Cytomegalovirus (CMV)
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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Risk factors
- 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
- Viral hepatitis — Marked transaminitis, jaundice; hepatitis A/B/C serologies
- Drug-induced hepatitis — Recent medication; resolves with discontinuation
- Other congenital infections (TORCH) — Toxoplasmosis, rubella, syphilis, HSV, Zika — overlapping features; targeted testing
Diagnostic workup
Diagnostic criteria
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)
- Immunocompromised: quantitative plasma CMV PCR (viral load monitoring guides preemptive therapy in transplant)
- 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 |
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
- Cidofovir — third-line; significant nephrotoxicity
- Letermovir — prophylaxis post-HSCT (terminase inhibitor; no marrow toxicity)
- Maribavir — refractory/resistant CMV post-transplant (UL97 inhibitor)
Complications
- Congenital: sensorineural hearing loss (progressive in 50%), developmental delay, seizures, cerebral palsy, vision loss
- Post-transplant CMV: tissue-invasive disease, indirect effects (acute and chronic allograft rejection, opportunistic infections, post-transplant lymphoproliferative disorder)
- 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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