The second largest series, by Naidoo et al (21), describes 43 patients with pneumonitis (27 of which had available CT images), with the following CT findings and categories described: (a) ground-glass opacities (37%), (b) interstitial (22%), (c) cryptogenic OP (19%), (d) hypersensitivity (7%), and (e) unclassified (15%). Figure 10b. OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. (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). (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. The CT appearance of ICI therapy–related pneumonitis generally parallels that visualized in nontreatment-related interstitial lung diseases and is summarized with the main differential considerations in Table 3. 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. 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. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Spectrum of treatment-related pneumonitis among various therapy types. HP pattern is indistinguishable from that of HP associated with allergen exposure (classically birds), and detailed exposure and occupational histories should be sought. 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. Figure 5b. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Radiation recall is an inflammatory reaction occurring within a previously irradiated area after exposure to an inciting agent that has been observed in multiple organs and systems, including skin, lung, digestive tract, muscle, and central nervous system. ICIs target the cell surface receptors cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, or programmed cell death ligand 1, which result in immune system–mediated destruction of tumor cells. Immunotherapy was subsequently held, and steroid therapy was administered. There are two tiny subcutaneous nodules in the medial aspect of the right breast. Figure 7a. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. 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. OP pattern most commonly manifests as patchy bilateral opacities with a peripheral or peribronchovascular predominance, often with a mid- to lower-lung predominance (Fig 3). These ICI agents have adverse effects including the uncommon but potentially serious pulmonary toxicity of pneumonitis. 3. Although not specifically addressed in published guidelines given the potential for high steroid doses administered for extended periods, infectious prophylaxis may be warranted. 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. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. 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. Figure 10d. Lucian Beer, Maximilian Hochmair, Helmut Prosch. {"url":"/signup-modal-props.json?lang=us\u0026email="}. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. Infection was excluded on the basis of clinical findings. (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. In the last decade, the introduction of immunotherapy has revolutionized the management and treatment approaches for a number of malignancies. 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. A baseline coronal chest CT image obtained before starting immunotherapy (not shown) showed no airspace abnormalities. 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. With conventional agents, the median time of onset of radiation recall pneumonitis after the end of radiation therapy is 95 days, although onset of 2 years after radiation therapy has been reported with nivolumab (38,41). Although this occurs through multiple mechanisms, the CTLA-4 and PD-1 pathways play an important role for tumor proliferation. Recurrent pneumonitis cases were further subcategorized as either provoked by treatment renewal or unprovoked. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. In cases of ICI therapy–related pneumonitis, the most common finding at bronchoalveolar lavage is T-lymphocytic alveolitis (25). The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. AIP–ARDS pattern is not a prevalent pattern of ICI therapy–related pneumonitis, although it is associated with the most severe clinical course and extent of lung involvement at imaging, manifesting with median CTCAE grade 3 symptoms (31). The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. The patient died 1 week later. Pulmonary nodules may also be depicted, typically in a peribronchovascular distribution and more commonly as smaller nodules (<10 mm). (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). 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. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. In this study, we investigated the clinical and CT features of IIP in non-small cell lung cancer (NSCLC) patients treated with ICI. NSIP pattern most commonly manifests with ground-glass and reticular opacities with lower lobe predominance (Fig 4) (35). (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). Pitfalls in the radiological response assessment of immunotherapy. 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 1b. Subpleural sparing of the posterior and dependent lower lobes has also been reported as a specific finding (34). (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). (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). This immune overreaction leads to the autoimmune-type reactions observed with irAEs. Published guidelines outline the treatment of ICI therapy–related pneumonitis based on the severity of symptoms. As OP pattern can manifest with new masslike consolidative opacities, an important differential diagnosis is progression of an underlying malignancy. In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. No fevers or raised septic markers. The results indicated the utility of a radiographic pattern–based approach as a guide for patient treatment and monitoring for immunotherapy-related pneumonitis. Truly idiopathic AIP tends to occur in those without pre-existing lung disease and typically affects middle-aged adults (mean ~ 50 years 5). Figure 7c. ICI therapy–related pneumonitis is an uncommon although potentially serious complication of ICI therapy. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). (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. However, early diagnosis may be challenging, especially in cancer patients under treatment with immunotherapy as drug-induced pneumonitis can present similar clinical and radiological features. 5, No. (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. On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. In passive therapy, immunoglobulins are administered and bind to tumor-associated antigens, prompting clearance by the immune system. When ICI therapy–related pneumonitis becomes clinically apparent, management should be initiated immediately. A bronchiolitis pattern may be difficult to distinguish from aspiration or infection. 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). Interlobular septal thickening and a “crazy-paving” pattern may also be present (34). However, little is known about the clinical and radiological features of checkpoint inhibitor-induced lung disease. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). Figure 4a. 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). 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). (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). (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. (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). INTRODUCTION:There is an increasing usage of immune-checkpoint inhibitors (ICI) including programmed cell death-1 inhibitors for several cancers including melanoma. To standardize terminology regarding treatment-related adverse events, pneumonitis symptoms are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (26). More invasive assessments with bronchoscopy and biopsy are generally unnecessary, particularly in lower grades, if other clinical data are suggestive of pneumonitis. Infection was excluded on the basis of clinical findings. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. NSIP pattern is the second most commonly described pattern of ICI therapy–related pneumonitis, although it is diagnosed in a minority of reported cases. 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. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. Immunotherapy-induced pneumonitis - metastatic melanoma. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. 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. (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. (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. 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. ICIs ultimately act by inhibiting the signal pathways responsible for the suppression of T-cell–mediated tumor destruction. 2. While many ICI therapies are initiated after failure of first-line or established therapies, several drugs are approved as first-line therapies. 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. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. Sarcoidlike reactions demonstrate identical histopathologic features to those of sarcoidosis, namely noncaseating granuloma formation. 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. Patients with grades 3 and 4 pneumonitis require permanent discontinuation of ICI therapy and more intensive care, requiring inpatient admission with close monitoring. HP pattern is an uncommon manifestation of ICI therapy–related pneumonitis. 18 (1): 42-53. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Patients with suspected pneumonitis should undergo initial clinical assessment with physical examination and pulse oximetry. Airspace disease is temporally homogeneous and relatively symmetric, with consolidative opacities uncommon, features that help in distinguishing NSIP from OP patterns. The patient previously underwent radiation therapy for multiple left posterior rib metastases. 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 Related to Melanoma Immunotherapy. Findings of radiation recall pneumonitis include consolidative or ground-glass opacities limited to a prior radiation field (Fig 8). For example, pembrolizumab, a PD-1 inhibitor, has FDA approval as frontline treatment of advanced epidermal growth factor receptor and anaplastic lymphoma kinase wild-type non–small cell lung cancer in which tumors have at least 50% PD-L1 expression. Immunotherapy was subsequently held, and steroid therapy was administered. Depending on the severity and initial response, other agents such as infliximab, mycophenolate, or intravenous immunoglobulin may also be added. This latter category includes immune checkpoint inhibitor (ICI) therapy. Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. Figure 8b. The patient previously underwent radiation therapy for multiple left posterior rib metastases. COVID-19 Pneumonia Mimicking Immunotherapy-Induced Pneumonitis on 18F-FDG PET/CT in a Patient Under Treatment With Nivolumab. 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). 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. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. (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). Findings include diffuse or upper lobe predominant centrilobular ground-glass nodules, which may be accompanied by air trapping (Fig 5) (21). Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Findings with lower lobe predominance can be depicted. The airways are unremarkable. Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. However, there are currently no specific histologic findings for ICI therapy–related pneumonitis. However, changes of fibrotic NSIP in nontreatment-related cases including lower lobe volume loss and traction bronchiectasis have not been reported in ICI therapy–related pneumonitis, likely because cases are detected and treated in the acute stage. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). Illustration shows the global effect of irAEs with associated manifestations. 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). (2017) Korean journal of radiology. 28, No. Imaging plays a critical role in pneumonitis detection. (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. 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. Because of their unique mechanism of action, ICI therapies may produce imaging response patterns that differ from those depicted with conventional chemotherapies. Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. If the address matches an existing account you will receive an email with instructions to reset your password. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. (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. 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. (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. How Do Cytotoxic Lymphocytes Kill Cancer Cells? Similar to the NSIP pattern, HP pattern is associated with lower-grade symptoms (median CTCAE grade 1) (31). Immune check… National Institutes of Health, National Cancer Institute, Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary, Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy, Ipilimumab-Induced Organizing Pneumonia on 18F-FDG PET/CT in a Patient With Malignant Melanoma, Pneumonitis Related to Melanoma Immunotherapy, PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course, A Case of Organizing Pneumonia (OP) Associated with Pembrolizumab, Lung CT: Part 2—The interstitial pneumonias: clinical, histologic, and CT manifestations, Drug-Related Pneumonitis in the Era of Precision Cancer Therapy, Bronchiolitis obliterans after combination immunotherapy with pembrolizumab and ipilimumab, Pembrolizumab-Induced Bronchiolitis in a Patient with Stage IV Non-Small Cell Lung Cancer (abstr), Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer, Nivolumab-Induced Radiation Recall Pneumonitis, Nivolumab induced radiation recall pneumonitis after two years of radiotherapy, Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors, Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients, Pembrolizumab-induced Sarcoid-like Reactions during Treatment of Metastatic Melanoma, PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis, Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy, PD-1 inhibitor-related pneumonitis in lymphoma patients treated with single-agent pembrolizumab therapy, Open in Image (2018) memo - Magazine of European Medical Oncology. As opposed to conventional cytotoxic chemotherapy, which acts by a variety of mechanisms and stages of the cell cycle to directly interfere with cancer cell growth, cancer immunotherapy harnesses the immune system to limit the ability of cancer cells to evade the immune system and combat proliferation. Figure 5a. Braschi-Amirfarzan M, Tirumani SH, Hodi FS, Nishino M. Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. However, true progression will often be associated with progressive disease elsewhere and will lack response to immunosuppressive therapy. With ongoing ICI clinical trials, the number of approvals and combinations and complexity of treatment regimens is expected to grow in the foreseeable future. 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. ■ Illustrate the imaging patterns of ICI therapy–related pneumonitis and related clinical classification schemes. 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