Ubiquitous beta-herpesvirus — usually asymptomatic in healthy hosts but causes serious disease in neonates and immunocompromised patients.
Also known as: CMV, HHV-5, cytomegalovirus, congenital CMV
Overview
Human cytomegalovirus (HHV-5) is a double-stranded DNA beta-herpesvirus establishing lifelong latency in myeloid progenitors and other cells after primary infection. Manifestations depend critically on host immune status and timing (congenital vs. acquired).
Epidemiology
Seroprevalence rises with age; ~50% of US adults by 40, >90% in lower-income settings. Most common congenital viral infection (~1 in 200 live births; ~10% symptomatic at birth). Leading non-genetic cause of childhood sensorineural hearing loss.
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Daycare exposure, healthcare work (high seroconversion)
Sexual contact, blood transfusion (rare with leukoreduction), organ/HSC transplantation
Pregnancy with primary CMV infection (highest risk of congenital transmission)
Immunocompromise: HIV with CD4 <50, solid organ/HSC transplant, high-dose immunosuppression
Pathophysiology
Initial replication in mucosal epithelium followed by dissemination via infected monocytes. Establishes latency in CD34+ progenitor cells; reactivation occurs with immune compromise. Pathogenic effects include direct cytopathic injury (giant cells with 'owl's-eye' intranuclear inclusions), endothelial dysfunction, and immune-mediated damage.
Clinical presentation
Symptoms
Immunocompetent adults: heterophile-negative mononucleosis (prolonged fever, fatigue, mild hepatitis, lymphocytosis); pharyngitis and adenopathy less prominent than EBV
Congenital CMV: hearing loss (most common, often progressive and late-onset), microcephaly, intracranial calcifications (periventricular), chorioretinitis, hepatosplenomegaly, jaundice, petechiae ('blueberry muffin' rash), IUGR
Immunocompromised (especially HIV CD4 <50 or post-transplant): retinitis (floaters, painless vision loss), colitis (diarrhea, abdominal pain, GI bleeding), esophagitis (large solitary ulcers), pneumonitis (post-HSCT), encephalitis/polyradiculitis
Signs / physical exam
Hepatosplenomegaly; transaminitis
CMV retinitis: 'pizza pie' or 'cottage cheese with ketchup' appearance — yellow-white retinal infiltrates with hemorrhage on funduscopy
Congenital: small for gestational age, microcephaly, blueberry muffin rash, sensorineural hearing loss
Classic findings
CMV retinitis in advanced HIV (CD4 <50): perivascular hemorrhages with fluffy yellow-white exudates. Congenital CMV: periventricular calcifications (vs. diffuse intracranial calcifications in toxoplasmosis).
Differential diagnosis
EBV mononucleosis — Pharyngitis and prominent lymphadenopathy; positive heterophile and VCA IgM
Acute HIV — Trunk rash, oral ulcers, recent high-risk exposure; HIV RNA
Toxoplasmosis — Cat exposure, lymphadenopathy without pharyngitis; toxo IgM/IgG
Congenital CMV: positive PCR on neonatal urine/saliva within 21 days of birth. End-organ disease: tissue biopsy with characteristic cytomegalic inclusions (owl's eye) and positive immunohistochemistry or PCR.
Labs
Immunocompetent: CMV IgM (acute) and IgG with avidity (low avidity supports primary infection); CMV PCR (viremia)
Tissue PCR or immunohistochemistry from biopsy (gold standard for end-organ disease — retina, colon, esophagus, lung)
Congenital: CMV PCR on neonatal urine or saliva within first 21 days of life (after 21 days cannot distinguish congenital from perinatal acquisition)
CBC, CMP, LFTs
Imaging
Head ultrasound or MRI for suspected congenital CMV — look for periventricular calcifications, ventriculomegaly, white matter abnormalities, polymicrogyria
Dilated funduscopy for retinitis screening if HIV CD4 <50
Endoscopy with biopsy for suspected GI CMV
Diagnostic algorithm
Host
Common Syndrome
Diagnostic Test
First-line Therapy
Healthy adult
Heterophile-negative mono
CMV IgM, PCR
Supportive
Newborn (congenital)
Hearing loss, calcifications
Urine/saliva PCR <21 days
Valganciclovir x 6 mo if symptomatic
HIV CD4 <50
Retinitis, colitis, esophagitis
Funduscopy, tissue PCR
IV ganciclovir → val maintenance
Post-transplant
Viremia, tissue-invasive disease
Quantitative plasma PCR
Val/ganciclovir; letermovir prophylaxis
CMV disease manifestations and management by host immune status.
Treatment
First-line
Immunocompetent: supportive care — antivirals not indicated
End-organ CMV disease (transplant, HIV): IV ganciclovir 5 mg/kg q12h induction × 14-21 days, then valganciclovir 900 mg PO daily maintenance
Valganciclovir 900 mg PO BID — oral option for many CMV syndromes including induction of mild-moderate retinitis
Congenital symptomatic CMV with CNS involvement or sensorineural hearing loss: valganciclovir 16 mg/kg PO BID × 6 months (improves hearing/developmental outcomes — Kimberlin NEJM 2015)
Second-line / adjunct
Foscarnet — ganciclovir resistance or marrow toxicity; nephrotoxic, electrolyte abnormalities
HIV: blindness from retinitis, severe colitis, encephalitis
Guillain-Barre, hemolytic anemia, immune thrombocytopenia (rare in immunocompetent)
PANCE pearls
Heterophile-negative mononucleosis in an adult — order CMV serology and HIV testing.
Universal newborn CMV screening is gaining traction; in many states targeted testing of newborns who fail hearing screen.
Pregnancy: behavioral hygiene (handwashing after diapers, no sharing of utensils/cups with young children) reduces maternal seroconversion; hyperimmune globulin and antivirals studied but not standard.
Solid organ transplant donor+/recipient- (D+/R-) is the highest CMV risk combination — extended valganciclovir prophylaxis recommended.
Letermovir has displaced ganciclovir for CMV prophylaxis after allogeneic HSCT due to safety profile.
References
Kimberlin 2015 — Valganciclovir for symptomatic congenital cytomegalovirus disease (NEJM)
AST IDCOP 2019 — Cytomegalovirus in solid organ transplant recipients — Guidelines of the American Society of Transplantation
DHHS OI Guidelines — Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults with HIV — CMV section
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