After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). The patient died 1 week later. Pneumonitis Related to Melanoma Immunotherapy. Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. The lungs and pleural spaces are clear, the mediastinal contours are within the normal limits. Treatment typically includes administering corticosteroids and/or discontinuing therapy (42). However, when to resume treatment after first episode of pneumonitis, total steroids duration & whether to make switch to other PD-1 inhibitors remains unclear. Unable to process the form. García-Gómez FJ(1), Álamo-de la Gala MC(2), de la Riva-Pérez PA(1), de la Cruz-Merino L(2), de la Cinta Calvo-Morón M(1). For example, patients receiving ICI therapy have shown greater susceptibility to the development of treatment-related pneumonitis, with increased risk of high-grade pneumonitis (45). The results indicated the utility of a radiographic pattern–based approach as a guide for patient treatment and monitoring for immunotherapy-related pneumonitis. Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. COVID-19 Pneumonia Mimicking Immunotherapy-Induced Pneumonitis on 18F-FDG PET/CT in a Patient Under Treatment With Nivolumab. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. While better recognized with conventional chemotherapy agents, cases of radiation recall pneumonitis have now been described with ICI therapy (40,41). The largest study to date by Delaunay et al (25) includes 64 cases of pneumonitis with the following CT patterns described: (a) OP (23%), (b) hypersensitivity pneumonitis (HP) (16%), (c) nonspecific interstitial pneumonia (NSIP) (8%), and (d) bronchiolitis (6%). As with the NSIP pattern, changes of chronic HP including upper lobe fibrosis, volume loss, and traction bronchiectasis have not been reported with ICI therapy–related pneumonitis. Braschi-Amirfarzan M, Tirumani SH, Hodi FS, Nishino M. Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. 2017 and had a recorded diagnosis of pneumonitis related to immunotherapy. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. No fevers or raised septic markers. (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). 4, Respiratory Investigation, Vol. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. The differential diagnosis for AIP–ARDS pattern is broad and includes pulmonary edema (often associated with other findings of cardiac failure), hemorrhage (associated with hemoptysis and underlying coagulopathy), and infection. 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). (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. 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). (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). This axial CT image in lung windowing shows multifocal alveolar consolidations in a subpleural and peribronchovascular location, predominating at the level of the left upper lobe. Recurrence of metastasis to the bilateral lungs and left pleura was detected in April 2018. ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. 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. This article reviews the mechanism of ICIs and ICI therapy complications, with subsequent management techniques and illustrations of the various radiologic patterns of ICI–therapy related pneumonitis. The left lower lobe mass also increased in size (white arrow). Some patients were diagnosed Although checkpoint inhibitor pneumonitis (CIP) has a low clinical incidence, it is likely to cause the delay or termination of immunotherapy and treatment-related death in some severe cases. 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. Correspondence from The New England Journal of Medicine — Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy Imaging plays a critical role in pneumonitis detection. (b) Axial chest CT image obtained 2 months after initiating trastuzumab therapy shows a focal region of ground-glass opacities within the posterior and medial left lower lobe (arrow), with a well-defined linear demarcation from the adjacent normal lung. (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). Combinations of PD-1 and CTLA-4 inhibitors with nivolumab and ipilimumab have also demonstrated higher irAE rates compared with those of respective monotherapies in patients with advanced melanoma (20). (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. (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. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. Bronchoscopy and/or bronchoalveolar lavage are typically performed, and transbronchial biopsy can be considered at this stage. The symptoms improved on discontinuation of atezolizumab and a course of prednisone. 3. cases.29 On CT, radiographic findings might be variable, with reported patterns including cryptogenic organising pneumonia, nonspecific interstitial pneumonia, hyper sensitivity pneumonitis, and bronchiolitis (figure 217,30–33). (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). Patients with grades 3 and 4 pneumonitis require permanent discontinuation of ICI therapy and more intensive care, requiring inpatient admission with close monitoring. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. Although the disruption of the immune checkpoint pathway is the principle mechanism behind stimulating immune response against tumor cells, this same pathway is also responsible for various irAEs. A majority of irAEs occur in the induction phase, usually within the first 12 weeks of initiating therapy, although reactions manifesting after 1 year have been observed (18,19). Histopathologic findings include cellular interstitial pneumonitis, organizing pneumonia (OP), and less commonly diffuse alveolar damage (21). Immune-Related Adverse Event Guideline: Pneumonitis Severe new onset of symptoms limiting ARDS Invest calcium, CRP) antigen Pulmonary irAEs have been observed following treatment with immunotherapy and have occurred after a single dose and after as many as 48 treatments. A few months later, the lungs have mostly cleared, but a small right pleural effusion has developed and now multiple liver metastases are seen. When ICI therapy–related pneumonitis becomes clinically apparent, management should be initiated immediately. 1115, © 2021 Radiological Society of North America, Improved survival with ipilimumab in patients with metastatic melanoma, Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents, Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. Immunotherapy has been withheld and, some weeks later, the lungs have improved and there are some residual perihilar upper lobes infiltrates. Immune checkpoint therapy–related pneumonitis is an uncommon but potentially serious complication with several distinct radiologic patterns that overlap with those of other infectious and inflammatory conditions. (a) Axial CT image in a 65-year-old man undergoing ipilimumab therapy for metastatic melanoma shows large bilateral lower lobe pleural-based consolidative and ground-glass opacities (arrows). Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. Reported recurrence rate after rechallenge is 17%–29% (21,25,31). Infection was excluded on the basis of clinical findings. Spectrum of treatment-related pneumonitis among various therapy types. (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. The patient previously underwent radiation therapy for multiple left posterior rib metastases. Imaging. Also, ICI therapy–related pneumonitis is more commonly associated with multiorgan involvement with other irAEs. 16, The British Journal of Radiology, Vol. Extensive bone metastatic disease. Although not specifically addressed in the American Society of Clinical Oncology Practice Guideline, recurrent pneumonitis is often treated with methods similar to those used in the treatment of the initial occurrence. Conventional chemotherapy agents have demonstrated a dose-dependent risk of pneumonitis, while overall this has not been shown with ICI therapy (45,46). However, true progression will often be associated with progressive disease elsewhere and will lack response to immunosuppressive therapy. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy, PD-L1 regulates the development, maintenance, and function of induced regulatory T cells, The blockade of immune checkpoints in cancer immunotherapy, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria, Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements, iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma, Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma, Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies, Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management, MDX010-20 Investigators. Background: Pneumonitis (Pn) is a potentially life-threatening adverse event of some anticancer drugs. (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. Adjacent bronchial wall thickening is also frequently depicted (Fig 7). In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. Similar to the NSIP pattern, HP pattern is associated with lower-grade symptoms (median CTCAE grade 1) (31). Currently in its fifth version, the CTCAE categorizes symptoms on a five-point grading scale according to increasing severity (Table 2). The left lower lobe mass also increased in size (white arrow). (b) Axial chest CT image obtained 2 months after initiating trastuzumab therapy shows a focal region of ground-glass opacities within the posterior and medial left lower lobe (arrow), with a well-defined linear demarcation from the adjacent normal lung. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. Figure 2. (b) Follow-up coronal chest CT image obtained 1 month later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis, with a return to near-baseline findings. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. The diagnosis of immune-related pneumoni-tis was based on typical clinical features and on new typical imaging changes such as ground glass opacities in chest com-puted tomography (CT) scan. To date, little is known about immunotherapy-induced pneumonitis (IIP). There are two tiny subcutaneous nodules in the medial aspect of the right breast. Pitfalls in the radiological response assessment of immunotherapy. Outside of the lung, the skin is a common site of involvement. Immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved outcomes in a range of malignancies but are associated with a range of potentially fatal immune-mediated toxicities such as pneumonitis. We describe the findings of a SARS-CoV-2 infection on PET/CT with F-FDG in a 51-year-old man with metastatic renal cell carcinoma under treatment with nivolumab. Published guidelines outline the treatment of ICI therapy–related pneumonitis based on the severity of symptoms. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. ICI therapy can also be used with nivolumab, a PD-1 inhibitor, and ipilimumab, a combination that has FDA approval for the treatment of colorectal cancer and renal cell carcinoma. A bronchiolitis pattern is not a well-described pattern, only evident in one large case series and several case reports (25,36,37). NSIP pattern should be distinguished from atypical infectious processes, which can often be determined on the basis of clinical parameters. Sarcoidlike reaction may mimic recurrent or worsening malignancy, and lymphadenopathy may also be mistaken for reactive lymphadenopathy from an infectious process of other irAEs. Figure 7b. Despite researchers’ increasing awareness and experience with ICI therapy–related pneumonitis, large-scale studies categorizing the various radiologic patterns are somewhat limited. 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. 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