para>CMV infection in pregnancy may cause broad range of illness in the newborn, ranging from asymptomatic infection to severe disease or even death.
Infection may occur in utero, intrapartum, or postnatally.
Preexisting maternal CMV seropositivity substantially decreases (but does not eliminate) fetal infection.
Pediatric Considerations
Breastfeeding can transmit virus to high-risk preterm infants. However, there is a low risk of symptomatic disease and no evidence of long-term sequelae from transmission via breastfeeding. Currently, there are no recommendations for avoidance or treating breast milk.
EPIDEMIOLOGY
Incidence
- Common but frequently asymptomatic
- <2 to 3 cases of end-organ disease per 100 person-years in HIV patients
- CMV infection is more prevalent in populations at higher risk for HIV infection (IV drug users, 75%; homosexual males, 90%).
- CMV reactivation frequently occurs in immunocompromised hosts (organ transplant recipients and HIV patients).
- Predominant age: all ages, peaks at <3 months, 16 to 40 years, and 40 to 75 years
- Predominant sex: male > female
Prevalence
- Occurs worldwide; higher prevalence in underdeveloped countries
- 40-100% of the general U.S. population is seropositive from exposure during childhood or early adulthood.
- 20% of children in the United States are seropositive before reaching puberty.
- Most common perinatally transmitted infection: 0.2-2.2% of births in the United States
ETIOLOGY AND PATHOPHYSIOLOGY
- Primary infection. Virus infects epithelial cells, macrophages, and T cells causing coalescence (protects from antibody). Intact host cell-mediated immunity required for host's defense against CMV infection.
- Reinfection with different CMV strains
- Reactivation of latent virus in patients who are immunosuppressed
RISK FACTORS
- HIV infection with specific risks, including the following:
- CD4 count <50 cells/μL
- Absence of treatment or failure to respond to ART
- Previous opportunistic infections
- HIV viral load >100,000
- Organ transplantation
- Blood transfusion
- Immunocompromise
- Living in closed population, daycare, nursing home, military barracks, correctional facilities
- Corticosteroid therapy
- Maternal infection during pregnancy (neonatal disease)
- Low socioeconomic status
- Critically ill immunocompetent adults in ICU settings (up to 1/3 develop CMV, primarily between days 4 and 12 after admission)
- Inflammatory bowel disease
GENERAL PREVENTION
- Hand washing/personal hygiene
- Avoid immunosuppression; maintain CD4 count >100 cells/mm3 in HIV patients.
- Highly active antiretroviral therapy (HAART) is the best method of prevention for high-risk HIV patients.
- Primary prophylaxis is not recommended.
- Chronic maintenance therapy for secondary prophylaxis in HIV patients (1,2)[A]
- Options include:
- Parenteral or PO ganciclovir
- Parenteral foscarnet
- Combined parenteral ganciclovir and foscarnet
- Parenteral cidofovir
- Ganciclovir via intraocular implant or repetitive intravitreous injection of fomivirsen
- CMV antibody+ and HIV+ children who are severely immunosuppressed require PO ganciclovir 1,000 mg TID.
- Antiviral suppression of CMV reactivation in CMV+ transplant recipients or recipients of CMV+ organs
- Solid organ transplant: prophylactic or preemptive treatment with PO ganciclovir, valganciclovir
- Bone marrow transplant: IV ganciclovir
- CMV immunoglobulins decrease rate of severe disease after liver transplant and decrease incidence of disease after renal transplant.
COMMONLY ASSOCIATED CONDITIONS
AIDS, corticosteroid therapy, transplantation, or immunosuppression
DIAGNOSIS
HISTORY
- Congenital
- ~1% (0.2-2.5%) of newborns are congenitally infected with CMV.
- Most infected newborns appear normal and are asymptomatic.
- As many as 15% develop progressive hearing loss, which is most often unilateral.
- ~5-15% of congenitally infected newborns are symptomatic at birth (small size for gestational age, hepatosplenomegaly, petechial or purpuric rash, and jaundice).
- Perinatal: exposure to CMV in maternal cervicovaginal secretions, breast milk, or from blood product transfusions; often asymptomatic
- Acute infection in a normal host commonly presents as an acute mononucleosis syndrome.
- Latent infection: Higher IgG titers may contribute to development of atherosclerotic disease.
- History of bone marrow or solid organ transplant
- Heart transplant: early myocarditis followed by late atherosclerosis
- Lung and bone marrow transplants often present with interstitial pneumonia
- Liver transplant: hepatitis and colitis
- Kidney transplant: graft loss
- AIDS: most commonly CMV retinitis; then colitis, followed by esophagitis and neurologic disease
- Infections in other immunocompromised patients: pulmonary, GI, or renal disease
PHYSICAL EXAM
- Congenital
- Asymptomatic cytomegaloviremia
- Symptomatic: small for gestational age, purpura/petechiae, jaundice, hepatosplenomegaly, chorioretinitis, microcephaly, intracranial calcifications, hearing impairment
- 90% have late complications: sensorineural hearing loss in 14%; 3-5% moderate to severe
- Mental retardation, chorioretinitis, optic atrophy, seizures, learning disabilities
- Acquired: acute infection in a normal host
- Usually asymptomatic
- Mononucleosis syndrome: fever, malaise, sore throat, headache, antibiotic rash
- Less common: exudative pharyngitis, splenomegaly, cervical adenopathy, rash
- Infections in AIDS patients
- Retinitis: usually unilateral, floaters, scotomata, peripheral field defects. Diagnosis is made when characteristic retinal changes are noted by ophthalmologist on funduscopic exam.
- Colitis: fever, weight loss, anorexia, abdominal pain, diarrhea, malaise; hemorrhage or perforation rare but serious
- Esophagitis: fever, odynophagia, nausea, abdominal discomfort
- Pneumonitis: dyspnea with or without exertion, nonproductive cough, hypoxemia
- Neurologic disease: dementia, lethargy, confusion, fever, focal neurologic signs
- Infections in transplant recipients
- Persistent fever (most common)
- Bone marrow transplant: interstitial pneumonia
- Liver transplant: hepatitis
- Kidney transplant: CMV syndrome (fever, leukopenia, atypical lymphocytes, hepatomegaly, myalgia, arthralgia)
DIFFERENTIAL DIAGNOSIS
- Congenital toxoplasmosis, rubella, syphilis, HBV
- Early infancy: chlamydia, respiratory syncytial virus
- Acquired in immunocompetent: Epstein-Barr virus (EBV) mononucleosis, viral hepatitis
- Acquired immunocompromised: other viral, bacterial, fungal opportunistic infections
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Congenital (3)[C]
- Isolation of the virus in urine or saliva collected within the first 3 weeks of life
- Direct hyperbilirubinemia >3 mg/dL
- Thrombocytopenia (<75,000/mL)
- Elevated liver transaminases
- Acute infection in a normal host
- Elevated liver transaminases in 92%, up to >5 times normal
- Anemia; thrombocytopenia
- Positive cold agglutinins
- Lymphocytosis with >10% atypical
- Negative heterophil antibody test (rules out EBV mononucleosis)
- Positive CMV IgM antibodies; may not peak until 4 to 7 weeks after acute infection
- CMV IgG increases 4-fold during acute infection.
- Immunocompromised
- Viremia: PCR, antigen assays (pp65 lower matrix protein in leukocytes), blood culture; although viremia can be present without CMV disease
- Serum CMV antibodies not useful; can be falsely negative due to immunosuppression
- Neurologic disease: CMV detected in CSF or brain tissue clinches diagnosis; enhanced by PCR
- Recovery of virus from tissue in symptomatic patient (GI or pulmonary tissue) indicates infection, although 1 to 6 weeks are required for distinctive cytopathic events to occur.
- Quantitative DNA PCR can be used for diagnosis and to monitor therapy.
- Head CT or MRI: periventricular enhancement (CMV neurologic disease in neonate)
- Chest x-ray: interstitial infiltrates (CMV pneumonitis)
Diagnostic Procedures/Other
- Bronchoscopy: CMV inclusion bodies in lung tissue in context of pulmonary infiltrates (pneumonitis)
- GI endoscopy: mucosal ulcerations and colitis, esophagitis on biopsy
Test Interpretation
Giant cells with basophilic inclusion bodies
TREATMENT
MEDICATION
First Line
- Congenital disease: ganciclovir 5 mg/kg IV q12h for 6 weeks
- Pediatric disseminated disease: IV ganciclovir
- CMV mononucleosis/asymptomatic viremia: no treatment
- Retinitis: Effective treatments include the following and should be chosen in consultation with an ID specialist:
- PO valganciclovir (for peripheral lesions)
- IV ganciclovir
- IV ganciclovir followed by PO valganciclovir
- IV foscarnet
- IV cidofovir
- Ganciclovir intraocular implant with PO or IV valganciclovir
- Treat until CD4 >100 for 3 to 6 months.
- Colitis or esophagitis: Treat 21 to 42 days or until symptom resolution: IV ganciclovir or PO valganciclovir
- IV foscarnet
- Neurologic disease: prompt treatment with IV ganciclovir and IV foscarnet. Pneumonitis: IV ganciclovir or IV foscarnet
- CMV disease in transplant patients: IV ganciclovir for 2 to 4 weeks
Second Line
- Adult CMV retinitis: fomivirsen
- Pediatric disseminated disease: foscarnet 60 mg/kg q8h for 14 to 21 days, combination ganciclovir and foscarnet CMV disease in transplant patients: valganciclovir
- CMV in bone marrow transplant patients
- Prophylaxis: valacyclovir
- Preemptive: foscarnet
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- CMV urine culture at birth for all HIV-infected or exposed with annual testing in CMV seronegative/HIV+ children
- Patients with CD4 counts <50 should have ophthalmologic screening every 3 to 6 months.
- Patients on therapy should be followed for neutropenia, anemia, and thrombocytopenia.
PROGNOSIS
Severe disease with primary infection in newborns and reactivation in immunocompromised
COMPLICATIONS
- Congenital: hearing loss, mental retardation, optic atrophy, seizures, learning disabilities
- Colitis: hemorrhage and perforation
REFERENCES
11 Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the CDC, the NIH, and IDSA. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed 2014.22 Mofenson LM, Oleske J, Serchuck L, et al. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004;53(RR-14):1-92.33 Kotton CN. CMV: prevention, diagnosis and therapy. Am J Transplant. 2013;13(Suppl 3):24-40.
ADDITIONAL READING
- Cascio A, Iaria C, Ruggeri P, et al. Cytomegalovirus pneumonia in patients with inflammatory bowel disease: a systematic review. Int J Infect Dis. 2012;16(7):e474-e479.
- Grosse SD, Ross DS, Dollard SC. Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol. 2008;41(2):57-62.
- Kadambari S, Williams EJ, Luck S, et al. Evidence based management guidelines for the detection and treatment of congenital CMV. Early Hum Dev. 2011;87(11):723-728.
- Kurath S, Halwachs-Baumann G, M ¼ller W, et al. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clin Microbiol Infect. 2010;16(8):1172-1178.
- Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13(3):R68.
CODES
ICD10
- B25.9 Cytomegaloviral disease, unspecified
- P35.1 Congenital cytomegalovirus infection
- B25.8 Other cytomegaloviral diseases
ICD9
- 078.5 Cytomegaloviral disease
- 771.1 Congenital cytomegalovirus infection
SNOMED
- Cytomegalovirus infection (disorder)
- Congenital cytomegalovirus infection
CLINICAL PEARLS
- CMV mononucleosis syndrome has less cervical adenopathy and/or splenomegaly than EBV mononucleosis in adults.
- CMV is a major cause of sensorineural hearing loss in young children.
- Up to 80% of adults worldwide have antibodies to CMV.