Refractory/unexplained chronic cough (RCC/UCC) is a disease associated with substantial clinical and humanistic burden. A variety of endpoints have been used in RCC/UCC research to measure cough outcomes and impact on patients’ quality of life (QoL), including clinical measures of cough using digital devices, or digital measures, and patient-reported outcomes (PROs). The aim of this review was to determine which endpoints are currently used in studies of RCC/UCC, and to explore the recent evolution of new digital measures used across research and clinical settings. We conducted a scoping literature review (January 1, 2019–October 31, 2024), assessing studies of adults diagnosed with chronic cough (refractory/unexplained or newly diagnosed). Clinical trials and observational/real-world studies were included that evaluated objective and PRO measures of cough frequency, severity, symptoms, other cough characterization, and QoL. Overall, 70 studies (29 manuscripts, 35 clinicaltrials.gov entries, 6 posters/abstracts) were included: 36 clinical trials (Phase 2, 3, or 4), 34 observational/real-world studies. Objective cough frequency was the primary endpoint in 24/36 clinical trials. In contrast, objective cough frequency was reported in 10/34 observational/real-world studies. Observational/real-world studies had a greater variety of endpoints for cough outcomes and PROs compared with clinical trials. Clinical trials and observational/real-world studies of chronic cough and RCC use a wide range of outcome measures, including objective measures of cough frequency using digital devices (digital endpoints) and subjective PROs. New approaches to digital endpoints and PROs are being developed as the study and treatment of cough evolves.
Cough hypersensitivity contributes to the heterogeneity of gastroesophageal reflux-induced chronic cough (GERC), but its associated factors remain unclear. This study aimed to investigate factors associated with cough hypersensitivity and evaluate the relative contributions of reflux characteristics and esophageal motility across reflux phenotypes. This retrospective study included 195 patients with GERC who underwent 24-hour multichannel intraluminal impedance-pH monitoring and high-resolution esophageal manometry. Cough hypersensitivity was assessed using the Hull Airway Reflux Questionnaire (HARQ). Multivariable regression assessed independent associations with continuous HARQ scores, whereas random forest and SHAP analyses ranked the relative contributions of reflux-related and esophageal motility variables to HARQ score prediction. Patients with higher cough hypersensitivity exhibited increased capsaicin cough sensitivity, poorer quality of life, lower response rates to standard anti-reflux therapy (all P < 0.05), and a higher prevalence of ineffective esophageal motility (62.1
Inhaled corticosteroids (ICS) are recommended for select patients with chronic obstructive pulmonary disease (COPD) based on exacerbation history and blood eosinophil counts. Prior studies suggest that ICS are frequently prescribed outside of guideline-based criteria, and eosinophil testing is inconsistently performed in clinical practice. This study evaluated adherence to Global Initiative for Chronic Obstructive Lung Disease (GOLD) eosinophil criteria for ICS prescribing and associated clinical outcomes. This retrospective observational cohort study included adults with COPD receiving care within Cleveland Clinic outpatient practices in Ohio who were newly initiated on an ICS-containing regimen between January 1, 2021, and July 31, 2023. Patients were classified based on whether ICS prescribing aligned with GOLD eosinophil criteria. Outcomes included adherence to GOLD eosinophil recommendations for ICS use, pneumonia incidence, ICS de-escalation, and predictors of prescribing outside guideline-based criteria. A total of 688 patients were included. Most patients received ICS outside of GOLD eosinophil criteria (589/688, 86
The differential diagnosis of tuberculous pleural effusion (TPE) and lung adenocarcinoma-associated malignant pleural effusion (LA-MPE) remains challenging. This study aimed to measure interleukin‑9 (IL‑9) levels in pleural fluid and evaluate its diagnostic utility in distinguishing between these two conditions. The study enrolled 105 patients with PE (51 TPE and 54 LA-MPE). IL-9 levels in pleural fluid were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was employed to identify the optimal cutoff value and assess diagnostic performance, including area under the curve (AUC), sensitivity, and specificity, with adenosine deaminase (ADA) and carcinoembryonic antigen (CEA) as comparators. Internal cross-validation was conducted to examine model robustness, and decision curve analysis was used to evaluate the clinical net benefit of IL-9 alone and in combination with ADA and CEA. IL-9 levels were significantly elevated in TPE compared with LA-MPE (2828.13 vs. 310.55 ng/L, P < 0.001). At a cutoff of 748.47 ng/L, IL-9 distinguished TPE from LA-MPE with a sensitivity of 98.0
Fatigue is a common symptom in lymphangioleiomyomatosis (LAM) and is associated with reduced physical activity and quality of life. Coexistent skeletal muscle dysfunction has been reported for other chronic lung diseases but has not been investigated in LAM. Fifteen patients with LAM and 15 matched individuals without LAM (NL) underwent computerized lower extremity dynamometry, standardized functional tests, and fatigue surveys. Immunohistochemistry to detect LAM+ cells and to characterize fiber-type distribution was performed on vastus lateralis (VL) samples of LAM and NL. Maximal cardiopulmonary exercise test (CPET) and six-minute walk test (6MWT) were additionally conducted for LAM. Welch’s t-testing compared measures between LAM and NL. Pearson correlation tested relationships between variables. Data are mean ± SD. LAM exhibited lower (p < 0.05) muscular force (by 220 ± 89 N), power (by 312 ± 129 W), and endurance (by 4674 ± 1974 N*sec) in dynamometry and functional tests (by 119 ± 45s in wall squat test), and worse fatigue survey scores (p = 0.02 to 0.0004). Poorer muscular endurance in LAM was associated with less distance achieved in 6MWT (r = 0.68), lower VO2max (r = 0.58), and worse fatigue (r = 0.56). LAM with worse fatigue also exhibited lower relative fat utilization in CPET (r = 0.75, p = 0.005). No LAM+ cells were detected in VL samples, nor between-group differences in fiber type distribution. Muscular endurance and strength is lower in LAM, coincident with greater self-reported fatigue. Fiber type shift reported for skeletal muscle in other chronic lung disease is not observed in LAM. Further work is needed to elucidate peripheral muscle mechanisms for fatigue and exercise intolerance in LAM.
Malnutrition is common in lung cancer and may contribute to impaired functional status and poor survival. This study evaluated the association between GLIM-defined malnutrition, morphofunctional nutritional parameters, and one-year mortality in patients with lung cancer. We conducted a multicentre prospective cohort study including 374 patients with primary lung cancer referred for nutritional and morphofunctional assessment before oncological treatment. Nutritional status was classified according to GLIM criteria. Body composition was assessed by bioelectrical impedance analysis, muscle ultrasound, handgrip strength and Timed Up and Go. Associations with severe malnutrition were explored using logistic regression, ROC analyses, and random forest models. One-year survival was evaluated using Kaplan–Meier curves and Cox regression models adjusted for age, sex, BMI, and ECOG performance status. Severe malnutrition was present in 87 patients and was associated with lower albumin and prealbumin, higher C-reactive protein, poorer ECOG performance status, and higher one-year mortality. ECOG performance status worsened progressively across GLIM categories. Severe GLIM-defined malnutrition was associated with increased one-year mortality in unadjusted analysis (HR 4.31, 95
Obstructive sleep apnea (OSA) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF), yet symptom-based screening frequently lacks reliability in this population. We aimed to identify a blood-based biomarker for detecting OSA in patients with IPF. Public peripheral-blood transcriptomic datasets for OSA and IPF were analyzed to identify shared candidate genes. The leading candidate, ZNF331, was validated by reverse transcription-quantitative polymerase chain reaction in an independent clinical cohort comprising normal controls, patients with OSA, and non-oxygen-dependent patients with IPF. Diagnostic performance was assessed using receiver operating characteristic analysis and further corroborated through adjusted and internal validation analyses. ZNF331 was prioritized as a shared candidate gene through the integrated bioinformatics analysis and was subsequently selected for clinical validation. In the validation cohort, ZNF331 expression exhibited an overall downward trend across the normal control, OSA, IPF, and IPF + OSA groups, reaching its lowest levels in patients with IPF complicated by OSA. ZNF331 demonstrated high diagnostic accuracy in differentiating IPF + OSA from IPF-only cases (area under the curve = 0.932, 95
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard of care for advanced non-small cell lung cancer (NSCLC). However, their comparative efficacy and safety profile in early-stage versus advanced-stage disease remains systematically unexplored. We performed a systematic review and meta-analysis of PubMed, Embase, Cochrane Library, and Web of Science through January 4, 2025. Included studies reported objective response rate (ORR), disease control rate (DCR), or treatment-related adverse events (TRAEs) for EGFR-TKI monotherapy. Pooled estimates were synthesized using a generalized linear mixed model (GLMM). Forty-two studies comprising 46 treatment groups and 3713 patients (343 early-stage; 3370 advanced-stage) were included. Efficacy: The pooled ORR was significantly higher in advanced-stage NSCLC (0.59, 95
The U.S. Food and Drug Administration’s proposal to adopt a single randomized controlled trial (RCT) as the default evidentiary standard for drug approval marks a substantial change in regulatory philosophy. Although advances in mechanistic science, biomarkers, and statistical methods may justify this approach for conditions with significant, biologically coherent treatment effects, applying it to chronic obstructive pulmonary disease (COPD) raises substantial concerns. COPD is a heterogeneous, multifactorial syndrome with variable disease trajectories, modest treatment effects, and limited validated biomarkers. In this context, reliance on a single trial increases inferential fragility, risks type I error, and limits generalizability due to restrictive eligibility criteria and contextual variability. Although biomarker- and trait-based strategies are promising, they remain insufficiently validated to ensure robust estimation of treatment effects across populations. Similarly, the modest effect sizes and endpoint variability in COPD trials amplify the risk of false-positive or context-specific findings. Replication across independent studies primarily serves to test the consistency and robustness of observed effects under varying conditions, rather than to increase statistical power. We discuss a conceptual regulatory framework in which a single RCT may be acceptable only if it meets strict criteria, including large effect sizes, strong biological plausibility, a low risk of bias, and consistent subgroup effects. However, for highly heterogeneous conditions such as COPD, at least two independent studies remain preferable. Alternatively, if a single robust RCT is conducted, equivalent post-marketing validation is required. Ultimately, regulatory standards should be calibrated to biological and methodological uncertainty, balancing timely patient access with evidentiary reliability.
The cough severity visual analogue scale (VAS) and the Leicester Cough Questionnaire (LCQ) are commonly used in chronic cough. While continuous scores are useful for tracking change, categorization is needed to define clinically relevant states. However, patient-anchored thresholds for cough control remain undefined. Using the Korean Chronic Cough Registry (n = 890), we derived VAS and LCQ cutoffs anchored to a patient-reported cough control item. Receiver operating characteristic (ROC) analyses were performed using operational definitions of very well-controlled cough (“strongly agree” vs. all others), well-controlled cough (“strongly agree” + “agree” vs. all others), and uncontrolled cough (“disagree” + “strongly disagree” vs. all others). Both scores demonstrated stepwise gradients across cough control categories (p < 0.001). ROC-derived cutoffs for very well-controlled cough were VAS ≤ 10 (area under the curve [AUC], 0.911) and LCQ ≥ 15.8 (AUC, 0.877). For well-controlled cough, the corresponding cutoffs were VAS ≤ 30 (AUC, 0.866) and LCQ ≥ 15 (AUC, 0.856). For uncontrolled cough, the cutoffs were VAS ≥ 50 (AUC, 0.879) and LCQ ≤ 13.0 (AUC, 0.872). Cutoffs were consistent across newly referred chronic cough and refractory chronic cough subgroups. Concordance between VAS- and LCQ-derived classifications was moderate-to-substantial (weighted kappa = 0.55). Based on these findings, we propose a patient-anchored classification framework for cough control: very well-controlled cough (VAS ≤ 10, LCQ ≥ 16), well-controlled cough (VAS 11–30, LCQ 15.0–15.9), intermediate cough control (VAS 31–49, LCQ 13.1–14.9), and uncontrolled cough (VAS ≥ 50, LCQ ≤ 13). These thresholds warrant validation in diverse populations.
Diaphragmatic dysfunction contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). Although diaphragmatic excursion during deep breathing (DEmax) is associated with exercise capacity, the relationship between computed tomography (CT)-derived diaphragm morphology and diaphragmatic function remains unclear. We investigated the association of CT-derived diaphragmatic crus thickness with diaphragmatic excursion and exercise capacity in COPD. This retrospective single-centre study included 100 patients with stable COPD who underwent chest CT, spirometry, ultrasonographic assessment of DEmax, and 6-minute walk distance (6MWD) testing. Diaphragmatic crus thickness was measured on axial CT images, and the diaphragmatic thickness index (DTI) was calculated after adjustment for body mass index. Multivariable linear regression analyses were performed to identify factors independently associated with DEmax and 6MWD. Patients were stratified according to DTI and DEmax to evaluate combined structural and functional diaphragm phenotypes. In multivariable analyses, DTI was independently associated with DEmax (β = 0.57, p < 0.001) and 6MWD (β = 0.25, p < 0.01) after adjustment for age, pulmonary function, and skeletal muscle indices. The combined low-DTI/low- DEmax phenotype was independently associated with reduced exercise capacity (6MWD < 350 m; odds ratio 14.89, 95
Urinary incontinence (UI) is common among female patients with chronic cough; however, factors associated with persistent UI and related clinical outcomes remain insufficiently defined. Longitudinal data were analyzed from female patients with chronic cough enrolled in the Korean Chronic Cough Registry. Study participants received cough guideline-based management. Cough-associated UI status and patient-reported outcome (PRO) measures were evaluated at baseline and at 6 months. UI status was categorized as persistent, resolved, or absent based on findings at both time points. Baseline clinical characteristics were compared across groups, and regression analyses were conducted to identify factors associated with persistent UI and to estimate longitudinal changes in PROs. Among 206 female study participants, 24.3
Type 2 (T2) inflammatory biomarkers are established therapeutic targets in asthma and non-asthmatic eosinophilic bronchitis (NAEB), but their relevance in chronic cough remains unclear. Therefore, the objective of our study was to evaluate the relationship between T2 biomarkers and cough outcomes, and to determine their ability to predict treatment response and cough control. This post-hoc analysis of the prospective PROCOUGH cohort included 100 patients with chronic cough. Patients underwent comprehensive phenotyping and were classified as chronic cough secondary to asthma/NAEB (CCAst/EB) or refractory chronic cough (RCC). Patients with CCAst/EB received inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy, while those without evidence of T2 inflammation or who had failed ICS/LABA were treated with neuromodulators. Cough outcomes included 24-h cough frequency, Leicester cough questionnaire (LCQ), and cough severity visual analogue scale (VAS). Baseline and post-treatment FeNO, blood eosinophils, and sputum eosinophils were measured. Correlation, logistic regression, and receiver operating characteristic (ROC) analyses were performed. Baseline FeNO and sputum eosinophils were higher in CCAst/EB than RCC. In CCAst/EB, ICS/LABA treatment reduced FeNO and sputum eosinophils and improved cough frequency, LCQ, and VAS. However, only changes in FeNO correlated with changes in cough frequency (r = 0.43, p = 0.007). In multivariable analysis, baseline FeNO independently predicted cough control (OR 1.03, 95
Dysregulation of lipid metabolism has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We aimed to evaluated the predictive value of adipokines in IPF diagnosis and prognosis. Clinical data of patients with IPF (n = 100) and healthy controls (n = 64) were retrospectively analysed. Plasma adipokine levels including leptin and adiponectin were measured using enzyme-linked immunosorbent assay. The mean age of patients with IPF was 68.4 years and 83.0
The COVID-19 pandemic further emphasized the global demand for heparin and its expanding clinical relevance, indicating that even one of the oldest drugs in medicine continues to reveal new therapeutic horizons. Traditionally recognized for its anticoagulant and antithrombotic activities, heparin is increasingly being explored for its versatile therapeutic potential in the treatment of a range of pulmonary diseases, including respiratory infections (e.g. COVID-19), Acute Respiratory Distress Syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In all of these diseases, inhaled unfractionated heparin (UFH) therapy has been investigated in a number of clinical trials that have demonstrated promise for this drug when administered directly to the lungs. However, using heparin by this “off label” route of administration, poses a number of technical challenges: the physicochemical properties of heparin at therapeutic doses often results in highly viscous formulations, causing device blockage and drug sorption during nebulization. These limitations underscore the need for innovative formulation strategies to improve aerosol flow, reduce dosing inefficiencies, and enable reliable pulmonary administration. Advancing heparin formulations for delivery to the lung could therefore unlock significant benefits for a wide spectrum of respiratory disorders, marking a new chapter in the long medical history of this drug as discussed below.
Smoking history and age are established lung cancer risk factors incorporated into screening guidelines. Social vulnerability index (SVI), a social determinant of health, has also been associated with cancer risk. We investigated the association between SVI and malignancy in high-risk, screen-detected pulmonary nodules. Patients with lung-RADS 4A, 4B, or 4X nodules identified on low-dose computed tomography screening at a single institution (2015–2024) were included. Non-Illinois residents, patients with incomplete address data, loss to follow-up, or declined evaluation were excluded. Malignancy was confirmed through clinical assessment, staging, and positron emission tomography imaging. SVI was determined by geocoding patient addresses to census tracts and applying the CDC tract-level SVI calculator. Logistic regression assessed associations between SVI and malignancy, including interaction models evaluating whether the association varied by dominant nodule size. Youden’s analysis identified the optimal SVI cutpoint. Among 398 patients, 50
