What is the management of pembrolizumab (pembrolizumab, an anti-PD-1 antibody)-induced pneumonitis, including the use of prednisone (a corticosteroid)?

Pembrolizumab-Induced Pneumonitis: Pathophysiology and Corticosteroid Management

Pembrolizumab-induced pneumonitis is an immune-mediated inflammatory lung injury occurring in 3-4% of patients, requiring immediate drug discontinuation and corticosteroid therapy for grade 2 or higher severity, with fatal outcomes accounting for 35% of all PD-1/PD-L1-related deaths. 1, 2

Mechanism and Incidence

Pembrolizumab, a PD-1 inhibitor, causes pneumonitis through dysregulated T-cell activation leading to pulmonary parenchymal inflammation. 3 The overall incidence is:

• 3.4-3.8% across all cancer types 2, 1
• Higher in lung cancer patients (up to 6%), particularly those with prior thoracic radiation 1, 2
• Fatal pneumonitis in 0.1-0.2% of cases, representing the most common fatal immune-related adverse event 1, 2

High-Risk Populations

Specific patient groups face elevated pneumonitis risk 1:

• Prior thoracic radiation (6.0% incidence)
• Underlying asthma or COPD (5.3% incidence)
• NSCLC and renal cell carcinoma patients (1.5-2 times higher than melanoma)
• Male patients and current/former smokers
• Combination immunotherapy (10% vs 3% monotherapy) 3

Temporal Presentation

Median onset occurs at 2.8 months (range: 9 days to 19.2 months), with earlier presentation in lung cancer patients (2.1 months) versus melanoma patients (5.2 months). 3, 1 Critically, pneumonitis can develop even after pembrolizumab discontinuation, with documented cases occurring 4-7 months post-cessation. 4

Clinical and Radiographic Features

Symptoms

Presenting manifestations include 3, 1:

• Dry cough (most common)
• Progressive dyspnea
• Fatigue
• Chest pain
• Fever
• Note: 20% of patients remain asymptomatic 5

CT Imaging Patterns

Four distinct radiographic patterns correlate with severity 3, 1:

1. Organizing pneumonia (OP) pattern (23%): Patchy consolidation, ground-glass opacities, perilobular distribution
2. Hypersensitivity pneumonitis (HP) pattern (16%): Centrilobular nodules, ground-glass opacities, mosaic attenuation
3. Nonspecific interstitial pneumonia (NSIP) pattern: Bilateral ground-glass opacities, lower lobe predominance
4. Diffuse alveolar damage (DAD) pattern: Associated with highest mortality, diffuse consolidation

The DAD pattern carries the worst prognosis, followed by OP pattern, while NSIP and HP patterns have lower severity grades. 1

Diagnostic Algorithm

When pneumonitis is suspected 3, 1:

1. Obtain chest CT immediately to identify radiographic pattern and extent
2. Establish temporal correlation between pembrolizumab administration and symptom onset
3. Exclude infectious etiologies through:
   • Bronchoscopy with bronchoalveolar lavage
   • Culture and PCR testing
   • Rule out CMV reactivation in corticosteroid-refractory cases 2
4. Lung biopsy is generally not required unless diagnostic uncertainty exists regarding infection or disease progression 3

Corticosteroid Management Protocol

Immediate Intervention

Discontinue pembrolizumab immediately upon suspicion of grade 2 or higher pneumonitis. 1, 2 The FDA label specifies permanent discontinuation for grade 3-4 pneumonitis. 2

Corticosteroid Dosing by Grade

Grade 1 (asymptomatic, radiographic findings only):

• Withhold pembrolizumab 2
• Monitor closely; corticosteroids not routinely required 3

Grade 2 (symptomatic, not interfering with ADLs):

• Prednisone 1 mg/kg/day orally (or equivalent) 2
• Withhold pembrolizumab until improvement to grade ≤1 2
• Taper over minimum 1 month 2
• May resume pembrolizumab after resolution 2

Grade 3-4 (severe symptoms, life-threatening):

• Methylprednisolone 1-2 mg/kg/day IV or prednisone equivalent 2
• Permanently discontinue pembrolizumab 2
• Continue until improvement to grade ≤1, then taper over ≥1 month 2

Critical Steroid Tapering Principles

Rapid steroid withdrawal precipitates pneumonitis recurrence. 5 The evidence demonstrates:

• 67% of patients with pneumonitis required systemic corticosteroids 2
• Median corticosteroid duration: 10 days (range: 1 day to 2.3 months) 2
• Taper must extend over minimum 4 weeks to prevent rebound inflammation 2
• 23% of patients who resumed pembrolizumab after grade 2 pneumonitis experienced recurrence 2

Refractory Pneumonitis Management

If no improvement after 48 hours of high-dose corticosteroids, add additional immunosuppression: 1, 2

• Infliximab (anti-TNF-α antibody): Single dose can produce rapid temporal improvement within days 6
• Mycophenolate mofetil: Alternative immunosuppressant 1
• Consider repeat infliximab dosing: The half-life of infliximab is 7-12 days; a second dose at 2 weeks may be necessary, though current guidelines do not explicitly recommend this 6

One autopsy case demonstrated histologic resolution in lung regions treated with infliximab, suggesting therapeutic efficacy despite ultimate fatal outcome from re-exacerbation. 6

Outcomes and Prognosis

• 59-77% resolution rate with appropriate treatment 2, 5
• Grade 5 (fatal) pneumonitis in 9% of severe cases 1
• Treatment-related deaths more common in NSCLC patients 3
• Chronic pneumonitis develops in ~2% of patients, persisting despite discontinuation and >3 months of corticosteroids 3

Critical Clinical Pitfalls

Do Not Rechallenge

Never restart pembrolizumab after grade 3-4 pneumonitis. 1, 2 In one series, 2 of 7 patients (29%) re-treated developed recurrent pneumonitis. 1

Infection Exclusion

Corticosteroid-refractory pneumonitis mandates repeat infectious workup, as CMV reactivation occurs in immunosuppressed patients. 2 Fatal cases have resulted from superimposed infections during prolonged steroid therapy. 6, 7

Late-Onset Recognition

Maintain vigilance for pneumonitis months after pembrolizumab cessation, as documented cases occur 4-7 months post-treatment. 4 One patient developed fatal pneumonitis 4 months after discontinuation despite aggressive methylprednisolone therapy. 4

Radiographic Monitoring

Ground-glass opacities and organizing pneumonia patterns are not pathognomonic and require correlation with clinical context to distinguish from disease progression or infection. 3

Baseline and Ongoing Surveillance

• Baseline chest imaging prior to pembrolizumab initiation 3
• Any new respiratory symptom warrants immediate chest CT 3
• Do not wait for symptom progression—early detection improves outcomes 8
• Pneumonitis can present within 48 hours of first dose, though this is rare 8