What is the initial treatment for immunotherapy-induced pneumonitis, specifically regarding steroid (corticosteroid) use?

Steroid Treatment for Immunotherapy-Induced Pneumonitis

For symptomatic immunotherapy-induced pneumonitis (grade 2 or higher), initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent) immediately after holding the immune checkpoint inhibitor and ruling out infection. 1

Grade-Based Treatment Algorithm

Grade 1 (Asymptomatic, radiographic findings only)

• Hold the immune checkpoint inhibitor and monitor closely 1
• No steroids required at this stage 1
• Reimage at least every 3 weeks (prior to each treatment cycle) 1
• Self-monitor oxygen saturation every 2-3 days with pulse oximetry 1
• Weekly clinic visits to assess for symptom development 1
• If radiographic findings resolve, resume therapy with close monitoring 1
• If progression occurs or symptoms develop, escalate to grade 2 management 1

Grade 2 (Symptomatic, limiting instrumental activities of daily living)

• Permanently hold the immune checkpoint inhibitor 1
• Initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent) 1
• Consider hospitalization for pulmonary and infectious disease consultation 1
• Obtain bronchoscopy with bronchoalveolar lavage to rule out infection; consider biopsies for atypical lesions 1
• Reassess on day 2-3 of corticosteroid therapy: 1
  • If symptoms improve to ≤ grade 1: Begin slow steroid taper over >1 month 1
  • If no improvement or worsening: Escalate to grade 3-4 management 1
• Consider drug re-challenge only if symptoms and imaging abnormalities completely resolve 1

Grade 3-4 (Severe symptoms requiring oxygen or life-threatening)

• Permanently discontinue the immune checkpoint inhibitor 1
• Hospitalize immediately; consider ICU-level care 1
• Initiate methylprednisolone IV 2 mg/kg/day 1
• Obtain pulmonary consultation for bronchoscopy with bronchoalveolar lavage and consider biopsies 1
• Reassess on day 2-3 of corticosteroid therapy: 1
  • If no clinical improvement: Add second-line immunosuppression with infliximab, cyclophosphamide, mycophenolate mofetil, or IVIG 1
  • If clinical improvement: Reduce corticosteroids to 1 mg/kg/day and taper slowly over >2 months 1
• Grade 4 pneumonitis: Never re-challenge with immune checkpoint inhibitor 1
• Grade 3 pneumonitis: Consider re-challenge only on case-by-case basis after complete resolution and thorough risk-benefit discussion 1

Steroid-Refractory Pneumonitis Management

Steroid-refractory pneumonitis is defined as lack of clinical improvement after 48 hours of high-dose corticosteroids. 1, 2, 3

Second-Line Immunosuppression Options

• IVIG appears to have better outcomes than infliximab based on mortality data (43% vs 100% mortality respectively) 2
• Infliximab carries higher risk of infectious complications and mechanical ventilation requirements 2
• Cyclophosphamide may be considered, particularly in combination therapy 4, 5
• Mycophenolate mofetil is an alternative option 1, 3
• Triple combination therapy (high-dose corticosteroids + tacrolimus + cyclophosphamide) has shown success in case reports 5
• Pulse corticosteroid therapy (methylprednisolone 500 mg for 3 days) may be attempted before switching to alternative immunosuppressants 6

Prognosis of Steroid-Refractory Disease

• Occurs in approximately 10-18.5% of patients with immune checkpoint inhibitor pneumonitis 4, 2
• Associated with 50-67% mortality rate at 90 days 4, 2, 3
• Most commonly presents with diffuse alveolar damage pattern on imaging (50% of cases) 2
• Typically occurs early in treatment course (mean of 5 doses) 2
• Durable improvement with additional immunomodulators achieved in only 38% of patients 3

Critical Supportive Care Measures

Infection Prophylaxis

• Pneumocystis jirovecii pneumonia (PCP) prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks 1
• Proton pump inhibitor therapy for GI prophylaxis in all patients with grade 2-4 pneumonitis receiving steroids 1
• T-spot testing to exclude tuberculosis before initiating anti-TNF therapy 1

Bone Health

• Calcium and vitamin D supplementation with prolonged steroid use 1

Infectious Workup (Grade 2 or Higher)

• Nasal swab, sputum culture and sensitivity 1
• Blood culture and sensitivity 1
• Urine culture and sensitivity 1
• COVID-19 evaluation per institutional guidelines 1
• Pulse oximetry and CT chest (preferably with contrast if concerned for pulmonary embolus) 1

Common Pitfalls to Avoid

• Do not use high-dose corticosteroids (1 mg/kg/day) for endocrine immune-related adverse events (thyroid, diabetes)—these are NOT routinely required 1
• Do not delay steroid initiation in symptomatic patients while awaiting bronchoscopy results 1
• Do not taper steroids too quickly—grade 2 requires >1 month taper, grade 3-4 requires >2 months 1, 7
• Do not use infliximab as first-line second-line agent—IVIG has superior outcomes 2
• Do not re-challenge with immune checkpoint inhibitor in grade 4 pneumonitis—this is an absolute contraindication 1
• Do not forget infection prophylaxis—PCP prophylaxis and PPI are essential for grade 2-4 pneumonitis 1

Evidence Quality Note

The SITC (Society for Immunotherapy of Cancer) 2017 consensus guidelines 1 and ASCO 2021 guideline update 1 provide the strongest evidence base for these recommendations. The steroid dosing and tapering schedules are consistent across both major guidelines. Research evidence on steroid-refractory disease 4, 2, 3 reveals concerning mortality rates and suggests IVIG may be preferred over infliximab for second-line therapy, though overall outcomes remain poor with 50-67% mortality.