Effects of donor smoking history on early post-transplant lung function measured by oscillometry.

Introduction: Prior studies assessing outcomes of lung transplants from cigarette-smoking donors found mixed results. Oscillometry, a non-invasive test of respiratory impedance, detects changes in lung function of smokers prior to diagnosis of COPD, and identifies spirometrically silent episodes of rejection post-transplant. We hypothesise that oscillometry could identify abnormalities in recipients of smoking donor lungs and discriminate from non-smoking donors. Methods: This prospective single-center cohort study analysed 233 double-lung recipients. Oscillometry was performed alongside routine conventional pulmonary function tests (PFT) post-transplant. Multivariable regression models were constructed to compare oscillometry and conventional PFT parameters between recipients of lungs from smoking vs non-smoking donors. Results: The analysis included 109 patients who received lungs from non-smokers and 124 from smokers. Multivariable analysis identified significant differences between recipients of smoking and non-smoking lungs in the oscillometric measurements R5-19, X5, AX, R5z and X5z, but no differences in %predicted FEV1, FEV1/FVC, %predicted TLC or %predicted DLCO. An analysis of the smoking group also demonstrated associations between increasing smoke exposure, quantified in pack years, and all the oscillometry parameters, but not the conventional PFT parameters. Conclusion: An interaction was identified between donor-recipient sex match and the effect of smoking. The association between donor smoking and oscillometry outcomes was significant predominantly in the female donor/female recipient group.

Respiratory oscillometry with CT image analysis in idiopathic pulmonary fibrosis following single lung transplant.

Oscillometry is an emerging pulmonary function testing tool that is conducted during tidal breaths with minimal patient effort. It is highly sensitive to changes in lung mechanics. Oscillometry was recently shown to be highly associated with disease severity in idiopathic pulmonary fibrosis (IPF). The usefulness of oscillometry after single lung transplant in IPF patients is not well understood. Our study demonstrated that oscillometry can detect changes in the graft despite presence of a native fibrotic lung to provide useful information to complement spirometry.

Association of ever use of e-cigarettes with health and lifestyle variables among young adults: a Canadian health measure survey study.

Research suggests that vaping raises oxidative stress levels and has been implicated in poor mental health. The objective of this study is to assess cross-sectional associations between quality of life (QOL) indicators and e-cigarette (EC) use in young Canadian adults. We used data from the 2016-2017 Canadian Health Measures Survey. We compared physical activity (daily steps), physiological measurements (high-density lipoprotein for cholesterol level), self-perceived life stress, mental health, and QOL between ever-use EC users and non-users. Multivariable binary or ordinal logistic regressions were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Analyses included 905 participants (15-30 years) with 115 (12.7%) reporting EC use and 790 non-users. After adjusting for confounders, compared to non-users, EC users had significantly higher odds of being physically active (OR = 2.19, 95%CI: 1.14-4.20) but also with self-reported extreme life stress (OR = 2.68, 95%CI: 1.45-4.92). Albeit statistically non-significant, EC users also had higher odds of poorer QOL (OR = 1.12, 95%CI: 0.64-1.95). No statistically significant interactions between EC use, cigarette smoking, cannabis consumption and health outcomes were observed. CONCLUSION: Our study found that EC use was independently and significantly associated with increased odds of life stress and an indication of poorer QOL. Ongoing surveillance on young EC users is important to measure the long-term impact of vaping on their physical, mental health and quality of life to target for interventions. WHAT IS KNOWN: • E-cigarette use has been associated with high-risk behaviours and adverse mental health outcomes, such as depression and anxiety. WHAT IS NEW: • E-cigarette users had significantly higher odds of being physically active and higher amounts of life stress.

Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Bronchodilator Efficacy of High-Flow Nasal Cannula in COPD: Vibrating Mesh Nebulizer Versus Jet Nebulizer.

BACKGROUND: Jet nebulizers are commonly used for bronchodilator therapy in COPD. High-flow nasal cannula with vibrating mesh nebulizer (HFNC-VMN) is a recently developed system; however, few studies have compared the efficacy of bronchodilator administration via HFNC-VMN to jet nebulizer in stable COPD. This study aimed to compare the effect of salbutamol administered via HFNC-VMN versus jet nebulizer on airway and lung function in subjects with stable COPD. METHODS: This randomized non-inferiority crossover physiologic study enrolled subjects with stable COPD. Salbutamol was nebulized via HFNC-VMN or jet nebulizer in random order with a 4-h washout period between crossover sequences. Spirometry, lung volume, and impulse oscillometry were performed at baseline and after each intervention. The primary outcome was change in FEV1 from baseline. Secondary outcomes included changes in other respiratory-related parameters and nebulization time compared between the 2 devices. RESULTS: Seventeen subjects were enrolled. HFNC-VMN and jet nebulizer both significantly improved FEV1 from baseline (P = .005 and P = .002, respectively). The difference between respiratory resistance at 5 Hz and 20 Hz significantly decreased after HFNC-VMN compared to baseline (P = .02), while no significant change was observed after jet nebulizer (P = .056). Area of reactance and resonant frequency of reactance were both significantly decreased (P = .035 and P = .03, respectively), and respiratory reactance at 5 Hz significantly increased (P = .02) in the HFNC-VMN group compared to baseline indicating improved lung mechanics, with no significant changes with the jet nebulizer. HFNC-VMN had a shorter nebulization time (6 [5-9] min vs 20 [16-22] min, respectively, P < .001). CONCLUSIONS: Bronchodilator therapy via HFNC-VMN was not inferior to jet nebulizer for subjects with stable COPD and can significantly improve airway oscillometry mechanics and decrease nebulization time compared to jet nebulizer.

Quality control in respiratory oscillometry: reproducibility measures ignoring reactance?

This study demonstrates the inadequacy of the current technical standards of oscillometry that are based on the within-trial reproducibility of the lowest-frequency Rrs, and suggests the use of a simple variability measure encompassing both Rrs and Xrs https://bit.ly/3AYRid6.

Intra-subject variability in oscillometry correlates with acute rejection and CLAD post-lung transplant.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death post-lung transplantation, with acute cellular rejection (ACR) being the biggest contributing risk factor. Although patients are routinely monitored with spirometry, FEV1 is stable or improving in most ACR episodes. In contrast, oscillometry is highly sensitive to respiratory mechanics and shown to track graft injury associated with ACR and its improvement following treatment. We hypothesize that intra-subject variability in oscillometry measurements correlates with ACR and risk of CLAD. Methods: Of 289 bilateral lung recipients enrolled for oscillometry prior to laboratory-based spirometry between December 2017 and March 2020, 230 had ≥ 3 months and 175 had ≥ 6 months of follow-up. While 37 patients developed CLAD, only 29 had oscillometry at time of CLAD onset and were included for analysis. These 29 CLAD patients were time-matched with 129 CLAD-free recipients. We performed multivariable regression to investigate the associations between variance in spirometry/oscillometry and the A-score, a cumulative index of ACR, as our predictor of primary interest. Conditional logistic regression models were built to investigate associations with CLAD. Results: Multivariable regression showed that the A-score was positively associated with the variance in oscillometry measurements. Conditional logistic regression models revealed that higher variance in the oscillometry metrics of ventilatory inhomogeneity, X5, AX, and R5-19, was independently associated with increased risk of CLAD (p < 0.05); no association was found for variance in %predicted FEV1. Conclusion: Oscillometry tracks graft injury and recovery post-transplant. Monitoring with oscillometry could facilitate earlier identification of graft injury, prompting investigation to identify treatable causes and decrease the risk of CLAD.

Cardiovascular Considerations in the Management of People With Suspected Long COVID.

Approximately 15% of adult Canadians with SARS-CoV-2 infection develop lingering symptoms beyond 12 weeks after acute infection, known as post-COVID condition or long COVID. Some of the commonly reported long COVID cardiovascular symptoms include fatigue, shortness of breath, chest pain, and palpitations. Suspected long-term cardiovascular complications of SARS-CoV-2 infection might present as a constellation of symptoms that can be challenging for clinicians to diagnose and treat. When assessing patients with these symptoms, clinicians need to keep in mind myalgic encephalomyelitis/chronic fatigue syndrome, postexertional malaise and postexertional symptom exacerbation, dysautonomia with cardiac manifestations such as inappropriate sinus tachycardia, and postural orthostatic tachycardia syndrome, and occasionally mast cell activation syndrome. In this review we summarize the globally evolving evidence around management of cardiac sequelae of long COVID. In addition, we include a Canadian perspective, consisting of a panel of expert opinions from people with lived experience and experienced clinicians across Canada who have been involved in management of long COVID. The objective of this review is to offer some practical guidance to cardiologists and generalist clinicians regarding diagnostic and treatment approaches for adult patients with suspected long COVID who continue to experience unexplained cardiac symptoms.

Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Generalized Hypermobility Spectrum Disorder: Protocol for a Pilot and Feasibility Randomized Controlled Trial.

BACKGROUND: Dyspnea is a prevalent symptom in individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and generalized hypermobility spectrum disorder (G-HSD), yet its contributors have not been identified. One known contributor to dyspnea is respiratory muscle weakness. The feasibility and effectiveness of inspiratory muscle training (IMT) in combination with standard-of-care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) in improving respiratory muscle strength and patient-reported outcomes in patients with hEDS or G-HSD have not been evaluated. OBJECTIVE: This study aims to evaluate dyspnea, respiratory muscle strength, and patient-reported outcome measures (PROMs) in hEDS or G-HSD compared with healthy controls and to assess the feasibility of a randomized controlled trial of IMT and standard-of-care rehabilitation for improving respiratory muscle strength, exercise capacity, and PROMs compared with standard-of-care rehabilitation in hEDS and G-HSD. METHODS: The study will include 34 participants with hEDS or G-HSD and 17 healthy, age- and sex-matched controls to compare respiratory muscle structure and function and PROMs. After baseline assessments, participants with hEDS or G-HSD will be randomized into the intervention group and provided IMT combined with Ehlers-Danlos Syndrome standard-of-care rehabilitation or into the usual care group, and provided only standard-of-care rehabilitation for 8 weeks. The intervention group will be prescribed IMT in their home environment using the POWERbreathe K5 IMT device (POWERbreathe International Ltd). IMT will comprise 2 daily sessions of 30 breaths for 5 days per week, with IMT progressing from 20% to 60% of the baseline maximal inspiratory pressure (MIP) over an 8-week period. Feasibility will be assessed through rates of recruitment, attrition, adherence, adverse events, and participant satisfaction. The primary pilot outcome is MIP change over an 8-week period in hEDS or G-HSD. Secondary outcomes will include the evaluation of dyspnea using Medical Research Council Scale and 18-point qualitative dyspnea descriptors; diaphragmatic thickening fraction using ultrasound; respiratory muscle endurance; pulmonary function; prefrontal cortical activity using functional near-infrared spectroscopy; aerobic capacity during cardiopulmonary exercise testing; quality of life using Short Form-36; and scores from the Depression, Anxiety, and Stress scale-21. These measures will also be performed once in healthy controls to compare normative values. Multivariable regression will be used to assess the contributors to dyspnea. Paired 2-tailed t tests will be used to assess the changes in MIP and secondary measures after 8 weeks of IMT. RESULTS: Study recruitment began in August 2021 and, with several disruptions owing to COVID-19, is expected to be completed by December 2023. CONCLUSIONS: This study will provide a better understanding of the factors associated with dyspnea and the feasibility and effectiveness of IMT combined with standard-of-care rehabilitation. IMT may be a novel therapeutic strategy for improving respiratory muscle function and patient-reported outcomes in individuals with hEDS or G-HSD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04972565; https://clinicaltrials.gov/ct2/show/NCT04972565. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44832.

Vaping and Health Service Use: A Canadian Health Survey and Health Administrative Data Study.

Rationale: Emerging research suggests that e-cigarette (EC) use may have detrimental health effects, increasing the burden on healthcare systems. Objectives: To determine whether young EC users had increased asthma, asthma attacks, and health services use (HSU). Methods: This cohort study used the linked Canadian Community Health Survey (cycles 2015-16 and 2017-18) and health administrative data (January 2015-March 2018). A propensity score method matched self-reported EC users to up to five control subjects. Matched multivariable logistic and negative binomial regressions were used to calculate odds ratios, rate ratios (RRs), and 95% confidence intervals (CIs) with EC use as the exposure and asthma, asthma attacks, and all-cause HSU as the outcomes. Results: Analyses included 2,700 matched Canadian Community Health Survey participants (15-30 yr), 505 (2.4% of 20,725 participants) EC users matched to 2,195 nonusers. After adjusting for confounders, EC users with asthma had over twofold higher odds of having an asthma attack in the last 12 months (odds ratio, 2.30; 95% CI, 1.29-4.12). Dual EC and conventional tobacco users had a twofold increased all-cause HSU rate compared with nonusers who never smoked tobacco (RR, 2.13; 95% CI, 1.53-2.98). This rate was greater than that for EC users who never smoked tobacco (RR, 1.73; 95% CI, 1.00-3.00) and non-EC users who regularly smoke tobacco (RR, 1.72; 95% CI, 1.29-2.29). Compared with male nonusers, female EC users had the highest increased all-cause HSU (RR, 1.94; 95% CI, 1.39-2.69) over male EC users and female nonusers (RR, 1.13; 95% CI, 0.86-1.48; RR, 1.41; 95% CI, 1.16-1.71, respectively). Conclusions: Current EC use is associated with significantly increased odds of having an asthma attack. Furthermore, concurrent EC use and conventional cigarette smoking are associated with a higher rate of all-cause HSU. The odds of asthma attack and all-cause HSU were highest among women. Thus, EC use may be an epidemiological biomarker for youth and young adults with increased health morbidity.

Deep learning using multilayer perception improves the diagnostic acumen of spirometry: a single-centre Canadian study.

RATIONALE: Spirometry and plethysmography are the gold standard pulmonary function tests (PFT) for diagnosis and management of lung disease. Due to the inaccessibility of plethysmography, spirometry is often used alone but this leads to missed or misdiagnoses as spirometry cannot identify restrictive disease without plethysmography. We aimed to develop a deep learning model to improve interpretation of spirometry alone. METHODS: We built a multilayer perceptron model using full PFTs from 748 patients, interpreted according to international guidelines. Inputs included spirometry (forced vital capacity, forced expiratory volume in 1 s, forced mid-expiratory flow25-75), plethysmography (total lung capacity, residual volume) and biometrics (sex, age, height). The model was developed with 2582 PFTs from 477 patients, randomly divided into training (80%), validation (10%) and test (10%) sets, and refined using 1245 previously unseen PFTs from 271 patients, split 50/50 as validation (136 patients) and test (135 patients) sets. Only one test per patient was used for each of 10 experiments conducted for each input combination. The final model was compared with interpretation of 82 spirometry tests by 6 trained pulmonologists and a decision tree. RESULTS: Accuracies from the first 477 patients were similar when inputs included biometrics+spirometry+plethysmography (95%±3%) vs biometrics+spirometry (90%±2%). Model refinement with the next 271 patients improved accuracies with biometrics+pirometry (95%±2%) but no change for biometrics+spirometry+plethysmography (95%±2%). The final model significantly outperformed (94.67%±2.63%, p<0.01 for both) interpretation of 82 spirometry tests by the decision tree (75.61%±0.00%) and pulmonologists (66.67%±14.63%). CONCLUSIONS: Deep learning improves the diagnostic acumen of spirometry and classifies lung physiology better than pulmonologists with accuracies comparable to full PFTs.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

Cannabis use and risks of respiratory and all-cause morbidity and mortality: a population-based, data-linkage, cohort study.

INTRODUCTION: Although cannabis is frequently used worldwide, its impact on respiratory health is characterised by controversy. OBJECTIVE: To evaluate the association between cannabis use and respiratory-related emergency room (ER) visits and hospitalisations. METHODS: A retrospective, population-based, cohort study was carried out, linking health survey and health administrative data for residents of Ontario, Canada, aged 12-65 years, between January 2009 and December 2015. Individuals self-reporting cannabis use within the past year were matched to control individuals (people who reported never using cannabis, or used cannabis only once, and more than 12 months ago) in upwards of a 1:3 ratio on 31 different variables, using propensity score matching methods. Respiratory-related and all-cause ER visits or hospitalisations, and all-cause mortality, were evaluated up to 12 months following the index date. RESULTS: We identified 35 114 individuals who had either used cannabis in the past year or were controls, of whom 6425 (18.3%) used cannabis in the past year. From this group, 4807 (74.8%) were propensity-score matched to 10 395 control individuals. In the propensity score matched cohort, there was no significant difference in odds of respiratory-related ER visit or hospitalisation between cannabis users and the control group (OR 0.91, 95% CI 0.77 to 1.09). Compared with control individuals, cannabis users had significantly increased odds of all-cause ER visit or hospitalisation (OR 1.22, 95% CI 1.13 to 1.31) and there was no significant difference with respect to all-cause mortality (OR 0.99, 95% CI 0.49 to 2.02). CONCLUSIONS: Although no significant association was observed between cannabis use and respiratory-related ER visits or hospitalisations, the risk of an equally important morbidity outcome, all-cause ER visit or hospitalisation, was significantly greater among cannabis users than among control individuals. Therefore, cannabis use is associated with increased risk for serious adverse health events and its recreational consumption is not benign.

Conducting Respiratory Oscillometry in an Outpatient Setting.

Respiratory oscillometry is a different modality of pulmonary function testing that is increasingly used in a clinical and research setting to provide information regarding lung mechanics. Respiratory oscillometry is conducted through three acceptable measurements of tidal breathing and can be performed with minimal contraindications. Young children and patients who cannot perform spirometry due to cognitive or physical impairment can usually complete oscillometry. The main advantages of respiratory oscillometry are that it requires minimal patient cooperation and is more sensitive in detecting changes in small airways than conventional pulmonary function tests. Commercial devices are now available. Updated technical guidelines, standard operating protocols, and quality control/assurance guidelines have recently been published. Reference values are also available. We conducted oscillometry test audits before and after implementing a formal respiratory oscillometry training program and standard operating protocol. We observed improvement in the quality of tests completed, with a significant increase in the number of acceptable and reproducible measurements. The current paper outlines and demonstrates a standard operating protocol to conduct respiratory oscillometry in an outpatient setting. We highlight the key steps to ensuring acceptable and reproducible quality measurements according to the recommended European Respiratory Society (ERS) guidelines, as quality control is critical to measurement accuracies. Potential problems and pitfalls are also discussed with suggestions to resolve technical errors.

Correlation of respiratory oscillometry with CT image analysis in a prospective cohort of idiopathic pulmonary fibrosis.

BACKGROUND: Markers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative and independent prognostic structural indicator derived from automated CT analysis. The current prospective cross-sectional study investigated whether respiratory oscillometry provides complementary data to pulmonary function tests (PFTs) and is correlated with PVV. METHODS: From September 2019 to March 2020, we enrolled 89 patients with IPF diagnosed according to international guidelines. We performed standard spectral (5-37 Hz) and novel intrabreath tracking (10 Hz) oscillometry followed by PFTs. Patients were characterised with the gender-age-physiology (GAP) score. CT images within 6 months of oscillometry were analysed in a subgroup (26 patients) using automated lung texture analysis. Correlations between PFTs, oscillometry and imaging variables were investigated using different regression models. FINDINGS: The cohort (29F/60M; age=71.7±7.8 years) had mild IPF (%FVC=70±17, %DLCO=62±17). Spectral oscillometry revealed normal respiratory resistance, low reactance, especially during inspiration at 5 Hz (X5in), elevated reactance area and resonance frequency. Intrabreath oscillometry identified markedly low reactance at end-inspiration (XeI). XeI and X5in strongly correlated with FVC (r2=0.499 and 0.435) while XeI was highly (p=0.004) and uniquely correlated with the GAP score. XeI and PVV exhibited the strongest structural-functional relationship (r2=0.690), which remained significant after adjusting for %FVC, %DLCO and GAP score. INTERPRETATION: XeI is an independent marker of IPF severity that offers additional information to standard PFTs. The data provide a cogent rationale for adding oscillometry in IPF assessment.

Diffusing capacity of the lung for carbon monoxide: association with long-term outcomes after lung transplantation in a 20-year longitudinal study.

RATIONALE: The diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (D LCOcor) measures gas movement across the alveolar-capillary interface. We hypothesised that D LCOcor is a sensitive measure of injurious allograft processes disrupting this interface. OBJECTIVES: To determine the prognostic significance of the D LCOcor trajectory on chronic lung allograft dysfunction (CLAD) and survival. METHODS: A retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or more D LCOcor measurements. Low baseline D LCOcor was defined as the failure to achieve a D LCOcor >75% predicted. Drops in D LCOcor were defined as >15% below recent baseline. RESULTS: 1259 out of 1492 lung transplant recipients were included. The median (range) time to peak D LCOcor was 354 (181-737) days and the mean±sd D LCOcor was 80.2±21.2% pred. Multivariable analysis demonstrated that low baseline D LCOcor was significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27-2.20; p<0.001). Low baseline D LCOcor was not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. Any D LCOcor declines ≥15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predicted D LCOcor values at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01). CONCLUSION: Low baseline D LCOcor and post-transplant declines in D LCOcor were significantly associated with survival, independent of spirometric measurements. We propose that D LCOcor testing may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring of D LCOcor after lung transplantation to identify patients at risk of poor outcomes.

Chronic lung allograft dysfunction phenotype and prognosis by machine learning CT analysis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the principal cause of graft failure in lung transplant recipients and prognosis depends on CLAD phenotype. We used a machine learning computed tomography (CT) lung texture analysis tool at CLAD diagnosis for phenotyping and prognostication compared with radiologist scoring. METHODS: This retrospective study included all adult first double lung transplant patients (January 2010-December 2015) with CLAD (censored December 2019) and inspiratory CT near CLAD diagnosis. The machine learning tool quantified ground-glass opacity, reticulation, hyperlucent lung and pulmonary vessel volume (PVV). Two radiologists scored for ground-glass opacity, reticulation, consolidation, pleural effusion, air trapping and bronchiectasis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of machine learning and radiologist for CLAD phenotype. Multivariable Cox proportional hazards regression analysis for allograft survival controlled for age, sex, native lung disease, cytomegalovirus serostatus and CLAD phenotype. RESULTS: 88 patients were included (57 bronchiolitis obliterans syndrome (BOS), 20 restrictive allograft syndrome (RAS)/mixed and 11 unclassified/undefined) with CT a median 9.5 days from CLAD onset. Radiologist and machine learning parameters phenotyped RAS/mixed with PVV as the strongest indicator (area under the curve (AUC) 0.85). Machine learning hyperlucent lung phenotyped BOS using only inspiratory CT (AUC 0.76). Radiologist and machine learning parameters predicted graft failure in the multivariable analysis, best with PVV (hazard ratio 1.23, 95% CI 1.05-1.44; p=0.01). CONCLUSIONS: Machine learning discriminated between CLAD phenotypes on CT. Both radiologist and machine learning scoring were associated with graft failure, independent of CLAD phenotype. PVV, unique to machine learning, was the strongest in phenotyping and prognostication.

Changes in interpretation of spirometry by implementing the GLI 2012 reference equations: impact on patients tested in a hospital-based PFT lab in a large metropolitan city.

BACKGROUND: The Global Lung Function Initiative (GLI-2012) focused on race/ethnicity as an important factor in determining reference values. This study evaluated the effects of changing from Canadian reference equations developed from an all-Caucasian cohort with European ancestry to the GLI-2012 on the interpretation of spirometry in a multiethnic population and aimed to identify the ethnic groups affected by discrepant interpretations. METHODS: Clinically indicated spirometry in a multiethnic population (aged 20-80 years) collected from 2018 to 2021 was analysed. The predicted and lower limit of normal (LLN) values were calculated using three sets of reference equations: Canadian, GLI-race/ethnic-based (GLI-Race) and GLI-race/ethnic-neutral (GLI-Other). We compared the prevalence of concordance in the abnormal diagnoses (defined as

Pulmonary Dysfunction Augmenting Bacterial Aerosols in Leather Tanneries of Punjab, Pakistan.

BACKGROUND: Particulate matter-associated microbes in the workplace are a burning issue in occupational toxicology. Studies have reported on respiratory infections among tannery cohorts. This study uniquely presents measurements of airborne bacterial concentrations associated with varied particulate-matter sizes, their exposure, and consequent severity in occupational respiratory problems, all for different microenvironments within leather tanneries. METHODS: Analyses included molecular identification of isolates, computation of mass median aerodynamic diameter of aerosols, tannery process-exposure dose (TPED) to bacterial aerosols, and spirometry and symptom assessment of impaired pulmonary function. RESULTS: The highest bacterial concentrations were for rawhide treatment and finishing units, showing 3.6×103 and 3.7×103 CFU/m3, respectively. Identified bacterial species included Ochrobactrum pseudogrignonense, Neisseria bacilliformis, Enterobacter cloacae, Alcaligenes faecalis, Klebsiella pneumoniae, and Corynebacterium spp. Maximum and minimum values of mass median aerodynamic diameter were 8.3 µm and 0.65 µm for buffing and snuffing and production units, respectively. The highest TPED was 1,516.9 CFU/kg for finishing units. Respiratory symptoms in order of incidence were dyspnea > phlegm > cough > wheezing and tachypnea (equivalent). Bronchodilator measurements of FEV1, FVC, and PEF represent decline in lung function. Of 26 patients identified with COPD, most were working in rawhide treatment. CONCLUSION: We conclude that exposure-infection synergy is also a cause of pulmonary ailments and COPD development, rather than the better-known exposure-smoking synergy.

Significance of phenotype change after chronic lung allograft dysfunction onset.

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR = 4.00, CI 2.74-5.83, P < 0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P < 0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.