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Imaging Features of Pulmonary Immune-related Adverse Events

Open ArchivePublished:May 31, 2021DOI:https://doi.org/10.1016/j.jtho.2021.05.017

      Abstract

      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.

      Keywords

      Introduction

      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.
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      Nevertheless, especially in patients requiring immunosuppressive treatment for irAEs, the risk of opportunistic infection is increased.
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      Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis.
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      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.
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      • Carbonnel F.
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      Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Xing P.
      • Zhang F.
      • Wang G.
      • et al.
      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.
      ,
      • Brahmer J.R.
      • Lacchetti C.
      • Schneider B.J.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.
      Incidence of ICI-induced pneumonitis (IP) is higher in combined therapy (6.5%–10%) than in monotherapy (3%–4%).
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
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      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
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      Anti–CTLA-4 therapy usually triggers a sarcoid-like reaction (5%–7%) rather than a pneumonitis (<1%).
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      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.
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      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      ,
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      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      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.
      • Sears C.R.
      • Peikert T.
      • Possick J.D.
      • et al.
      Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement.
      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.
      • Nishino M.
      • Giobbie-Hurder A.
      • Hatabu H.
      • Ramaiya N.H.
      • Hodi F.S.
      Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis.
      ,
      • Pozzessere C.
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      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
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      Cytomegalovirus infection as an underestimated trigger for checkpoint inhibitor-related pneumonitis in lung cancer: a retrospective study.
      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.
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      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.
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      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
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      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.
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      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
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      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.
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      Nevertheless, while reassuring on a comparable risk of severe adverse events,
      • Shaverdian N.
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      • Bornazyan K.
      • et al.
      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.
      • Antonia S.J.
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      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      • Peters S.
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      • Dafni U.
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      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.
      ,
      • Bauml J.M.
      • Mick R.
      • Ciunci C.
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      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
      ,
      • Theelen W.S.M.E.
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      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.
      these trials reported a moderately increased incidence of all-grade pneumonitis in patients with previous thoracic RT.
      • Shaverdian N.
      • Lisberg A.E.
      • Bornazyan K.
      • et al.
      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.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      • Peters S.
      • Felip E.
      • Dafni U.
      • et al.
      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.
      • Bauml J.M.
      • Mick R.
      • Ciunci C.
      • et al.
      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
      • Theelen W.S.M.E.
      • Peulen H.M.U.
      • Lalezari F.
      • et al.
      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.
      • Brahmer J.R.
      • Lacchetti C.
      • Schneider B.J.
      • et al.
      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.
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      ,
      • Suresh K.
      • Naidoo J.
      • Zhong Q.
      • et al.
      The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis.
      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.
      Hence, familiarity with irAEs is crucial.
      • Sears C.R.
      • Peikert T.
      • Possick J.D.
      • et al.
      Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement.
      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.
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      ,
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      Chest radiograph is not adequate in this setting, as abnormalities are not identified in up to 25% of cases
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      ,
      • Mathieson J.R.
      • Mayo J.R.
      • Staples C.A.
      • Müller N.L.
      Chronic diffuse infiltrative lung disease: comparison of diagnostic accuracy of CT and chest radiography.
      (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 thumbnail gr1
      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 thumbnail gr2
      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 A), 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.

      Imaging Features

      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.
      • Dromain C.
      • Beigelman C.
      • Pozzessere C.
      • Duran R.
      • Digklia A.
      Imaging of tumour response to immunotherapy.
      ,
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      • Delaunay M.
      • Cadranel J.
      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      .
      The main radiologic patterns of presentation are found in Table 1. The most frequent imaging pattern of IP is organizing pneumonia (OP).
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      • Delaunay M.
      • Cadranel J.
      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      ,
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      OP is characterized by patchy peribronchovascular and subpleural consolidations, often associated with GGOs.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      ,
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      The typical migratory feature can be identified on subsequent scans (Fig. 3).
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      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.
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      • Delaunay M.
      • Cadranel J.
      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      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.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      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.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      These patterns are generally associated with low-grade events.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      Conversely, an acute interstitial pneumonitis/diffuse alveolar damage pattern has been identified in the most severe cases.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      ,
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      It is characterized by diffuse bilateral GGOs with consolidation in the dependent parts of the lungs.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      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.
      • Mitropoulou G.
      • Daccord C.
      • Sauty A.
      • et al.
      Immunotherapy-induced airway disease: a new pattern of lung toxicity of immune checkpoint inhibitors.
      • Maeno K.
      • Fukuda S.
      • Oguri T.
      • Niimi A.
      Nivolumab-induced asthma in a patient with non-small-cell lung cancer.
      • Yamaya T.
      • Hee H.M.
      • Aoyagi T.
      • et al.
      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).
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      • Delaunay M.
      • Cadranel J.
      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      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 PatternImaging FeaturesBronchoalveolar Lavage
      OPPatchy 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%)
      NSIPBilateral 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
      HPBilateral GGOs, centrilobular micronodules, and patchy hypoattenuated lobules

      Upper lobe predominance
      Usually purely lymphocytic alveolitis with high lymphocyte count
      AIP/DADDiffuse GGOs with alveolar consolidation in the dependent parenchyma

      ± Small pleural effusion
      Usually neutrophilic alveolitis
      BronchiolitisCentrilobular micronodules with tree-in-bud appearance

      Bronchial wall thickening
      Not precisely defined. Mixed lymphocytic/eosinophilic and neutrophilic patterns have been reported
      Pulmonary nodules or mass-like lesionsSolitary nodule or mass
      Unclassifiable patternAbnormalities with no typical aspect/distribution or isolated features, such as ill-defined patchy GGOsVarious patterns
      Sarcoidosis likeSymmetrical bilateral hilar and mediastinal enlargement

      Bilateral micronodules in a perilymphatic distribution
      Moderate lymphocytic alveolitis
      AIP/DAD, acute interstitial pneumonitis/diffuse alveolar damage; GGOs, ground-glass opacities; HP, hypersensitivity pneumonitis; ICI, immune checkpoint inhibitor; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia.
      Figure thumbnail gr3
      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 thumbnail gr4
      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 thumbnail gr5
      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.
      • Dromain C.
      • Beigelman C.
      • Pozzessere C.
      • Duran R.
      • Digklia A.
      Imaging of tumour response to immunotherapy.
      ,
      • Gkiozos I.
      • Kopitopoulou A.
      • Kalkanis A.
      • Vamvakaris I.N.
      • Judson M.A.
      • Syrigos K.N.
      Sarcoidosis-like reactions induced by checkpoint inhibitors.
      ,
      • Montaudié H.
      • Pradelli J.
      • Passeron T.
      • Lacour J.P.
      • Leroy S.
      Pulmonary sarcoid-like granulomatosis induced by nivolumab.
      Sarcoidosis-like active granulomatosis is hypermetabolic at 18F-FDG PET/CT (Fig. 6).
      Figure thumbnail gr6
      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.

      Relationship Between IP and Radiation Therapy

      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.
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      ,
      • Louvel G.
      • Bahleda R.
      • Ammari S.
      • et al.
      Immunotherapy and pulmonary toxicities: can concomitant immune-checkpoint inhibitors with radiotherapy increase the risk of radiation pneumonitis?.
      • Shibaki R.
      • Akamatsu H.
      • Fujimoto M.
      • Koh Y.
      • Yamamoto N.
      Nivolumab induced radiation recall pneumonitis after two years of radiotherapy.
      • McGovern K.
      • Ghaly M.
      • Esposito M.
      • Barnaby K.
      • Seetharamu N.
      Radiation recall pneumonitis in the setting of immunotherapy and radiation: a focused review.
      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.
      • Choi Y.W.
      • Munden R.F.
      • Erasmus J.J.
      • et al.
      Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis.
      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.
      • Burris 3rd, H.A.
      • Hurtig J.
      Radiation recall with anticancer agents.
      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.
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      ,
      • Choi Y.W.
      • Munden R.F.
      • Erasmus J.J.
      • et al.
      Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis.
      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.
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      ,
      • Louvel G.
      • Bahleda R.
      • Ammari S.
      • et al.
      Immunotherapy and pulmonary toxicities: can concomitant immune-checkpoint inhibitors with radiotherapy increase the risk of radiation pneumonitis?.
      ,
      • Shibaki R.
      • Akamatsu H.
      • Fujimoto M.
      • Koh Y.
      • Yamamoto N.
      Nivolumab induced radiation recall pneumonitis after two years of radiotherapy.
      ,
      • Choi Y.W.
      • Munden R.F.
      • Erasmus J.J.
      • et al.
      Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis.
      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 thumbnail gr7
      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

      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.
      • Del Castillo M.
      • Romero F.A.
      • Argüello E.
      • Kyi C.
      • Postow M.A.
      • Redelman-Sidi G.
      The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma.
      Among these, the most common manifestation is pneumonia, and it is often caused by bacteria.
      • Fujita K.
      • Kim Y.H.
      • Kanai O.
      • Yoshida H.
      • Mio T.
      • Hirai T.
      Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy.
      Moreover, reactivation of latent infections, such as tuberculosis, has also been described.
      • Lu M.
      • Zhang L.
      • Li Y.
      • et al.
      Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections.
      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.
      • Calabrò L.
      • Peters S.
      • Soria J.C.
      • et al.
      Challenges in lung cancer therapy during the COVID-19 pandemic.
      ,
      • Pozzessere C.
      • Rotzinger D.C.
      • Ghaye B.
      • Lamoth F.
      • Beigelman-Aubry C.
      Incidentally discovered COVID-19 pneumonia: the role of diagnostic imaging.
      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.
      • Pozzessere C.
      • Bouchaab H.
      • Jumeau R.
      • et al.
      Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study.
      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 thumbnail gr8
      Figure 8(A) Same patient as in . 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 thumbnail gr9
      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 PatternDifferential Diagnosis
      OPMultifocal 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
      NSIPCollagen 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
      HPAcute eosinophilic pneumonia

      Infectious pneumonia

      Other drug-induced pneumonitis
      AIP/DADInfectious pneumonia

      Cardiogenic edema:

      Bilateral and symmetrical interlobular septal thickening/peribronchovascular thickening

      GGO/alveolar consolidation in a batwing distribution

      Pleural effusion

      Common cardiomegaly
      BronchiolitisInfectious bronchiolitis, including the following:

      Viral

      Bacterial

      Fungal

      Tuberculosis, atypical mycobacteria

      Aspiration bronchiolitis
      Pulmonary nodules or mass-like lesionsPrimary or metastatic tumor

      Infectious pneumonia, including the following:

      Bacterial infection

      Septic emboli

      Fungal infection

      Other causes (rheumatoid arthritis, etc.)
      Unclassifiable patternInfectious pneumonia

      Hypersensitivity pneumonitis
      Sarcoidosis likeCarcinomatous lymphangitis

      Unilateral or bilateral

      Thickened linear/nodular septal lines

      Peribronchovascular thickening
      AIP/DAD, acute interstitial pneumonitis/diffuse alveolar damage; COVID-19, coronavirus disease 2019; GGO, ground-glass opacity; HP, hypersensitivity pneumonitis; ICI, immune checkpoint inhibitor; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia.

      Complications

      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
      • Sears C.R.
      • Peikert T.
      • Possick J.D.
      • et al.
      Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement.
      ,
      • Lu M.
      • Zhang L.
      • Li Y.
      • et al.
      Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections.
      (Fig. 10). Superimposed infection may lead to death in the most severe cases.
      • Sears C.R.
      • Peikert T.
      • Possick J.D.
      • et al.
      Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement.
      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.
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      • Nishino M.
      • Ramaiya N.H.
      • Awad M.M.
      • et al.
      PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course.
      • Delaunay M.
      • Cadranel J.
      • Lusque A.
      • et al.
      Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients.
      Figure thumbnail gr10
      Figure 10Same patient as in . 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.

      Conclusion

      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.

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      Linked Article

      • A Wake-Up Call for Immune Checkpoint Inhibitor–Related Pneumonitis
        Journal of Thoracic OncologyVol. 16Issue 9
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          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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