What is the treatment for immunotherapy-induced pneumonitis?

Treatment of Immunotherapy-Induced Pneumonitis

For grade 1-2 pneumonitis, initiate oral prednisone 1 mg/kg/day; for grade 3-4 pneumonitis, hospitalize immediately and start intravenous methylprednisolone 2-4 mg/kg/day, permanently discontinue the checkpoint inhibitor, and taper steroids slowly over 6+ weeks. 1

Grade-Specific Treatment Algorithm

Grade 1 (Asymptomatic, Radiographic Changes Only)

• Hold the checkpoint inhibitor and monitor closely with clinical assessment every 2-3 days and repeat chest CT every 3 weeks 2, 3
• No corticosteroids are required at this stage 2, 3
• Continue surveillance with home pulse oximetry monitoring 2
• May consider reintroducing immunotherapy if imaging abnormalities resolve completely 2

Grade 2 (Symptomatic, Not Limiting ADLs)

• Permanently hold the checkpoint inhibitor 3
• Initiate oral prednisone 1 mg/kg/day (or IV methylprednisolone equivalent) 1, 3
• Rule out infection with bronchoscopy and bronchoalveolar lavage before starting immunosuppression when feasible 1
• If infection cannot be excluded, administer broad-spectrum antibiotics concurrently with steroids 1
• Reassess clinically every 2-3 days and radiologically to confirm improvement 1
• Taper steroids over 4-6 weeks after recovery 1
• Consider hospitalization for pulmonary and infectious disease consultation 3

Grade 3-4 (Severe, Limiting Self-Care or Life-Threatening)

• Hospitalize immediately and permanently discontinue checkpoint inhibitor 1, 3
• Initiate high-dose IV methylprednisolone 2-4 mg/kg/day 1
• Consider ICU-level care for grade 4 pneumonitis 3
• If no improvement after 48 hours, add second-line immunosuppression: infliximab, mycophenolate mofetil, or cyclophosphamide 1
• Taper steroids very slowly over 6+ weeks to minimize relapse risk 1

Critical Supportive Care Measures

Infection Prophylaxis

• Pneumocystis jirovecii pneumonia (PCP) prophylaxis for patients receiving ≥20 mg prednisone equivalent for ≥4 weeks 4, 3
• Proton pump inhibitor therapy for GI prophylaxis in all patients receiving steroids for grade 2-4 pneumonitis 4, 3
• T-spot testing to exclude tuberculosis before initiating anti-TNF therapy 3

Bone and Metabolic Protection

• Calcium and vitamin D supplementation with prolonged steroid use 4, 3
• Consider bone density testing and prophylactic bisphosphonates for long-term steroid therapy 4
• Monitor blood glucose regularly and treat hyperglycemia per standard guidelines 4

Infectious Workup (Grade 2+)

• Nasal swab, sputum culture, blood culture, urine culture 3
• COVID-19 testing per institutional guidelines 3
• Pulse oximetry and CT chest with contrast (if pulmonary embolus suspected) 3

Steroid-Refractory Pneumonitis

Approximately 10% of patients with ICI pneumonitis will be steroid-refractory or steroid-resistant, requiring second-line immunosuppression 5. When steroids fail after 48 hours:

Second-Line Options

• Cyclophosphamide appears most promising based on limited data, with 2/2 survivors at 5 months in one series 5
• Infliximab (single dose may suffice) 1, 5
• Mycophenolate mofetil 1, 4
• Intravenous immunoglobulin (IVIG) for severe cases unresponsive to steroids 6
• Pulse corticosteroid therapy (methylprednisolone 500 mg for 3 days) for steroid-refractory cases 7

Critical caveat: Mortality in steroid-refractory pneumonitis is high at 67%, emphasizing the importance of early recognition and aggressive management 5.

Chronic ICI Pneumonitis

Approximately 2% of patients with NSCLC or melanoma will develop chronic pneumonitis requiring ≥12 weeks of immunosuppression 8. These patients have distinct features:

• Recrudescence typically occurs when steroids tapered to ≤10 mg prednisone 8
• Median total steroid duration is 37 weeks (range: 16-43+ weeks) 8
• Characterized by persistent BALF lymphocytosis and organizing pneumonia pattern on biopsy 8
• Low-dose prednisone maintenance (10 mg daily) may be required long-term to prevent recurrence 9, 8
• Despite prolonged immunosuppression, most maintain disease control from ICIs 8

Rechallenge Considerations

• Grade 1: May rechallenge after complete resolution with close monitoring 1
• Grade 2: Rechallenge can be considered on an individual basis upon complete symptom resolution, only after steroids tapered to ≤10 mg prednisone daily 1
• Grade 3-4: Checkpoint inhibitor should be permanently discontinued 1, 3

Common Pitfalls to Avoid

• Never delay steroid initiation in symptomatic patients while awaiting bronchoscopy results 3
• Avoid rapid steroid tapers: Grade 2 requires >1 month taper; grade 3-4 requires >2 months 3
• Do not use high-dose steroids (1 mg/kg/day) for endocrine immune-related adverse events 3
• Never continue long-term corticosteroid monotherapy without objective evidence of benefit 4
• Relapses during steroid tapering are common—maintain vigilance and be prepared to re-escalate 1

Risk Factors and Epidemiology

• Higher incidence with combination immunotherapy (10%) versus monotherapy (3%) 1
• NSCLC patients have higher rates and more treatment-related deaths than melanoma patients 1
• Median time to onset: 2.5-2.8 months, occurring earlier with combination therapy 1
• Pre-existing COPD, prior radiation therapy, and smoking history may increase risk 1