(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. In the last decade, the introduction of immunotherapy has revolutionized the management and treatment approaches for a number of malignancies. 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. 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. 2. (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. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. We describe the findings of a SARS-CoV-2 infection on PET/CT with 18 F- FDG in a 51-year-old man with metastatic renal cell carcinoma under treatment with nivolumab . Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. (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). (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). Figure 7c. Key differences in these updated criteria include the need for repeat imaging (ie, performed 4 weeks after initial response assessment) to confirm disease progression and the principle that the appearance of new lesions does not necessarily constitute disease progression. Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. (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. 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. More severe forms of pulmonary toxicity, such as acute interstitial pneumonia leading to acute respiratory The symptoms improved on discontinuation of atezolizumab and a course of prednisone. Outside of the lung, the skin is a common site of involvement. Also, ICI therapy–related pneumonitis is more commonly associated with multiorgan involvement with other irAEs. 4, Respiratory Investigation, Vol. The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. (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. Figure 8b. ICI therapy–related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. Its mechanism is likely multifactorial and is thought to be an autoimmune response with T-cell upregulation and ultimately increased granuloma formation. 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. Although generally considered separate from ICI therapy–related pneumonitis, sarcoidlike reaction is another potential pulmonary irAE reported with ICI therapy. 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). 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. Given the cytotoxic effect of conventional therapies, therapy success (for example in the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) is determined by the interval disappearance of or decrease in the size of lesions, with treatment failure suggested by increased lesion size or the appearance of new lesions (8). 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. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). However, a combination of immunotherapy (pembrolizumab) with chemotherapy was not linked to an increased risk of pneumonitis in lung cancer . In this study, we investigated the clinical and CT features of IIP in non-small cell lung cancer (NSCLC) patients treated with ICI. (b) Follow-up axial CT image obtained 4 months later after administering nivolumab therapy shows multiple predominantly peripheral and subpleural airspace consolidative opacities (arrows), findings consistent with an OP pneumonitis pattern. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. Previous history of metastatic melanoma. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Increased FDG uptake within adenopathy has also been observed at PET/CT (44). The lungs and pleural spaces are clear, the mediastinal contours are within the normal limits. 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. Treatment typically includes administering corticosteroids and/or discontinuing therapy (42). Pneumonitis is a potential consequence of both lung-directed radiation and immune checkpoint blockade (ICB), particularly treatment with PD-1/PD-L1 inhibitors. (2017) Korean journal of radiology. Reduced baseline pulmonary function and history of smoking may increase the risk of 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 immunotherapy was initiated. Many of these adverse events are unique from those previously observed with conventional chemotherapy regimens. 58, No. Infection was excluded on the basis of clinical findings. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. 33 Everolimus and temsirolimus are specific inhibitors of mTOR and are used as anticancer therapeutic agents. HP pattern is an uncommon manifestation of ICI therapy–related pneumonitis. Grade 1 immune-related pneumonitis is managed with close observation and consideration of holding immunotherapy. 93, No. (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. (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). The main differential diagnosis is infection, which does not respect the boundaries and occurs outside of the prior radiation field. Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. 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). Associated focal ground-glass and consolidative opacities may be visualized, although this should not the predominant feature. (b) Follow-up axial CT image obtained 4 months later after administering nivolumab therapy shows multiple predominantly peripheral and subpleural airspace consolidative opacities (arrows), findings consistent with an OP pneumonitis pattern. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. 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. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. Enter your email address below and we will send you the reset instructions. HP pattern is indistinguishable from that of HP associated with allergen exposure (classically birds), and detailed exposure and occupational histories should be sought. Spectrum of treatment-related pneumonitis among various therapy types. 5, World Chinese Journal of Digestology, Vol. Airspace disease is temporally homogeneous and relatively symmetric, with consolidative opacities uncommon, features that help in distinguishing NSIP from OP patterns. (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. Truly idiopathic AIP tends to occur in those without pre-existing lung disease and typically affects middle-aged adults (mean ~ 50 years 5). (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. (b) Follow-up axial CT image obtained 4 months later after administering nivolumab therapy shows multiple predominantly peripheral and subpleural airspace consolidative opacities (arrows), findings consistent with an OP pneumonitis pattern. Furthermore, ICI therapy may also be combined with conventional chemotherapies given the ability of cytotoxic chemotherapy to potentiate the immune response of ICIs (2). For example, trimethoprim and sulfamethoxazole may be administered for Pneumocystis jirovecci prophylaxis (47). (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 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 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. 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… (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). Several key differences in the response patterns of ICI therapeutic agents compared with those of cytotoxic agents include the potential initial transient worsening of disease burden, either through lesion enlargement or the appearance of new lesions (ie, pseudoprogression), and delayed time to treatment response (10). 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). AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. 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. (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. Active immunotherapy, on the other hand, stimulates the immune system to target tumor antigens and attack tumor cells. A few months later, the lungs have mostly cleared, but a small right pleural effusion has developed and now multiple liver metastases are seen. NSIP pattern is associated with a lower toxicity grade (median CTCAE grade 1) (31). Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. Figure 4b. 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. ICI therapy–related pneumonitis is an uncommon although potentially serious complication of ICI therapy. 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). Figure 9a. (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). 16, The British Journal of Radiology, Vol. Spectrum of treatment-related pneumonitis among various therapy types. Patient and drug-related factors predicting the development of pneumonitis are currently under investigation. Interlobular septal thickening and a “crazy-paving” pattern may also be present (34). 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). 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. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Adjacent bronchial wall thickening is also frequently depicted (Fig 7). ICIs ultimately act by inhibiting the signal pathways responsible for the suppression of T-cell–mediated tumor destruction. 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. (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). There are two tiny subcutaneous nodules in the medial aspect of the right breast. More invasive assessments with bronchoscopy and biopsy are generally unnecessary, particularly in lower grades, if other clinical data are suggestive of pneumonitis. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Sarcoidlike reactions demonstrate identical histopathologic features to those of sarcoidosis, namely noncaseating granuloma formation. Recurrence of metastasis to the bilateral lungs and left pleura was detected in April 2018. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. A subset of irAEs is pneumonitis, which is an important and potentially fatal complication of ICI therapy and is the focus of this article. 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. Common Terminology Criteria for Adverse Events (CTCAE). In cases of ICI therapy–related pneumonitis, the most common finding at bronchoalveolar lavage is T-lymphocytic alveolitis (25). Figure 5b. Repeat the CT in three to four weeks and continue monitoring prior to each immunotherapy treatment. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. (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. Patients with grades 3 and 4 pneumonitis require permanent discontinuation of ICI therapy and more intensive care, requiring inpatient admission with close monitoring. 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. Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. Her previous chest imaging was normal (following study - chest radiograph). Despite treatment of pneumonitis, approximately one-fourth of patients will develop recurrence (21) (Fig 10). (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. However, little is known about the clinical and radiological features of checkpoint inhibitor-induced lung disease. Infection was excluded on the basis of clinical findings. Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [ 2 – 11 ]. 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. GI = gastrointestinal. A bronchiolitis pattern may be difficult to distinguish from aspiration or infection. (2018) memo - Magazine of European Medical Oncology. HP pattern can often be differentiated from atypical infection on clinical grounds. The diagnosis of immunotherapy-induced pneumonitis was made after careful exclusion of other pulmonary conditions such as infection and malignancy. The airways are unremarkable. (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). OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. Author information: (1)From the Department of Nuclear Medicine and. ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). In addition, undergoing combination immunotherapy, concurrent radiation therapy, and previous high-dose chemotherapy are also thought to be risk factors (48). Other immune cells and mediators such as B cells, granulocytes, and cytokines have also been implicated (16). NSIP pattern should be distinguished from atypical infectious processes, which can often be determined on the basis of clinical parameters. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. However, when to resume treatment after first episode of pneumonitis, total steroids duration & whether to make switch to other PD-1 inhibitors remains unclear. (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. ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. Reported recurrence rate after rechallenge is 17%–29% (21,25,31). However, if uncertainty persists, tissue sampling can be pursued to differentiate pneumonitis from the main clinical and radiographic differential considerations of infection and tumor spread. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. Airspace disease may manifest as either consolidative or ground-glass opacities or a combination of both, frequently depicted on air bronchograms with or without a component of bronchial dilatation. To date, little is known about immunotherapy-induced pneumonitis (IIP). How Do Cytotoxic Lymphocytes Kill Cancer Cells? On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. 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). 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. Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. Immunotherapy-induced pneumonitis - metastatic melanoma. Airspace disease can also be migratory, changing location or configuration over time (33). NSIP pattern most commonly manifests with ground-glass and reticular opacities with lower lobe predominance (Fig 4) (35). 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). 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). Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. The mechanism of radiation recall reactions remains unclear, although possibilities include changes in the function of stem cells in the irradiated field versus idiosyncratic drug hypersensitivity reactions (39). 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. 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). 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. Resolved pneumonitis a clinical challenge `` url '': '' /signup-modal-props.json? lang=us\u0026email= '' } the address matches existing! Ct in three to four weeks and continue monitoring prior to each immunotherapy treatment by systemic agents typically! On 18F-FDG PET/CT in a tree-in-bud pattern metastatic melanoma PD-1 pathways play important. Malignancy ( 34 ) noncaseating granuloma formation 50 years 5 ) with 3. 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