Figure 9a. Figure 1a. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. However, there are currently no specific histologic findings for ICI therapy–related pneumonitis. Viewer, https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf, https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A4008, Nonspecific Interstitial Pneumonia: Radiologic, Clinical, and Pathologic Considerations, Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society, Thoracic Complications of Precision Cancer Therapies: A Practical Guide for Radiologists in the New Era of Cancer Care, Bronchiolitis: A Practical Approach for the General Radiologist, Hypersensitivity Pneumonitis: A Historical, Clinical, and Radiologic Review, 3D Multiplanar Imaging in the Diagnosis and Management of Lung Transplantation Complications, Patterns of Drug-Related Pulmonary Injury: A Pictorial Review, Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias: Revised Concepts and Radiologic Implications. 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. Interlobular septal thickening and a “crazy-paving” pattern may also be present (34). Recurrence of metastasis to the bilateral lungs and left pleura was detected in April 2018. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. Common Terminology Criteria for Adverse Events, Advances in Radiation Oncology, Vol. 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). (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. No fevers or raised septic markers. 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. Figure 5b. Furthermore, the use of serum markers for the prediction and monitoring of ICI therapy–related pneumonitis is also an active area of investigation. 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 axial chest CT image shows the lungs before immunotherapy was initiated. (2)Clinical Oncology Department, Virgen Macarena University Hospital, Seville, Spain. Repeat the CT in three to four weeks and continue monitoring prior to each immunotherapy treatment. Many of these adverse events are unique from those previously observed with conventional chemotherapy regimens. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. Although not specifically addressed in published guidelines given the potential for high steroid doses administered for extended periods, infectious prophylaxis may be warranted. Published guidelines outline the treatment of ICI therapy–related pneumonitis based on the severity of symptoms. Figure 7b. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. 93, No. 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). NSIP pattern should be distinguished from atypical infectious processes, which can often be determined on the basis of clinical parameters. Figure 8b. 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. 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. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. The largest study to date by Delaunay et al (25) includes 64 cases of pneumonitis with the following CT patterns described: (a) OP (23%), (b) hypersensitivity pneumonitis (HP) (16%), (c) nonspecific interstitial pneumonia (NSIP) (8%), and (d) bronchiolitis (6%). 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). Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. A complete response was achieved following treatment with pembrolizumab, with lower limb rashes the only adverse events occurring during therapy. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. (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. This immune overreaction leads to the autoimmune-type reactions observed with irAEs. However, large-scale head-to-head studies comparing various ICI therapies are lacking. (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). (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). Infection was excluded on the basis of clinical findings. Histopathologic findings include cellular interstitial pneumonitis, organizing pneumonia (OP), and less commonly diffuse alveolar damage (21). (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). Pneumonitis may manifest with other irAEs, such as dermatitis, colitis, and endocrinopathies (21). Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [2–11]. In patients with non–small cell lung carcinoma, the incidence and severity of pneumonitis has been shown to be higher in patients undergoing treatment with PD-1 inhibitors compared with those undergoing treatment with PD-L1 inhibitors (3.6% vs 1.3%, respectively), with a lower incidence in those patients undergoing treatment with CTLA-4 inhibitors (23,24). Pneumonitis Related to Melanoma Immunotherapy. Furthermore, basilar predominance and subpleural sparing in the NSIP pattern are less typical findings of infection. Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. Adjacent bronchial wall thickening is also frequently depicted (Fig 7). HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. Table 2: National Cancer Institute CTCAE Pneumonitis Grading System. 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. Immune check… Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Its mechanism is likely multifactorial and is thought to be an autoimmune response with T-cell upregulation and ultimately increased granuloma formation. ), and Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (N.H.R., K.R.L., A.G.). The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. (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 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. 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. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). ■ Discuss the management of irAEs and the role of the radiologist in treatment course planning in these complex cases. 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. This patient was not clinically septic and the pattern of consolidation/groundglass is relatively symmetrical. (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. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. HP pattern is an uncommon manifestation of ICI therapy–related pneumonitis. To date, little is known about immunotherapy-induced pneumonitis (IIP). Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. However, PET lacks in diagnostic specificity in this scenario, given the potential overlap of hypermetabolic activity with malignancy and infectious processes. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. From the Department of Radiology, Duke University Medical Center, Durham, NC (K.R.K. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. 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). 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). (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. Aspiration is typically found in the dependent lungs, with accompanying fluid or debris-filled airways, and esophagus, while infection can often be delineated clinically. The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. Bronchoscopy and/or bronchoalveolar lavage are typically performed, and transbronchial biopsy can be considered at this stage. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. (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). Associated focal ground-glass and consolidative opacities may be visualized, although this should not the predominant feature. Also, tumors may increasingly express PD-L1 receptors causing decreased T-cell activity and tumor proliferation (7). However, a combination of immunotherapy (pembrolizumab) with chemotherapy was not linked to an increased risk of pneumonitis in lung cancer . Imaging features are similar to those of sarcoidosis and include mediastinal and hilar lymphadenopathy and pulmonary nodules in a perilymphatic distribution, with upper lung predominance (42). 16, The British Journal of Radiology, Vol. In cases of ICI therapy–related pneumonitis, the most common finding at bronchoalveolar lavage is T-lymphocytic alveolitis (25). Treatment is often effective, although recurrence is possible. Conventional chemotherapy agents have demonstrated a dose-dependent risk of pneumonitis, while overall this has not been shown with ICI therapy (45,46). Imaging plays a critical role in pneumonitis detection. If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. NSIP pattern most commonly manifests with ground-glass and reticular opacities with lower lobe predominance (Fig 4) (35). 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). Findings with lower lobe predominance can be depicted. Patient and drug-related factors predicting the development of pneumonitis are currently under investigation. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Pneumonitis is a potential consequence of both lung-directed radiation and immune checkpoint blockade (ICB), particularly treatment with PD-1/PD-L1 inhibitors. 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). 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). ICI therapy–related pneumonitis is an uncommon although potentially serious complication of ICI therapy. The diagnosis of immunotherapy-induced pneumonitis was made after careful exclusion of other pulmonary conditions such as infection and malignancy. (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. Several distinct radiographic patterns of pneumonitis have been observed: (a) organizing pneumonia, (b) nonspecific interstitial pneumonia, (c) hypersensitivity pneumonitis, (d) acute interstitial pneumonia–acute respiratory distress syndrome, (e) bronchiolitis, and (f) radiation recall pneumonitis. Airspace disease can also be migratory, changing location or configuration over time (33). 2. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. The patient previously underwent radiation therapy for multiple left posterior rib metastases. 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 … 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. Reported recurrence rate after rechallenge is 17%–29% (21,25,31). AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. Bronchoscopy with bronchoalveolar lavage and empirical antibiotics can be considered at this stage, although it should not significantly delay initiating treatment (47). (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. Some patients were diagnosed with concomitant patterns, and a distinctive pattern was not identified in 36% of cases. Radiologic response to respective treatments (ie, bronchopulmonary hygiene physical therapy and antibiotic therapy) is also often helpful. (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. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). ARDS findings may also be due to extrapulmonary causes such as pancreatitis, sepsis and/or shock, and transfusion reaction. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). Patients with suspected pneumonitis should undergo initial clinical assessment with physical examination and pulse oximetry. 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). 58, No. (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. Grade 1 immune-related pneumonitis is managed with close observation and consideration of holding immunotherapy. If the address matches an existing account you will receive an email with instructions to reset your password. Figure 2. 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. Table 3: ICI Therapy–related Pneumonitis Patterns. NSIP pattern is associated with a lower toxicity grade (median CTCAE grade 1) (31). (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). Classically, bronchiolitis appears as a region of centrilobular nodularity, often in a tree-in-bud pattern. The patient died 1 week later. Table 4: American Society of Clinical Oncology Clinical Practice Guideline for the Management of ICI-related Pneumonitis. Figure 6a. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). Figure 6c. 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. Pulmonary nodules may also be depicted, typically in a peribronchovascular distribution and more commonly as smaller nodules (<10 mm). (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). Described findings of HP pattern mirror those typically found in cases of subacute HP depicted in other settings. Pitfalls in the radiological response assessment of immunotherapy. More invasive assessments with bronchoscopy and biopsy are generally unnecessary, particularly in lower grades, if other clinical data are suggestive of pneumonitis. These adverse events can be temporary or chronic, mild or life-threatening, and may involve nearly any organ system, sometimes multiple sites simultaneously (Fig 2). Spectrum of treatment-related pneumonitis among various therapy types. 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). Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. 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). ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. There are two tiny subcutaneous nodules in the medial aspect of the right breast. (a) Baseline axial chest CT image shows the lungs after completion of radiation therapy. Figure 5a. Despite treatment of pneumonitis, approximately one-fourth of patients will develop recurrence (21) (Fig 10). Figure 10a. (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. Figure 1b. 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 … 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. Braschi-Amirfarzan M, Tirumani SH, Hodi FS, Nishino M. Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know. The patient died 1 week later. Background: Pneumonitis (Pn) is a potentially life-threatening adverse event of some anticancer drugs. Immunotherapy-induced pneumonitis - metastatic melanoma. Imaging. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. Previously, the bronchiolitis pattern may have been overlooked as a distinct pneumonitis pattern given its identical appearance to infectious and other inflammatory causes of bronchiolitis. Chest radiography can be considered to track evolving pneumonitis findings. (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. (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). 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. 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