Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes

Abstract

Background: Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.

Methods: Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.

Results: Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.

Conclusions: Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).

Keywords: immunotherapy; inflammation; programmed cell death 1 receptor.

Figure 1

Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.

Figure 2

Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.

Figure 3

Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O₂, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.