Immune Checkpoint Inhibitor Pneumonitis

Immune checkpoint inhibitor pneumonitis is an immune related inflammatory lung injury caused by drugs that block PD-1, PD-L1 or CTLA-4. It occurs in about 3 to 5% of patients on single agents and up to 10 to 13% with combination treatment, and it is a leading cause of treatment related death.

Onset is at a median of 2 to 3 months, but can be within days or after more than a year, including after stopping treatment. Risk is higher in lung cancer, pre-existing interstitial lung disease or COPD, previous thoracic radiotherapy, smoking and combination treatment.

Pathophysiology. Release of T cell inhibition leads to activated T cells infiltrating the lung, with loss of tolerance to lung antigens, cytokine release and, sometimes, enhanced autoantibodies. Patterns include organising pneumonia, nonspecific interstitial pneumonia, hypersensitivity like pneumonitis and diffuse alveolar damage.

Dry cough, dyspnoea, fever, chest pain and fatigue, or an asymptomatic radiological finding. Severity is graded: grade 1 asymptomatic and confined to one lobe, grade 2 symptomatic with limited daily activity, grade 3 severe symptoms and oxygen need, grade 4 life threatening respiratory compromise.

Oxygen saturation below 92% or rapid progression needs urgent care, since deterioration can be very rapid.

• Clinical and radiological diagnosis of exclusion in a patient on or recently treated with a checkpoint inhibitor.
• High resolution CT: organising pneumonia pattern (peripheral patchy consolidation), ground glass, nonspecific interstitial pneumonia or hypersensitivity like pattern, or diffuse alveolar damage in severe cases.
• Oxygen saturation at rest and on walking, arterial blood gas for severe cases, and spirometry with DLCO.
• Exclude infection (sputum, blood cultures, respiratory viral PCR, Pneumocystis testing, tuberculosis and fungal tests), tumour progression, lymphangitic spread, pulmonary embolism, heart failure and radiation pneumonitis.
• Bronchoscopy with lavage for grade 2 or higher disease, or when the picture is unclear, and biopsy rarely.
• Baseline tests for other immune related toxicities: thyroid, liver, cortisol, glucose and creatine kinase.

Differential diagnosis.

• Infection (bacterial, viral, Pneumocystis, tuberculosis)
• Tumour progression or pseudoprogression
• Radiation pneumonitis
• Pulmonary embolism
• Heart failure
• Other drug induced pneumonitis
• Lymphangitic carcinomatosis

• Grade 1: continue or hold the drug with close review, repeating imaging in 3 to 4 weeks, and weekly symptom checks.
• Grade 2: hold the drug and start prednisolone 1 mg/kg daily (oral), with a taper over at least 4 to 6 weeks once symptoms improve to grade 1 or less. Add empirical antibiotics until infection is excluded. Bronchoscopy if there is no improvement after 48 to 72 hours. If there is no improvement, escalate to the grade 3 regimen.
• Grades 3 and 4: stop the checkpoint inhibitor permanently, admit, and give methylprednisolone 1 to 2 mg/kg intravenously daily. If there is no improvement in 48 hours, add one of: infliximab 5 mg/kg intravenously (may repeat once after 14 days, and avoided in hepatitis), mycophenolate mofetil 1 g twice daily, intravenous immunoglobulin 2 g/kg over 2 to 5 days, or cyclophosphamide, with specialist advice. Taper over 6 weeks or longer once improved.
• Empirical antimicrobials until infection is excluded: ceftriaxone 2 g intravenously daily with azithromycin 500 mg daily.
• Prophylaxis against Pneumocystis when prednisolone is 20 mg or more daily for 4 weeks or longer: co-trimoxazole 960 mg three times weekly. Proton pump inhibitor, calcium and vitamin D, and glucose monitoring.
• Rechallenge: possible after resolution of grade 2 pneumonitis with steroid tapered to 10 mg or less, with careful review of risk and benefit, and not after grade 3 or 4 events.
• Prevention: baseline chest imaging and spirometry, patient education to report cough or breathlessness, and caution in those with interstitial lung disease or previous thoracic radiotherapy.

Complications and prognosis. Most grade 1 to 2 events resolve with treatment, and high grade disease has a mortality of about 10 to 20% or higher. Recurrence happens in about a quarter on rechallenge.

Monitoring. Review weekly in the first month, then every 2 weeks during the taper, with oxygen saturation, symptoms and imaging at 3 to 4 weeks. Monitor for other immune related events.

Referral and escalation. Refer to oncology the same day and to a respiratory physician for grade 2 or higher disease. Refer to intensive care for respiratory failure.