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.
Try two board-style Cytomegalovirus questions
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Question 1Infectious DiseaseMedium
A 45-year-old man with HIV (CD4 count 45 cells/µL, not on antiretroviral therapy) develops painless, progressive visual changes, including floaters and a curtain-like loss of vision. Ophthalmologic examination shows hemorrhagic retinal lesions with perivascular exudates in a 'pizza pie' pattern. Which of the following is the most likely diagnosis?
ACryptococcal chorioretinitis
BAcute retinal necrosis
CToxoplasma retinochoroiditis
DCytomegalovirus retinitis
Reveal answer & full explanation
Correct answer: D — Cytomegalovirus retinitis
ACryptococcal chorioretinitis
BAcute retinal necrosis
CToxoplasma retinochoroiditis
DCytomegalovirus retinitis✓
Why Cytomegalovirus retinitis is correct
CMV retinitis is the most common ocular opportunistic infection in advanced AIDS and characteristically appears once the CD4 count falls below 50 cells/µL, as in this patient.
The painless, progressive floaters and a curtain of vision loss reflect full-thickness necrotizing retinitis.
The 'pizza pie' fundus — hemorrhage plus perivascular exudates and necrosis — is the classic sign.
Management is systemic valganciclovir (with intravitreal ganciclovir for sight-threatening lesions) plus prompt antiretroviral therapy.
Why the others are wrong
Cryptococcal chorioretinitis — Cryptococcus in AIDS causes meningitis and, rarely, papilledema, not hemorrhagic 'pizza pie' retinitis; picking it confuses the feared CNS opportunist with the ocular one (buzzword-matching on HIV).
Acute retinal necrosis — a VZV/HSV peripheral necrotizing retinitis that is typically painful with prominent anterior-chamber and vitreous inflammation and occurs in immunocompetent hosts; the painless course and CD4 <50 point away (premature closure on 'viral retinitis').
Toxoplasma retinochoroiditis — produces a focal yellow-white 'headlight in the fog' lesion next to an old chorioretinal scar with dense vitritis, not diffuse hemorrhagic perivascular exudates (confused-with-CMV trap).
Teaching point
In AIDS with CD4 <50, painless visual loss and a hemorrhagic 'pizza pie' retina is CMV retinitis until proven otherwise.
Question 2Infectious DiseaseMedium
A 3-day-old term newborn is evaluated after failing the universal newborn hearing screen in both ears. He was small for gestational age at birth. On examination he has microcephaly, hepatosplenomegaly, and scattered petechiae. Laboratory studies show conjugated hyperbilirubinemia, mild transaminitis, and thrombocytopenia. Head ultrasound reveals periventricular calcifications. Which of the following is the most appropriate next diagnostic test?
ACMV PCR on a neonatal urine or saliva sample
BToxoplasma IgM and IgG serology on infant serum
CQuantitative plasma CMV PCR at one month of age
DCMV IgM and IgG serology on infant serum sample
Reveal answer & full explanation
Correct answer: A — CMV PCR on a neonatal urine or saliva sample
ACMV PCR on a neonatal urine or saliva sample✓
BToxoplasma IgM and IgG serology on infant serum
CQuantitative plasma CMV PCR at one month of age
DCMV IgM and IgG serology on infant serum sample
Why CMV PCR on a neonatal urine or saliva sample is correct
This newborn has the classic congenital CMV phenotype: SGA, microcephaly, hepatosplenomegaly, petechiae, conjugated hyperbilirubinemia, thrombocytopenia, periventricular calcifications, and a failed hearing screen (CMV is the leading non-genetic cause of childhood sensorineural hearing loss).
The confirmatory test is CMV PCR on neonatal urine or saliva obtained within the first 21 days of life; sampling during this window distinguishes true congenital infection from perinatally acquired CMV.
Early diagnosis matters because symptomatic congenital CMV with CNS involvement or hearing loss is treated with oral valganciclovir for 6 months, which improves hearing and developmental outcomes.
Why the others are wrong
CMV IgM and IgG serology on infant serum sample: neonatal antibody testing is unreliable because IgG reflects transplacental maternal antibody and IgM is insensitive in the newborn, so it cannot confirm congenital infection.
Toxoplasma IgM and IgG serology on infant serum: congenital toxoplasmosis is on the TORCH differential but classically produces diffuse (not periventricular) intracranial calcifications and chorioretinitis, so pursuing it first delays the higher-yield CMV PCR.
Quantitative plasma CMV PCR at one month of age: a positive test after 21 days of life cannot distinguish congenital from perinatally acquired infection, defeating the purpose of testing in this window.
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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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