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Cytomegalovirus Infection, Pediatric

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Cytomegalovirus Infection, Pediatric

Basics

Description

Epidemiology

Cytomegalovirus (CMV) is a ubiquitous double-stranded DNA virus that is a member of the herpesvirus family. It establishes latency in peripheral blood mononuclear cells and endothelial cells.

Seroprevalence increases with age and varies with socioeconomic status; 50% of middle- and 80% of lower socioeconomic status adults are seropositive.

Infection leads to intranuclear inclusions with massive enlargement of cells. Almost any organ may become infected with CMV in severe disseminated infection.

- Blurred vision - Cough, dyspnea, wheezing - Vomiting, abdominal pain, diarrhea (watery or bloody)

- Microcephaly - White, perivascular retinal infiltrates and hemorrhage - Hearing loss (may require audiogram, brainstem evoked auditory responses) - Photophobia, headache, nuchal rigidity - Meningitis/encephalitis - Tachypnea, rales - Pneumonitis - Hepatomegaly and/or splenomegaly - Mononucleosis-like syndrome

Majority of transplant experts prefer prophylaxis over preemptive therapy in high-risk patients (donor CMV positive, recipient negative).

  • Primary infection occurs from early childhood into adolescence and childbearing years.
  • Transmission occurs by contact with infected body fluids such as saliva, urine, blood, or breast milk through sexual contact or solid organ transplantation. Intrauterine transmission is the most common route of acquiring congenital infection.

General Prevention

  • Pregnant women should receive education about CMV transmission. Precautions should be instituted for hospitalized patients known to be shedding CMV.
  • Seriously ill neonates should receive blood products from CMV-negative donors.
  • CMV-seronegative solid organ transplantation recipients should receive organs (and all blood products) from CMV-negative donors whenever possible.
  • Hyperimmunoglobulin has been used in high-risk CMV-negative recipients of CMV-positive donors to prevent severe CMV disease.

Pathophysiology

Commonly Associated Conditions

  • Congenital infectionOccurs in about 1% of newborns in United StatesIntrauterine transmission is more common in pregnant women mothers with primary infection during pregnancy (40-50%) compared to recurrent infection (<1%). Postnatal acquisition of CMV via breast milk: controversy exists over whether this precludes breastfeeding in premature infants (has a lower risk for neurological sequelae than congenital infection).10% of infected infants are symptomatic at birth, with severe disease characterized by growth retardation, hepatosplenomegaly, thrombocytopenia, and CNS involvement.10-20% of infants who are asymptomatically infected at birth may develop hearing loss.Of symptomatically infected infants, 90% will have some neurologic sequelae. Degree of impairments may be predicted by CT findings and microcephaly at birth.
  • Mononucleosis syndromeCMV can cause a mononucleosis-like syndrome similar to that caused by Epstein-Barr virus (EBV) infection in immunocompetent patients.The most common symptoms are malaise (67%) and fever (50%). ~70% of patients have abnormal liver enzymes.Pharyngitis and splenomegaly less common and severe than observed with EBV-induced mononucleosis.
  • Interstitial pneumonitisSeen primarily in severely immunosuppressed children and adultsBegins with fever and nonproductive cough but may progress to dyspnea and severe hypoxia over 1-2 weeksMild, self-limited pneumonitis may occur in immunocompetent patients.
  • RetinitisObserved in infants with symptomatic congenital infection and in patients with advanced AIDSImmunosuppressed children should have regular eye exams.
  • HepatitisOccurs in healthy individuals with primary infections and in immunosuppressed patients with either primary or reactivated diseaseFever, mild elevation of liver enzymes, and hepatomegaly are typical. Jaundice and severe hepatitis are uncommon.
  • GI diseaseSeverely immunosuppressed patients may experience esophagitis, gastritis, colitis, or pancreatitis.Diagnosis requires endoscopy with biopsy.
  • CNS diseaseCommonly seen in infants with symptomatic congenital infectionCharacterized by microcephaly, periventricular calcifications, seizures, developmental delay, and sensorineural hearing lossEncephalitis or meningoencephalitis may occur in immunocompromised patients and very rarely reported in literature in immunocompetent hosts.
  • Hearing lossCongenital CMV is the most common infectious cause of deafness.Onset of deafness often seen after 1st month of life and is progressive. May be missed by newborn hearing screen (if only done in first 2 weeks of life)
  • Occurs in about 1% of newborns in United States
  • Intrauterine transmission is more common in pregnant women mothers with primary infection during pregnancy (40-50%) compared to recurrent infection (<1%). Postnatal acquisition of CMV via breast milk: controversy exists over whether this precludes breastfeeding in premature infants (has a lower risk for neurological sequelae than congenital infection).
  • 10% of infected infants are symptomatic at birth, with severe disease characterized by growth retardation, hepatosplenomegaly, thrombocytopenia, and CNS involvement.
  • 10-20% of infants who are asymptomatically infected at birth may develop hearing loss.
  • Of symptomatically infected infants, 90% will have some neurologic sequelae. Degree of impairments may be predicted by CT findings and microcephaly at birth.
  • CMV can cause a mononucleosis-like syndrome similar to that caused by Epstein-Barr virus (EBV) infection in immunocompetent patients.
  • The most common symptoms are malaise (67%) and fever (50%). ~70% of patients have abnormal liver enzymes.
  • Pharyngitis and splenomegaly less common and severe than observed with EBV-induced mononucleosis.
  • Seen primarily in severely immunosuppressed children and adults
  • Begins with fever and nonproductive cough but may progress to dyspnea and severe hypoxia over 1-2 weeks
  • Mild, self-limited pneumonitis may occur in immunocompetent patients.
  • Observed in infants with symptomatic congenital infection and in patients with advanced AIDS
  • Immunosuppressed children should have regular eye exams.
  • Occurs in healthy individuals with primary infections and in immunosuppressed patients with either primary or reactivated disease
  • Fever, mild elevation of liver enzymes, and hepatomegaly are typical. Jaundice and severe hepatitis are uncommon.
  • Severely immunosuppressed patients may experience esophagitis, gastritis, colitis, or pancreatitis.
  • Diagnosis requires endoscopy with biopsy.
  • Commonly seen in infants with symptomatic congenital infection
  • Characterized by microcephaly, periventricular calcifications, seizures, developmental delay, and sensorineural hearing loss
  • Encephalitis or meningoencephalitis may occur in immunocompromised patients and very rarely reported in literature in immunocompetent hosts.
  • Congenital CMV is the most common infectious cause of deafness.
  • Onset of deafness often seen after 1st month of life and is progressive. May be missed by newborn hearing screen (if only done in first 2 weeks of life)

Diagnosis

History

  • Day care attendanceIncreased risk of infection
  • Recent blood transfusionTransfusion-associated CMV
  • Use of immunosuppressive medicationsIncreased cause of serious infection
  • Increased risk of infection
  • Transfusion-associated CMV
  • Increased cause of serious infection
  • Prolonged feverMononucleosis-like syndrome
  • Blurred visionCMV retinitis
  • Cough, dyspnea, wheezingCMV pneumonitis
  • Vomiting, abdominal pain, diarrhea (watery or bloody)CMV colitis
  • Mononucleosis-like syndrome
  • CMV retinitis
  • CMV pneumonitis
  • CMV colitis

Physical Exam

  • MicrocephalyCongenital infection
  • White, perivascular retinal infiltrates and hemorrhageRetinitis
  • Hearing loss (may require audiogram, brainstem evoked auditory responses)Congenital infection
  • Photophobia, headache, nuchal rigidityMeningitis/encephalitisTachypnea, ralesPneumonitisHepatomegaly and/or splenomegalyMononucleosis-like syndrome
  • RashPetechiae, purpura, "blueberry muffin" lesions, rubelliform rash
  • AdenopathyMononucleosis-like syndrome
  • Congenital infection
  • Retinitis
  • Congenital infection
  • Meningitis/encephalitis
  • Tachypnea, rales
  • Pneumonitis
  • Hepatomegaly and/or splenomegaly
  • Mononucleosis-like syndrome
  • Petechiae, purpura, "blueberry muffin" lesions, rubelliform rash
  • Mononucleosis-like syndrome

Diagnostic Tests & Interpretation

  • Shell-vial assay: (staining for immediate early antigen production) allows detection of virus 24-48 hours after inoculation
  • Viral culture: Virus may be isolated from nasopharyngeal/oropharyngeal secretions, urine, stool, and WBC. Isolation may take up to 4 weeks. Urine or saliva samples are most common way to diagnose congenital disease.
  • Highly sensitive CMV quantitative polymerase chain reaction (PCR) assay: Measure viral DNA in plasma, whole blood, urine, and CSF. Real-time PCR has replaced most diagnostic tests in monitoring response to therapy or identifying viral quantitation. Recently standardized to be reported as IU/mL.
  • Quantitative antigenemia assay: detection of circulating CMV-infected polymorphonuclear cells by indirect immunofluorescence. In an immunocompromised patient, may monitor response to therapy or identify viral reactivation.
  • Serology: Enzyme-linked immunosorbent assay or indirect fluorescent antibody assay to detect the presence of CMV IgM, or IgG has a limited role. IgG avidity test can be used in certain circumstances, particularly in pregnant women, to diagnose a recent infection.
  • Due to frequency of asymptomatic shedding, mere isolation of virus does not necessarily establish an etiologic association.
  • Severely immunocompromised patients who are actively infected with CMV may be seronegative. 4-fold rise in CMV IgG is not diagnostic of primary infection. Increased antibody titers may occur with reactivation. DNA quantification by real-time PCR is useful in these circumstances to make a timely diagnosis.
  • Noncontrast head CTPeriventricular calcifications, cystic abnormalities, ventriculomegaly, periventricular leukomalacia
  • Brain MRIHas higher sensitivity than ultrasound for brain abnormalities and greater predictor of symptomatic infection
  • Periventricular calcifications, cystic abnormalities, ventriculomegaly, periventricular leukomalacia
  • Has higher sensitivity than ultrasound for brain abnormalities and greater predictor of symptomatic infection

Differential Diagnosis

  • Congenital infectionCongenital rubella syndromeToxoplasmosisSyphilisNeonatal herpes simplex virusHuman immunodeficiency virusEnteroviral infection
  • Mononucleosis syndromeEBV infectionToxoplasmosisHepatitis A or B infection
  • Interstitial pneumonitisRespiratory syncytial virusAdenovirusMeaslesVaricellaPneumocystis jiroveci (previously carinii)ChlamydiaMycoplasmaFungalDrug/toxin-induced pneumonitis
  • RetinitisOcular toxoplasmosisCandidal retinitisSyphilisHerpes simplex virus
  • HepatitisEBV infectionHepatitis A, B, or C infectionEnterovirusAdenovirusHerpes simplex virusDrug/toxin-induced
  • GI diseaseHerpes simplex virusAdenovirusSalmonellaShigellaCampylobacterYersiniaClostridium difficileGiardiaCryptosporidium
  • CNS diseaseCongenital disease (see congenital infection earlier)Meningoencephalitis in immunocompetent host: herpes simplex virus, EBV, varicella-zoster virus, enterovirus, arbovirus
  • Meningoencephalitis in immunocompromised host: in addition to organisms listed previously, should include HIV encephalitis, fungal meningitis, toxoplasmosis
  • Congenital rubella syndrome
  • Toxoplasmosis
  • Syphilis
  • Neonatal herpes simplex virus
  • Human immunodeficiency virus
  • Enteroviral infection
  • EBV infection
  • Toxoplasmosis
  • Hepatitis A or B infection
  • Respiratory syncytial virus
  • Adenovirus
  • Measles
  • Varicella
  • Pneumocystis jiroveci (previously carinii)
  • Chlamydia
  • Mycoplasma
  • Fungal
  • Drug/toxin-induced pneumonitis
  • Ocular toxoplasmosis
  • Candidal retinitis
  • Syphilis
  • Herpes simplex virus
  • EBV infection
  • Hepatitis A, B, or C infection
  • Enterovirus
  • Adenovirus
  • Herpes simplex virus
  • Drug/toxin-induced
  • Herpes simplex virus
  • Adenovirus
  • Salmonella
  • Shigella
  • Campylobacter
  • Yersinia
  • Clostridium difficile
  • Giardia
  • Cryptosporidium
  • Congenital disease (see congenital infection earlier)
  • Meningoencephalitis in immunocompetent host: herpes simplex virus, EBV, varicella-zoster virus, enterovirus, arbovirus

Treatment

Medication

  • Ganciclovir: suppresses viral replication by inhibiting the viral DNA polymeraseIndications: symptomatic congenital CMV in a neonate meeting clinical criteria; CMV chorioretinitis in immunocompromised patients; tissue diagnosis (hepatitis, enteritis, pneumonitis) of CMV infection; and in immunocompromised patients with CMV disease (viremia + symptoms)Side effects: neutropenia (60%), thrombocytopenia (~5%)
  • Foscarnet: suppresses viral replication by inhibiting viral DNA polymeraseIndications: same as earlier, but in patients who have failed to improve on ganciclovir therapy or who has experienced significant bone marrow toxicity related to ganciclovir use or with resistance to ganciclovirSide effects: renal impairment (12-33%), headache (26%), seizures (10%)
  • Indications: symptomatic congenital CMV in a neonate meeting clinical criteria; CMV chorioretinitis in immunocompromised patients; tissue diagnosis (hepatitis, enteritis, pneumonitis) of CMV infection; and in immunocompromised patients with CMV disease (viremia + symptoms)
  • Side effects: neutropenia (60%), thrombocytopenia (~5%)
  • Indications: same as earlier, but in patients who have failed to improve on ganciclovir therapy or who has experienced significant bone marrow toxicity related to ganciclovir use or with resistance to ganciclovir
  • Side effects: renal impairment (12-33%), headache (26%), seizures (10%)

Ongoing Care

Prognosis

Complications

Additional Reading

  • Alexander BT, Hladnik LM, Augustin KM, et al. Use of cytomegalovirus intravenous immune globulin for the adjunctive treatment of CMV in hematopoietic stem cell transplant patients. Pharmacotherapy. 2010;30(6):554-561. [View Abstract]
  • Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoetic cell transplant recipients. Blood. 2009;113(23):5711-5719. [View Abstract]
  • Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202-213. [View Abstract]
  • Dollard SC, Schleiss MR, Grosse SD. Public health and laboratory considerations regarding newborn screening for congenital cytomegalovirus. J Inherit Metab Dis. 2010;33(Suppl 2):S249-S254. [View Abstract]
  • Foulon I, Naessens A, Foulon W, et al. Hearing loss in children with congenital cytomegalovirus infection in relation to the maternal trimester in which the maternal primary infection occurred. Pediatrics. 2008;122(6):e1123-e1127. [View Abstract]
  • Grangeot-Keros L, Mayaux MJ, Lebon P, et al. Value of cytomegalovirus (CMV) IgG avidity index for the diagnosis of primary CMV infection in pregnant women. J Infect Dis. 1997;175(4):944-946. [View Abstract]
  • Istas AS, Demmler GJ, Dobbins JG, et al. Surveillance for congenital cytomegalovirus disease: a report from the National Congenital Cytomegalovirus Disease Registry. Clin Infect Dis. 1995;20(3):665-670. [View Abstract]
  • Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16-25. [View Abstract]
  • Noyola DE, Demmler GJ, Nelson CT, et al. Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J Pediatr. 2001;138(3):325-331. [View Abstract]
  • Revello MG, Zavattoni M, Sarasini A, et al. Human cytomegalovirus in blood of immunocompetent persons during primary infection: prognostic implications for pregnancy. J Infect Dis. 1998;177(5):1170-1175. [View Abstract]
  • Wreghitt TG, Teare EL, Sule O, et al. Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis. 2003;37(12):1603-1606. [View Abstract]

Codes

ICD09

  • 78.5 Cytomegaloviral disease
  • 771.1 Congenital cytomegalovirus infection

ICD10

  • B25.9 Cytomegaloviral disease, unspecified
  • P35.1 Congenital cytomegalovirus infection
  • B25.0 Cytomegaloviral pneumonitis
  • B25.1 Cytomegaloviral hepatitis
  • B25.2 Cytomegaloviral pancreatitis
  • B25.8 Other cytomegaloviral diseases

SNOMED

  • 28944009 Cytomegalovirus infection (disorder)
  • 59527008 Congenital cytomegalovirus infection
  • 7678002 cytomegaloviral pneumonia (disorder)
  • 186698009 Cytomegalovirus hepatitis (disorder)
  • 429300008 Cytomegaloviral gastritis (disorder)
  • 235947007 Cytomegaloviral pancreatitis (disorder)

FAQ

  • Q: Should children with congenital CMV infection be excluded from day care settings?
  • A: No. Due to the high frequency of shedding of CMV in the urine and saliva of asymptomatic children, especially those younger than 2 years of age, exclusion from out-of-home care is not justified for any child known to be infected with CMV. Careful attention to hygienic practices, especially hand washing, is important.