Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Utility of Bronchoalveolar Lavage for the Diagnosis and Management of COVID-19 in Patients With Cancer.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) on nasopharyngeal swab (NPS), remains the most reliable and practical test to diagnose coronavirus disease 2019 (COVID-19). Current literature is sparse regarding the rates of discordance between NPS and bronchoalveolar lavage (BAL) in patients with cancer. METHODS: We conducted a retrospective cohort study of adult patients with cancer who had BAL samples tested for SARS-CoV-2 at a comprehensive cancer center. Patients without NPS PCR for SARS-CoV-2 before BAL were excluded. RESULTS: In a cohort of 345 patients, 12% and 17% tested positive for SARS-CoV-2 on NPS and BAL, respectively. There was a 6.3% NPS-/BAL+ discordance rate and a 9.5% NPS+/BAL- discordance rate. Patients with lymphoma (adjusted odds ratio [aOR] = 4.06; P = .007) and Hispanic patients (aOR = 3.76; P = .009) were more likely to have NPS-/BAL+ discordance on multivariate analysis. Among patients with NPS- /BAL- for SARS-CoV-2, an alternate infectious (23%) and a noninfectious etiology (16%) were identified in BAL. CONCLUSIONS: Our discordance rates between NPS and BAL were sufficient to recommend BAL in certain patients with cancer with a high clinical suspicion of COVID-19. BAL has value in identifying alternative etiologies of illness in patients with suspected or confirmed COVID-19.

Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience.

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. RESULTS: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). CONCLUSION: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.

Immunotherapy-related pneumonitis and the synergic impact of thoracic radiation and preexisting interstitial lung disease.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) are the frontline of therapy for most cancers. Although ICIs are sometimes considered to be less harmful than systemic chemotherapies, ICIs may cause immune-related adverse events, which are cases of off-target inflammation in healthy tissues. Pneumonitis, an immune-related adverse event, is the leading cause of therapy-related mortality with ICIs. The aim of this review is to discuss how preexisting interstitial lung disease (ILD) and thoracic radiation increase the risk for ICI-pneumonitis. We discuss potential mechanisms of lung injury and how pneumonitis may impact cancer treatments. RECENT FINDINGS: Preexisting ILD and thoracic radiation are major risk factors for ICI-pneumonitis. The mechanisms of injury are still not fully understood but may involve the same inflammatory and profibrotic cytokines as those seen in sporadic ILD. Thoracic radiation increases the risk for ICI-pneumonitis and may synergize with preexisting ILD to worsen toxicity. SUMMARY: Preexisting ILD and thoracic radiation may increase the risk for the future development of ICI-pneumonitis. However, while these should not preclude potentially life-saving immunotherapy, in some cases, an alternative treatment strategy may be advisable. A multidisciplinary approach is required involving oncologists, pulmonologists, and radiation oncologists to guide in the selection of cancer treatment and in the diagnosis and treatment of pneumonitis.

Machine Learning Models for the Identification of Prognostic and Predictive Cancer Biomarkers: A Systematic Review.

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome of cancer, regardless of treatment, and a predictive biomarker predicts the effectiveness of a therapeutic intervention. Misclassifying a prognostic biomarker as predictive (or vice versa) can have serious financial and personal consequences for patients. To address this issue, various statistical and machine learning approaches have been developed. The aim of this study is to present an in-depth analysis of recent advancements, trends, challenges, and future prospects in biomarker identification. A systematic search was conducted using PubMed to identify relevant studies published between 2017 and 2023. The selected studies were analyzed to better understand the concept of biomarker identification, evaluate machine learning methods, assess the level of research activity, and highlight the application of these methods in cancer research and treatment. Furthermore, existing obstacles and concerns are discussed to identify prospective research areas. We believe that this review will serve as a valuable resource for researchers, providing insights into the methods and approaches used in biomarker discovery and identifying future research opportunities.

Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. METHODS: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models. RESULTS: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37). CONCLUSIONS: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality. LAY SUMMARY: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

Quantitative CT Characteristics of Cluster Phenotypes in the Severe Asthma Research Program Cohorts.

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Imaging of Immune Checkpoint Inhibitor Immunotherapy for Non-Small Cell Lung Cancer.

The normal immune system identifies and eliminates precancerous and cancerous cells. However, tumors can develop immune resistance mechanisms, one of which involves the exploitation of pathways, termed immune checkpoints, that normally suppress T-cell function. The goal of immune checkpoint inhibitor (ICI) immunotherapy is to boost T-cell-mediated immunity to mount a more effective attack on cancer cells. ICIs have changed the treatment landscape of advanced non-small cell lung cancer (NSCLC), and numerous ICIs have now been approved as first-line treatments for NSCLC by the U.S. Food and Drug Administration. ICIs can cause atypical response patterns such as pseudoprogression, whereby the tumor burden initially increases but then decreases. Therefore, response criteria have been developed specifically for patients receiving immunotherapy. Because ICIs activate the immune system, they can lead to inflammatory side effects, termed immune-related adverse events (irAEs). Usually occurring within weeks to months after the start of therapy, irAEs range from asymptomatic abnormal laboratory results to life-threatening conditions such as encephalitis, pneumonitis, myocarditis, hepatitis, and colitis. It is important to be aware of the imaging appearances of the various irAEs to avoid misinterpreting them as metastatic disease, progressive disease, or infection. The basic principles of ICI therapy; indications for ICI therapy in the setting of NSCLC; response assessment and atypical response patterns of ICI therapy, as compared with conventional chemotherapy; and the spectrum of irAEs seen at imaging are reviewed. An invited commentary by Nishino is available online. ©RSNA, 2022.

Nucleic Acid-based Testing for Noninfluenza Viral Pathogens in Adults with Suspected Community-acquired Pneumonia. An Official American Thoracic Society Clinical Practice Guideline.

Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP).Methods: A multidisciplinary panel developed a Population-Intervention-Comparison-Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid-based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review.Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid-based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: Results from SARP-3.

BACKGROUND: Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. OBJECTIVES: We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. METHODS: We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity. RESULTS: Greater baseline wall area percent (ß = -0.15 [95% CI = -0.26 to -0.05]; P < .01), hyperinflation percent (ß = -0.25 [95% CI = -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal ß = 10.64 [95% CI = 3.79-17.49]; P < .01; posterior-anterior ß = -9.14, [95% CI = -15.49 to -2.78]; P < .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P < .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires. CONCLUSIONS: Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

Pulmonary Function Testing in Patients with Tracheostomies: Feasibility and Technical Considerations.

PURPOSE: Pulmonary function testing (PFT) in patients with tracheostomies has been perceived as difficult to perform and clinically unreliable. We studied the feasibility, quality, repeatability and clinical significance of PFT. METHODS: Patients with tracheostomies that underwent PFT from January 1, 2010 to February 29, 2012 were identified. Clinical history and PFT data were reviewed retrospectively. RESULTS: Fifty patients (88% men) were identified. Forty-seven (94%) patients were able to perform PFT. Acceptable repeatability was obtained for FVC in 39 (83%) and for FEV1 in 41 (87%). Patients with tracheostomies showed difficulty in meeting ATS end-of-test criteria; only 9 (19%) met plateau criteria and 25 (53%) had exhalation times of greater than 6 s. Obstructive pattern was observed in 30 (64%) and restrictive pattern in 9 (19%). DLCO measurements were attempted in 43 patients and satisfactorily obtained in 34 (79%). CONCLUSIONS: PFT can be performed with reliability in patients with tracheostomies, and they are useful for detecting and classifying types of lung dysfunction.

Pulmonary Toxicities of Immunotherapy.

Immune checkpoint inhibitors are a form of immunotherapy that are increasingly being used in a wide variety of cancers. Immune-related adverse events (irAEs) pose a major challenge in the treatment of cancer patients. Pneumonitis, the most common lung irAE, can cause significant disruptions in the treatment of cancer and may be life-threatening. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.

Complications following symptom-limited thoracentesis using suction.

BACKGROUND: Thoracentesis using suction is perceived to have increased risk of complications, including pneumothorax and re-expansion pulmonary oedema (REPO). Current guidelines recommend limiting drainage to 1.5 L to avoid REPO. Our purpose was to examine the incidence of complications with symptom-limited drainage of pleural fluid using suction and identify risk factors for REPO. METHODS: A retrospective cohort study of all adult patients who underwent symptom-limited thoracentesis using suction at our institution between January 1, 2004 and August 31, 2018 was performed, and a total of 10 344 thoracenteses were included. RESULTS: Pleural fluid ≥1.5 L was removed in 19% of the procedures. Thoracentesis was stopped due to chest discomfort (39%), complete drainage of fluid (37%) and persistent cough (13%). Pneumothorax based on chest radiography was detected in 3.98%, but only 0.28% required intervention. The incidence of REPO was 0.08%. The incidence of REPO increased with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥3 compounded with ≥1.5 L (0.04-0.54%; 95% CI 0.13-2.06 L). Thoracentesis in those with ipsilateral mediastinal shift did not increase complications, but less fluid was removed (p<0.01). CONCLUSIONS: Symptom-limited thoracentesis using suction is safe even with large volumes. Pneumothorax requiring intervention and REPO are both rare. There were no increased procedural complications in those with ipsilateral mediastinal shift. REPO increased with poor ECOG PS and drainage ≥1.5 L. Symptom-limited drainage using suction without pleural manometry is safe.

Immune-Related Adverse Events: Pneumonitis.

Checkpoint inhibitors are part of the family of immunotherapies and are increasingly being used in a wide variety of cancers. Immune-related adverse events pose a major challenge in the treatment of cancer patients. Pneumonitis is a rare immune-related adverse event that presents in distinct patterns. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.

Pulmonary Impairment after Respiratory Viral Infections Is Associated with High Mortality in Allogeneic Hematopoietic Cell Transplant Recipients.

Pulmonary impairment predicts increased mortality in many settings, and respiratory viral infection (RVI) causes considerable morbidity and mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT). We hypothesized that pulmonary impairment after RVI, defined as a decline of forced expiratory volume in 1 second values by ≥10%, may identify allo-HCT recipients at high risk for mortality. We studied all allo-HCT recipients at our institution who had RVI with respiratory syncytial virus, parainfluenza virus, or influenza from 2004 to 2013 and had pre-RVI and post-RVI pulmonary function tests. We used competing risk regression models to identify risk factors for 2-year nonrelapse mortality (NRM) as the primary outcome after RVI and relapse-related mortality as a competing risk. From 223 eligible patients, pulmonary impairment after RVI was associated with over a 3-fold increase in 2-year NRM (pulmonary impairment, 25.3%; no impairment, 7.4%; univariate subhazard ratio [SHR], 3.9; 95% confidence interval [CI], 1.9 to 8.1; P < .001). After adjusting for age and systemic steroid use, pulmonary impairment after RVI was still associated with increased 2-year NRM (SHR, 3.3 [95% CI, 1.6 to 6.9]; P = .002). After adjustment for race and graft-versus-host disease (GVHD) prophylaxis, chronic GVHD at the time of RVI (odds ratio [OR], 2.8 [95% CI, 1.4 to 5.4]; p = .003) and lymphopenia (OR, 2.2 [95% CI, 1.1 to 4.2]; P = .02) were associated with increased odds of pulmonary impairment, whereas use of nonmyeloablative conditioning was associated with reduced odds of pulmonary impairment (OR, .4 [95% CI, .2 to .8]; P = .006). In allo-HCT recipients with RVIs, pulmonary impairment after RVI is associated with high NRM at 2years.

Refinement of estimates of mortality risk using the Radiologic Severity Index in hematologic malignancy patients with respiratory syncytial virus infection.

BACKGROUND: Immunocompromised hematologic malignancy (HM) patients experience high mortality after respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI). We measured radiologic severity to determine whether it could improve the performance of 60-day mortality models based only upon immunodeficiency severity. METHODS: We studied 155 HM patients, including 84 hematopoietic cell transplant recipients, who developed RSV LRTI from 2001 to 2013. We measured immunodeficiency using lymphopenia (lymphocyte count <200 cells/mm3 ), Immunodeficiency Severity Index (ISI), and Severe Immunodeficiency (SID) criteria. Radiologic severity was measured by the Radiologic Severity Index (RSI, range 0-72) at time of LRTI (baseline-RSI) and peak severity (peak-RSI). Delta-RSI was defined as the difference between baseline-RSI and peak-RSI. We used logistic regression models to measure the association of immunodeficiency and RSI with 60-day all-cause mortality, and measured model discrimination using areas under the receiver-operating characteristics curves, calibration using Brier scores, and explained variance using pseudo-R2 values. RESULTS: Forty-one patients died within 60 days of RSV LRTI. Severe immunodeficiency was associated with higher mortality. Peak-RSI (odds ratio [OR] 1.06/point, 95% confidence interval [CI] 1.04-1.08), and delta-RSI (OR 1.07/point, 95% CI 1.05-1.10) were associated with 60-day mortality after RSV LRTI, but not baseline-RSI. Addition of peak-RSI or delta-RSI to baseline immunodeficiency improved the discrimination, calibration, and explained variance (P < 0.001) of 60-day mortality models. CONCLUSIONS: Although baseline immunodeficiency in HM patients helps predict 60-day mortality after RSV LRTI, mortality risk estimates can be further refined by also measuring LRTI progression using RSI. RSI is well-suited as a marker of LRTI severity in RSV infection.

A Design-Based Stereologic Method to Quantify the Tissue Changes Associated with a Novel Drug-Eluting Tracheobronchial Stent.

BACKGROUND: Granulation tissue is a common complication of airway stenting, but no published methods can quantify the volume and type of tissue that develops. OBJECTIVE: To use design-based stereology to quantify changes in tissue volume and type associated with airway stenting. METHODS: We compared drug-eluting stents (DES) filled with gendine to standard silicone stents in pigs in an assessor-blinded randomized trial. Tracheal stents were placed via rigid bronchoscopy. After 1 month, animals were euthanized and necropsies were performed. Antimicrobial effects of the DES were assessed in trachea tissue samples, on the DES surface, and with residual gel from the DES reservoir. Tracheal thickness was measured using orthogonal intercepts. Design-based stereology was used to quantify the volume density of tissues using a point-counting method. The volume of each tissue was normalized to cartilage volume, which is unaffected by stenting. RESULTS: Pigs were randomized to DES (n = 36) or control stents (n = 9). The drug was successfully eluted from the DES, and the stent surface showed antibacterial activity. DES and controls did not differ in tissue microbiology, tracheal thickness, or granulation tissue volume. Compared to nonstented controls, stented airways demonstrated a 110% increase in soft-tissue volume (p = 0.005). Submucosal connective tissue (118%; p < 0.0001), epithelium (70%; p < 0.0001), submucosal glands (47%; p = 0.001), and smooth muscle (41%; p < 0.0001) increased in volume. CONCLUSION: Stenting doubles the volume of soft tissue in the trachea. Design-based stereology can quantify the tissue changes associated with airway stenting.

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept.

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted.