Cytomegalovirus Infection, Pediatric

Basics

Description

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.

Epidemiology

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.

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

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

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

Commonly Associated Conditions

Congenital infection
- 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.
Mononucleosis syndrome
- 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.
Interstitial pneumonitis
- 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.
Retinitis
- Observed in infants with symptomatic congenital infection and in patients with advanced AIDS
- Immunosuppressed children should have regular eye exams.
Hepatitis
- 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.
GI disease
- Severely immunosuppressed patients may experience esophagitis, gastritis, colitis, or pancreatitis.
- Diagnosis requires endoscopy with biopsy.
CNS disease
- 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.
Hearing loss
- 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

Exposures

Day care attendance
- Increased risk of infection
Recent blood transfusion
- Transfusion-associated CMV
Use of immunosuppressive medications
- Increased cause of serious infection

Symptoms

Prolonged fever
- Mononucleosis-like syndrome
Blurred vision
- CMV retinitis
Cough, dyspnea, wheezing
- CMV pneumonitis
Vomiting, abdominal pain, diarrhea (watery or bloody)
- CMV colitis

Physical Exam

Microcephaly
- Congenital infection
White, perivascular retinal infiltrates and hemorrhage
- Retinitis
Hearing loss (may require audiogram, brainstem evoked auditory responses)
- Congenital infection
Photophobia, headache, nuchal rigidity
- Meningitis/encephalitis
- Tachypnea, rales
- Pneumonitis
- Hepatomegaly and/or splenomegaly
- Mononucleosis-like syndrome
Rash
- Petechiae, purpura, "blueberry muffin" lesions, rubelliform rash
Adenopathy
- Mononucleosis-like syndrome

Diagnostic Tests & Interpretation

Lab

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.

Alert

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.

Imaging

Noncontrast head CT
- Periventricular calcifications, cystic abnormalities, ventriculomegaly, periventricular leukomalacia
Brain MRI
- Has higher sensitivity than ultrasound for brain abnormalities and greater predictor of symptomatic infection

Differential Diagnosis

Congenital infection
- Congenital rubella syndrome
- Toxoplasmosis
- Syphilis
- Neonatal herpes simplex virus
- Human immunodeficiency virus
- Enteroviral infection
Mononucleosis syndrome
- EBV infection
- Toxoplasmosis
- Hepatitis A or B infection
Interstitial pneumonitis
- Respiratory syncytial virus
- Adenovirus
- Measles
- Varicella
- Pneumocystis jiroveci (previously carinii)
- Chlamydia
- Mycoplasma
- Fungal
- Drug/toxin-induced pneumonitis
Retinitis
- Ocular toxoplasmosis
- Candidal retinitis
- Syphilis
- Herpes simplex virus
Hepatitis
- EBV infection
- Hepatitis A, B, or C infection
- Enterovirus
- Adenovirus
- Herpes simplex virus
- Drug/toxin-induced
GI disease
- Herpes simplex virus
- Adenovirus
- Salmonella
- Shigella
- Campylobacter
- Yersinia
- Clostridium difficile
- Giardia
- Cryptosporidium
CNS disease
- Congenital 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

Treatment

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

Medication

First Line

Ganciclovir: suppresses viral replication by inhibiting the viral DNA polymerase
- 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%)
Foscarnet: suppresses viral replication by inhibiting viral DNA polymerase
- 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

Varies with nature of infection (see "Commonly Associated Conditions")

Complications