elevated direct & indirect serum bilirubin
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CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE
Primary maternal infection Symptomatic congenital CMV infection Presence of neonatal neurological Presence of neonatal neurological
abnormalities Abnormal head CT scan Chorioretinitis in the newborn
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CLINICAL IMPACT OF CONGENITAL CMV INFECTION
Frequency of sequelae Symptomatic (7%) Asymptomatic (93%)
Infant death 10% 0
Hearing loss 60% 715%Hearing loss 60% 715%
Mental retardation 45% 210%Cerebral palsy 35%
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Diagnosis of CongenitalCMV Infections
Isolation of CMV from urine or other body fluid (CSF, blood, saliva) in the first 21 days of life is considered proof of congenital infectioninfection
Infants often have very high titers of virus and culture (+) within 1-3 days of incubation
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Diagnosis of CongenitalCMV Infections
Serologic tests are unreliable; IgM tests currently available have both false positive and false negative results
PCR may be useful in selected cases PCR may be useful in selected cases> more expensive , less available ,often
less reliable
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Detection: screening for maternalCMV infectionDetection: screening for maternalCMV infection
CMV IgG antibody sensitive and specific screen for past infection
CMV IgM antibody variable sensitivity and specificity CMV IgM antibody variable sensitivity and specificity Antibody avidity testing can increase accuracy of detection
of primary infection No test for immune mothers who will transmit
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Evaluation of mothers at risk of transmitting CMV to the fetusEvaluation of mothers at risk of transmitting CMV to the fetus
Positive Negative
Test for IgG antibodyat first prenatal visit
Negative,no further testing
Positive =primary infection
Test for IgM Antibody
IgG Positive =Seroconversion
Negative,no further tests
Retest later
Refer for prenatal diagnosis
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Intervention: using results of maternal screening to prevent congenital CMV diseaseIntervention: using results of maternal screening to prevent congenital CMV disease
Possible intervention Counsel regarding prevention
(seroneg mother) Use prenatal diagnosis, abort
Problems No proven means to
prevent maternal infection Use prenatal diagnosis, abort
infected fetus Use antivirals to prevent or
treat fetal infection
~75% infected fetuses will be normal
No available antiviral treatment for prenatal use
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SCREENING FOR CONGENITAL CMV INFECTION
Rationale early detection of hearing loss and identification of children at risk
Specimens urine or saliva Serology costly and less accurate than virus detection Technical virus easily and reliably detected by: Technical virus easily and reliably detected by:
urine culture urine PCR mouth swab culture
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Antiviral Therapy for Congenital CMV Congenital CMV
Infection?
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Treatment
Treatment of asymptomatic CMV congenital and acquired infection in the normal host is not recommendednormal host is not recommended
No clinical trials to document efficacy
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Treatment among neonates with congenital & acquired infection
controversialWho are likely to benefit with ganciclovir ?? Viral sepsis like syndrome Viral sepsis like syndrome Pneumonitis or severe refractile
thrombocytopenia Sight threatening retinitis
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Treatment among neonates with congenital & acquired infection
Newborns that may benefit long term form of antiviral therapy
Sensorineural hearing loss microcephaly
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Case Report: Oral ganciclovir for the treatment of intrauterine cytomegalovirus infection
Nulligravid cmv seronegative pt. received renal allograft from seropositive donor
Pt. became pregnant 3 months following acute CMV infection
AF CMV DNA+(80 copies) at 21 wks. Oral CGV administered at 22 wks. AF CMV DNA-at 26 weeks (8 copies) Vigorous female delivered at birth Newborn urine and blood CMV DNA- Normal development @ 3 years of age
Puliyandaet al. (2005)Transplant Infectious Disease 7:71-7
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100 Neonates enrolled to receive 6 weeks of IV ganciclovir (6 mg/kg/dose q 12 hours)
No significant difference in mortality (6% GCV, 12% untreated)
Phase lll randomized trial of ganciclovir for symptomatic congenital CMV infections involving the CNS
Hearing Improvement was more likely in the GCV treated group at 6 and 12 mos (OR 4.31, 4.03) : prevents hearing deterioration at 6 months and possibly beyond
29/46 (63%) GCV recipients experienced neutropenia, compared with 9/43 (21%) untreated control patients
Kimberlin et al, J. Pediatrics,143:17,2003
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USE OF GANCICLOVIR IN SYMPTOMATIC CONGENITAL CMV INFECTION
12 newborns treated for 2 weeks with 5 mg/kg/day or 7.5 mg/kg/day + 3 months of 10 mg/day 3x/week
Higher, but not lower dose, cleared viruria Abnormal liver and haematologic function appeared to Abnormal liver and haematologic function appeared to
clear faster with higher dose Although outcome appeared better with higher dose,
CNS sequelae appeared in both groups
from Nigro et al, J Pediatr 1994; 124: 318
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A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION
47 patients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks
19 % of participants had neutropenia requiring dose modificationmodification
12 mg/kg reduced viral shedding; shedding returned when drug was discontinued
3 patients(16%) had improved hearing at 6 months; 25 had abnormal hearing
from Whitley et al, J Infect Dis, 1997; 175: 1080
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Antiviral Therapy for Congenital CMV Infection?
Ganciclovir has been shown to be effective therapy for certain CMV infections in immunocompromised hosts (e.g., retinitis or enterocolitis in HIV-infected patients)patients)
Neonatal experience with ganciclovir is limited, the toxicity of the drug is considerable (e.g., platelets, neutrophils), and oral bioavailability unreliable
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Ganciclovir Therapy for Congenital CMV? 2006
A six week course of IV ganciclovir may reduce the rate of long-term hearing loss in neonates with symptomatic CMV infection
However, this regimen is associated with significant toxicity, long-term followup data are lacking, and the toxicity, long-term followup data are lacking, and the optimal duration of therapy (if any) is unknown
Potential benefits of antiviral therapy for asymptomatically infected neonates may be greater
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Antiviral Therapy for Congenital CMV? 2006
Current role for IV ganciclovir uncertain: therapy may be considered for patients with symptomatic congenital CMV disease involving the CNS (Kimberlin et al, 2003)
2006 Red Book says that it is not recommended 2006 Red Book says that it is not recommended routinely because of insufficient efficacy data
?? Treatment of neonates with worsening retinitis or hepatitis, severe pneumonia, or persistent severe thrombocytopenia ?? Duration of therapy ??
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USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION
Pro- Antiviral effect Might prevent death or
improve newborn disease No other options
Con- Most damage done prior to
birth Limited antiviral effect Potential reproductive toxicity No other options Potential reproductive toxicity Potential rebound retinitis or
other disease Lack of evidence of efficacy
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Prevention of CMV Infections?
A vaccine to prevent CMV infections is desperately needed
Trials of candidate vaccines are underway CMV Vaccine development a Level One
priority !!
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INVESTIGATIONAL CMV VACCINES, 1997
Vaccine Composition Manufacturer
Towne Live virus Merck/Microbiological Associates
CMVgB Recomb gB/MF59 Chiron Vaccines
ALVAC-CMVgB Viral vector/recomb gB Pasteur-Merieux Connaught
Chimeric CMV Live virus, Avironrecomb Towne/Toledo
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POTENTIAL GOAL OF CMV VACCINE PROGRAMME
Prevent maternal primary infection
Reduce rate of congenital Reduce rate of congenital infections
Reduce rate of disease
from Whitley et al, J Infect Dis, 1997; 175: 1080
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How is congenital CMV prevented?
Many different ways toprevent CMV
Our approach:
Hygiene, especially handwashing
Education about CMV and how to prevent it through hygiene
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Thank you