What is the role of corticosteroids (steroids) in treating immunotherapy-related pneumonitis?

Corticosteroids in Immunotherapy-Related Pneumonitis

Corticosteroids are the recommended first-line treatment for symptomatic immunotherapy-related pneumonitis, with clinical improvement reported in over 80% of cases, and treatment should be initiated immediately based on severity grading. 1

Treatment Algorithm by Severity Grade

Grade 1 (Asymptomatic, <25% lung involvement)

• Hold immunotherapy and monitor closely without initiating corticosteroids 2, 3
• Monitor weekly with pulse oximetry, history, physical examination 1
• Repeat chest imaging in 3-4 weeks or sooner if symptoms develop 1
• Corticosteroids are not required at this stage 4, 3

Grade 2 (Symptomatic, limiting instrumental ADLs)

• Discontinue immunotherapy immediately 1, 2
• Initiate oral prednisone 1 mg/kg daily or equivalent 1, 2, 3
• Perform bronchoscopy with bronchoalveolar lavage to exclude infection before starting steroids when feasible 1, 2
• Assess clinically every 2-3 days initially 1, 3
• Taper steroids over 4-6 weeks minimum after recovery 1, 2
• Delay immunotherapy rechallenge until daily steroid dose ≤10 mg prednisone equivalent 1

Grade 3-4 (Severe/Life-threatening)

• Hospitalize immediately and permanently discontinue immunotherapy 1, 2, 4
• Administer high-dose IV methylprednisolone 2-4 mg/kg/day or equivalent 1, 2, 3
• Consider broad-spectrum antibiotics in parallel if infectious status cannot be reliably assessed 1, 2
• If no improvement after 48 hours of corticosteroids, add second-line immunosuppression 1, 2
• Taper steroids very slowly over 6+ weeks due to high relapse risk 1, 2, 4

Second-Line Immunosuppression for Steroid-Refractory Disease

When pneumonitis fails to improve after 48 hours of corticosteroid therapy, it is deemed steroid-refractory and requires additional immunosuppression 1:

• Options include infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide 1
• Steroid-refractory disease occurs in approximately 10% of patients treated with corticosteroids 5
• Mortality in steroid-refractory pneumonitis is high at 50-67% 5, 6
• Cyclophosphamide may offer better outcomes than other agents, with some patients achieving durable improvement 5, 6
• Pulse corticosteroid therapy (methylprednisolone 500 mg for 3 days) has shown success in case reports for steroid-refractory disease 7

Critical Evidence Supporting Corticosteroid Use

The recommendation for corticosteroids is based on multiple studies demonstrating clinical improvement in >80% of symptomatic cases 1. However, important nuances exist:

• Approximately 2% of patients develop chronic pneumonitis that persists despite immunotherapy discontinuation and may not resolve after >3 months of corticosteroids 1, 4
• Relapses during steroid tapering are well-documented, necessitating slow tapers 1, 2, 4
• Fatal pneumonitis occurs in 0.2% of patients receiving anti-PD-1/PD-L1 therapy 4, 3
• Combination immunotherapy (anti-PD-1/PD-L1 plus anti-CTLA-4) increases pneumonitis risk 3-fold compared to monotherapy (10% vs 3%) 1, 4, 3

Common Pitfalls to Avoid

• Do not delay corticosteroid initiation in symptomatic patients - early treatment with steroids in grade 2 pneumonitis prevents progression to severe disease 8
• Do not taper steroids too quickly - rapid tapers lead to relapses; minimum 4-6 weeks for grade 2, and 6+ weeks for grade 3-4 1, 2, 4
• Do not wait beyond 48 hours to add second-line immunosuppression if no improvement on corticosteroids 1, 2
• Do not overlook infection - bronchoscopy with BAL should be performed in grade 2 or higher to exclude infectious etiologies before or concurrent with steroid initiation 1, 2
• Do not rechallenge immunotherapy while on >10 mg prednisone daily 1

Diagnostic Confirmation

• Improvement following immunotherapy cessation without glucocorticoids strongly supports the diagnosis 2, 4
• Clinical improvement with glucocorticoid therapy supports but does not definitively confirm drug-related pneumonitis 2, 4
• CT chest imaging showing ground-glass opacities, patchy nodular infiltrates (often lower lobe predominant), or interstitial patterns is characteristic 1, 2
• Transbronchial biopsy is generally not required but may help distinguish chronic organizing pneumonia-like patterns or exclude malignancy/infection 1