Chronic immune checkpoint inhibitor pneumonitis

Abstract

Background: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.

Methods: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.

Results: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.

Conclusions: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.

Keywords: inflammation; lung neoplasms; melanoma; programmed cell death 1 receptor.

Figure 1

Serial radiological imaging in patients with chronic immune checkpoint inhibitor pneumonitis. Representative CT images at baseline—1: (pre-bronch): prior to first bronchoscopy, 1 (recovery): after treatment of first pneumonitis episode, 2: second episode of pneumonitis, 3: third episode of pneumonitis. Solid boxes show initial sites of pneumonitis and recrudescence, with radiographic pattern in keeping with acute lung injury or organizing pneumonia. Dotted line box highlights a new area of airspace opacity.

Figure 2

Pathological assessment by H&E staining in chronic immune checkpoint inhibitor pneumonitis. (A) Patient 1: bronchiolitis obliterans organizing pneumonia (BOOP), described in manuscript as organizing pneumonia, with an intra-alveolar fibroblast plug and organizing alveolar fibrin. (B) Patient 2: acute lung injury with acute fibrinous organizing pneumonia and organizing diffuse alveolar damage. (C) Patient 3: organizing alveolar fibrin consistent with exudative phase of BOOP. (D) Patient 4: organizing pneumonia (BOOP) with organizing alveolar fibrin. (E) Patient 5: organizing alveolar fibrin consistent with exudative phase of BOOP. (F) Patient 6: organizing pneumonia (BOOP). PD-1, programmed death 1.

Figure 3

Highly proliferative PD-1⁺ cell accumulation characterizes chronic immune checkpoint inhibitor pneumonitis. Low power H&E and immunofluorescence images highlight the relative abundance of Ki67⁺ PD-1⁺ lymphocytes in chronic pneumonitis (top row) relative to sparse inflammatory cells seen in histologically unremarkable lung tissue (bottom row). Original magnification 200×. PD-1, programmed death 1.