Do sirolimus (rapamycin) and mycophenolate mofetil increase the risk of pneumonia?

Sirolimus and Mycophenolate: Immunosuppressants That Increase Pneumonia Risk

Yes, both sirolimus and mycophenolate are immunosuppressants that significantly increase the risk of pneumonia, particularly Pneumocystis jirovecii pneumonia (PCP), with specific high-risk combinations and patient populations requiring heightened vigilance.

Evidence for Increased Pneumonia Risk

Sirolimus (Rapamycin)

• Sirolimus-containing regimens are strongly associated with PCP development, particularly when combined with other immunosuppressants 1
• The combination of tacrolimus and sirolimus carries a 3.6-fold increased risk of PCP compared to other regimens (adjusted hazard ratio 3.60, CI 2.03-6.39) 1
• Sirolimus plus mycophenolate mofetil increases PCP risk 2.77-fold (CI 1.40-5.47) 1
• Patients on sirolimus-based immunosuppression develop direct pulmonary toxicity manifesting as pneumonitis, requiring evaluation when new or worsening respiratory symptoms appear 2
• Sirolimus-induced pneumonitis presents as lymphocytic pneumonitis and bronchiolitis obliterans on bronchoscopy 3

Mycophenolate Mofetil

• Mycophenolate combined with cyclosporine (Neoral) increases PCP risk 2.09-fold (CI 1.31-3.31) 1
• In patients with impaired renal function (eGFR <60 mL/min/1.73 m²), mycophenolate causes severe delayed pneumonia including PCP around the third month of treatment 4
• Six of 16 patients (37.5%) with chronic renal impairment developed severe pneumonia on mycophenolate, with a mortality rate of 67% (4 of 6 deaths) 4
• The mechanism involves profound lymphopenia in renally impaired patients (absolute lymphocyte count dropping to 0.22 ± 0.04 × 10⁹/L in those who developed pneumonia versus 1.91 ± 0.20 × 10⁹/L in those who did not) 4

Clinical Implications and Monitoring

High-Risk Populations Requiring Extended Prophylaxis

• Median time to PCP development is 9.6 months (0.80 ± 0.95 years) after transplant, occurring well beyond standard 3-6 month prophylaxis periods 1
• Patients on sirolimus-based regimens warrant longer PCP prophylaxis duration given the delayed onset pattern 1
• Nosocomial PCP clusters have emerged in transplant units, suggesting de novo infection rather than reactivation, particularly affecting patients on mycophenolate-containing regimens 2

Monitoring Requirements

• For sirolimus therapy: Monitor for new or worsening respiratory symptoms with prompt evaluation for drug-induced pulmonary toxicity (Grade 1B recommendation) 2
• For mycophenolate therapy in patients with eGFR <60 mL/min/1.73 m²: Monitor absolute lymphocyte counts monthly, as counts <0.5 × 10⁹/L signal high pneumonia risk 4
• Weekly complete blood counts should be performed initially in all patients starting mycophenolate 5

Specific Drug Combination Risks

The highest-risk immunosuppressive combinations for pneumonia are:

1. Tacrolimus + sirolimus (3.6-fold increased PCP risk) 1
2. Sirolimus + mycophenolate mofetil (2.77-fold increased PCP risk) 1
3. Cyclosporine + mycophenolate mofetil (2.09-fold increased PCP risk) 1

Critical Pitfalls to Avoid

• Do not assume standard 3-6 month PCP prophylaxis is adequate for sirolimus or high-risk mycophenolate regimens; median onset is 9.6 months 1
• Do not overlook renal function when prescribing mycophenolate—patients with eGFR <60 mL/min/1.73 m² have 37.5% risk of severe pneumonia 4
• Do not attribute respiratory symptoms solely to infection—sirolimus causes direct pulmonary toxicity requiring drug evaluation 2
• Do not ignore lymphocyte counts—profound lymphopenia (especially <0.5 × 10⁹/L) predicts imminent severe pneumonia in mycophenolate-treated patients 4

Mortality Impact

• PCP infection is associated with increased risk of both graft loss and patient death as a time-dependent variable 1
• In mycophenolate-treated IgA nephropathy patients with renal impairment, severe pneumonia carried 67% mortality (4 of 6 deaths) 4
• Most cases presented with abrupt onset and rapid progression to respiratory failure 4