Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Resistin Pathway as Novel Mechanism of Post-lung Transplantation Bronchial Stenosis.

BACKGROUND: Bronchial stenosis remains a significant source of morbidity among lung transplant recipients. Though infection and anastomotic ischemia have been proposed etiologies of the development of bronchial stenosis, the pathophysiologic mechanism has not been well elucidated. METHODS: In this single-centered prospective study, from January 2013 through September 2015, we prospectively collected bronchoalveolar lavage (BAL) and endobronchial epithelial brushings from the direct anastomotic site of bronchial stenosis of bilateral lung transplant recipients who developed unilateral post-transplant bronchial stenosis. Endobronchial epithelial brushings from the contralateral anastomotic site without bronchial stenosis and BAL from bilateral lung transplant recipients who did not develop post-transplant bronchial stenosis were used as controls. Total RNA was isolated from the endobronchial brushings and real-time polymerase chain reaction reactions were performed. Electrochemiluminescence biomarker assay was used to measure 10 cytokines from the BAL. RESULTS: Out of 60 bilateral lung transplant recipients, 9 were found to have developed bronchial stenosis with 17 samples adequate for analysis. We observed a 1.56 to 70.8 mean-fold increase in human resistin gene expression in the anastomotic bronchial stenosis epithelial cells compared with nonstenotic airways. Furthermore, IL-1ß (21.76±10.96 pg/mL; control 0.86±0.44 pg/mL; P <0.01) and IL-8 levels (990.56±326.60 pg/mL; control 20.33±1.17 pg/mL; P <0.01) were significantly elevated in the BAL of the lung transplant patients who developed anastomotic bronchial stenosis. CONCLUSION: Our data suggest that the development of postlung transplantation bronchial stenosis may be in part mediated through the human resistin pathway by IL-1ß induced transcription factor nuclear factor-κß activation and downstream upregulation of IL-8 in alveolar macrophages. Further study is needed in the larger patient cohorts and to determine its potential therapeutic role in the management of post-transplant bronchial stenosis.

Current Practices in Airway Stent Management: A National Survey of US Practitioners.

BACKGROUND: Despite a growing number of tracheobronchial stent types and indications, complications remain frequent, and high-quality evidence on practices to prevent stent-related complications is lacking. Understanding current management practice is a first step to designing prospective studies to assess whether specific practices aimed at mitigating stent-related complications improve patient-centered outcomes. OBJECTIVES: In this study, we aimed to understand current management strategies following tracheobronchial stenting. METHOD: We performed a nationwide survey of members of the American Association of Bronchology and Interventional Pulmonology (AABIP) and the General Thoracic Surgical Club (GTSC) who place airway stents. The electronic survey captured data on practitioners' demographics, practice setting, airway stent volume, and standard post-stent practices (if any) including the use of medications, mucus clearance devices, surveillance imaging, and surveillance bronchoscopy. RESULTS: One hundred thirty-eight physicians completed the survey. Respondents were majority male (75.4%) and had diverse training (50.0% completed interventional pulmonary fellowship; 18.1% thoracic surgery; 31.9% other stent training). Post-stent management strategies varied markedly across respondents; 75.4% prescribe at least one medication to prevent post-stent complications, 52.9% perform routine surveillance bronchoscopy in asymptomatic patients, 26.1% prescribe mucus clearance regimens, 16.7% obtain routine computed tomography scans in asymptomatic patients, and 8.3% routinely replace their stents prior to stent failure. CONCLUSIONS: In this national survey of practitioners who place airway stents, there was marked heterogeneity in post-stent management approaches. Further studies are needed to identify which, if any, of these strategies improve patient-centered outcomes.

Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.

Bronchoalveolar Lavage (BAL) and Pathologic Assessment of Electronic Cigarette or Vaping Product Use-associated Lung Injury (EVALI): The EVALI-BAL Study, A Multicenter Cohort.

BACKGROUND: E-cigarette or vaping-use related acute lung injury (EVALI) is a spectrum of radiographic and histologic patterns consistent with acute to subacute lung injury. However, limited data exist characterizing bronchoalveolar lavage (BAL) findings. The goal of this study is to further define the pathologic findings from BAL and biopsy samples of subjects with EVALI across 7 institutions. METHODS: A multicentered registry of patients admitted with EVALI who underwent flexible bronchoscopy with BAL+/-transbronchial biopsy from July 2019 to April 2021 was compiled for retrospective evaluation from 7 academic institutions throughout the United States. Radiographic and cytopathologic findings and frequencies were correlated with the substance vaped. RESULTS: Data from 21 subjects (42.9% women) who were predominantly White (76.2%) with a median age of 25 years (range, 16 to 68) with EVALI were included in this study. Sixteen patients (76.2%) reported use of tetrahydrocannabinol; the remainder used nicotine. BAL was performed in 19 of the 21 subjects, and transbronchial lung biopsy was performed in 7 subjects. BAL findings revealed neutrophilic predominance (median, 59.5%, range, 3.1 to 98) in most cases. Ten BAL samples demonstrated pulmonary eosinophilia ranging from 0.2% to 49.1% with one subject suggesting a diagnosis of acute eosinophilic pneumonia associated with the use of e-cigarettes. Lipid-laden macrophages were noted in 10 of 15 reports (66.7%). Transbronchial biopsy most frequently demonstrated patterns of organizing pneumonia (57.1%). CONCLUSION: EVALI-associated BAL findings typically demonstrate a spectrum of nonspecific inflammatory changes, including neutrophilia, lipid-laden macrophages, and in some cases eosinophilia.

Comparing modalities for risk assessment in patients with pulmonary lesions and nondiagnostic bronchoscopy for suspected lung cancer.

BACKGROUND: Bronchoscopy is commonly utilized for non-surgical sampling of indeterminant pulmonary lesions, but nondiagnostic procedures are common. Accurate assessment of the risk of malignancy is essential for decision making in these patients, yet we lack tools that perform well across this heterogeneous group of patients. We sought to evaluate the accuracy of three previously validated risk models and physician-assessed risk (PAR) in patients with a newly identified lung lesion undergoing bronchoscopy for suspected lung cancer where the result is nondiagnostic. METHODS: We performed an analysis of prospective data collected for the Percepta Bronchial Genomic Classifier Multicenter Registry. PAR and three previously validated risk models (Mayo Clinic, Veteran's Affairs, and Brock) were used to determine the probability of lung cancer (low, intermediate, or high) in 375 patients with pulmonary lesions who underwent bronchoscopy for possible lung cancer with nondiagnostic pathology. Results were compared to the actual adjudicated prevalence of malignancy in each pre-test risk group, determined with a minimum of 12 months follow up after bronchoscopy. RESULTS: PAR and the risk models performed poorly overall in the assessment of risk in this patient population. PAR most closely matched the observed prevalence of malignancy in patients at 12 months after bronchoscopy, but all modalities had a low area under the curve, and in all clinical models more than half of all the lesions labeled as high risk were truly or likely benign. The studied risk model calculators overestimate the risk of malignancy compared to PAR, particularly in the subset in older patients, irregularly bordered nodules, and masses > 3 cm. Overall, the risk models perform only slightly better when confined to lung nodules < 3 cm in this population. CONCLUSION: The currently available tools for the assessment of risk of malignancy perform suboptimally in patients with nondiagnostic findings following a bronchoscopic evaluation for lung cancer. More accurate and objective tools for risk assessment are needed. TRIAL REGISTRATION: not applicable.

Correlation of Vital Signs and Depth of Sedation by Modified Observer's Assessment of Alertness and Sedation (MOAA/S) Scale in Bronchoscopy.

BACKGROUND: With complex, lengthy bronchoscopies, there is a need for safe, effective sedation. Most bronchoscopists strive for moderate sedation, though often difficult without compromising vital signs. The Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale is a validated 6-point scale assessing responsiveness of patients coinciding with the American Society of Anesthesiologists (ASA) continuum of sedation. It is commonly used in studying bronchoscopic sedation, but depth of sedation by MOAA/S and correlation with vital signs and adverse events has not been determined. METHODS: This study was a post hoc analysis of a prospective, double-blind, randomized trial evaluating the safety and efficacy of remimazolam. MOAA/S and corresponding vital signs were used to assess the effect of the level of sedation on vital signs and adverse events. RESULTS: A total of 23,341 MOAA/S scores from 431 patients were recorded. Older and higher ASA class patients spent more time in deeper sedation (MOAA/S 0 to 1) (6% vs. 2%, P=0.01). Oxygen saturation was equal in deep sedation (MOAA/S 0 to 1) (97±3%) compared with moderate sedation (96±3%) (P=0.11). Mean systolic and diastolic blood pressures were significantly lower when comparing MOAA/S 0 to 1 to MOAA/S 5 (systolic blood pressure: 126±19 vs. 147±24 mm Hg, P<0.01; diastolic blood pressure: 68±14 vs. 84±15 mm Hg, P<0.01). There was a nonsignificant trend towards lower heart rate at deep versus moderate sedation (84±15 vs. 94±18 beats/min, P=0.07). Respiratory rate was also comparable with moderate and deep sedation (17±5 vs. 18±6 beats/min, P=0.94). CONCLUSION: There was no clinically meaningful correlation between vital signs and depth of sedation assessed by MOAA/S. Older and higher ASA class patients spend more time in deeper sedation. However, when in deep sedation, there was no difference in vital signs other than a slightly increased incidence of clinically insignificant hypotension.

Pleural Interventions in the Management of Hepatic Hydrothorax.

Hepatic hydrothorax can be present in 5% to 15% of patients with underlying cirrhosis and portal hypertension, often reflecting advanced liver disease. Its impact can be variable, because patients may have small pleural effusions and minimal pulmonary symptoms or massive pleural effusions and respiratory failure. Management of hepatic hydrothorax can be difficult because these patients often have a number of comorbidities and potential for complications. Minimal high-quality data are available for guidance specifically related to hepatic hydrothorax, potentially resulting in pulmonary or critical care physician struggling for best management options. We therefore provide a Case-based presentation with management options based on currently available data and opinion. We discuss the role of pleural interventions, including thoracentesis, tube thoracostomy, indwelling tunneled pleural catheter, pleurodesis, and surgical interventions. In general, we recommend that management be conducted within a multidisciplinary team including pulmonology, hepatology, and transplant surgery. Patients with refractory hepatic hydrothorax that are not transplant candidates should be managed with palliative intent; we suggest indwelling tunneled pleural catheter placement unless otherwise contraindicated. For patients with unclear or incomplete hepatology treatment plans or those unable to undergo more definitive procedures, we recommend serial thoracentesis. In patients who are transplant candidates, we often consider serial thoracentesis as a standard treatment, while also evaluating the role indwelling tunneled pleural catheter placement may play within the course of disease and transplant evaluation.

Joining Forces: How to Coordinate Large, Multicenter Randomized Trials.

This article details the pros, cons, challenges/pitfalls, and elements required for the successful conduct of multicenter randomized trials, with specific focus on trials related to pleural diseases. Several networks dedicated to the multicenter study of important pleural conditions have developed, yielding practice-changing studies in pleural disease. This review describes the importance of multicenter trials, major elements required for the conduct of such trials, and lessons learned from the ongoing development of the Interventional Pulmonary Outcomes Group, a consortium of interventional pulmonologists dedicated to advancing diagnostic and management strategies in pleural, pulmonary parenchymal, and airway disease by generating high-quality multicenter evidence.

Variable Learning Curve of Basic Rigid Bronchoscopy in Trainees.

BACKGROUND: Despite increased use of rigid bronchoscopy (RB) for therapeutic indications and recommendations from professional societies to use performance-based competency, an assessment tool has not been utilized to measure the competency of trainees to perform RB in clinical settings. OBJECTIVES: The aim of the study was to evaluate a previously developed assessment tool - Rigid Bronchoscopy Tool for Assessment of Skills and Competence (RIGID-TASC) - for determining the RB learning curve of interventional pulmonary (IP) trainees in the clinical setting and explore the variability of learning curve of trainees. METHODS: IP fellows at 4 institutions were enrolled. After preclinical simulation training, all RBs performed in patients were scored by faculty using RIGID-TASC until competency threshold was achieved. Competency threshold was defined as unassisted RB intubation and navigation through the central airways on 3 consecutive patients at the first attempt with a minimum score of 89. A regression-based model was devised to construct and compare the learning curves. RESULTS: Twelve IP fellows performed 178 RBs. Trainees reached the competency threshold between 5 and 24 RBs, with a median of 15 RBs (95% CI, 6-21). There were differences among trainees in learning curve parameters including starting point, slope, and inflection point, as demonstrated by the curve-fitting model. Subtasks that required the highest number of procedures (median = 10) to gain competency included ability to intubate at the first attempt and intubation time of <60 s. CONCLUSIONS: Trainees acquire RB skills at a variable pace, and RIGID-TASC can be used to assess learning curve of IP trainees in clinical settings.

Sex differences in M2 polarization, chemokine and IL-4 receptors in monocytes and macrophages from asthmatics.

Allergic asthma affects more women than men. It is mediated partially by IL-4/IL-13-driven polarization of monocyte-derived macrophages in the lung. We tested whether sex differences in asthma are due to differential IL-4 responsiveness and/or chemokine receptor expression in monocytes and monocyte-derived macrophages from healthy and allergic asthmatic men and women. We found female cells expressed M2 genes more robustly following IL-4 stimulation than male cells, as did cells from asthmatics than those from healthy controls. This likely resulted from increased expression ofγC, part of the type I IL-4 receptor, and reduced IL-4-induced SOCS1, a negative regulator of IL-4 signaling, in asthmatic compared to healthy macrophages. Monocytes from asthmatic women expressed more CX3CR1, which enhances macrophage survival. Our findings highlight how sex differences in IL-4 responsiveness and chemokine receptor expression may affect monocyte recruitment and macrophage polarization in asthma, potentially leading to new sex-specific therapies to manage the disease.

Computed Tomography During Bronchoscopic Lung Splinting for Atelectasis.

A 64-year-old man experienced persistent atelectasis of the right lung after right upper lobectomy. To simultaneously visualize the airways and lung parenchyma in real time, chest computed tomography was performed while pneumatically splinting the lung open via insufflation through the working channel of a bronchoscope. The bronchi were patent but peripheral consolidations within the remaining right lung were visualized, representative of pneumonia. The patient fully recovered with antimicrobial therapy. Computed tomography during bronchoscopic pneumatic lung splinting is an advanced diagnostic for the investigation of persistent atelectasis.

Association between Tunneled Pleural Catheter Use and Infection in Patients Immunosuppressed from Antineoplastic Therapy. A Multicenter Study.

Rationale: Patients with malignant or paramalignant pleural effusions (MPEs or PMPEs) may have tunneled pleural catheter (TPC) management withheld because of infection concerns from immunosuppression associated with antineoplastic therapy.Objectives: To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency, and overall survival (OS).Methods: We performed an international, multiinstitutional study of patients with MPEs or PMPEs undergoing TPC management from 2008 to 2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or whether or not they were immunocompromised. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional hazards modeling were performed to examine for independent effects on OS.Results: A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%), or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range, 19-87) days after TPC insertion. Multivariable competing risk analyses demonstrated that longer TPC duration was associated with a higher risk of TPC-related infection (subdistribution hazard ratio, 1.03; 95% confidence interval [CI], 1.00-1.06; P = 0.028). Cox proportional hazards analysis showed antineoplastic therapy was associated with better OS (hazard ratio, 0.84; 95% CI, 0.73-0.97; P = 0.015).Conclusions: The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable with those of immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE or PMPEs regardless of plans for antineoplastic therapy.

Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination therapy with ICIs is frequently used in order to enhance the treatment response rates. Yet, this regimen is still associated with poor treatment outcome. Therefore, identification of potential therapeutic targets for this subgroup of NSCLC is strongly desired. Here, we report the distinct methylation signatures of this special subgroup. Moreover, several druggable targets and relevant drugs for targeted therapy were incidentally identified. We found hypermethylated differentially methylated regions (DMRs) in three regions (TSS200, TSS1500, and gene body) are significantly higher than hypomethylated ones. Downregulated methylated genes were found to be involved in negative regulation of immune response and T cell-mediated immunity. Moreover, expression of four methylated genes (PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), BAIAP2L2 (BAR/IMD Domain Containing Adaptor Protein 2 Like 2), NPR3 (Natriuretic Peptide Receptor 3), SNX10 (Sorting Nexin 10)) can influence patients' prognosis. Subsequently, based on DrugBank data, NetworkAnalyst 3.0 was used for protein-drug interaction analysis of up-regulated differentially methylated genes. Protein products of nine genes were identified as potential druggable targets, of which the tumorigenic potential of XDH (Xanthine Dehydrogenase), ATIC (5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase), CA9 (Carbonic Anhydrase 9), SLC7A11 (Solute Carrier Family 7 Member 11), and GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) have been demonstrated in previous studies. Next, molecular docking and molecular dynamics simulation were performed to verify the structural basis of the therapeutic targets. It is noteworthy that the identified pemetrexed targeting ATIC has been recently approved for first-line use in combination with anti-PD1 inhibitors against lung cancer, irrespective of PD-L1 expression. In future work, a pivotal clinical study will be initiated to further validate our findings.

Coupled immune stratification and identification of therapeutic candidates in patients with lung adenocarcinoma.

In recent years, personalized cancer immunotherapy, especially stratification-driven precision treatments have gained significant traction. However, due to the heterogeneity in clinical cohorts, the uncombined analysis of stratification/therapeutics may lead to confusion in determining ideal therapeutic options. We report that the coupled immune stratification and drug repurposing could facilitate identification of therapeutic candidates in patients with lung adenocarcinoma (LUAD). First, we categorized the patients into four groups based on immune gene profiling, associated with distinct molecular characteristics and clinical outcomes. Then, the weighted gene co-expression network analysis (WGCNA) algorithm was used to identify co-expression modules of each groups. We focused on C3 group which is characterized by low immune infiltration (cold tumor) and wild-type EGFR, posing a significant challenge for treatment of LUAD. Five drug candidates against the C3 status were identified which have potential dual functions to correct aberrant immune microenvironment and also halt tumorigenesis. Furthermore, their steady binding affinity against the targets was verified through molecular docking analysis. In sum, our findings suggest that such coupled analysis could be a promising methodology for identification and exploration of therapeutic candidates in the practice of personalized immunotherapy.

Poor Monitor Screen Height Positioning by Pulmonologists During Flexible Bronchoscopy: A Nested, Prospective Observational Trial / Colocación de la pantalla del monitor a una altura inadecuada por los neumólogos durante la broncoscopia flexible: un estudio observacional prospectivo anidado

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Management of Indwelling Tunneled Pleural Catheters: A Modified Delphi Consensus Statement.

BACKGROUND: The management of recurrent pleural effusions remains a challenging issue for clinicians. Advances in management have led to increased use of indwelling tunneled pleural catheters (IPC) because of their effectiveness and ease of outpatient placement. However, with the increase in IPC placement there have also been increasing reports of complications, including infections. Currently there is minimal guidance in IPC-related management issues after placement. RESEARCH QUESTION: Our objective was to formulate clinical consensus statements related to perioperative and long-term IPC catheter management based on a modified Delphi process from experts in pleural disease management. STUDY DESIGN AND METHODS: Expert panel members used a modified Delphi process to reach consensus on common perioperative and long-term management options related to IPC use. Members were identified from multiple countries, specialties, and practice settings. A series of meetings and anonymous online surveys were completed. Responses were used to formulate consensus statements among panel experts, using a modified Delphi process. Consensus was defined a priori as greater than 80% agreement among panel constituents. RESULTS: A total of 25 physicians participated in this project. The following topics were addressed during the process: definition of an IPC infection, management of IPC-related infectious complications, interventions to prevent IPC infections, IPC-related obstruction/malfunction management, assessment of IPC removal, and instructions regarding IPC management by patients and caregivers. Strong consensus was obtained on 36 statements. No consensus was obtained on 29 statements. INTERPRETATION: The management of recurrent pleural disease with IPC remains complex and challenging. This statement offers statements for care in numerous areas related to IPC management based on expert consensus and identifies areas that lack consensus. Further studies related to long-term management of IPC are warranted.

Chronic immune checkpoint inhibitor pneumonitis.

BACKGROUND: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression. METHODS: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.