Background:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used for evaluating mediastinal lymphadenopathy, particularly in lung cancer diagnosis. However, its diagnostic effectiveness may be limited for conditions such as granulomatous disease and lymphoma, which often require preserved tissue architecture. Endobronchial ultrasound-guided mediastinal cryobiopsy (EBUS-MCB) is an emerging technique with promising diagnostic potential. This study evaluates the additive diagnostic yield of EBUS-MCB in patients with inconclusive or inadequate rapid on-site evaluation (ROSE) during EBUS-TBNA. Research Question:Does the addition of EBUS-MCB improve diagnostic yield in patients with inconclusive or absent ROSE during EBUS-TBNA, and is the technique safe in clinical practice? Study Design and Methods:We conducted a retrospective multicenter study of patients with inconclusive or inadequate ROSE during EBUS-TBNA. EBUS-MCB was performed in addition to standard transbronchial needle aspiration sampling. Diagnostic yield and procedural complications were assessed. Results:Among 145 patients, EBUS-MCB was performed after inconclusive ROSE. Most procedures were conducted under general anesthesia (98.6%), with endotracheal intubation in 71.7%. The mean lymph node diameter was 20.95 mm, with an average of 5.1 transbronchial needle aspiration passes and 3.6 cryobiopsy samples per node. EBUS-TBNA alone achieved a diagnostic yield of 91.7%, identifying 34 malignancies. EBUS-MCB detected 15 additional malignancies, increasing the total to 49 and raising overall diagnostic yield to 97.7%. EBUS-MCB also identified 25 additional granulomatous cases beyond the 29 detected by EBUS-TBNA. A definitive diagnosis of malignancy or granulomatous disease was established in 106 patients (73.1%). No major complications occurred; minor bleeding was managed conservatively. Interpretation:Our results show that EBUS-MCB identified additional diagnoses of granulomatous disease and lymphoma in patients with inconclusive ROSE after EBUS-TBNA and appears to be a safe and effective adjunctive technique for enhancing diagnostic yield in mediastinal lymphadenopathy.
Background: Although robotic-assisted bronchoscopy (RAB) primarily aims to diagnose early stage lung cancer, many pulmonary nodules stem from benign causes, including atypical infections (ie, Coccidioides species, Aspergillus species, nontuberculous mycobacteria). Data on prevalence of atypical infections in patients undergoing RAB with biopsy of pulmonary nodules are limited. Research Question: What is the prevalence of atypical and bacterial infections in patients undergoing robotic-assisted bronchoscopy with biopsy of pulmonary nodules in a coccidioidomycosis endemic area? Study Design and Methods: This single-center, retrospective study examined 526 patients who underwent RAB with a shape-sensing platform at our institution from June 2021 through December 2023. Results: Of the 526 patients, 261 (49.6%) had malignancy without infection, 107 (20.3%) had cultures positive for infection without malignancy, and 35 (6.65%) were diagnosed with both malignancy and a coexisting bacterial and/or atypical infection. Coccidioides serology (IgG) or clinical history was significantly more prevalent in the infection without malignancy group (32.7%) and the malignancy with infection group (42.9%) compared with the malignancy-only group (0%; P < .001). Complication rates (pneumothorax, bleeding, and hospitalization) did not differ significantly between groups. In a subgroup analysis, 73 patients (13.9%) with granulomatous inflammation on pathology had higher rates of positive fungal (P = .002), Aspergillus (P = .042), and acid-fast bacilli (P < .001) cultures than patients in the nongranuloma group. Positive cultures of acid-fast bacilli, Coccidioides species, or Aspergillus species also had granulomatous inflammation in 76%, 29%, and 29% of cases, respectively. Fifty-two patients had > 1 positive culture result. Interpretation: This study highlights the importance of obtaining bronchoscopy cultures in patients undergoing RAB, especially when rapid on-site evaluation of the pulmonary nodule biopsy does not reveal malignancy.
Background: The long-term performance characteristics of digital tomosynthesis-assisted electromagnetic navigation bronchoscopy (DT-ENB) has not been evaluated in the community setting. Research Question: What is the diagnostic yield and 2-year diagnostic accuracy of DT-ENB in a typical pulmonary practice? Study Design and Methods: This was a single-center, community hospital-based retrospective observational performance evaluation over 2 years assessing the long-term diagnostic accuracy of DT-ENB using the ILLUMISITE Fluoroscopic Navigation Platform (Medtronic). Other performance characteristics assessed included diagnostic yield, negative predictive value (NPV), and sensitivity. Factors affecting diagnostic yield were analyzed, and subsequent workup for false negatives and outcomes were described. Results: A total of 227 patients underwent DT-ENB, resulting in a specific diagnosis for 175 patients, for a diagnostic yield of 77.1% (95% CI, 71.2-82.1). Of these, 202 patients either had a confirmatory diagnosis or 2 years of CT scan follow-up. Among the 202 patients included in the NPV and sensitivity analysis, 135 (66.8%) were determined to be true positives, 47 (23.3%) were true negatives, 20 (9.9%) were false negatives, and there were no false positives. Overall, 2-year diagnostic accuracy was 71.4% (95% CI, 65.2-76.9). The 2-year NPV was 70.1% (95% CI, 61.0-78.0), and sensitivity was 87.1% (95% CI, 80.8-91.9). Nodule size was associated with higher diagnostic yield (P = .001), with a median nodule size for nondiagnostic procedures of 1.5 cm (95% CI, 1.25-2.15 cm) and a median nodule size for diagnostic procedures of 2.2 cm (95% CI, 1.4-4.0 cm). Interpretation: Our results show that DT-ENB when used in the community setting for lung nodule biopsy resulted in a diagnostic yield of 77.1% and diagnostic accuracy of 71.4% at 2-year follow-up.
Background: Pulmonary infections caused by Mycobacterium abscessus complex (MABC) are notoriously difficult to treat due to high levels of mutational and inducible antibiotic resistance. Omadacycline (OMC), an aminomethylcycline antibiotic with both oral and IV formulations, has shown in vitro activity against MABC and may offer a more tolerable alternative to conventional therapies. However, clinical data specific to pulmonary MABC with macrolide resistance remain limited. The aim of this study was to evaluate the clinical and microbiological outcomes of OMC-based therapy in patients with pulmonary MABC infections. Research Question: What are the clinical and microbiological outcomes of OMC-based therapy in patients with pulmonary MABC infections, including those with macrolide resistant isolates? Study Design and Methods: This was a retrospective subgroup analysis of a previously published multicenter cohort study conducted across 16 US academic medical centers. Adult patients with pulmonary MABC infections who received OMC for ≥ 72 hours and had ≥ 3 months of follow-up were included. The primary outcome was clinical success at 3, 6, and 12 months, defined as a composite of clinical improvement, survival, continued OMC use, and absence of microbiologic recurrence. Secondary outcomes included sputum culture improvement, outcomes by MABC subspecies and macrolide susceptibility, and adverse drug reactions. Results: Thirty-five patients were included (68.6% macrolide resistance). The median treatment duration was 8 months (interquartile range, 3.9-15.7). Clinical success was achieved in 71.4%, 89.7%, and 90.9% at 3, 6, and 12 months, respectively. Culture improvement occurred in 73.9% of evaluable patients, including 100% of those with macrolide-resistant strains. OMC was discontinued in 8 patients (22.9%) due to adverse drug reactions, most commonly gastrointestinal intolerance (26%) and transaminitis (11%). Interpretation: Our results show that OMC demonstrated high clinical success and culture improvement rates in pulmonary MABC, including macrolide-resistant cases. These findings support its potential role as a tolerable and effective oral agent within multidrug regimens. Prospective studies are needed to confirm these results and define optimal use strategies.
Background Respiratory impairment evaluations for disability determinations often rely on spirometry thresholds derived from predicted lung function values. When race-neutral reference equations replace race-specific equations, small shifts in predicted values can change the identification of impairment and its timing. Research question Among emergency responders, how does applying race-neutral Global Lung Function Initiative (GLI-Global) equations versus race-specific Third National Health and Nutrition Examination Survey (NHANES-III) equations impact impairment identification and its timing? Study Design and Methods We evaluated 9,350 emergency responders with spirometry within two years of retirement (8,296 non-Hispanic White; 552 Hispanic; 502 non-Hispanic Black). We calculated FEV1 and FVC percent predicted and z-scores using NHANES-III and GLI-Global equations. We defined the impairment threshold for disability as FEV1 or FVC <70% predicted and separately as FEV1 or FVC z-score <-2.5. Secondary analyses used other common thresholds. We compared impairment classifications at the exam closest to retirement. For time-to-event analyses (N=9,199), follow-up began on 1/1/1998 and ended at first threshold crossing or the exam closest to retirement. Interval-censored Weibull proportional hazards models with frailty compared time to threshold crossing between GLI-Global and NHANES-III, stratified by race/ethnicity. Results At retirement, the proportion of White and Hispanic responders with FEV1 or FVC <70% predicted decreased when GLI-Global replaced NHANES-III (from 4.9% to 2.4% [White]; from 7.8% to 4.7% [Hispanic]). In contrast, the proportion of Black responders more than doubled, from 6.6% to 14.9%. In time-to-event models, GLI-Global identified impairment later for White (HR=0.48; 95%CI=0.42-0.55) and Hispanic responders (HR=0.55; 95%CI=0.38-0.79), but earlier for Black responders (HR=2.87; 95%CI=2.07-3.96). Results were similar using z-scores. Interpretation GLI-Global race-neutral equations classified Black responders as impaired more frequently and sooner, and classified White and Hispanic responders as impaired less frequently and later. Impairment/disability determinations should require individual evaluations that consider spirometry in the context of clinical and work-function assessments.
Background A 2021 Veterans Health Administration (VHA) formulary change replaced budesonide-formoterol (BUD-FORM) metered-dose inhaler (MDI) with fluticasone-salmeterol (FLU-SAL) dry-powder inhaler (DPI) as the preferred controller agent for asthma and chronic obstructive pulmonary disease (COPD). This transition was associated with increased health care utilization among veterans, but the mechanisms underlying these outcomes remain poorly understood. Research Question How was the 2021 inhaler conversion implemented across VHA facilities, and how might clinician and veteran perspectives on the transition process inform future inhaler formulary changes? Study Design and Methods We conducted semistructured interviews with VHA pharmacists and pulmonologists purposively sampled from facilities with high (≥80%), medium (60-79%), and low (≤59%) conversion rates and with veterans affected by the conversion (those who remained on the FLU-SAL DPI and those who switched back to BUD-FORM MDI or to another inhaler). Interviews were conducted from January to April 2025, transcribed, and analyzed using qualitative content analysis, with iterative team consensus discussions to ensure the credibility, validity, and confirmability of findings. Results We interviewed 26 clinicians (13 pharmacists; 13 pulmonologists) and 12 veterans. Four themes emerged: (1) negative patient experiences with FLU-SAL DPI, including insufficient patient education, uncertainty about dose delivery, and challenges among veterans with limited dexterity or inspiratory force; (2) concerns about inhaler selection and conversion implementation, which were perceived as top-down and cost-driven, alongside veterans’ frustration with limited notification and lack of choice in the switch; (3) facility-level variation in conversion goals, perceived autonomy, and decision-making roles; and (4) shared local constraints across facilities, including limited specialty expertise, staffing strain, and substantial workload related to patient complaints and non-formulary requests. Interpretation Clinicians and veterans described a high-complexity medication-and-device switch characterized by reactive rather than proactive education and substantial administrative burden, offering insight into potential mechanisms underlying previously observed adverse outcomes after this conversion.
Background Studies comparing individuals with FEV1%predicted ≥80% but FEV1/FVC <0.7 to those with both FEV1%predicted ≥80% and FEV1/FVC ≥0.7 have reported inconsistent results. However, these studies were limited by the use of a fixed FEV1/FVC threshold and the absence of adjustment for baseline FEV1. Given that individuals with preserved FEV1 but airflow limitation (ALp) often have lower FEV1 than those with normal spirometry, this imbalance may have influenced the observed outcomes. Research Question Is airflow limitation in the context of preserved FEV1 a clinically significant spirometry pattern? Study Design and Methods We aimed to assess the association of FEV1/FVC< lower limit of normal (LLN) with clinical, functional, and radiographic features, and outcomes in individuals with preserved FEV1, while accounting for baseline FEV1. Using COPDGene data, we categorized ever-smokers with post-bronchodilator FEV1 ≥ LLN into 2 groups based on FEV1/FVC: Normal and ALp (airflow limitation). We applied multiple statistical models adjusting for demographics, smoking history, and baseline FEV1. Analyses were replicated in the SPIROMICS cohort. Results Of the 6,067 participants with normal FEV1, 5,192 had normal spirometry, and 875 had ALp. Compared to normal spirometry, ALp was associated with chronic bronchitis (OR=1.65; 95%CI: 1.35 to 2.01; P< 0.001), greater CT-assessed emphysema, gas trapping, and functional small airway disease. ALp was associated with an additional FEV1 decline of 9.3 mL/year (95% CI: 6.5 to 12.0; P < 0.001), more respiratory exacerbations (incidence rate ratio=1.50; 95%CI: 1.26 to 1.81; P<0.001) but not increased mortality compared to normal spirometry. Findings were consistent in SPIROMICS. Interpretation Airflow Limitation with Preserved FEV1 in individuals with cigarette smoking history represents a clinically meaningful obstructive phenotype, that warrants recognition in clinical practice.
Background Inhaled corticosteroids (ICS) are foundational therapy in pediatric asthma, yet evidence guiding initiation and response in preschool-aged children remains limited due to diagnostic uncertainty and inflammatory heterogeneity. Research Question Among young children with asthma, is initiation of ICS associated with changes in severe asthma exacerbation trajectories? Study Design and Methods We conducted a retrospective longitudinal quasi-experimental study using electronic health record data from the Indiana Network for Patient Care (2010–2024). Children who initiated ICS between 2010 and 2023 and had ≥12 months of observation before and after initiation were included (n=1,396). Annualized severe asthma exacerbations (hospitalization or emergency department visits) were analyzed using piecewise generalized linear mixed-effects models to estimate pre- and post-initiation slopes. Recurrent exacerbations were evaluated using Andersen-Gill models, and marginal structural models were applied to address time-varying confounding. Results Severe asthma exacerbation incidence increased in the year preceding ICS initiation (13% to 38%) and declined during the 1–3 years after initiation. In adjusted models, the odds of ≥1 severe asthma exacerbations decreased by 34% per year following initiation (adjusted odds ratio, 0.66; 95% CI, 0.59–0.74). ICS initiation was associated with lower recurrent exacerbation hazard in Andersen–Gill models and remained associated with reduced risk in marginal structural models. Greater reductions were observed among children with higher baseline asthma risk, whereas age at initiation did not significantly modify response. Interpretation ICS initiation was associated with significant attenuation of severe exacerbation burden in young children with asthma. These findings support early controller therapy in high-risk preschool populations while underscoring persistent heterogeneity and disparities in asthma outcomes.
Background Next-generation sequencing and polymerase chain reaction–based molecular testing are central to the management of non–small cell lung cancer. CT-guided lung biopsy (CTBx) is commonly used, but shape-sensing robotic-assisted bronchoscopy (ssRAB) may offer the additional benefits of mediastinal staging and sampling of multiple lesions during a single procedure. Comparative data on molecular testing yield between these approaches remain limited. Research Question Does ssRAB provide tissue adequacy for molecular profiling comparable to CT-guided lung biopsy in patients with NSCLC while maintaining a favorable safety profile? Study Design and Methods All NSCLC patients who underwent ssRAB or CTBx between 2020 and 2023 for diagnosis and molecular profiling were included. The primary outcome was yield for molecular analysis. Secondary outcomes included percent tissue cellularity and procedure complications. Results 308 patients had ssRAB (130, 42%) or CTbx (178, 58%). No differences were found in baseline patient characteristics, mean nodule size (3.3cm ± 1.8 vs 3.1 ± 2.0cm, p = 0.517), adequacy for NGS (130 nodules (91.5%) vs. 165 nodules (92.2%), p =0.999) or mean percent tissue cellularity of the samples (36.9 ± 21.9 vs 37.6 ± 21.4, p = 0.778), respectively. ssRAB group waited less time for surgery (27.3 ± 37 days vs. 56 ± 45 days, p = 0.009). Both groups had similar surgical resection rate(31.5% for ssRAB vs. 32.0% for CTbx, p=0.985). In ssRAB, 18 (13.8%) patients had >1 nodule biopsied compared to 1 patient in CTbx (p < 0.001). 63.1% of ssRAB had concomitant mediastinal staging whereas 20.2% of CTbx patients had subsequent staging (p < 0.001). There were no complications with ssRAB, and 4 pneumothoraces required chest tube placement in the CTbx group (p = 0.224). Interpretation ssRAB may provide a diagnostic yield for biomarker identification comparable to CT-guided biopsy and may allow for concomitant mediastinal staging and biopsy of synchronous pulmonary nodules, with a favorable safety profile.
Background Many patients with lung cancer receive guideline-discordant nodal staging. However, existing studies lack clinical details—such as imaging indications for biopsy—that obscure attempts to characterize guideline-discordant nodal staging. Research question What are the frequency and types of guideline-discordant nodal staging, and what factors are associated with discordance? Study design and methods We conducted a cohort study of patients diagnosed with non-metastatic non-small cell lung cancer (2010-2021) staged by computed tomography and positron emission tomography four months prior to initiating treatment. We linked data from administrative, cancer, and vital status registries to electronic health records from two health systems. Guideline-discordant nodal staging was defined as no biopsy when one was indicated (e.g. tumor >3cm, central tumor, or lymphadenopathy on imaging), or a non-diagnostic, non-thorough, or negative needle biopsy despite high suspicion for nodal disease. We used generalized estimating equations to investigate imaging factors associated with guideline-discordant nodal staging. We performed a sensitivity analysis to evaluate the robustness of our findings across two national practice guidelines. Results Among 5,582 patients, 3,580 (64%) had an indication for biopsy, of which 2,798 (78%) experienced guideline-discordant nodal staging. Types of guideline-discordant nodal staging included no biopsy despite an indication for one (82%), negative needle biopsy despite a high suspicion of nodal disease (9%), a non-thorough procedure (7%), a non-diagnostic biopsy (1%), and other (1%). These findings were robust across sensitivity analyses—the only factor consistently associated with a higher risk of guideline-discordant nodal staging was higher standardized uptake values for the primary tumor. Interpretation When estimated among patients with an indication for biopsy, rates of guideline-discordant nodal staging were in the upper range of prior reports. The predominant type of guideline-discordant staging was no biopsy despite an indication. These findings further motivate the need for improved adoption and performance of nodal staging.
Background Immune checkpoint inhibitors (ICIs) have improved survival in advanced NSCLC; yet the trajectory of objective physical performance during immunotherapy remains poorly characterized. Pulmonary rehabilitation (PR) has not been evaluated in this setting in randomized trials. Research Question Does supervised pulmonary rehabilitation modify functional capacity and multidimensional physical performance during first-line immunotherapy for advanced NSCLC? Study Design and Methods In this randomized controlled trial, patients with stage IV NSCLC initiating first-line ICI-based therapy were randomized 1:1 to supervised PR or usual care for 8 weeks. The primary outcome was change in 6-minute walk distance (6MWD). Secondary outcomes included multidimensional physical performance, symptom burden, and health-related quality of life. Exploratory outcomes included inflammatory biomarkers and oncologic endpoints. Results Of 148 individuals screened, 48 were randomized (PR, n = 24; usual care, n = 24). At 8 weeks, supervised PR significantly improved 6-minute walk distance compared with usual care (adjusted mean difference, 25.8 m; 95% CI, 10.1–41.5 m; p = .002). Significant between-group differences favoring PR were observed in lower-extremity performance (SPPB), quadriceps strength, fine motor dexterity, respiratory symptom burden (CAT), anxiety, and depressive symptoms. Participants receiving usual care demonstrated decline across multiple functional domains despite stable ECOG performance status. No between-group differences were observed in inflammatory biomarkers. Exploratory analyses demonstrated a trend toward longer progression-free survival (median, 15.0 vs 10.0 months) in the pulmonary rehabilitation group; however, the study was not powered to detect differences in survival outcomes. Interpretation Among patients receiving first-line ICI-based therapy for advanced NSCLC, early functional deterioration occurred despite stable ECOG performance status, indicating that oncologic stability does not necessarily reflect physiologic stability. Supervised PR modified functional trajectories during active treatment in this randomized trial, supporting early rehabilitation as an integral component of immunotherapy care rather than a survivorship intervention.
