Figure 8c. Bronchoscopy and/or bronchoalveolar lavage are typically performed, and transbronchial biopsy can be considered at this stage. However, there are currently no specific histologic findings for ICI therapy–related pneumonitis. Background: Pneumonitis (Pn) is a potentially life-threatening adverse event of some anticancer drugs. At imaging, ICI therapy–related pneumonitis tends to be more extensive at patient presentation, with findings likely to be lower lung predominant (Fig 9). (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. For patients with grade 2 pneumonitis, diagnostic evaluation to rule out infection may be pursued, which can include nasopharyngeal, sputum, and urine culture and sensitivity tests (27). 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. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). ICI therapy–related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. Treatment-naïve patients have also demonstrated higher rates of pneumonitis relative to those patients who were previously treated (23). (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. During PET/CT surveillance, ... delaying nivolumab for grade 2 & discontinuation of immunotherapy for grade 3 & 4 pneumonitis 2. A baseline coronal chest CT image obtained before starting immunotherapy (not shown) showed no airspace abnormalities. (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. GI = gastrointestinal. The patient died 1 week later. 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. Furthermore, basilar predominance and subpleural sparing in the NSIP pattern are less typical findings of infection. 5, World Chinese Journal of Digestology, Vol. ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. NSIP pattern is the second most commonly described pattern of ICI therapy–related pneumonitis, although it is diagnosed in a minority of reported cases. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. 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. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. In the last decade, the introduction of immunotherapy has revolutionized the management and treatment approaches for a number of malignancies. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. (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. 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. (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 after completion of radiation therapy. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. 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. Currently in its fifth version, the CTCAE categorizes symptoms on a five-point grading scale according to increasing severity (Table 2). 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. Subpleural sparing of the posterior and dependent lower lobes has also been reported as a specific finding (34). Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [2–11]. If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. Although not specifically addressed in published guidelines given the potential for high steroid doses administered for extended periods, infectious prophylaxis may be warranted. Infection was excluded on the basis of clinical findings. Increased FDG uptake within adenopathy has also been observed at PET/CT (44). Many of these adverse events are unique from those previously observed with conventional chemotherapy regimens. In passive therapy, immunoglobulins are administered and bind to tumor-associated antigens, prompting clearance by the immune system. (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). Immunotherapy was subsequently held, and steroid therapy was administered. Figure 1b. Braschi-Amirfarzan M, Tirumani SH, Hodi FS, Nishino M. Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. 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. (2018) memo - Magazine of European Medical Oncology. The patient died 1 week later. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. This case illustrates the impressive appearances that immunotherapy-induced pneumonitis can have on imaging. (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). These ICI agents have adverse effects including the uncommon but potentially serious pulmonary toxicity of pneumonitis. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. 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). 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. Immunotherapy-induced pneumonitis - metastatic melanoma. 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. (2017) Korean journal of radiology. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. Figure 3a. 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. Thus, blockade of key portions of either or both of these immune checkpoint pathways is thought to be responsible for the antitumoral activity with ICIs (Fig 1). 16, The British Journal of Radiology, Vol. (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. However, in certain conditions such as leflunomide-induced acute interstitial pneumonia, patients have pre-existing lung disease. (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). This immune overreaction leads to the autoimmune-type reactions observed with irAEs. Patients with grade 1 or 2 pneumonitis have no or milder symptoms and are typically managed as outpatients, while patients with grade 3 or higher require more intensive management. 28, No. Figure 7c. Treatment typically includes administering corticosteroids and/or discontinuing therapy (42). Her previous chest imaging was normal (following study - chest radiograph). 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. 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. Unable to process the form. The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. Patient symptoms and pulse oximetry results should be closely monitored every 3 days, and if no improvement is seen 48–72 hours after starting steroid therapy, care should be escalated. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Extensive bone metastatic disease. Figure 10a. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. Furthermore, ICI therapy may also be combined with conventional chemotherapies given the ability of cytotoxic chemotherapy to potentiate the immune response of ICIs (2). HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. 1. Infection, including atypical and fungal causes such as invasive aspergillosis, should also be considered and often can be distinguished by clinical and laboratory findings. 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. After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). 2. Lucian Beer, Maximilian Hochmair, Helmut Prosch. Figure 9a. 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). Airspace disease can also be migratory, changing location or configuration over time (33). Patients with suspected pneumonitis should undergo initial clinical assessment with physical examination and pulse oximetry. Classically, bronchiolitis appears as a region of centrilobular nodularity, often in a tree-in-bud pattern. 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). Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. A bronchiolitis pattern is not a well-described pattern, only evident in one large case series and several case reports (25,36,37). 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. Immunotherapy can be classified as either passive or active. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. 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). ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. Bronchoscopy with bronchoalveolar lavage and empirical antibiotics can be considered at this stage, although it should not significantly delay initiating treatment (47). Pneumonitis is more likely to manifest in patients receiving ICI combination therapy compared with those receiving monotherapy (21). (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. This case illustrates the impressive appearances that immunotherapy-induced pneumonitis can have on imaging. (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). Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma, Immune-related adverse events with immune checkpoint blockade: a comprehensive review, Nivolumab plus ipilimumab in advanced melanoma, Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy, Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis, Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials, Toxicities of Immunotherapy for the Practitioner, Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients, U.S. Department of Health and Human Services. The patient died 1 week later. ICI therapy–related pneumonitis is an irAE, potentially resulting in significant morbidity with possible discontinuation of therapy and possible mortality. ICI therapy–related pneumonitis manifests as several distinct radiologic patterns that overlap with other infectious and inflammatory conditions. 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. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. 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 … Chest radiography can be considered to track evolving pneumonitis findings. 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. (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). (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. Despite researchers’ increasing awareness and experience with ICI therapy–related pneumonitis, large-scale studies categorizing the various radiologic patterns are somewhat limited. Published guidelines outline the treatment of ICI therapy–related pneumonitis based on the severity of symptoms. A baseline coronal chest CT image obtained before starting immunotherapy (not shown) showed no airspace abnormalities. 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 . 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). 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). (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (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). Recurrent pneumonitis cases were further subcategorized as either provoked by treatment renewal or unprovoked. Previous history of metastatic melanoma. (2015) Cancer immunology research. Immune check… (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. 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. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). More invasive assessments with bronchoscopy and biopsy are generally unnecessary, particularly in lower grades, if other clinical data are suggestive of pneumonitis. Figure 5a. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. 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. Reduced baseline pulmonary function and history of smoking may increase the risk of pneumonitis. 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%). Common Terminology Criteria for Adverse Events (CTCAE). 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. 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. Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. (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. Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. Infection was excluded on the basis of clinical findings. The patient previously underwent radiation therapy for multiple left posterior rib metastases. 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). Reported recurrence rate after rechallenge is 17%–29% (21,25,31). (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. 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. 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. In May 2017, a follow-up chest CT demonstrated resolution of ground glass opacification (figure 1C,D) at which time nivolumab 3 mg/kg monotherapy was initiated and continued for 25 doses until April 2018 without recurrence of pneumonitis.In April 2018, brain MRI showed postsurgical changes without evidence of metastases and chest and abdominal CT scans showed interval additional … Also, ICI therapy–related pneumonitis is more commonly associated with multiorgan involvement with other irAEs. (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). Some weeks later, the British Journal of Digestology, Vol: Radiopaedia free! Further subcategorized as either passive or active effective, although this occurs through mechanisms... 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