Pneumonitis is inflammation of the lung parenchyma; although rare, it can be fatal. Nishino et al. found that the overall incidence of pneumonitis with PD-1 inhibitor monotherapy was 2.7% for all-grade and 0.8% for grade 3 or higher pneumonitis.
Naidoo et al. reported an approximate 5% incidence of all-grade pneumonitis, although the incidence of all-grade pneumonitis is higher with combination immunotherapy (up to 10%). The incidence is more common with higher grades in PD-1 inhibitors (versus PD-L1 inhibitors), but it occurs less often with anti-CTLA4 monoclonal antibodies.
Diagnosing Pneumonitis
About one-third of patients are asymptomatic and pneumonitis is found incidentally, but the most common presenting symptoms are dyspnea and cough. Other symptoms include wheezing, fatigue, decreased pulse oximetry, and chest pain. Time to onset after initiation of therapy varies (reported at 9 days to 19 months), but the median is 2.8 months. It can occur earlier in combination therapy versus monotherapy.
Order a chest x-ray, computed tomography (CT) scan of the chest, and pulse oximetry as part of the diagnostic workup for suspected pneumonitis. Grade it per the Common Terminology Criteria for Adverse Events and direct further workup and management by the toxicity grade. For grade 2 or higher, perform a nasal swab and sputum and urine culture and sensitivity as part of an infectious workup. Pneumonitis is a diagnosis of exclusion and may mimic infection or disease progression.
Pneumonitis has no true diagnostic criteria on scanning, although ground-glass opacities or patchy nodular infiltrates may be apparent, more commonly in lower lung lobes. Biopsy is only used to rule out a malignant process (e.g., lymphangitic spread or infection). No specific pathology will confirm immune-related pneumonitis.
Managing Pneumonitis
Grade 1 immune-related pneumonitis is managed with close observation and consideration of holding immunotherapy. Repeat the CT in three to four weeks and continue monitoring prior to each immunotherapy treatment. If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. If grade 1 pneumonitis does not improve at three to four weeks, treat it as grade 2.
Grade 2 pneumonitis requires that immunotherapy be held until resolution to grade 1 or less. Administer prednisone 1–2 mg/kg per day, tapering by 5–10 mg per week over four to six weeks after it improves to less than grade 2. Bronchoscopy with bronchoalveolar lavage may help identify infections. Empirical antibiotics may also be indicated. Monitor patients every three days with physical examination, pulse oximetry, and chest x-ray as indicated. If pneumonitis does not improve 48–72 hours after initiation of steroids, treat it as grade 3. Drug rechallenge can be considered, but close monitoring is required.
For grade 3 and 4 pneumonitis, permanently discontinue immunotherapy. However, in grade 3 pneumonitis, consider rechallenge on a case-by-case basis under close observation. Hospitalize patients and treat with empirical antibiotics and IV methylprednisolone IV 1–2 mg/kg per day, tapering over four to six weeks. If pneumonitis does not improve in 48 hours, administer IV infliximab 5 mg/kg or mycophenolate mofetil 1 g twice a day, IV immunogloblin for five days, or cyclophosphamide. Consider pulmonary or infectious disease consult as well as bronchoscopy with bronchoalveolar lavage with or without transbronchial biopsy.
Oncology advanced practitioners should be familiar with signs and symptoms of pneumonitis. A high index of suspicion and prompt management of any suspected pulmonary toxicity will lead to better outcomes.