Can Cytomegalovirus Cause Ongoing Fever in Patients on Methotrexate?
Yes, cytomegalovirus (CMV) can absolutely provoke ongoing fever in patients on methotrexate and should be actively considered as a cause of persistent fever in this population.
Mechanism and Risk
Methotrexate is an immunosuppressive agent that increases susceptibility to infections, including CMV reactivation. 1 The FDA drug label explicitly lists CMV infection, including cytomegaloviral pneumonia, as a recognized complication of methotrexate therapy, with sometimes fatal opportunistic infections reported. 1
Key Clinical Evidence
CMV-induced infectious mononucleosis-like syndrome (IMLS) has been documented in rheumatoid arthritis patients treated with methotrexate, presenting with intermittent high fever, general fatigue, liver dysfunction, and lymphocytosis. 2
In immunocompromised patients, CMV causes severe disseminated or localized end-organ disease, with fever being a prominent symptom across multiple manifestations including colitis (fever, weight loss, anorexia), esophagitis (fever with painful swallowing), and neurologic disease (fever with lethargy and confusion). 3
Purine analogues are identified as independent risk factors for CMV reactivation, and while methotrexate is not a purine analogue, it shares immunosuppressive properties that create similar vulnerability. 4
Clinical Presentation to Recognize
When evaluating fever in methotrexate patients, look for:
- Intermittent high-grade fever with general fatigue and malaise 2
- Liver enzyme elevations and lymphocytosis (though methotrexate itself can cause transient liver enzyme increases) 2
- Gastrointestinal symptoms: abdominal pain, diarrhea, weight loss, anorexia (CMV colitis) 3
- Respiratory symptoms: dyspnea, nonproductive cough, hypoxemia (CMV pneumonitis, which can be fatal) 3, 5
- Visual symptoms: floaters, blind spots, decreased visual acuity (CMV retinitis) 3
Diagnostic Approach
Do not rely on serum CMV testing alone for diagnosis. 4 The British Society of Gastroenterology guidelines emphasize that serum antigen and PCR tests do not correlate well with colonic or tissue infection. 4
Recommended Testing Strategy:
- Obtain tissue diagnosis when possible: gastrointestinal tissue immunohistochemistry or PCR from actively inflamed areas provides definitive diagnosis 4
- CMV viremia by PCR or antigen assays can support the diagnosis but may occur without end-organ involvement 3
- Sample multiple sites: minimum of 11-16 samples from affected organs increases diagnostic yield 4
- Consider bronchoscopy with biopsy if respiratory symptoms are present, as endobronchial ulceration from CMV has been documented in methotrexate patients 6
Management Decisions
The decision to treat CMV should consider patient history, serological findings (antigen/DNA titer, leucopenia, low platelet count, elevated liver enzymes), and tissue viral load. 4
Treatment Indications:
- High tissue viral load warrants treatment 4
- Systemic illness with fever and organ dysfunction requires treatment 4
- Low-level serological reactivation without symptoms often does not need treatment 4
Important Caveat:
- Some cases resolve with cessation of methotrexate alone, without requiring antiviral therapy like ganciclovir, particularly in CMV-IMLS presentations 2
- However, severe cases (pneumonitis, disseminated disease) require prompt ganciclovir therapy 5, 6
- Consultation with infectious disease or microbiology teams aids treatment decisions 4
Critical Pitfall to Avoid
Do not assume fever in methotrexate patients is simply disease flare or drug toxicity without ruling out CMV. The immunosuppressive nature of methotrexate creates a window for opportunistic infections that can be fatal if missed. 1, 5 CMV should be in your differential for any methotrexate patient with new or persistent fever, especially when accompanied by cytopenias, liver dysfunction, or respiratory/gastrointestinal symptoms. 2, 6