Cytomegalovirus (CMV) Infection: Clinical Features, Diagnosis and Management

Clinical Medicine Year 3 • CMV in immunocompetent people, pregnancy, newborns, HIV and transplant patients

Learning outcomes

• Explain CMV classification, latency, reactivation and the major routes of transmission.
• Distinguish primary infection, reinfection, reactivation, congenital infection and perinatal infection.
• Recognise CMV mononucleosis, congenital CMV, retinitis, pneumonitis, gastroenteritis, encephalitis and disseminated disease.
• Select and interpret PCR, serology, antigen testing, histology, ophthalmology and newborn tests.
• Plan supportive care, antiviral induction/maintenance, monitoring, prevention and follow-up.

Definition and virology

CMV, also called human herpesvirus type 5 (HHV-5), is an enveloped double-stranded DNA virus in the Herpesviridae family and Betaherpesvirinae subfamily. It has a large genome and replicates slowly. Infected cells enlarge and may show basophilic intranuclear inclusions surrounded by a clear halo—the classic “owl-eye” appearance—although immunohistochemistry and molecular tests are now more sensitive in many settings.

Like other herpesviruses, CMV persists after the first infection. Latent virus remains mainly in cells of the monocyte/macrophage lineage and other tissues. Immunosuppression, inflammation, transplantation, HIV immune failure or severe illness can allow reactivation and renewed viral replication.

Epidemiology and risk groups

CMV infection is common worldwide, with seroprevalence varying by age, crowding, breastfeeding, sexual exposure and socioeconomic conditions. A positive CMV-IgG result is therefore common and does not by itself prove active disease.

Transmission

CMV is present in saliva, urine, blood, semen, vaginal secretions, cervical secretions, breast milk and transplanted tissues. Transmission normally requires close or repeated contact rather than casual contact across a room.

• Congenital: transplacental infection during pregnancy after maternal primary infection, reinfection or reactivation. Primary infection generally carries the greater fetal risk, but reactivation can still transmit.
• Perinatal: exposure to genital secretions during delivery and breast milk. In a term infant this is often asymptomatic; very premature infants can develop clinically important disease.
• Child-to-child: saliva and urine from toddlers are important sources. Sharing utensils, kissing on the mouth and contact with nappies can transmit virus.
• Sexual: semen and cervical/vaginal secretions.
• Blood and organs: transfusion of infected cellular products and transplantation from a CMV-positive donor.

Pathogenesis: how latent virus becomes disease

1. CMV enters mucosal or damaged tissue cells and spreads locally and through blood leukocytes.
2. The immune system usually suppresses replication but does not eradicate the virus.
3. Latency is maintained in monocytes and progenitor cells; inflammation or immunosuppression activates viral gene expression.
4. New virions infect endothelial, epithelial, stromal and neural tissues. The resulting tissue injury may be direct viral cytopathy plus immune-mediated inflammation.
5. In pregnancy, placental infection can impair fetal growth and neurodevelopment. In advanced HIV, inadequate T-cell control permits high viral load and destructive retinitis, colitis or encephalitis.

Clinical presentations

1. Asymptomatic infection

Most infections in children and healthy adults are silent. The patient may have no illness but can intermittently shed CMV in saliva or urine for months or years. A positive IgG often represents remote infection rather than current disease.

2. CMV mononucleosis in an immunocompetent host

After an incubation period commonly measured in weeks, some adolescents and adults develop prolonged fever, profound fatigue, malaise, myalgia, headache, sore throat, cervical or generalised lymphadenopathy and mild hepatitis. Atypical lymphocytosis and raised transaminases are common. Unlike Epstein–Barr virus mononucleosis, prominent exudative tonsillitis and heterophile antibody positivity are less typical.

• Usually self-limited over several weeks.
• Possible complications include hepatitis, haemolysis, thrombocytopenia, myocarditis, pneumonitis, meningoencephalitis and Guillain–Barré syndrome, but these are uncommon in healthy people.

3. Congenital CMV

Congenital CMV means infection acquired before birth. Some infants are normal at birth but later develop hearing loss or developmental difficulty. Symptomatic disease may include:

• Intrauterine growth restriction, prematurity and poor feeding.
• Microcephaly, seizures, hypotonia or abnormal neurologic examination.
• Periventricular calcifications, ventriculomegaly, white-matter abnormalities or cortical malformations.
• Petechiae and purpura (“blueberry muffin” appearance), thrombocytopenia and anaemia.
• Jaundice, hepatosplenomegaly, hepatitis and cholestasis.
• Chorioretinitis, optic abnormalities and sensorineural hearing loss.

4. CMV disease in advanced HIV

CMV disease is classically associated with severe immune suppression, particularly a very low CD4 count, although effective ART has reduced its frequency. Presentations include:

• Retinitis: painless floaters, blurred vision, scotomata, photopsia or progressive visual-field loss. Examination may show necrotising retinal lesions with haemorrhage along vessels (“pizza pie” or “brush-fire” appearance). Untreated disease can lead to retinal detachment and blindness.
• Gastrointestinal disease: odynophagia, dysphagia, epigastric pain, abdominal pain, fever, diarrhoea, weight loss, ulceration, bleeding or perforation. Colitis may cause frequent watery or bloody stool.
• Neurologic disease: subacute encephalitis, ventriculitis, myelitis, radiculopathy, cranial neuropathy, confusion, seizures or urinary retention.
• Pneumonitis: fever, dry cough, dyspnoea, hypoxaemia and diffuse interstitial infiltrates; consider Pneumocystis, TB and bacterial pneumonia as important alternatives.
• Disseminated disease: fever, cytopenias, hepatitis, adrenal involvement or multiorgan dysfunction.

5. CMV in transplant recipients

CMV may produce an isolated viral syndrome—fever, malaise, leukopenia and thrombocytopenia—or tissue-invasive pneumonitis, hepatitis, colitis, oesophagitis, retinitis and graft dysfunction. Risk is especially high when the donor is CMV positive and the recipient is CMV negative, after T-cell-depleting therapy, during treatment for rejection, or when prophylaxis is stopped too early.

History and examination

Examine temperature, hydration, weight, lymph nodes, oral cavity, jaundice, liver and spleen, skin petechiae, fundus/visual function, respiratory system, abdomen and a complete neurologic system. Any visual symptom in advanced HIV or a transplant recipient is an urgent ophthalmology problem.

Investigations and interpretation

1. CMV serology

• CMV-IgG: indicates previous exposure; it does not prove active disease and does not identify the site of disease.
• CMV-IgM: may support recent primary infection but can persist, cross-react and appear during reactivation. It must be interpreted with clinical findings and sometimes IgG avidity or paired sera.
• IgG avidity: low avidity supports a recent primary infection; high avidity suggests older infection. It is especially useful in pregnancy but is not a stand-alone fetal diagnosis.

2. CMV PCR and viral load

Quantitative nucleic-acid testing in plasma or whole blood is useful for diagnosing and monitoring CMV in transplant and advanced HIV patients. A falling viral load supports response, but the numerical threshold for disease is laboratory- and patient-specific. Blood PCR can be negative in localised tissue disease and can be positive without invasive disease; always match it to the organ syndrome.

3. Tissue and organ-specific confirmation

• Retinitis: urgent dilated retinal examination by an experienced clinician; CMV PCR in aqueous/vitreous may help when the diagnosis is uncertain.
• Gastrointestinal disease: endoscopy with biopsy for histology, immunohistochemistry and PCR. Stool CMV PCR alone is not enough to prove tissue-invasive colitis.
• Pneumonitis: chest radiograph/CT, oxygenation assessment, bronchoscopy and BAL studies; histology may be needed because CMV DNA in BAL can represent shedding.
• CNS disease: MRI brain/spine as indicated, CSF cell count, protein, glucose, CMV PCR and tests for HSV, VZV, cryptococcus, TB and bacterial infection.
• Congenital disease: urine or saliva CMV PCR within 21 days of life, followed by confirmatory testing, hearing assessment, eye examination, blood count, liver tests and neuroimaging.

4. Basic assessment

Order a full blood count, renal function, liver enzymes, bilirubin, urinalysis, inflammatory markers, HIV test/viral load/CD4 when appropriate, blood cultures if septic, and targeted imaging. Before ganciclovir or valganciclovir, document neutrophils, haemoglobin, platelets and renal function because marrow suppression and renal accumulation are important toxicities.

Differential diagnosis

Management principles

1. Immunocompetent patient

Most CMV mononucleosis-like infections require rest, oral fluids, nutrition, antipyretic treatment and follow-up rather than antiviral therapy. Use paracetamol safely and assess for hepatitis before repeated dosing. Avoid unnecessary antibiotics and avoid relying on a positive IgG as proof of active CMV. Admit or refer patients with severe hepatitis, pneumonitis, neurologic disease, haemolysis, thrombocytopenia or organ failure.

2. Tissue-invasive disease in immunocompromised adults

Continue induction until clinical improvement and a substantial fall in viral replication; the exact duration depends on the organ involved, immune recovery and repeat testing. Maintenance is particularly important for CMV retinitis until immune recovery on ART or after transplant, according to specialist guidance.

3. CMV retinitis

Start systemic antiviral treatment urgently. Sight-threatening lesions near the optic disc or macula may need intravitreal ganciclovir or foscarnet in addition to systemic therapy. Arrange regular retinal examinations to document lesion inactivity, monitor the fellow eye and detect retinal detachment. In a patient with HIV, initiate or optimise ART at a carefully chosen time with an HIV specialist because immune recovery can produce ocular IRIS.

4. Congenital CMV

Symptomatic congenital CMV, especially with central nervous system involvement, may be treated with oral valganciclovir for approximately six months in specialist paediatric care. Monitor full blood count, liver function, renal function, growth, hearing and vision. The benefit is greatest when therapy is started early, but the decision depends on confirmation of congenital infection and severity. Newborns require developmental surveillance even when initially well.

5. HIV and transplant care

• Start or optimise effective ART in people with HIV and treat other OIs; immune recovery reduces recurrent CMV.
• Review interactions with antiretrovirals, calcineurin inhibitors, mTOR inhibitors, mycophenolate and chemotherapy.
• Transplant teams may use universal prophylaxis or pre-emptive CMV PCR monitoring depending on donor/recipient risk and transplant type.
• Reduce immunosuppression only with the transplant team because abrupt reduction may cause graft rejection.

Monitoring toxicity

Prevention

• Pregnant women should wash hands after changing nappies or contact with saliva/urine, avoid sharing food or utensils with toddlers and avoid kissing a child on the mouth.
• Use safer-sex practices and avoid sharing needles or untested blood products.
• Use CMV-appropriate blood products and leukoreduction according to local transfusion policy for high-risk recipients.
• Screen transplant donors and recipients, use risk-based prophylaxis or pre-emptive PCR monitoring, and educate patients about symptoms.
• There is no widely available licensed CMV vaccine; prevention currently relies on hygiene, screening, prophylaxis and immune restoration.

Exam-focused clinical pearls

• A positive CMV-IgG means previous exposure, not active disease.
• CMV mononucleosis is classically heterophile-negative.
• Congenital CMV is an important cause of delayed or progressive sensorineural hearing loss.
• CMV retinitis can progress silently; every visual symptom in advanced HIV is urgent.
• CMV PCR in blood supports replication but does not by itself prove tissue-invasive disease.
• The “owl-eye” inclusion is a classic histologic clue, but modern diagnosis commonly uses PCR and immunohistochemistry.

References and further reading

• SlideShare: Cytomegalovirus
• CDC: About Cytomegalovirus
• CDC: Congenital CMV and clinical overview
• NIH Clinical Guidelines: HIV-related opportunistic infections
• NCBI: Newborn screening and congenital CMV review