irAEs have been shown to occur in up to 90% of patients undergoing CTLA-4 inhibitor therapy and 70% of those undergoing PD-1 and/or PD-L1 inhibitor therapy (17). Clinically, ICI therapy–related pneumonitis tends to occur with overall higher severity, potentially requiring higher doses of steroid therapy or more potent immunosuppressive therapy compared with that of conventional chemotherapy pneumonitis. (a) Baseline axial chest CT image shows a medial left lower lobe lung mass with surrounding ground-glass halo sign (arrow), a finding corresponding to adenocarcinoma. Despite treatment of pneumonitis, approximately one-fourth of patients will develop recurrence (21) (Fig 10). Two critical pathways for ICIs are the CTLA-4 and PD-1 pathways, which normally function to attenuate T-cell response and action (Fig 1) (5,6). Her previous chest imaging was normal (following study - chest radiograph). Airspace disease can also be migratory, changing location or configuration over time (33). Active immunotherapy, on the other hand, stimulates the immune system to target tumor antigens and attack tumor cells. Figure 10d. In patients with non–small cell lung carcinoma, the incidence and severity of pneumonitis has been shown to be higher in patients undergoing treatment with PD-1 inhibitors compared with those undergoing treatment with PD-L1 inhibitors (3.6% vs 1.3%, respectively), with a lower incidence in those patients undergoing treatment with CTLA-4 inhibitors (23,24). Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. ARDS findings may also be due to extrapulmonary causes such as pancreatitis, sepsis and/or shock, and transfusion reaction. (c) Axial chest CT image obtained 1 month later after withholding ICI therapy and administering steroid therapy shows residual, although significantly improved, airspace disease (arrows). Similar to the NSIP pattern, HP pattern is associated with lower-grade symptoms (median CTCAE grade 1) (31). (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). AIP–ARDS pattern is characterized by geographic or diffuse ground-glass or consolidative opacities involving a majority, and sometimes the entirety, of the lungs, although areas of lobular sparing can also be visualized (Fig 6). Illustration shows the global effect of irAEs with associated manifestations. Despite the presence of various cell-mediated immune response pathways, tumor cells have developed means of evading the natural tumor response system of the body. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. Conventional chemotherapy agents have demonstrated a dose-dependent risk of pneumonitis, while overall this has not been shown with ICI therapy (45,46). ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. 2017 and had a recorded diagnosis of pneumonitis related to immunotherapy. Pulmonary nodules may also be depicted, typically in a peribronchovascular distribution and more commonly as smaller nodules (<10 mm). (b) Axial chest CT image obtained 4 months later after nivolumab therapy shows multifocal peripheral and subpleural mid- and lower-lung airspace consolidations (arrows), a finding consistent with an OP pattern of pneumonitis. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Many of these adverse events are unique from those previously observed with conventional chemotherapy regimens. (b) Axial CT image in a 63-year-old woman undergoing gemcitabine therapy for pancreatic cancer shows bilateral subpleural reticular opacities, with background faint ground-glass and interstitial opacities (arrows) that are more pronounced in the left lower lobe. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. history of melanoma on the left side of the face (resected in December 2012) and metastasis to the left lung upper lobe (resected in November 2016). Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. 2. Immunotherapy can be classified as either passive or active. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). A high index of suspicion and prompt recognition of pneumonitis by the radiologist are critical to initiate prompt treatment and prevent further morbidity and mortality for these patients. The left lower lobe mass also increased in size (white arrow). Immunotherapy has been withheld and, some weeks later, the lungs have improved and there are some residual perihilar upper lobes infiltrates. Going forward, given the potential complexity of diagnosis and management of ICI therapy–related pneumonitis, radiologists must work in conjunction with a broader multidisciplinary team to provide optimal care for these patients. Bronchoscopy with bronchoalveolar lavage and empirical antibiotics can be considered at this stage, although it should not significantly delay initiating treatment (47). However, suspicion for this entity as a distinct pneumonitis pattern should be raised in the absence of infectious symptoms and be confirmed at imaging by documenting resolution of findings after withholding therapy or after a trial of steroid therapy. Treatment is often effective, although recurrence is possible. Pneumonitis is a potential consequence of both lung-directed radiation and immune checkpoint blockade (ICB), particularly treatment with PD-1/PD-L1 inhibitors. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. We review the mechanism of ICIs, discuss the pathophysiology and clinical presentation of ICI therapy–related pneumonitis with associated imaging manifestations, and highlight important aspects of treatment and monitoring. Table 4: American Society of Clinical Oncology Clinical Practice Guideline for the Management of ICI-related Pneumonitis. A bronchiolitis pattern is not a well-described pattern, only evident in one large case series and several case reports (25,36,37). (2018) memo - Magazine of European Medical Oncology. Truly idiopathic AIP tends to occur in those without pre-existing lung disease and typically affects middle-aged adults (mean ~ 50 years 5). Figure 8b. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. The development of an irAE is mainly T-cell mediated, and infiltration of CD4 and CD8 cells has been observed in association with irAEs (15). Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. (2015) Cancer immunology research. However, in certain conditions such as leflunomide-induced acute interstitial pneumonia, patients have pre-existing lung disease. In passive therapy, immunoglobulins are administered and bind to tumor-associated antigens, prompting clearance by the immune system. ICIs ultimately act by inhibiting the signal pathways responsible for the suppression of T-cell–mediated tumor destruction. 5, World Chinese Journal of Digestology, Vol. Illustrations show the mechanisms of action (left) of ICIs and the downstream tumor effects (right) for PD-1 and PD-L1 (a) and CTLA-4 (b) inhibitors. Figure 9a. irAE risk has been shown to have a dose-dependent relationship for CTLA-4 inhibitors, but this has not been consistently observed in PD-1 and/or PD-L1 inhibitors (19). A majority of patients do not develop recurrence after restarting immunotherapy, although reports of rechallenge mainly describe patients with initial grade 1 or 2 pneumonitis. Findings include diffuse or upper lobe predominant centrilobular ground-glass nodules, which may be accompanied by air trapping (Fig 5) (21). No fevers or raised septic markers. In the presence of a foreign cell such as a tumor cell, antigen-presenting cells, including dendritic cells or macrophages, incorporate and present a tumor antigen through a major histocompatibility complex, which subsequently binds to a T-cell receptor. Figure 9c. (d) Axial CT image obtained after completing steroid therapy and restarting nivolumab therapy shows recurrence of an OP pneumonitis pattern with new areas of involvement (arrows). (c) Axial CT image in a 57-year-old man undergoing imatinib therapy for metastatic gastrointestinal stromal tumor shows small patchy peripheral ground-glass opacities (arrows) in the bilateral lower lobes. Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [ 2 – 11 ]. Airspace disease is temporally homogeneous and relatively symmetric, with consolidative opacities uncommon, features that help in distinguishing NSIP from OP patterns. Reduced baseline pulmonary function and history of smoking may increase the risk of pneumonitis. (c) Axial chest CT image obtained 5 months after discontinuation of therapy shows minimal residual (although markedly improved) pneumonitis (arrow) in the left lower lobe. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Infection was excluded on the basis of clinical findings. Although not yet incorporated in official immunotherapy response criteria, the combination of anatomic and functional imaging such as fluorine 18 fluorodeoxyglucose (18F-FDG) PET/CT or diffusion-weighted imaging with MRI may be beneficial in predicting treatment response in patients receiving ICI therapy (13,14). Figure 7: Axial chest CT scans show programmed cell death protein 1 (PD-1) inhibitor–related pneumonitis in a patient with advanced non–small cell lung cancer treated with nivolumab. Common Terminology Criteria for Adverse Events, Advances in Radiation Oncology, Vol. Pneumonitis is an uncommon but potentially fatal toxicity of anti-PD(L)1 immune checkpoint inhibitors (ICI) for cancer.1–3 The incidence of this toxicity is approximately 5% in patients with solid tumors treated with anti-PD(L)1 monotherapy, and up to 10%, in patients receiving anti-PD(L)1-based combinations such as ipilimumab/nivolumab, or those with non-small cell lung cancer … (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. (b) Axial chest CT image obtained 2 months later after starting pembrolizumab therapy shows bilateral lower lobe ground-glass and reticular opacities (black arrows), with regions of immediate subpleural sparing (white arrows). The skin is a potentially life-threatening adverse event of some anticancer drugs reaction. Grade 1 ) from the Department of Radiology, Vol related to immunotherapy be associated with multiorgan with... 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