What are the clinical manifestations of cytomegalovirus (CMV) infection in immunocompetent, immunocompromised, and congenital patients?

Cytomegalovirus Clinical Manifestations

CMV manifests differently across patient populations: in immunocompetent adults it typically causes mild mononucleosis-like illness or remains asymptomatic, while in severely immunocompromised patients (CD4+ <50 cells/µL) it causes devastating end-organ disease with retinitis being the most common manifestation, and in congenital infection it produces severe developmental consequences. 1, 2, 3

Immunocompromised Patients (HIV/AIDS and Other Immunosuppression)

Risk Stratification

• End-organ CMV disease occurs almost exclusively when CD4+ counts fall below 50 cells/µL in HIV patients not receiving or failing antiretroviral therapy (ART). 1
• Additional risk factors include previous opportunistic infections (particularly MAC disease), high plasma HIV RNA levels (>100,000 copies/mL), and use of immunosuppressive medications including purine analogues and methotrexate. 1, 4
• Before potent ART, approximately 30% of AIDS patients developed CMV retinitis between AIDS diagnosis and death; this has declined by 75-80% with modern ART to <6 cases per 100 person-years. 1

Ocular Disease (Most Common)

• Retinitis is the most frequent manifestation, presenting as unilateral disease in two-thirds of patients initially, but progressing to bilateral involvement without treatment. 1, 2
• Peripheral retinitis causes floaters, scotomata (blind spots), or peripheral visual field defects, while central lesions impinging on the macula or optic nerve cause decreased visual acuity or central field defects. 1, 2
• The characteristic ophthalmologic appearance includes fluffy yellow-white retinal infiltrates representing full-thickness necrotizing retinitis, with or without intraretinal hemorrhage, minimal vitreous inflammation (unless immune recovery occurs), and blood vessel sheathing near lesions. 1, 2
• Without treatment, retinitis invariably progresses within 10-21 days in a "brushfire pattern" with a granular white leading edge advancing before an atrophic gliotic scar. 1, 2
• Even with immune recovery (CD4+ >100 cells/µL) sufficient to discontinue anti-CMV therapy, relapse occurs at 0.03/person-year and can happen at CD4+ counts as high as 1,250 cells/µL, necessitating ongoing ophthalmologic surveillance. 1

Gastrointestinal Disease

• CMV colitis occurs in 5-10% of AIDS patients with CMV end-organ disease, presenting with fever, weight loss, anorexia, abdominal pain, debilitating diarrhea, and malaise. 1, 2, 4
• Life-threatening complications include extensive mucosal hemorrhage and bowel perforation. 1, 2
• CMV esophagitis occurs in <5-10% of cases, causing fever, odynophagia (painful swallowing), nausea, and mid-epigastric or retrosternal discomfort. 1, 2
• Tissue diagnosis through gastrointestinal immunohistochemistry or PCR from actively inflamed areas provides definitive diagnosis; serum CMV testing alone is inadequate as it does not correlate well with tissue infection. 4
• Sampling multiple sites (minimum 11-16 samples from affected organs) increases diagnostic yield. 4

Pulmonary Disease

• CMV pneumonitis is uncommon but presents with shortness of breath, dyspnea on exertion, nonproductive cough, and hypoxemia with interstitial infiltrates on chest radiograph. 1, 2, 4
• This manifestation can be fatal in immunocompromised patients. 4

Neurologic Disease

• CMV dementia presents with lethargy, confusion, and fever, mimicking HIV-associated dementia. 1, 2
• CSF typically shows lymphocytic pleocytosis (though neutrophils and lymphocytes may be mixed), low-to-normal glucose, and normal-to-elevated protein. 1
• Ventriculoencephalitis has a more acute course with focal neurologic signs, cranial nerve palsies, nystagmus, and rapid progression to death. 2
• Ascending polyradiculomyelopathy presents as Guillain-Barré-like syndrome with urinary retention, progressive bilateral leg weakness, loss of bowel and bladder control, and flaccid paraplegia. 2

Immunocompetent Adults

General Presentation

• CMV infection in healthy adults is usually asymptomatic or causes a mild mononucleosis-like syndrome. 5, 6, 3
• The incidence of severe CMV disease in immunocompetent adults appears greater than previously recognized, possibly due to immune dysfunction related to comorbidities such as kidney disease or diabetes mellitus. 3
• CMV has an incubation period of approximately 4-6 weeks. 7

Severe Disease in Immunocompetent Hosts

• CMV colitis is the most common manifestation of severe disease in immunocompetent adults. 3
• Acute CMV hepatitis can occur, presenting with low-grade fever and elevated liver enzymes, responding favorably to antiviral therapy with valganciclovir. 7
• CMV disease can mimic numerous alternative diagnoses and pose significant diagnostic challenges, leading to delayed diagnosis, adverse health outcomes, and unnecessary expense. 3

Congenital CMV Infection

• Congenital CMV can produce devastating illness in a small proportion of infected babies, causing severe developmental consequences. 6, 3

Diagnostic Considerations

Laboratory Testing

• CMV viremia detected by PCR, antigen assays, or blood culture is usually present in end-organ disease but may also occur without end-organ involvement. 2, 4
• Non-invasive testing for CMV is widely available and can facilitate early diagnosis when used appropriately. 3
• Critical pitfall: qPCR testing of body fluids cannot reliably differentiate between viral shedding and tissue-invasive infection, which requires histopathological confirmation. 8

Organ-Specific Diagnosis

• Retinitis requires ophthalmologic examination for definitive diagnosis. 2
• Colitis/esophagitis requires endoscopic examination with biopsy; tissue diagnosis through immunohistochemistry or PCR from actively inflamed areas is essential. 2, 4
• Neurologic disease requires compatible clinical syndrome plus presence of CMV in CSF or brain tissue. 2

Treatment Decision Framework

• Treatment decisions should consider patient history, serological findings, and tissue viral load. 4
• High tissue viral load warrants treatment as it is associated with severe disease and poor outcomes. 4
• Systemic illness with fever and organ dysfunction requires treatment as it can be life-threatening. 4
• Consultation with infectious disease or microbiology teams aids treatment decisions. 4
• Current evidence suggests targeted antiviral therapy with ganciclovir or valganciclovir is appropriate for severe CMV disease in immunocompetent adults, though evidence is limited. 3