What are the clinical presentation, imaging findings, diagnostic approach, and first‑line therapy for cytomegalovirus pneumonitis in severely immunocompromised patients such as solid‑organ or hematopoietic‑stem‑cell transplant recipients, individuals with advanced HIV infection (CD4 < 50 cells/µL), or patients receiving high‑dose steroids?

Cytomegalovirus Pneumonitis in Severely Immunocompromised Patients

In severely immunocompromised patients with suspected CMV pneumonitis, initiate intravenous ganciclovir 5 mg/kg every 12 hours immediately while pursuing bronchoscopy with BAL for CMV immunostaining and quantitative PCR, and continue treatment for 14–21 days if confirmed, recognizing that mortality remains high even with optimal therapy. 1, 2

Clinical Presentation

CMV pneumonitis presents with nonspecific respiratory symptoms that make clinical diagnosis challenging:

• Fever, dyspnea, and nonproductive cough are the most common presenting symptoms, often developing insidiously over days to weeks 3, 4
• Hypoxemia is frequently present and may progress rapidly to respiratory failure requiring mechanical ventilation 5
• Symptoms are often indistinguishable from other opportunistic pneumonias (Pneumocystis, fungal infections, bacterial pneumonia), necessitating aggressive diagnostic workup 3, 4
• In HIV patients with CD4 < 50 cells/µL, CMV pneumonitis may occur alongside CMV retinitis or colitis as part of disseminated disease 5
• Hematopoietic stem cell transplant recipients typically develop CMV pneumonitis in the early post-engraftment phase (30–100 days post-transplant), though late disease can occur with ongoing immunosuppression 5
• Solid organ transplant recipients are at highest risk in the first 3–6 months post-transplant, particularly during periods of augmented immunosuppression for rejection 6, 7

Imaging Findings

Chest imaging demonstrates nonspecific patterns that overlap with other etiologies:

• Ground-glass opacities are the most common CT finding, often bilateral and diffuse 3, 6
• Interstitial infiltrates may be present, sometimes with a reticulonodular pattern 3
• Consolidation can occur but is less common than ground-glass changes 6
• Small bowel thickening may be seen concurrently if CMV colitis is present, which can help differentiate from other viral pneumonias 5
• Imaging findings are not diagnostic and cannot distinguish CMV from other opportunistic infections; tissue diagnosis is mandatory 3, 4

Diagnostic Approach

Bronchoscopy with bronchoalveolar lavage (BAL) is the diagnostic gold standard and should be performed urgently:

BAL Fluid Analysis (Preferred Diagnostic Method)

• CMV immunostaining of BAL cells using monoclonal anti-CMV antibodies has a sensitivity of 88.9%, specificity of 98.6%, and negative predictive value of 99.5% for CMV pneumonitis 3
• Positive immunostaining indicates tissue-invasive disease and distinguishes pneumonitis from mere viral shedding 3, 4
• Quantitative CMV PCR on BAL fluid should be performed, though viral load thresholds are not standardized and high loads do not definitively prove pneumonitis 4, 7
• Histopathology showing "owl's eye" intranuclear inclusions on biopsy is definitive but less sensitive than immunostaining 5, 3

Blood Testing (Adjunctive, Not Diagnostic)

• Plasma CMV PCR (viremia) should be checked but does not confirm pneumonitis—many patients have viremia without end-organ disease 5, 4
• CMV serology (IgG) has no diagnostic value in acute disease, as 70% of adults are seropositive at baseline 5
• Weekly CMV PCR monitoring is recommended during treatment to assess viral suppression 5, 1

Critical Diagnostic Pitfall

• CMV detection in blood or BAL does not equal CMV disease—immunocompromised patients frequently shed virus without tissue invasion 4, 7
• Do not delay bronchoscopy to obtain blood PCR results; BAL immunostaining provides the definitive answer 3

First-Line Therapy

Intravenous ganciclovir is the first-line treatment and must be initiated promptly:

Standard Induction Regimen

• Ganciclovir 5 mg/kg IV every 12 hours infused over 1–2 hours for 14–21 days 1, 2
• Each dose must be infused slowly over 1–2 hours to minimize acute toxicity 1, 2
• Do not use oral valganciclovir for initial treatment of severe pneumonitis—IV therapy is required for life-threatening disease 1, 2

Combination Therapy for Severe or Refractory Disease

• For severe pneumonitis or treatment failure, add foscarnet: ganciclovir 5 mg/kg IV every 12 hours PLUS foscarnet 60 mg/kg IV every 8 hours for 3 weeks 1, 2
• This combination achieved improvement or stabilization in 74% of patients with severe CMV end-organ disease 2

Renal Dose Adjustment (Critical)

• Creatinine clearance 50–69 mL/min: reduce to 2.5 mg/kg every 24 hours 2
• CrCl 25–49 mL/min: reduce to 1.25 mg/kg every 24 hours 2
• CrCl 10–24 mL/min: reduce to 0.625 mg/kg every 24 hours 2
• Hemodialysis: 0.625 mg/kg three times weekly after each dialysis session 2

Mandatory Monitoring During Treatment

• Complete blood count twice weekly during induction and once weekly during maintenance—myelosuppression occurs in up to 40% of patients and may require dose reduction, treatment interruption, or G-CSF 1, 2
• Serum creatinine at least weekly to detect nephrotoxicity requiring dose adjustment 1, 2
• Weekly CMV PCR (plasma or whole blood) to assess viral suppression 5, 1

Maintenance Therapy

• After completing induction, transition to ganciclovir 5 mg/kg IV once daily or valganciclovir 900 mg PO once daily for chronic suppression until immune reconstitution 1, 2
• In HIV patients, continue suppression until CD4 > 100–150 cells/µL sustained for ≥3 months on antiretroviral therapy 5, 2
• In transplant recipients, duration depends on ongoing immunosuppression; consider continuing for at least 3–6 months 5

Resistance and Treatment Failure

• Ganciclovir-resistant CMV (IC₅₀ > 3 µg/mL) can emerge with prolonged therapy; switch to foscarnet or maribavir if resistance is suspected 5, 1, 8
• Maribavir is approved for refractory or resistant CMV infection in transplant recipients 5, 8

Prognosis and Critical Pitfalls

• Mortality remains high (approaching 70% in some series) despite antiviral therapy, particularly in patients with advanced immunosuppression 5, 4
• Do not delay treatment while awaiting BAL results—start ganciclovir empirically if clinical suspicion is high 1, 4
• Do not discontinue therapy prematurely—complete the full 14–21 day induction course even if symptoms improve 1, 2
• Ensure adequate hydration before and during infusions to mitigate nephrotoxicity 2
• Avoid rapid infusion—always infuse over 1–2 hours to prevent acute toxicity 1, 2