Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others. This article is a simultaneous joint publication in Radiology and CHEST. The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society.

With more than 900 000 confirmed cases worldwide and nearly 50 000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. Although mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography and CT are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pretest probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing patients with COVID-19 across a spectrum of health care environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based on the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of chest radiography and CT in the management of COVID-19.

Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure.

Noninvasive mechanical ventilation (NIV) is widely used in the acute care setting for acute respiratory failure (ARF) across a variety of aetiologies. This document provides European Respiratory Society/American Thoracic Society recommendations for the clinical application of NIV based on the most current literature.The guideline committee was composed of clinicians, methodologists and experts in the field of NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology for each actionable question. The GRADE Evidence to Decision framework in the guideline development tool was used to generate recommendations. A number of topics were addressed using technical summaries without recommendations and these are discussed in the supplementary material.This guideline committee developed recommendations for 11 actionable questions in a PICO (population-intervention-comparison-outcome) format, all addressing the use of NIV for various aetiologies of ARF. The specific conditions where recommendations were made include exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema, de novo hypoxaemic respiratory failure, immunocompromised patients, chest trauma, palliation, post-operative care, weaning and post-extubation.This document summarises the current state of knowledge regarding the role of NIV in ARF. Evidence-based recommendations provide guidance to relevant stakeholders.

Chronic Thromboembolic Pulmonary Hypertension: Clinical and Imaging Evaluation.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and is an important cause of pulmonary hypertension. As a clinical entity, it is frequently underdiagnosed with prolonged diagnostic delays. This study reviews the clinical and radiographic findings associated with CTEPH to improve awareness and recognition. Strengths and limitations of multiple imaging modalities are reviewed. Accompanying images are provided to supplement the text and provide examples of important findings for the reader.

Thoracic Applications of Spectral CT Scan.

TOPIC IMPORTANCE: Thoracic imaging with CT scan has become an essential component in the evaluation of respiratory and thoracic diseases. Providers have historically used conventional single-energy CT; however, prevalence of dual-energy CT (DECT) is increasing, and as such, it is important for thoracic physicians to recognize the utility and limitations of this technology. REVIEW FINDINGS: The technical aspects of DECT are presented, and practical approaches to using DECT are provided. Imaging at multiple energy spectra allows for postprocessing of the data and the possibility of creating multiple distinct image reconstructions based on the clinical question being asked. The data regarding utility of DECT in pulmonary vascular disorders, ventilatory defects, and thoracic oncology are presented. A pictorial essay is provided to give examples of the strengths associated with DECT. SUMMARY: DECT has been most heavily studied in chronic thromboembolic pulmonary hypertension; however, it is increasingly being used across a wide spectrum of thoracic diseases. DECT combines morphologic and functional assessments in a single imaging acquisition, providing clinicians with a powerful diagnostic tool. Its role in the evaluation and treatment of thoracic diseases will likely continue to expand in the coming years as clinicians become more experienced with the technology.

Prevalence and patient risk factors for pneumothorax in COVID-19 and in influenza pneumonia: a nationwide comparative analysis.

Background: Pneumothorax is a rare but deadly complication in patients who require mechanical ventilation. As with any condition associated with acute respiratory distress syndrome (ARDS), coronavirus disease 2019 (COVID-19) is known to be associated with pneumothorax. However, in the literature, comparative data on the risk factors for pneumothorax in COVID-19 and other diseases like influenza are limited. The aim of this study is to determine the prevalence and risk factors for pneumothorax in hospitalized COVID-19 patients and compare them with influenza pneumonia patients. Methods: This study is a retrospective analysis of the National Inpatient Sample (NIS) 2020 database cohort. Univariate and multivariate logistic regression were used to identify the prevalence and risk factors for pneumothorax in COVID-19 patients and compared with the risk of pneumothorax in influenza patients. Results: The NIS 2020 database includes 1,608,980 hospitalizations of COVID-19 patients, of which 22,545 [95% confidence interval (CI): 21,491-23,598] (1.4%) developed pneumothorax. On multivariate analysis, factors associated with pneumothorax in COVID-19 included patient age of 41-64 years; male sex; Hispanics, Native Americans, and other races; hospitals with large-bed size; privately owned hospitals; urban teaching hospitals; hospitals in the southern United States (US); stroke; malnutrition; chronic obstructive pulmonary disease (COPD); bronchiectasis; pulmonary fibrosis; liver disease; non-invasive and invasive ventilation; and extracorporeal membrane oxygenation (ECMO). Of 184,980 influenza patients, 1,630 (95% CI: 1,448-1,811) (0.88%) developed pneumothorax. The prevalence of pneumothorax was higher (1.4%) in COVID-19 patients compared to patients with influenza pneumonia (0.88%). Conclusions: COVID-19 patients who develop pneumothorax have a poor prognosis. Several risk factors for the development of pneumothorax were identified. Patients with these risk factors should be prioritized in applying evidence-based guidelines to prevent pneumothorax.

A predictive model for lung cancer screening nonadherence in a community setting health-care network.

BACKGROUND: Lung cancer screening (LCS) decreases lung cancer mortality. However, its benefit may be limited by nonadherence to screening. Although factors associated with LCS nonadherence have been identified, to the best of our knowledge, no predictive models have been developed to predict LCS nonadherence. The purpose of this study was to develop a predictive model leveraging a machine learning model to predict LCS nonadherence risk. METHODS: A retrospective cohort of patients who enrolled in our LCS program between 2015 and 2018 was used to develop a model to predict the risk of nonadherence to annual LCS after the baseline examination. Clinical and demographic data were used to fit logistic regression, random forest, and gradient-boosting models that were internally validated on the basis of accuracy and area under the receiver operating curve. RESULTS: A total of 1875 individuals with baseline LCS were included in the analysis, with 1264 (67.4%) as nonadherent. Nonadherence was defined on the basis of baseline chest computed tomography (CT) findings. Clinical and demographic predictors were used on the basis of availability and statistical significance. The gradient-boosting model had the highest area under the receiver operating curve (0.89, 95% confidence interval = 0.87 to 0.90), with a mean accuracy of 0.82. Referral specialty, insurance type, and baseline Lung CT Screening Reporting & Data System (LungRADS) score were the best predictors of nonadherence to LCS. CONCLUSIONS: We developed a machine learning model using readily available clinical and demographic data to predict LCS nonadherence with high accuracy and discrimination. After further prospective validation, this model can be used to identify patients for interventions to improve LCS adherence and decrease lung cancer burden.

Lung Imaging in COPD Part 1: Clinical Usefulness.

COPD is a condition characterized by chronic airflow obstruction resulting from chronic bronchitis, emphysema, or both. The clinical picture is usually progressive with respiratory symptoms such as exertional dyspnea and chronic cough. For many years, spirometry was used to establish a diagnosis of COPD. Recent advancements in imaging techniques allow quantitative and qualitative analysis of the lung parenchyma as well as related airways and vascular and extrapulmonary manifestations of COPD. These imaging methods may allow prognostication of disease and shed light on the efficacy of pharmacologic and nonpharmacologic interventions. This is the first of a two-part series of articles on the usefulness of imaging methods in COPD, and it highlights useful information that clinicians can obtain from these imaging studies to make more accurate diagnosis and therapeutic decisions.

Lung Imaging in COPD Part 2: Emerging Concepts.

The diagnosis, prognostication, and differentiation of phenotypes of COPD can be facilitated by CT scan imaging of the chest. CT scan imaging of the chest is a prerequisite for lung volume reduction surgery and lung transplantation. Quantitative analysis can be used to evaluate extent of disease progression. Evolving imaging techniques include micro-CT scan, ultra-high-resolution and photon-counting CT scan imaging, and MRI. Potential advantages of these newer techniques include improved resolution, prediction of reversibility, and obviation of radiation exposure. This article discusses important emerging techniques in imaging patients with COPD. The clinical usefulness of these emerging techniques as they stand today are tabulated for the benefit of the practicing pulmonologist.

Factors Associated With Lung Cancer Screening Adherence Among Patients With Negative Baseline CT Results in a Community Health Care Setting.

PURPOSE: Lung cancer screening (LCS) decreases lung cancer mortality; however, that reduction depends upon screening adherence. The purpose of this study was to determine factors associated with adherence rate for LCS among patients with negative baseline CT results in a multi-integrated health care network. METHODS: A retrospective analysis was conducted among patients with negative baseline CT results in a multi-integrated health care network LCS program between January 2015 and January 2020. The two outcomes were adherence for the first and second subsequent LCS studies. Negative baseline result was defined as a Lung CT Screening Reporting and Data System score 0, 1, or 2. Adherence was defined as undergoing a follow-up study within 11 to 15 months of a prior scan. Multivariable logistic regression was used to determine significant predictors of adherence, adjusting for patient demographics, median household income (on the basis of geocoding ZIP codes from the US Census Bureau), smoking history, screening sites, and provider specialty. RESULTS: A total of 30.7% (512 of 1,668) and 16.3% (270 of 1,660) of patients were adherent for the first two annual subsequent screens, respectively. First-year adherence was higher among former smokers and varied by site and provider specialty. Second-year adherence was higher among former smokers and varied by site, provider specialty, and pack-years smoked. CONCLUSIONS: Adherence to LCS in a multihospital integrated health care network was poor and even lower at year 2. The identified factors associated with adherence may serve as targets to increase LCS adherence and decrease lung cancer mortality.

Algorithmic Approach to the Diagnosis of Organizing Pneumonia: A Correlation of Clinical, Radiologic, and Pathologic Features.

Organizing pneumonia (OP), characterized histopathologically by patchy filling of alveoli and bronchioles by loose plugs of connective tissue, may be seen in a variety of conditions. These include but are not limited to after an infection, drug reactions, radiation therapy, and collagen vascular diseases. When a specific cause is responsible for this entity, it is referred to as "secondary OP." When an extensive search fails to reveal a cause, it is referred to as "cryptogenic OP" (previously called "bronchiolitis obliterans with OP"), which is a clinical, radiologic, and pathologic entity classified as an interstitial lung disease. The clinical presentation of OP often mimics that of other disorders, such as infection and cancer, which can result in a delay in diagnosis and inappropriate management of the underlying disease. The radiographic presentation of OP is polymorphous but often has subpleural consolidations with air bronchograms or solitary or multiple nodules, which can wax and wane. Diagnosis of OP sometimes requires histopathologic confirmation and exclusion of other possible causes. Treatment usually requires a prolonged steroid course, and disease relapse is common. The aim of this article is to summarize the clinical, radiographic, and histologic presentations of this disease and to provide a practical diagnostic algorithmic approach incorporating clinical history and characteristic imaging patterns.

Imaging algorithm for COVID-19: A practical approach.

The global pandemic of COVID-19 pneumonia caused by the novel coronavirus (SARS-CoV-2) has strained healthcare resources across the world with emerging challenges of mass testing, resource allocation and management. While reverse transcriptase-polymerase chain reaction (RT-PCR) test is the most commonly utilized test and considered the current gold standard for diagnosis, the role of chest imaging has been highlighted by several studies demonstrating high sensitivity of computed tomography (CT). Many have suggested using CT chest as a first-line screening tool for the diagnosis of COVID-19. However, with advancement of laboratory testing and challenges in obtaining a CT scan without significant risk to healthcare providers, the role of imaging in diagnosis has been questioned. Several imaging societies have released consensus statements and guidelines on utilizing imaging resources and optimal reporting. In this review, we highlight the current evidence on various modalities in thoracic imaging for the diagnosis of COVID-19 and describe an algorithm on how to use these resources in an optimal fashion in accordance with the guidelines and statements released by major imaging societies.

The Usefulness of Chest CT Imaging in Patients With Suspected or Diagnosed COVID-19: A Review of Literature.

The COVID-19 pandemic has had devastating medical and economic consequences globally. The severity of COVID-19 is related, in a large measure, to the extent of pulmonary involvement. The role of chest CT imaging in the management of patients with COVID-19 has evolved since the onset of the pandemic. Specifically, the description of CT scan findings, use of chest CT imaging in various acute and subacute settings, and its usefulness in predicting chronic disease have been defined better. We performed a review of published data on CT scans in patients with COVID-19. A summary of the range of imaging findings, from typical to less common abnormalities, is provided. Familiarity with these findings may facilitate the diagnosis and management of this disease. A comparison of sensitivity and specificity of chest CT imaging with reverse-transcriptase polymerase chain reaction testing highlights the potential role of CT imaging in difficult-to-diagnose cases of COVID-19. The usefulness of CT imaging to assess prognosis, to guide management, and to identify acute pulmonary complications associated with SARS-CoV-2 infection is highlighted. Beyond the acute stage, it is important for clinicians to recognize pulmonary parenchymal abnormalities, progressive fibrotic lung disease, and vascular changes that may be responsible for persistent respiratory symptoms. A large collection of multi-institutional images were included to elucidate the CT scan findings described.

Impact of Timing of Tocilizumab Use in Hospitalized Patients With SARS-CoV-2 Infection.

BACKGROUND: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to be a global challenge due to the lack of definitive treatment strategies. We sought to determine the efficacy of early administration of anti-interleukin 6 therapy in reducing hospital mortality and progression to mechanical ventilation. METHODS: This was a retrospective chart review of 11,512 patients infected with SARS-CoV-2 who were admitted to a New York health system from March to May 2020. Tocilizumab was administered to subjects at the nasal cannula level of oxygen support to maintain an oxygen saturation of >88%. The Charlson comorbidity index was used as an objective assessment of the burden of comorbidities to predict 10-year mortality. The primary outcome of interest was hospital mortality. Secondary outcomes were progression to mechanical ventilation; the prevalence of venous thromboembolism and renal failure; and the change in C-reactive protein, D-dimer, and ferritin levels after tocilizumab administration. Propensity score matching by using a 1:2 protocol was used to match the tocilizumab and non-tocilizumab groups to minimize selection bias. The groups were matched on baseline demographic characteristics, including age, sex, and body mass index; Charlson comorbidity index score; laboratory markers, including ferritin, D-dimer, lactate dehydrogenase, and C-reactive protein values; and the maximum oxygen requirement at the time of tocilizumab administration. Mortality outcomes were evaluated based on the level of oxygen requirement and the day of hospitalization at the time of tocilizumab administration. RESULTS: The overall hospital mortality was significantly reduced in the tocilizumab group when tocilizumab was administered at the nasal cannula level (10.4% vs 22.0%; P = .002). In subjects who received tocilizumab at the nasal cannula level, the progression to mechanical ventilation was reduced versus subjects who were initially on higher levels of oxygen support (6.3% vs 18.7%; P < .001). There was no improvement in mortality when tocilizumab was given at the time of requiring non-rebreather, high-flow nasal cannula, noninvasive ventilator, or invasive ventilator. CONCLUSIONS: Early use of anti-interleukin 6 therapy may be associated with improved hospital mortality and reduction in progression to more severe coronavirus disease 2019.

Chest CT Diagnosis and Clinical Management of Drug-Related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper From the Fleischner Society.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others.

High-Flow, Noninvasive Ventilation and Awake (Nonintubation) Proning in Patients With Coronavirus Disease 2019 With Respiratory Failure.

The coronavirus disease 2019 pandemic will be remembered for the rapidity with which it spread, the morbidity and mortality associated with it, and the paucity of evidence-based management guidelines. One of the major concerns of hospitals was to limit spread of infection to health-care workers. Because the virus is spread mainly by respiratory droplets and aerosolized particles, procedures that may potentially disperse viral particles, the so-called "aerosol-generating procedures" were avoided whenever possible. Included in this category were noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and awake (nonintubated) proning. Accordingly, at many health-care facilities, patients who had increasing oxygen requirements were emergently intubated and mechanically ventilated to avoid exposure to aerosol-generating procedures. With experience, physicians realized that mortality of invasively ventilated patients was high and it was not easy to extubate many of these patients. This raised the concern that HFNC and NIV were being underutilized to avoid intubation and to facilitate extubation. In this article, we attempt to separate fact from fiction and perception from reality pertaining to the aerosol dispersion with NIV, HFNC, and awake proning. We describe precautions that hospitals and health-care providers must take to mitigate risks with these devices. Finally, we take a practical approach in describing how we use the three techniques, including the common indications, contraindications, and practical aspects of application.

An Algorithmic Approach to the Interpretation of Diffuse Lung Disease on Chest CT Imaging: A Theory of Almost Everything.

We propose an algorithmic approach to the interpretation of diffuse lung disease on high-resolution CT. Following an initial review of pertinent lung anatomy, the following steps are included. Step 1: a preliminary review of available chest radiographs, including the "scanogram" obtained at the time of the CT examination. Step 2: a review of optimal methods of data acquisition and reconstruction, emphasizing the need for contiguous high-resolution images throughout the entire thorax. Step 3: initial uninterrupted scrolling of contiguous high-resolution images throughout the chest to establish the quality of examination as well as an overview of the presence and extent of disease. Step 4: determination of one of three predominant categories - primarily reticular disease, nodular disease, or diseases associated with diffuse alteration in lung density. Based on this determination, one of the three following Steps are followed: Step 5: evaluation of cases primarily involving diffuse lung reticulation; Step 6: evaluation of cases primarily resulting in diffuse lung nodules; and Step 7: evaluation of cases with diffuse alterations in lung density including those with diffusely diminished lung density vs those with heterogenous or diffusely increased lung density, respectively. It is anticipated that this algorithmic approach will substantially enhance initial interpretations of a wide range of pulmonary disease.

High-resolution CT features distinguishing usual interstitial pneumonia pattern in chronic hypersensitivity pneumonitis from those with idiopathic pulmonary fibrosis.

PURPOSE: Radiologic diagnosis of chronic hypersensitivity pneumonitis (CHP) presenting a usual interstitial pneumonia (UIP) pattern is challenging. The aim of this study was to identify the high-resolution CT (HRCT) findings which are useful to discriminate CHP-UIP from idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: This study included 49 patients with well-established bird-related CHP-UIP, histologically confirmed, and 49 patients with IPF. Two groups of observers independently assessed HRCT, evaluated the extent of each abnormal HRCT finding. When their radiological diagnosis was CHP-UIP, they noted the HRCT findings inconsistent with IPF. RESULTS: Correct CT diagnoses were made in 79% of CHP-UIP and 53% of IPF. Although no apparent difference was seen in the extent of each HRCT finding, upper or mid-lung predominance, extensive ground-glass abnormality, and profuse micronodules were more frequently pointed out as inconsistent findings in CHP-UIP than IPF (p = 0.007, 0.010, 0.001, respectively). On regression analysis, profuse micronodules [OR 13.34 (2.85-62.37); p = 0.001] and upper or mid-lung predominance of findings [OR 2.86 (1.16-7.01); p = 0.022] remained as variables in the equation. CONCLUSION: In this cohort, some IPF cases were misdiagnosed as CHP-UIP. Profuse micronodules and upper or mid-lung predominance are important clues for the differentiation of CHP-UIP from IPF.

Association Between Inhaled Corticosteroids and Tracheobronchomalacia.

OBJECTIVE: The aim of this study was to assess any association between use of inhaled corticosteroids (ICS) and tracheobronchomalacia (TBM). METHODS: This study was a retrospective analysis of patients with asthma and COPD, with and without TBM. Patients were diagnosed with TBM on the basis of CT imaging, flexible bronchoscopy, or both. Patients were deemed to be on ICS if they had been receiving treatment for at least 3 months. Simple logistic regression models were used to assess the association between TBM status and each proposed factor. A multivariable logistic regression model was used to assess the association between TBM and steroid dose. RESULTS: A total of 463 patients with COPD (n = 153) and asthma (n = 310) were studied. In multivariate analysis, the odds of TBM were 3.5 times higher in patients on high-dose steroids compared with patients not on steroids (OR, 3.5; 95% CI, 1.4-8.5; P = .007). Age (P < .0001), presence of gastroesophageal reflux disease (P < .0001), use of long-acting muscarinic antagonists (P < .0001), and type of pulmonary disease (P = .002) were also associated with TBM. In patients using ICS, the odds of having TBM were 2.9 times greater in patients on high-dose inhaled steroids compared with those on low-dose inhaled steroids (OR, 2.9; 95% CI, 1.2-7.1; P = .02). Age (P = .003), presence of gastroesophageal reflux disease (P = .002), use of long-acting muscarinic antagonists (P = .004), type of ICS (P = .04), and number of months on ICS (P < .0001) were all associated with TBM. CONCLUSIONS: There was a significant association between ICS use in higher doses for a longer duration of time with TBM. Prospective randomized controlled trials are needed to show causality of this observed association.