Multi-Omic Biomarkers Improve Indeterminate Pulmonary Nodule Malignancy Risk Assessment.

The clinical management of patients with indeterminate pulmonary nodules is associated with unintended harm to patients and better methods are required to more precisely quantify lung cancer risk in this group. Here, we combine multiple noninvasive approaches to more accurately identify lung cancer in indeterminate pulmonary nodules. We analyzed 94 quantitative radiomic imaging features and 41 qualitative semantic imaging variables with molecular biomarkers from blood derived from an antibody-based microarray platform that determines protein, cancer-specific glycan, and autoantibody-antigen complex content with high sensitivity. From these datasets, we created a PSR (plasma, semantic, radiomic) risk prediction model comprising nine blood-based and imaging biomarkers with an area under the receiver operating curve (AUROC) of 0.964 that when tested in a second, independent cohort yielded an AUROC of 0.846. Incorporating known clinical risk factors (age, gender, and smoking pack years) for lung cancer into the PSR model improved the AUROC to 0.897 in the second cohort and was more accurate than a well-characterized clinical risk prediction model (AUROC = 0.802). Our findings support the use of a multi-omics approach to guide the clinical management of indeterminate pulmonary nodules.

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Chemokines, soluble PD-L1, and immune cell hyporesponsiveness are distinct features of SARS-CoV-2 critical illness.

Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both "cytokine storm" and "immune suppression." However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive (n = 204) or -negative (n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients (P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.

Radiographic Findings and Association With Clinical Severity and Outcomes in Critically Ill Patients With COVID-19.

PURPOSE: To describe evolution and severity of radiographic findings and assess association with disease severity and outcomes in critically ill COVID-19 patients. MATERIALS AND METHODS: This retrospective study included 62 COVID-19 patients admitted to the intensive care unit (ICU). Clinical data was obtained from electronic medical records. A total of 270 chest radiographs were reviewed and qualitatively scored (CXR score) using a severity scale of 0-30. Radiographic findings were correlated with clinical severity and outcome. RESULTS: The CXR score increases from a median initial score of 10 at hospital presentation to the median peak CXR score of 18 within a median time of 4 days after hospitalization, and then slowly decreases to a median last CXR score of 15 in a median time of 12 days after hospitalization. The initial and peak CXR score was independently associated with invasive MV after adjusting for age, gender, body mass index, smoking, and comorbidities (Initial, odds ratio [OR]: 2.11 per 5-point increase, confidence interval [CI] 1.35-3.32, P= 0.001; Peak, OR: 2.50 per 5-point increase, CI 1.48-4.22, P= 0.001). Peak CXR scores were also independently associated with vasopressor usage (OR: 2.28 per 5-point increase, CI 1.30-3.98, P= 0.004). Peak CXR scores strongly correlated with the duration of invasive MV (Rho = 0.62, P< 0.001), while the initial CXR score (Rho = 0.26) and the peak CXR score (Rho = 0.27) correlated weakly with the sequential organ failure assessment score. No statistically significant associations were found between radiographic findings and mortality. CONCLUSIONS: Evolution of radiographic features indicates rapid disease progression and correlate with requirement for invasive MV or vasopressors but not mortality, which suggests potential nonpulmonary pathways to death in COVID-19.

Combining Ivacaftor and Intensive Antibiotics Achieves Limited Clearance of Cystic Fibrosis Infections.

Drugs called CFTR modulators improve the physiologic defect underlying cystic fibrosis (CF) and alleviate many disease manifestations. However, studies to date indicate that chronic lung infections that are responsible for most disease-related mortality generally persist. Here, we investigated whether combining the CFTR modulator ivacaftor with an intensive 3.5-month antibiotic course could clear chronic Pseudomonas aeruginosa or Staphylococcus aureus lung infections in subjects with R117H-CFTR, who are highly ivacaftor-responsive. Ivacaftor alone improved CFTR activity, and lung function and inflammation within 48 h, and reduced P. aeruginosa and S. aureus pathogen density by ∼10-fold within a week. Antibiotics produced an additional ∼10-fold reduction in pathogen density, but this reduction was transient in subjects who remained infected. Only 1/5 P. aeruginosa-infected and 1/7 S. aureus-infected subjects became persistently culture-negative after the combined treatment. Subjects appearing to clear infection did not have particularly favorable baseline lung function or inflammation, pathogen density or antibiotic susceptibility, or bronchiectasis scores on CT scans, but they did have remarkably low sweat chloride values before and after ivacaftor. All persistently P. aeruginosa-positive subjects remained infected by their pretreatment strain, whereas subjects persistently S. aureus-positive frequently lost and gained strains. This work suggests chronic CF infections may resist eradication despite marked and rapid modulator-induced improvements in lung infection and inflammation parameters and aggressive antibiotic treatment. IMPORTANCE Recent work shows that people with CF and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy. We tested the approach of combining modulators and intensive antibiotics in rapid succession and found that while few subjects cleared their infections, combined treatment appeared most effective in subjects with the highest CFTR activity. These findings highlight challenges that remain to improve the health of people with CF.

Outcomes of Hematopoietic Cell Transplantation in Patients with Mixed Response to Pretransplantation Treatment of Confirmed or Suspected Invasive Fungal Infection.

Patients with hematologic malignancy or bone marrow failure are typically required to achieve radiographic improvement or stabilization of invasive fungal infection (IFI) before hematopoietic cell transplantation (HCT) owing to a concern for progression before engraftment. Refractory IFI with a mixture of improvement and progression on serial imaging (ie, mixed response) poses a clinical dilemma, because a delay in HCT may allow for a hematologic relapse or other complications. Furthermore, HCT itself may yield the immune reconstitution necessary for clearance of infection. We sought to describe the characteristics and outcomes of patients who underwent HCT with mixed response IFI. We performed a chart review of all patients who underwent HCT between 2014 and 2020 in whom imaging within 6 weeks before HCT indicated a mixed response to treatment of a diagnosed IFI. Fourteen patients had evidence of a mixed response in low-to-moderate burden of diagnosed IFI by imaging before HCT, including 9 with pulmonary aspergillosis, 2 with hepatosplenic candidiasis (1 also with aspergillosis), and 4 with pulmonary nodules of presumed fungal etiology. Five had refractory severe neutropenia at evaluation for HCT (median, 95 days). All 14 patients showed radiographic stability or improvement in imaging following engraftment; no IFI-related surgeries were required, and no IFI-related deaths occurred. For patients without relapse who underwent HCT more than 1 year earlier, 7 of 8 (88%) were alive at 1 year. Our findings suggest that low-to-moderate burden IFI with mixed response is unlikely to progress on appropriate therapy before engraftment during allogeneic HCT.

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study.

BACKGROUND: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19. METHODS: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission. RESULTS: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients. CONCLUSIONS: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.

A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients.

BACKGROUND: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. METHODS: Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/µL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28. RESULTS: From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, -0.33 log10 copies/mL; 95% confidence interval [CI] -.64 to -.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22-1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo. CONCLUSIONS: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia. CLINICAL TRIALS REGISTRATION: NCT02254408; EUDRA-CT#2014-002474-36.

Multidisciplinary Team-Based Management of Incidentally Detected Lung Nodules.

BACKGROUND: Each year, > 1.5 million Americans are diagnosed with an incidentally detected lung nodule. Practice guidelines attempt to balance the benefit of early detection of lung cancer with the risks of diagnostic testing, but adherence to guidelines is low. The goal of this study was to determine guideline adherence rates in the setting of a multidisciplinary nodule clinic and describe reasons for nonadherence as well as associated outcomes. METHODS: This cohort study included 3 years of follow-up of patients aged ≥ 35 years with an incidentally detected lung nodule evaluated in a multidisciplinary clinic that used the 2005 Fleischner Society Guidelines. RESULTS: Among 113 patients, 67% (95% CI, 58-76) were recommended a guideline-concordant nodule evaluation; 7.1% (95% CI, 3.1-13) and 26% (95% CI, 18-25) were recommended less or more intense evaluation, respectively. In contrast, 58% (95% CI, 48-67), 22% (95% CI, 18-25), and 23% (95% CI, 16-32) received a guideline-concordant, less intense, or more intense evaluation. The most common reason for recommending guideline-discordant care was concern for two different diagnoses that would each benefit from early detection and treatment. A majority of lung cancer diagnoses (88%) occurred in patients who received guideline-concordant care. There were no lung cancer cases in those who received less intense nodule care. CONCLUSIONS: A multidisciplinary nodule clinic may serve as a system-level intervention to promote guideline-concordant care, while also providing a multidisciplinary basis by which to deviate from guidelines to address the needs of a heterogeneous patient population.

Comparison of prediction models with radiological semantic features and radiomics in lung cancer diagnosis of the pulmonary nodules: a case-control study.

PURPOSE: To compare the ability of radiological semantic and quantitative texture features in lung cancer diagnosis of pulmonary nodules. MATERIALS AND METHODS: A total of N = 121 subjects with confirmed non-small-cell lung cancer were matched with 117 controls based on age and gender. Radiological semantic and quantitative texture features were extracted from CT images with or without contrast enhancement. Three different models were compared using LASSO logistic regression: "CS" using clinical and semantic variables, "T" using texture features, and "CST" using clinical, semantic, and texture variables. For each model, we performed 100 trials of fivefold cross-validation and the average receiver operating curve was accessed. The AUC of the cross-validation study (AUCCV) was calculated together with its 95% confidence interval. RESULTS: The AUCCV (and 95% confidence interval) for models T, CS, and CST was 0.85 (0.71-0.96), 0.88 (0.77-0.96), and 0.88 (0.77-0.97), respectively. After separating the data into two groups with or without contrast enhancement, the AUC (without cross-validation) of the model T was 0.86 both for images with and without contrast enhancement, suggesting that contrast enhancement did not impact the utility of texture analysis. CONCLUSIONS: The models with semantic and texture features provided cross-validated AUCs of 0.85-0.88 for classification of benign versus cancerous nodules, showing potential in aiding the management of patients. KEY POINTS: • Pretest probability of cancer can aid and direct the physician in the diagnosis and management of pulmonary nodules in a cost-effective way. • Semantic features (qualitative features reported by radiologists to characterize lung lesions) and radiomic (e.g., texture) features can be extracted from CT images. • Input of these variables into a model can generate a pretest likelihood of cancer to aid clinical decision and management of pulmonary nodules.

Diagnosis of idiopathic pulmonary fibrosis by virtual means using "IPFdatabase"- a new software.

BACKGROUND: The diagnostic algorithm for idiopathic pulmonary fibrosis (IPF) guidelines has some shortcomings. The aim of the present study was to develop a novel software, "IPFdatabase", that could readily apply the diagnostic criteria per IPF guidelines and make a 'virtual' diagnosis of IPF. METHODS: Software was developed as a step-by-step compilation of necessary information according to guidelines to enable a diagnosis of IPF. Software accuracy was validated primarily by comparing software diagnoses to those previously made at a Center for Interstitial Lung Diseases. RESULTS: Clinical validation on 98 patients (68 male, age 61.0 ±â€¯8.5 years), revealed high software accuracy for IPF diagnosis when compared to historical diagnoses (sensitivity 95.5%, specificity 96.2%; positive predictive value 95.5%, negative predictive value 96.2%). A general radiologist and a general pathologist reviewed relevant data with and without the new software: interobserver agreement increased when they used the IPFdatabase (kappa 0.18 to 0.64 for radiology, 0.13 to 0.59 for pathology). CONCLUSION: IPFdatabase is a useful diagnostic tool for typical cases of IPF, and potentially restricts the need for MDDs to atypical and complex cases. We propose this web-designed software for instant accurate diagnosis of IPF by virtual means and for educational purposes; the software is readily accessed with mobile apps, allows incorporation of updated version of guidelines, can be utilized for gathering data useful for future studies and give physicians rapid feedback in daily practice.

Poor Uptake of Lung Cancer Screening: Opportunities for Improvement.

Lung cancer screening with low-dose chest CT has been demonstrated to reduce lung cancer mortality among a subset of high-risk current and former smokers. Despite randomized trial evidence and widespread guideline recommendations, uptake of lung cancer screening among currently eligible individuals remains poor. Recent studies estimate that less than 5% of all eligible individuals have undergone screening. Moreover, inappropriate screening of ineligible individuals seems to be common, and among those who have been screened, follow-up may also be poor. In this review, the authors examine recent studies demonstrating the current state of suboptimal implementation of lung cancer screening. The authors also introduce both patient- and provider-facing evidence-based interventions that may improve implementation of screening. These include tailored navigation interventions to overcome patient barriers throughout the screening care continuum and interventions to improve the identification of eligible individuals for providers. Further evidence on best practices around the implementation of lung cancer screening is essential to ensure that recent evidence can be translated into practice to improve the early detection of lung cancer for high-risk individuals.

Tumor-derived Autoantibodies Identify Malignant Pulmonary Nodules.

Rationale: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm caused by invasive follow-up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor-specific biomarkers. Objectives: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules. Methods: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule control subjects. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule-positive patients. Measurements and Main Results: Thirteen tumor B-cell-derived autoantibodies isolated ex vivo showed greater than or equal to 50% sensitivity and greater than or equal to 70% specificity for lung cancer. In plasma, 11 of 13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5 of 13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of four of these autoantibodies could detect malignant nodules with an area under the curve of 0.74 and had an area under the curve of 0.78 in a subcohort of indeterminate (8-20 mm in the longest diameter) pulmonary nodules. Conclusions: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and noninvasive approach to determine nodule malignancy for widespread low-dose computed tomography screening.

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

BACKGROUND: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. METHODS: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. CONCLUSIONS: The guideline panel provided recommendations related to the diagnosis of IPF.

Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial.

BACKGROUND: Abnormal acid gastro-oesophageal reflux (GER) is hypothesised to play a role in progression of idiopathic pulmonary fibrosis (IPF). We aimed to determine whether treatment of abnormal acid GER with laparoscopic anti-reflux surgery reduces the rate of disease progression. METHODS: The WRAP-IPF trial was a randomised controlled trial of laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER recruited from six academic centres in the USA. We enrolled patients with IPF, abnormal acid GER (DeMeester score of ≥14·7; measured by 24-h pH monitoring) and preserved forced vital capacity (FVC). We excluded patients with a FVC below 50% predicted, a FEV1/FVC ratio of less than 0·65, a history of acute respiratory illness in the past 12 weeks, a body-mass index greater than 35, and known severe pulmonary hypertension. Concomitant therapy with nintedanib and pirfenidone was allowed. The primary endpoint was change in FVC from randomisation to week 48, in the intention-to-treat population with mixed-effects models for repeated measures. This trial is registered with ClinicalTrials.gov, number NCT01982968. FINDINGS: Between June 1, 2014, and Sept 30, 2016, we screened 72 patients and randomly assigned 58 patients to receive surgery (n=29) or no surgery (n=29). 27 patients in the surgery group and 20 patients in the no surgery group had an FVC measurement at 48 weeks (p=0·041). Intention-to-treat analysis adjusted for baseline anti-fibrotic use demonstrated the adjusted rate of change in FVC over 48 weeks was -0·05 L (95% CI -0·15 to 0·05) in the surgery group and -0·13 L (-0·23 to -0·02) in the non-surgery group (p=0·28). Acute exacerbation, respiratory-related hospitalisation, and death was less common in the surgery group without statistical significance. Dysphagia (eight [29%] of 28) and abdominal distention (four [14%] of 28) were the most common adverse events after surgery. There was one death in the surgery group and four deaths in the non-surgery group. INTERPRETATION: Laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER is safe and well tolerated. A larger, well powered, randomised controlled study of anti-reflux surgery is needed in this population. FUNDING: US National Institutes of Health National Heart, Lung and Blood Institute.

Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

Radiologic computed tomography features of Mycobacterium abscessus in cystic fibrosis.

INTRODUCTION: Mycobacterium abscessus infection in cystic fibrosis (CF) patients can lead to poor outcomes. Early diagnosis is important, but there are no studies outlining specific imaging features of M. abscessus in CF. OBJECTIVES: To describe the computed tomography (CT) findings of early M. abscessus infection in our CF population. METHODS: Thirteen CF patients with sputum cultures positive for M. abscessus from 2006 to 2013 were identified at our institution. Clinical characteristics including culture dates and lung function were reviewed. Positive cultures were classified as "disease" versus "colonization" based on published criteria. Chest CT scans were reviewed at times closest to initial infection, and features including bronchiectasis, mucous plugging, consolidation, ground glass opacities, nodules, and cavitation were evaluated. Brody scores were calculated to evaluate extent of CF lung disease. RESULTS: All patients had bronchiectasis and mucous plugging, with 10 of 13 (76.9%) in an upper lobe distribution. Consolidation was seen in 12 of 13 (92.3%) patients, 8 (61.5%) patients had nodules, and 5 (38.5%) with cavitation. The average Brody score was 59.5, which was no different than previously described CF cohorts without M. abscessus. There were no significant differences between subjects with disease versus colonization. CONCLUSION: The most common CT features of early M. abscessus in our CF population include bronchiectasis, mucus plugging, and consolidation, but the findings did not reveal a unique radiologic signature. CT at this initial time point may not distinguish early M. abscessus infection from background lung disease or mycobacterial colonization in CF patients.

Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.

RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) are interrelated diseases with substantial mortality, and the pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile immune cell composition and function in patients with NSCLC and describe the effects of COPD on lung and tumor microenvironments. METHODS: We profiled resected lung and tumor tissue using flow cytometry and T-cell receptor sequencing in patients with and without COPD from a prospective cohort of patients undergoing resection of NSCLC. A murine cigarette smoke exposure model was used to evaluate the effect on pulmonary immune populations. A separate retrospective cohort of patients who received immune checkpoint inhibitors (ICIs) was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS: We observed an increased number of IFN-γ-producing CD8+ and CD4+ (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In both humans and mice, increased Th17 content was seen with smoke exposure, but was not associated with the development or severity of COPD. COPD-affected lung tissue displayed increased Th1 differentiation that was recapitulated in the matching tumor sample. PD-1 (programmed cell death protein 1) expression was increased in tumors of patients with COPD, and the presence of COPD was associated with progression-free survival in patients treated with ICIs. CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with ICIs. This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.