Imaging. There are two tiny subcutaneous nodules in the medial aspect of the right breast. OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. 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). 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. If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. Because of the greater experience with larger clinical trials involving ICI therapies and emerging toxicity profiles, different patterns with respect to presentation, imaging findings, and management have become apparent between ICI therapy–related and conventional chemotherapy-related pneumonitis. INTRODUCTION:There is an increasing usage of immune-checkpoint inhibitors (ICI) including programmed cell death-1 inhibitors for several cancers including melanoma. Figure 8b. For example, increased CTLA-4 binding in the presence of certain tumors cells leads to competitive inhibition of costimulatory CD28 binding, leading to decreased T-cell activation. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. Immunotherapy was subsequently held, and steroid therapy was administered. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Despite researchers’ increasing awareness and experience with ICI therapy–related pneumonitis, large-scale studies categorizing the various radiologic patterns are somewhat limited. Repeat the CT in three to four weeks and continue monitoring prior to each immunotherapy treatment. 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. (c) Axial chest CT image obtained 5 days later after further respiratory decompensation (despite withholding ICI therapy and initiating intravenous steroid therapy) shows increasing severity and confluence of ground-glass opacities (arrows), with little intervening normal lung parenchyma. HP pattern can often be differentiated from atypical infection on clinical grounds. Figure 8c. Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username. (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 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 … We compared treatment associated pneumonitis (TAP) related to immune checkpoint inhibitors (ICI) or chemotherapies (chemo) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with and without (+/-) past medical history (PMH) of Pn, using data from clinical trials (CT… (c) Axial chest CT image obtained 5 days later after further respiratory decompensation (despite withholding ICI therapy and initiating intravenous steroid therapy) shows increasing severity and confluence of ground-glass opacities (arrows), with little intervening normal lung parenchyma. Classically, bronchiolitis appears as a region of centrilobular nodularity, often in a tree-in-bud pattern. 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). Figure 4c. NSIP pattern is the second most commonly described pattern of ICI therapy–related pneumonitis, although it is diagnosed in a minority of reported cases. Figure 3b. It has been advised that the immune checkpoint inhibitor regimen not be restarted until CT scans show improvement or there is complete resolution of pneumonitis. Reduced baseline pulmonary function and history of smoking may increase the risk of pneumonitis. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. Described findings of HP pattern mirror those typically found in cases of subacute HP depicted in other settings. Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor–related pneumonitis in advanced cancer patients. No fevers or raised septic markers. The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. Immune check… However, when to resume treatment after first episode of pneumonitis, total steroids duration & whether to make switch to other PD-1 inhibitors remains unclear. Spectrum of treatment-related pneumonitis among various therapy types. Braschi-Amirfarzan M, Tirumani SH, Hodi FS, Nishino M. Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. Because of their unique mechanism of action, ICI therapies may produce imaging response patterns that differ from those depicted with conventional chemotherapies. (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). Immune-related pneumonitis presenting as an organising pneumonia pattern in a patient with metastatic lung cancer that occurred after 13 cycles of anti-PD1 therapy. Figure 10b. Treatment-naïve patients have also demonstrated higher rates of pneumonitis relative to those patients who were previously treated (23). However, conventional imaging response criteria such as RECIST 1.1 have shortcomings in the evaluation of treatment response for ICI therapy, leading to the potential for premature cessation of therapy in patients who might otherwise show benefit with therapy (9). During PET/CT surveillance, ... delaying nivolumab for grade 2 & discontinuation of immunotherapy for grade 3 & 4 pneumonitis 2. ), and Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (N.H.R., K.R.L., A.G.). (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). 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. Lucian Beer, Maximilian Hochmair, Helmut Prosch. Truly idiopathic AIP tends to occur in those without pre-existing lung disease and typically affects middle-aged adults (mean ~ 50 years 5). Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Immunotherapy was subsequently held, and steroid therapy was administered. 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. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). The main differential diagnosis is infection, which does not respect the boundaries and occurs outside of the prior radiation field. 58, No. While the increased activation of the immune system is responsible for the therapeutic efficacy of ICI therapy, it is also the driver behind the immune-related adverse events (irAEs) of these therapies. Findings include diffuse or upper lobe predominant centrilobular ground-glass nodules, which may be accompanied by air trapping (Fig 5) (21). How Do Cytotoxic Lymphocytes Kill Cancer Cells? Figure 7c. More severe forms of pulmonary toxicity, such as acute interstitial pneumonia leading to acute respiratory Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Chest radiography can be considered to track evolving pneumonitis findings. The patient previously underwent radiation therapy for multiple left posterior rib metastases. ■ Discuss the management of irAEs and the role of the radiologist in treatment course planning in these complex cases. Figure 6a. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). Associated focal ground-glass and consolidative opacities may be visualized, although this should not the predominant feature. 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). (b) Axial CT image obtained 2 weeks after starting nivolumab therapy shows a region of centrilobular solid and ground-glass nodularity (black arrows) in the right lower lobe. Other immune cells and mediators such as B cells, granulocytes, and cytokines have also been implicated (16). Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. 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. 93, No. Figure 10d. This latter category includes immune checkpoint inhibitor (ICI) therapy. Immunotherapy has been withheld and, some weeks later, the lungs have improved and there are some residual perihilar upper lobes infiltrates. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). Patients with grade 2 pneumonitis (symptomatic pneumonitis) should receive prednisone, 0.5–1 mg/kg/d, or the equivalent, and patients with grade 3 pneumonitis should receive a higher dose: 1–2 mg/kg or the equivalent. HP pattern may also mimic other small airways processes such as respiratory and follicular bronchiolitis, which are classically associated with smoking and underlying connective tissue or autoimmune disease history, respectively. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. While this reaction is most commonly reported after exposure to chemotherapy agents, other precipitating agents have been implicated (38). Many of these adverse events are unique from those previously observed with conventional chemotherapy regimens. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. 11 (2): 138. Grade 1 immune-related pneumonitis is managed with close observation and consideration of holding immunotherapy. Increased FDG uptake within adenopathy has also been observed at PET/CT (44). Figure 2. In this study, we investigated the clinical and CT features of IIP in non-small cell lung cancer (NSCLC) patients treated with ICI. Airspace disease can also be migratory, changing location or configuration over time (33). In recent years, the use of immune checkpoint inhibitor (ICI) therapy has rapidly grown, with increasing U.S. Food and Drug Administration approvals of a variety of agents used as first- and second-line treatments of various malignancies. 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. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. 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). The time to pneumonitis onset is widely variable, reported to range from 9 days to over 19 months after initiation of therapy, with a median time of onset of 2.8 months. PNEUMONITIS DURING mTOR INHIBITOR THERAPY mTOR is a serine/threonine protein kinase that plays a key role in the phosphatidylinositol 3-kinase/Akt/mTOR pathway, which is an established oncogenic driver in human cancers. In passive therapy, immunoglobulins are administered and bind to tumor-associated antigens, prompting clearance by the immune system. COVID-19 Pneumonia Mimicking Immunotherapy-Induced Pneumonitis on 18F-FDG PET/CT in a Patient Under Treatment With Nivolumab. (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. (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. ICIs act through a unique mechanism of action when compared with those of conventional chemotherapeutic agents. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. However, little is known about the clinical and radiological features of checkpoint inhibitor-induced lung disease. Recipient of a Certificate of Merit award for an education exhibit at the 2018 RSNA Annual Meeting. Table 3: ICI Therapy–related Pneumonitis Patterns. Infection, including atypical and fungal causes such as invasive aspergillosis, should also be considered and often can be distinguished by clinical and laboratory findings. After completing this journal-based SA-CME activity, participants will be able to: ■ Describe the indications and mechanisms of action of ICIs and the pathophysiology of ICI therapy–related pneumonitis. A subset of irAEs is pneumonitis, which is an important and potentially fatal complication of ICI therapy and is the focus of this article. The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. 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. A smaller series by Nishino et al (31) with 20 pneumonitis cases described similar patterns as well as acute interstitial pneumonia (AIP)–acute respiratory distress syndrome (ARDS) occurring in 10% of patients. Tirumani SH, Ramaiya NH, Keraliya A, Bailey ND, Ott PA, Hodi FS, Nishino M. Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. (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. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. This patient was not clinically septic and the pattern of consolidation/groundglass is relatively symmetrical. (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 immunotherapy was initiated. An increasing number of CIP cases have been reported since 2015, which are attributed to the augment of approvals and uses of ICIs, but a comprehensive understanding of CIP is still lacking. If the address matches an existing account you will receive an email with instructions to reset your password. June 15, 2020 Within a few months, coronavirus disease 2019 (COVID-19) has become a pandemic with more than 2 million patients infected and a high mortality rate. (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. The airways are unremarkable. ICI therapy–related pneumonitis manifests as several distinct radiologic patterns that overlap with other infectious and inflammatory conditions. (b) Axial CT image obtained 2 weeks after starting nivolumab therapy shows a region of centrilobular solid and ground-glass nodularity (black arrows) in the right lower lobe. 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). A bronchiolitis pattern may be difficult to distinguish from aspiration or infection. 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. Illustration shows the global effect of irAEs with associated manifestations. Overall, the incidence of ICI therapy–related pneumonitis is estimated to be between 3% and 6% (21). (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). Spectrum of treatment-related pneumonitis among various therapy types. Onset has been shown to occur earlier in patients with lung cancer compared with those with melanoma (2.1 versus 5.2 months, respectively) (25). (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. The patient previously underwent radiation therapy for multiple left posterior rib metastases. HP pattern is an uncommon manifestation of ICI therapy–related pneumonitis. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. During the process of T-cell activation, various inhibitor receptors also become upregulated, acting as immune checkpoints to limit the overstimulation of the immune response (3). NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. The results indicated the utility of a radiographic pattern–based approach as a guide for patient treatment and monitoring for immunotherapy-related pneumonitis. Subsequently, updated treatment response criteria such as the immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immunotherapy RECIST (iRECIST) have been developed to account for these unique imaging features (10–12). It should be suspected in any patient with a history of radiation therapy with new airspace changes sharply demarcated from the adjacent lung in the appearance of a radiation field. As OP pattern can manifest with new masslike consolidative opacities, an important differential diagnosis is progression of an underlying malignancy. 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). NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. 3 (10): 1185-92. 18 (1): 42-53. While better recognized with conventional chemotherapy agents, cases of radiation recall pneumonitis have now been described with ICI therapy (40,41). 1. After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). 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. OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. NSIP pattern most commonly manifests with ground-glass and reticular opacities with lower lobe predominance (Fig 4) (35). (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). 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