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Corresponding author. Address for correspondence: Chiara Pozzessere, MD, Department of Radiology, AUSL Toscana Centro, San Giuseppe Hospital, Viale Giovanni Boccaccio, 16, 50053 Empoli, Italy
Department of Radiology, AUSL Toscana Centro, San Giuseppe Hospital, Empoli, ItalyDepartment of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
Pulmonary immune-related adverse events represent rare but potentially severe side effects of immunotherapies. Diagnosis is often challenging, as symptoms and imaging features are not specific and may mimic other lung diseases, thus potentially delaying appropriate patient management. In this setting, an accurate imaging evaluation is essential for a prompt detection and correct management of these drug-induced lung diseases. The purpose of this article is to review the different types of pulmonary immune-related adverse events, describe their imaging characteristics on both high-resolution computed tomography and positron emission tomography/computed tomography and stress their underlying diagnostic challenge by presenting the mimickers.
Immune checkpoint inhibitors (ICIs) are a new class of therapeutic agents, which have profoundly changed the landscape of cancer therapy. The ICIs target specific immune checkpoints located either on T cells or on neoplastic cells down-regulating T-cell stimulation and host immune response against cancer.
To date, several ICIs are approved globally, alone or in combination, in various locally advanced or metastatic cancers, such as follows: nivolumab, pembrolizumab, and cemiplimab, which target programmed cell death protein-1 (PD-1); durvalumab, atezolizumab, and avelumab, which target programmed death ligand-1 (PDL-1); and ipilimumab, which targets cytotoxic T-lymphocyte antigen-4 (CTLA-4).
ICIs administration is associated with specific side effects known as immune-related adverse events (irAEs), which most frequently arise during the first months after treatment initiation, although cases after therapy discontinuation have been reported.
Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis.
Although the physiopathology of irAEs remains to be fully understood, it is presumed that, in predisposed patients or in the presence of pre-existing conditions, ICIs may overstimulate the immune system and alter host homeostasis, causing an excessive inflammatory response. These irAEs are most often of low grade and can involve nearly any organ system. They are characterized by uncertain predictive features but are usually reversible with immunosuppression and discontinuation of therapy whenever needed.
Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.
These irAEs have been consistently correlated with a better outcome on ICIs across diseases, whereas their subsequent management has not been firmly found to affect tumor response to date.
Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis.
Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis.
Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.
Although most patients experience grade 1 to 2 events, such as mild dyspnea (53%), cough (35%), or may even be asymptomatic with irAE incidentally discovered on routine follow-up imaging, life-threatening pneumonitis has been reported in up to 2% of cases.
Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis.
Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.
Conversely, sarcoid-like reactions are uncommon with other ICIs. As for other irAEs, the development of IP is irrespective of the line of therapy and may occur between a few days and up to 1.5 years after the beginning of the therapy, with a mean time to onset of 2.3 to 2.8 months.
Although no risk factors have been clearly identified so far, it is believed that predisposing conditions contribute to the irAE development, according to a “two-hit” model.
It has been hypothesized that, in addition to possible systemic determinants, local pre-existing conditions, such as smoking exposure, chronic obstructive pulmonary disease, fibrosis, previous pulmonary infection, or radiotherapy (RT) alone or in combination with chemotherapy, may predispose to IP by altering the local homeostasis.
Among these, a special attention has been paid to RT. In fact, combined immuno-RT has been introduced as a standard of care after recent trials have reported a prolonged progression-free and overall survival compared with ICIs alone.
Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial.
Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
The rationale of combining RT with ICI is based on the fact that, besides a direct tumor-cell killing, radiations stimulate the immune system response, resulting in enhancement of the ICI effect.
Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial.
Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial.
Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
The lack of a pathognomonic feature makes pulmonary irAEs a diagnosis of exclusion, which is usually obtained by combining clinical evaluation, imaging findings, and laboratory analyses, including infectious workup and bronchoalveolar lavage (BAL) when feasible, whereas lung biopsy is rarely required.
Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.
BAL analysis is crucial to reach the diagnosis of IP, as it allows to rule out infection or neoplastic cells and to identify alveolar inflammatory cells. At BAL cytology, IP usually reveals a predominantly lymphocytic or a mixed pattern, although a pure neutrophilic pattern has also been observed in case of diffuse alveolar damage.
In clinical practice, ICI pneumonitis remains a diagnostic challenge. The variable time of IP onset during ICI therapy, the wide spectrum of clinical and radiologic presentation mimicking other lung pathologic conditions, especially infection or tumor progression, and the inherent invasive nature of bronchoscopy in patients suffering from respiratory impairment limiting its feasibility may all lead to diagnostic uncertainty and delay in dedicated management.
The purpose of this article is to review the imaging characteristics of pulmonary irAEs at high-resolution computed tomography (HRCT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), in order to make all involved physicians familiar with this condition, its potential complications, and diagnostic pitfalls.
The Role of Imaging
Imaging is a key tool in the management of patients receiving ICIs. The main goals of CT and 18F-FDG PET/CT, which are noninvasive and reproducible imaging modalities, are the routine assessment of response to therapy of malignancies. At the same time, they ensure an accurate diagnostic workup of pulmonary irAEs, allowing the detection of any new-onset pulmonary changes whatever their nature. In this case, an acquisition with thin slices at breath-hold full inspiration is required.
Any new respiratory symptoms occurring in patients receiving concurrent or previous ICIs should be promptly investigated to look for complications, such as disease progression, irAEs, or infections. In contrast, radiological manifestations of pulmonary irAEs can be found incidentally before the onset of symptoms in up to 40% of cases.
(Fig. 1). HRCT is the modality of choice, allowing early detection and accurate evaluation of pattern, distribution, and extent of lung abnormalities. Technically, thin contiguous slices during a unique breath-hold full inspiration are required with reconstruction with a sharp kernel, allowing a high-contrast resolution between the interstitium and the airspaces. Comparison with previous examinations, including the most recent and the older ones, is mandatory to identify any new-onset changes with confidence. Contrast agent administration is not required for the diagnosis of irAEs. HRCT is also useful to assess the evolution of irAEs.
Figure 1ICI pneumonitis detected at CT scan, whereas chest radiography result was negative. A 65-year-old male patient with metastatic renal cell carcinoma (bone, lung) treated with nivolumab since September 2016 underwent radiotherapy of dorsal vertebral metastasis in December 2016. (A) Restaging CT in March 2017. In April 2017, because of a new-onset grade 2 dyspnea, (B) chest radiography was performed revealing no abnormalities, whereas (C) a few ground-glass areas (arrows) in the apical segments of the upper lobes were detected at CT scan performed on the same day. An opportunistic infection was excluded at both serology and BAL; the BAL cytology result revealed a predominantly lymphocytic inflammation. Nivolumab was discontinued, and corticosteroid therapy was introduced. B, bone metastasis; BAL, bronchoalveolar lavage; CT, computed tomography; ICI, immune checkpoint inhibitor; L, lung metastasis.
At PET/CT, as other inflammatory abnormalities, pulmonary irAEs are 18F-FDG avid, which may allow an early detection even before the onset of symptoms. Nevertheless, their characterization may be difficult owing to several technical limitations in CT image acquisition, such as breathing artifacts in free-breathing acquisitions, thick slice thickness, and large field-of-view. Free-breathing acquisition may also generate dependent ground-glass opacities (GGOs) that may preclude a correct recognition of underlying changes that may be related to irAEs. For this reason, in case of new-onset lung changes unlikely to be metastatic, it may be advisable to perform an additional HRCT before BAL for a better assessment (Fig. 2).
Figure 2ICI pneumonitis with a diagnosis of unclassifiable pattern incidentally detected during a restaging PET/CT in a 64-year-old female patient with metastatic melanoma. The patient received four cycles of combined-therapy IPI plus nivolumab between June 2017 and September 2017, followed by maintenance therapy with nivolumab. (A) CT scan performed in September 2017. In November 2016, the patient was diagnosed with a rhinovirus bronchiolitis (see also Fig. 8A), successfully treated with oseltamivir and steroids. In January 2018, (B) bilateral multifocal slight FDG-avid pulmonary foci predominantly located at the upper part of the lungs and sparing the subpleural area (arrows) were found at PET/CT, (C) which were not confidently characterizable at the correspondent CT acquisition owing to respiratory motion artifacts; (D) HRCT confirmed the presence of multifocal ill-defined ground-glass opacities predominantly located within the left upper lobe (arrows), which were considered as features of an unclassifiable pattern. Alternative diagnosis of ICI pneumonitis included viral and Pneumocystis jirovecii infections. No pathogens were found at both serologic and cytologic examinations, whereas a lymphocytic-predominant pattern was detected at bronchoalveolar lavage. Because the patient developed a grade 2 dyspnea, immunotherapy was interrupted. CT, computed tomography; FDG, fluorodeoxyglucose; HRCT, high-resolution computed tomography; ICI, immune checkpoint inhibitor; IPI, ipilimumab; PET, positron emission tomography.
Pulmonary irAEs can be schematically divided into IP and sarcoidosis-like reactions.
The radiologic diagnosis of IP is challenging because there are no typical imaging findings. In fact, IP may display a wide range of imaging features, not classifiable in any specific pattern in some cases. Moreover, IP is a dynamic process, which evolves over time. Finally, the presence of underlying abnormalities, such as chronic obstructive pulmonary disease, tumoral spread, fibrotic changes owing to previous RT, or atelectasis, further make the identification of IP-related features difficult.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
This pattern can be found in all-grade IP, and the extent of pulmonary involvement generally reflects IP severity. Nonspecific interstitial pneumonia (NSIP) and hypersensitivity pneumonitis are two other possible patterns of IP.
NSIP most often presents as bilateral peripheral GGOs with irregular reticulations and traction bronchiectasis and bronchiolectasis, with a lower lung zone predominance and typically, but nonsystematically, sparing the subpleural parenchyma.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Nevertheless, in our experience, a pure NSIP pattern has been rarely observed in IP. Centrilobular micronodules and mosaic air-trapping are typical findings of hypersensitivity pneumonitis.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
This pattern is rare but reflects worsening in the clinical course of IP (Fig. 4). Rarely, airway disease without interstitial involvement has been observed.
Pembrolizumab-associated bronchiolitis in an elderly lung cancer patient required the treatment with an inhaled corticosteroid, erythromycin and bronchodilators.
These patients may present with asthma-like symptoms, bronchial wall thickening, and micronodules with a “tree in bud” appearance. Pleural effusion can also be present in some cases. Isolated pulmonary nodules or mass-like lesions have also been described and may be misdiagnosed as malignancy (Fig. 5). Finally, the imaging findings do not fill in all cases the criteria of a specific pattern, as with diffuse or patchy GGOs, which would better fit with an “unclassifiable pattern” category (Fig. 2).
Although the recognition of a particular imaging pattern may help physicians to detect/suspect an IP, other possible causes should be kept in mind during ICI treatment and should lead to further investigations to promptly achieve the correct diagnosis.
Table 1Imaging Features and Bronchoalveolar Lavage Findings of the Most Frequent Radiologic Patterns of ICI Pneumonitis
Radiologic Pattern
Imaging Features
Bronchoalveolar Lavage
OP
Patchy alveolar consolidations and/or GGOs Distribution: Peribronchovascular and/or subpleural Lower lobe predominance Other suggestive findings: Band-like consolidations Perilobular GGOs/consolidations Reverse halo sign Migratory aspect: location change over time, even without treatment ± Slight bronchial dilatation May arise in the same area of a tumor (primary or metastatic) and in radiation therapy field
Mixed pattern with predominance of lymphocytes (20%–40%) and mild elevation of neutrophils (~10%) and/or eosinophils (~5%)
NSIP
Bilateral GGOs with reticulations Distribution: Subpleural and/or peribronchovascular ± Sparing of the subpleural parenchyma Lower lobe predominance ± Bronchiectasis and bronchiolectasis
Mixed pattern similar to OP, with predominance of lymphocytes and mild elevation of neutrophils and/or eosinophils
Figure 3Grade III ICI pneumonitis with OP pattern. A 75-year-old male patient with multifocal HCC previously treated with chemoembolization and radiofrequency ablation received 4 cycles of nivolumab between August 2017 and October 2017, which were hold owing to progression of disease. After three months, the patient developed dyspnea, cough, asthenia, and thoracic pain. A CT was performed revealing (A) the appearance of patchy ill-defined GGOs (arrows) associated with subpleural GGOs (arrowheads). A lymphocytic-predominant pattern was found after bronchoalveolar lavage, and pulmonary infection was excluded. Steroid therapy was then started with progressive clinical and radiological improvement. Before the introduction of steroids, (B) a CT scan was repeated, revealing the evolution of the previously noted GGOs in peribronchovascular consolidations (arrows) and subpleural and fissural band-like consolidations (arrowheads). The morphologic features and BAL results were consistent with OP pattern. BAL, bronchoalveolar lavage; CT, computed tomography; GGO, ground-glass opacity; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; OP, organizing pneumonia.
Figure 4Grade IV ICI pneumonitis with AIP/DAD pattern in an 80-year-old man with parotid carcinoma metastatic to the lung and liver, under treatment with pembrolizumab complicated by Pseudomonas aeruginosa pneumonia in June 2017. CT images (A), (B), and (C) during Pseudomonas pneumonia reveal consolidations (stars) of the right lower lobe and middle lobe and bilateral pleural effusion (E). After initial recovery under antibiotic and steroid treatment, the patient was hospitalized for respiratory failure requiring intubation in July 2017. CT images (D), (E), and (F) reveal partial regression of the previously found consolidations (star), but with the appearance of diffuse ground-glass opacities with geographic distribution (arrows), consolidations in the dependent lung regions (arrowheads), and pleural effusion (E). Bronchoalveolar lavage cytology revealed neutrophilic inflammation and no pathogens. The patient was treated with high-dose steroids, and immunotherapy was interrupted. AIP/DAD, acute interstitial pneumonitis/diffuse alveolar damage; CT, computed tomography; ICI, immune checkpoint inhibitor.
Figure 5ICI pneumonitis with nodular pattern in a 63-year-old male patient with metastatic lung cancer (lung, kidney, adrenals, bone). The patient was treated with combination therapy IPI plus nivolumab between July 2015 and September 2015, followed by nivolumab. (A) CT scan in January 2016. (B) In April 2016, a new-onset lung nodule was detected; (C) which increased in size at the following scan in June 2016. (D) 18F-FDG PET/CT fusion image reveals the mild FDG uptake of the nodule. Because the findings were suggestive of malignancy, the patient underwent wedge resection of the nodule. No neoplastic cells were found at pathologic examination, but a chronic lymphocytic inflammation. Immunotherapy was continued. 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; ICI, immune checkpoint inhibitor; IPI, ipilimumab; PET, positron emission tomography.
Thoracic sarcoidosis-like reaction usually reveals symmetrical hilar and mediastinal lymph node enlargement, often associated with bilateral lung micronodules in a perilymphatic distribution, including peribronchovascular and fissural location.
Sarcoidosis-like active granulomatosis is hypermetabolic at 18F-FDG PET/CT (Fig. 6).
Figure 6Sarcoid-like reaction in a 50-year-old woman receiving nivolumab for metastatic cervical cancer (FIGO IV). (A) Whole-body MIP image of 18F-FDG PET/CT before immunotherapy reveals intense FDG uptake of metastatic left supraclavicular, retroperitoneal, iliac, and inguinal nodes (arrows). (B) Whole-body MIP image of PET/CT performed 2 months after the introduction of nivolumab reveals complete regression of the metastatic hypermetabolic areas consistent with complete response to therapy but the appearance of new symmetrical, moderately FDG-avid foci (arrowheads), (C) corresponding to mediastinal and hilar lymph nodes on PET/CT fusion image. (D) Fissural micronodules (arrowheads) are also found on CT image. Resolution of the inflammatory reaction was obtained with cyclophosphamide at immunomodulatory dose. (E) Whole-body MIP image of the next PET/CT reveals regression of the sarcoidosis-like mediastinal nodes, but with progression of the metastatic disease with bone metastasis and upper mediastinal and pelvic lymphadenopathies (arrows). 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; MIP, maximum intensity projection; PET, positron emission tomography.
Recently, it has been observed that in patients treated with radio-immunotherapy, pneumonitis often occurs in a previously irradiated area, irrespective of the time elapsed since RT, and even years after.
Although it is well known that RT can cause an acute “radiation pneumonitis” in the radiation field within 4 to 12 weeks after thoracic irradiation, additional mechanisms underlie RT-ICI pneumonitis.
Among these, a condition similar to “radiation recall” has been hypothesized. Radiation recall is a rare acute inflammation triggered by systemic drugs that occurs in a previously irradiated area and is mostly limited to a cutaneous reaction.
The time elapsed between RT and pneumonitis in some patients receiving ICIs has raised the hypothesis of a “radiation recall pneumonitis.” Another hypothesis involves a synergic effect of the modifications of the local pulmonary homeostasis by radiations within the radiation field and the hyperactivation of the immune system by the ICIs.
In any case, relationships between the radiation field and the development of pneumonitis are of high interest, as new-onset pulmonary changes in the irradiated area beyond 12 weeks may represent a form of pulmonary irAEs. Imaging features are similar to those of RP, with consolidations and/or GGOs often presenting as OP pattern, but with possible fibrotic changes.
Acute inflammation may arise in a fibrotic scar of a previous RT, thus making difficult the early identification and differentiation from superimposed infection or tumor recurrence. Although some imaging findings, such as an air bronchogram, may help to suggest radiation-related inflammation, BAL is often required. At PET/CT, these pulmonary changes are 18F-FDG avid in the inflammatory phase, whereas they may reveal a barely appreciable metabolism in the fibrotic phase (Fig. 7).
Figure 7ICI pneumonitis arising in a previously irradiated area (“radiation recall”) incidentally detected at 18F-FDG PET/CT in a 59-year-old man with metastatic melanoma (brain, lung, small bowel, bone, lymph nodes). In June 2014, the patient underwent wedge resection of a pulmonary metastasis of the right lower lobe followed by radiation therapy. (A) Radiation therapy field (dose delivered for each contoured area: orange area: 45 Gy; yellow areas: 40 to 30 Gy; green areas: 20 to 10 Gy; blue area: 5 Gy). (B) Radiation fibrosis in the irradiated area (arrow). Combined immunotherapy ipilimumab and nivolumab was introduced for progression disease in December 2014. In February 2015, at restaging 18F-FDG PET/CT, (C) the appearance of focal 18F-FDG–avid consolidations (arrows) in the previously irradiated area was reported. The patient was asymptomatic. After 1 month, the patient was admitted for fever and grade II dyspnea and (D) CT scan revealed an increase of the right lower lobe consolidation (arrow) and (E) the appearance of subpleural ground-glass opacities (arrowheads). A lymphocytic-predominant pattern was found at bronchoalveolar lavage, without pathogens or neoplastic cells. Immunotherapy was interrupted, and steroids were introduced. In August 2015, (F) 18F-FDG PET/CT revealed regression of the lung abnormalities, with a limited residual consolidation in the irradiated area compatible with fibrotic changes. Of note, during steroid treatment, the patient developed adrenal failure and opportunistic zoster infection. 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; ICI, immune checkpoint inhibitor; PET, positron emission tomography.
Differential diagnosis of IP mainly includes infection and tumor progression (Figs. 8A, 8B and 9), which share similar clinical symptoms and imaging findings. Although uncommon, infection may occur in patients treated by immunotherapy, particularly in those receiving combined ICIs.
In addition, in the time of coronavirus disease 2019 pandemic, severe acute respiratory syndrome coronavirus 2 infection should be considered in case of new-onset pulmonary changes detected on imaging. In fact, IP and coronavirus disease 2019 may present with similar clinical and radiologic features and both can be incidentally detected before the onset of symptoms.
Malignancy progression may be misdiagnosed as irAEs and vice versa, particularly in case of consolidations or lung nodules. This potential misdiagnosis has been reinforced by the predilection of IP around tumors, whether primary or metastatic, independently of a previous RT.
Confounding situations especially concern adenocarcinoma expressing as subsolid nodules. Sarcoidosis-like reaction radiological manifestation can overlap with those found in lymphangitis, dry pleural dissemination, and mediastinal nodal spread. The main differential diagnoses of ICI pneumonitis are presented in Table 2.
Figure 8(A) Same patient as in Figure 2. Rhinovirus bronchiolitis during maintenance therapy with nivolumab in a 64-year-old woman with metastatic melanoma. The patient was hospitalized for grade 4 dyspnea and cough. Extensive centrilobular micronodules with “tree in bud” appearance (circle) in the right upper lobe associated with bronchial wall thickening and bronchiectasis (arrows). (B) Legionella pneumonia during combination therapy ipilimumab plus nivolumab in a 44-year-old woman with metastatic melanoma. 18F-FDG PET/CT performed after two cycles of therapy introduction revealed the appearance of a pulmonary 18F-FDG–avid mass (arrows). The patient was asymptomatic, and a bronchoalveolar lavage was performed, revealing an infection by Legionella pneumophila. 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; ICI, immune checkpoint inhibitor; PET, positron emission tomography.
Figure 9Tumor progression mimicking an ICI pneumonitis in a 72-year-old female patient with lung adenocarcinoma receiving nivolumab. The patient underwent lobectomy of the right upper lobe and right lower lobe in 2010, followed by multiple lines of chemotherapy. In July 2013, palliative immunotherapy was introduced for tumor progression. (A) CT scan before immunotherapy reveals bilateral neoplastic lesions (N). (B) After 3 months, their regression is shown. (C) CT performed in June 2014 revealed the recurrence of the nodule in the left lower lobe (arrow) and the appearance of other lesions in the right lower lobe (arrowhead). Pathologic examination after biopsy was consistent with tumoral recurrence. CT, computed tomography; ICI, immune checkpoint inhibitor; N, neoplastic lesions.
Table 2Differential Diagnosis of the Most Frequent Radiologic Patterns of ICI Pneumonitis
Radiologic Pattern
Differential Diagnosis
OP
Multifocal adenocarcinoma Lymphoma Acute eosinophilic pneumonia: Peripheral GGO/alveolar consolidation Upper lobe predominance Radiation pneumonitis: In the radiation field Within 6 mo from radiotherapy Infectious pneumonia including the following: Bacterial Aspergillosis Other drug-induced pneumonitis
NSIP
Collagen vascular diseases Hypersensitivity pneumonitis Acute eosinophilic pneumonia Infectious pneumonia, especially nonopportunistic/opportunistic viral infections, including the following: - COVID-19, cytomegalovirus - Pneumocystis pneumonia Other drug-induced pneumonitis
HP
Acute eosinophilic pneumonia Infectious pneumonia Other drug-induced pneumonitis
AIP/DAD
Infectious pneumonia Cardiogenic edema: Bilateral and symmetrical interlobular septal thickening/peribronchovascular thickening GGO/alveolar consolidation in a batwing distribution Pleural effusion Common cardiomegaly
Bronchiolitis
Infectious bronchiolitis, including the following: Viral Bacterial Fungal Tuberculosis, atypical mycobacteria Aspiration bronchiolitis
Pulmonary nodules or mass-like lesions
Primary or metastatic tumor Infectious pneumonia, including the following: Bacterial infection Septic emboli Fungal infection Other causes (rheumatoid arthritis, etc.)
Opportunistic infection represents the most important complication of irAEs and is often owing to the steroid, immunosuppressive or immunomodulatory, treatment required to control the disease
Therefore, in patients diagnosed with irAEs, a regular clinical and radiological assessment is required to promptly recognize an opportunistic infection, particularly in those treated with immunosuppressive agents. In addition, the possibility of IP recurrence (“pneumonitis flare”) after initial resolution should be kept in mind, particularly in patients in whom treatment rechallenge with ICIs is attempted.
Figure 10Same patient as in Figure 1. Opportunistic infection during corticosteroid therapy for ICI pneumonitis in a 65-year-old man previously treated with nivolumab for metastatic renal cancer. (A) CT imaging at the diagnosis of the ICI pneumonitis revealed subtle ground-glass opacities. Immunotherapy was withheld, and corticosteroid therapy was administrated. During corticosteroid tapering, the patient had a grade II dyspnea and a CT scan was performed (B) revealing new-onset left upper lobe consolidations (arrows). An Aspergillus infection was found at bronchoalveolar lavage. CT, computed tomography; ICI, immune checkpoint inhibitor; L, lung metastasis.
Pulmonary irAEs are rare side effects of ICIs, which may strongly affect patient management. Because no definitive test is available, they represent a diagnosis of exclusion, which may potentially lead to a clinical emergency. An accurate radiologic assessment plays a critical role, particularly in patients who cannot undergo invasive procedures, such as BAL. The recognition of IP with imaging is not decisive, but awareness of the wide range of imaging features, the differential diagnoses, and the complications enable radiologist and nuclear medicine physician to adequately guide medical oncologist to optimize patient management.
References
Havel J.J.
Chowell D.
Chan T.A.
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis.
Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.
Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis.
Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.
Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial.
Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Pembrolizumab-associated bronchiolitis in an elderly lung cancer patient required the treatment with an inhaled corticosteroid, erythromycin and bronchodilators.
Disclosure: Dr. Lazor reports receiving personal fees and nonfinancial support from Boehringer Ingelheim and nonfinancial support from Roche and Vifor outside of the submitted work. Prof. Peters reports receiving education grants, provided consultation, attended advisory boards, or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda Pharmaceuticals, and Vaccibody, from whom she has received honoraria (all fees to institution). Dr. Beigelman-Aubry declares receiving personal fees for lectures from Gilead, AstraZeneca, and Boehringer Ingelheim outside of the submitted work. The remaining authors declare no conflict of interest.
The lungs are a common site of many different problems, including complications from cancer itself or secondary problems related to cancer treatment. To complicate this situation further, respiratory symptoms are vague and can be difficult to differentiate. In addition, monitoring systems are limited. As a result, in terms of treatment-induced pneumonitis, it is difficult to come up with a final decision. Furthermore, basically, diagnosis of treatment-related toxicity is a “process of elimination” achieved by excluding other potential causes.
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