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Nature Communications Nov 2023Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and...
Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
Topics: Humans; Neutrophils; COVID-19; CD8-Positive T-Lymphocytes; Lung; T-Lymphocytes, Cytotoxic
PubMed: 37940670
DOI: 10.1038/s41467-023-42421-0 -
Annals of the American Thoracic Society Jul 2023Currently used spirometry measures of airflow obstruction are influenced by demographics, predominantly by age, complicating selection of diagnostic thresholds for the...
Currently used spirometry measures of airflow obstruction are influenced by demographics, predominantly by age, complicating selection of diagnostic thresholds for the presence of airflow obstruction. To develop diagnostic thresholds for Parameter D, a new metric for detection of airflow obstruction, which quantifies the rate of rise of expiratory volume over time. We analyzed spirometry data of normal subjects enrolled in the 2007-2008, 2009-2010, and 2011-2012 NHANES (National Health and Nutrition Examination Survey) cohorts and calculated Parameter D using the expiratory volume-time curve. Relationships between demographics and lung function (forced expiratory volume in 1 second [FEV], FEV/forced vital capacity [FVC], and Parameter D) were tested using generalized linear models in NHANES and UK Biobank. The variation in lung function explained by demographics was estimated using . A diagnostic threshold was developed for Parameter D using population-based percentiles. Based on concordance between the lower limit of normal (LLN) for FEV/FVC and the Parameter D threshold, four groups were identified: normal (no airflow obstruction by either criterion), Dchronic obstructive pulmonary disease (DCOPD; positive by Parameter D only), DCOPD (positive by LLN only), and COPD (positive by both criteria), and associations with structural lung disease, exacerbations, and mortality were tested using multivariable analyses. In contrast to FEV and FEV/FVC, demographics cumulatively explained only 9% of the variance in Parameter D in NHANES ( = 4,945) and 3% in UK BioBank ( = 109,623). In COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) ( = 9,542), a diagnostic threshold of -3.15 resulted in the identification of an additional 10.8% of participants with airflow obstruction. A total of 3.7% had FEV/FVC < LLN but were missed by the Parameter D threshold. Compared with subjects in the normal group, after adjustment for age, sex, race, body mass index, pack-years of smoking, and current smoking status, DCOPD was associated with worse structural lung disease (odds ratio [OR] for ⩾5% emphysema, 1.71; 95% confidence interval [CI], 1.37-2.12; OR for functional small airway disease ⩾ 15%, 2.1; 95% CI, 1.79-2.67) and significant symptoms (OR for modified Medical Research Council dyspnea score ⩾ 2, 1.25; 95% CI, 1.07-1.47; OR for St. George's respiratory questionnaire ⩾ 25, 1.31; 95% CI, 1.13-1.53), a greater frequency of exacerbations (incidence rate ratio, 1.26; 95% CI, 1.10-1.46), and higher mortality (hazard ratio, 1.32; 95% CI, 1.10-1.57). Over 5 years, 28% of the DCOPD group versus 8% of normal group progressed to COPD by traditional criteria. Parameter D is not affected by age, and a normal population-based diagnostic threshold results in the early identification of additional individuals with airflow obstruction with a substantial amount of structural lung disease and respiratory symptoms.
Topics: Humans; Nutrition Surveys; Pulmonary Disease, Chronic Obstructive; Lung; Lung Diseases; Forced Expiratory Volume; Vital Capacity; Spirometry; Asthma
PubMed: 36989246
DOI: 10.1513/AnnalsATS.202209-816OC -
NPJ Primary Care Respiratory Medicine Aug 2023This cross-sectional study of 136 patients with chronic obstructive pulmonary disease (COPD) investigated the mechanism underlying overlap syndrome, defined as...
This cross-sectional study of 136 patients with chronic obstructive pulmonary disease (COPD) investigated the mechanism underlying overlap syndrome, defined as coexisting COPD and obstructive sleep apnea (OSA). OSA was defined as a respiratory event index (REI) ≥ 5 events/h, determined using type-3 portable monitors. The mean REI was 12.8 events/h. Most participants (60.1%) had mild OSA (REI: 5-15 events/h). The REI was positively correlated with forced expiratory volume in one second (%FEV) (r = 0.33, p < 0.001), body mass index (BMI) (r = 0.24, p = 0.005), and fat-free mass index (r = 0.31, p = 0.005), and negatively correlated with residual volume divided by total lung capacity (r = -0.27, p = 0.003). Receiver-operating characteristic curve analysis revealed an optimal BMI cutoff of 21.96 kg/m for predicting moderate/severe OSA. A BMI ≥ 21.96 kg/m was associated with OSA among participants with %FEV ≥ 50%, but not those with %FEV < 50%. This study revealed an interaction between airflow limitation and hyperinflation, nutritional status, and OSA.
Topics: Humans; Cross-Sectional Studies; Body Mass Index; Pulmonary Disease, Chronic Obstructive; Sleep Apnea, Obstructive; Lung
PubMed: 37582926
DOI: 10.1038/s41533-023-00351-w -
BMJ Open Respiratory Research Nov 2023Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results...
Association between serum high-density lipoprotein cholesterol and lung function in adults: three cross-sectional studies from US and Korea National Health and Nutrition Examination Survey.
INTRODUCTION
Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results regarding lung function. Therefore, we investigated the association between lung function and HDL-C levels in three cross-sectional studies conducted in the USA and South Korea.
METHODS
US National Health and Nutrition Examination Survey (NHANES) III, US NHANES 2007-2012, and Korea National Health and Nutrition Examination Survey (KNHANES) IV-VII performed spirometry and met the American Thoracic Society recommendations. Multiple linear regression models were used to determine the relationship between serum lipid levels and lung function. The models were adjusted for age, sex, household income, body mass index, smoking pack year, use of lipid-lowering medication and race. Serum HDL-C levels were classified into three groups to assess the dose-response relationship according to the guideline from the National Cholesterol Education Program-Adult Treatment Panel III.
RESULTS
The adult participants of the KNHANES (n=31 288), NHANES III (n=12 182) and NHANES 2007-2012 (n=9122) were analysed. Multivariate linear regression analysis of the serum cholesterol profiles revealed that only serum HDL-C was associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV) in all three studies. A 1 SD increase in the HDL-C level increased the percent predicted FVC by 0.5%-1.5% p, and the per cent predicted FEV by 0.5%-1.7% p. In terms of HDL-C levels, correlations between the HDL-C groups and the per cent predicted FVC and FEV showed dose-response relationships. Compared with the normal group, high HDL-C levels increased FVC by 0.75%-1.79% p and FEV by 0.55%-1.90% p, while low levels led to 0.74%-2.19% p and 0.86%-2.68% p reductions in FVC and FEV, respectively. Subgroup analyses revealed weaker associations in females from KNHANES and NHANES III.
CONCLUSION
In the three nationwide cross-sectional studies, high HDL-C levels were associated with improved FVC and FEV. However, future studies are needed to confirm this correlation and elucidate the underlying mechanisms.
Topics: Female; Humans; Adult; United States; Nutrition Surveys; Cross-Sectional Studies; Cholesterol; Republic of Korea; Lung; Lipoproteins, HDL
PubMed: 37940356
DOI: 10.1136/bmjresp-2023-001792 -
Lung Cancer (Amsterdam, Netherlands) Jul 2023Screening reduces lung cancer mortality of high-risk populations. Currently proposed screening eligibility criteria only identify half of those individuals, who later...
INTRODUCTION
Screening reduces lung cancer mortality of high-risk populations. Currently proposed screening eligibility criteria only identify half of those individuals, who later develop lung cancer. This study aimed to develop and validate a sensitive and simple model for predicting 10-year lung cancer risk.
METHODS
Using the 1991-94 examination of The Copenhagen City Heart Study in Denmark, 6,820 former or current smokers from the general population were followed for lung cancer within 10 years after examination. Logistic regression of baseline variables (age, sex, education, chronic obstructive pulmonary disease, family history of lung cancer, smoking status and cumulative smoking, secondhand smoking, occupational exposures to dust and fume, body mass index, lung function, plasma C-reactive protein, and AHRR(cg05575921) methylation) identified the best predictive model. The model was validated among 3,740 former or current smokers from the 2001-03 examination, also followed for 10 years. A simple risk chart was developed with Poisson regression.
RESULTS
Age, sex, education, smoking status, cumulative smoking, and AHRR(cg05575921) methylation identified 65 of 88 individuals who developed lung cancer in the validation cohort. The highest risk group, consisting of less educated men aged >65 with current smoking status and cumulative smoking >20 pack-years, had absolute 10-year risks varying from 4% to 16% by AHRR(cg05575921) methylation.
CONCLUSION
A simple risk chart including age, sex, education, smoking status, cumulative smoking, and AHRR(cg05575921) methylation, identifies individuals with 10-year lung cancer risk from below 1% to 16%. Including AHRR(cg05575921) methylation in the eligibility criteria for screening identifies smokers who would benefit the most from screening.
Topics: Humans; Male; Basic Helix-Loop-Helix Transcription Factors; DNA Methylation; Lung; Lung Neoplasms; Repressor Proteins; Risk Factors; Smoking; Female; Aged
PubMed: 37150141
DOI: 10.1016/j.lungcan.2023.107229 -
Life (Basel, Switzerland) Sep 2023Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, characterized by progressive parenchymal fibrosis and respiratory...
Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, characterized by progressive parenchymal fibrosis and respiratory failure. In a model of bleomycin-induced pulmonary fibrosis, the antifibrotic and anti-inflammatory activity of Longidaze (Bovhyaluronidase Azoxymer), which contains a conjugate of the hyaluronidase enzyme with a high molecular weight synthetic carrier azoxymer bromide, was investigated. Experiments were conducted in male C57BL/6 mice. Longidaze was administered at different doses by intranasal and intramuscular routes. Histology, hematology, and enzyme-linked immunosorbent assay were used in the study. The use of Longidaze reduced pulmonary fibrosis, as evidenced by an improvement in histopathologic damage to the lungs, a decrease in the area of connective tissue, and the levels of profibrotic factors (TGF-β1, hydroxyproline, collagen I) in lung tissue. In addition, Longidaze inhibited the inflammatory response in pulmonary fibrosis, and decreased the levels of IL-6, TNF-α, and hyaluronic acid in lung tissue and the recruitment of inflammatory cells into lung tissue. The highest therapeutic efficacy was observed with the use of Longidaze at doses of 120 and 1200 U/kg intramuscularly, which was superior to that of the reference drug pirfenidone axunio. The data presented in this study suggest that Longidaze is a new and promising drug for the treatment of IPF that warrants further investigation in patients with fibrotic interstitial lung disease.
PubMed: 37763335
DOI: 10.3390/life13091932 -
Thorax Sep 2023Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described.
INTRODUCTION
Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described.
OBJECTIVES
We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV)
METHODS
768 children, aged 7-12 years, underwent FE measurements and spirometry before and after salbutamol. Groups were compared using parametric tests; multinomial regression was used.
RESULTS
22.6% of 544 preterm-born (mean gestation: 31 weeks) and 9.2% of 195 term-born children, with satisfactory data available, were classified into one of four abnormal spirometry groups. Each phenotype was generally more prevalent in preterm-born children than in the term-born children. For the preterm group, POLD-reversible (4.4%) was associated with increased FE, bronchopulmonary dysplasia (BPD) and intrauterine growth restriction. POLD-fixed group (3.3%) did not have increased FE but was associated with BPD. 41% of the pDysanapsis group (5.9%) had bronchodilator response, 31% had increased FE and was associated with postnatal weight gain. In the pPRISm group (9%), 13% responded to bronchodilators, FE was not increased and was non-significantly associated with body mass index (p=0.064).
CONCLUSIONS
Further to airway obstruction, we describe airway dysanapsis and pPRISm spirometry phenotypes in survivors of prematurity, both of which have poor outlook in other disease groups. By identifying specific phenotypes, targeted therapy can be developed to improve long-term outcomes.
Topics: Humans; Infant, Newborn; Bronchodilator Agents; Bronchopulmonary Dysplasia; Forced Expiratory Volume; Lung; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Spirometry; Vital Capacity; Premature Birth; Infant, Premature
PubMed: 36725332
DOI: 10.1136/thorax-2022-219301 -
Advances in Therapy Dec 2023In the INBUILD trial in patients with progressive pulmonary fibrosis other than idiopathic pulmonary fibrosis (IPF), nintedanib slowed the rate of decline in forced...
INTRODUCTION
In the INBUILD trial in patients with progressive pulmonary fibrosis other than idiopathic pulmonary fibrosis (IPF), nintedanib slowed the rate of decline in forced vital capacity (FVC; mL/year) over 52 weeks compared with placebo. We assessed the efficacy of nintedanib across subgroups in the INBUILD trial by baseline characteristics.
METHODS
We assessed the rate of decline in FVC over 52 weeks and time to progression of interstitial lung disease (ILD) (absolute decline from baseline in FVC % predicted > 10%) or death over the whole trial in subgroups based on sex, age, race, body mass index (BMI), time since diagnosis of ILD, FVC % predicted, diffusing capacity of the lungs for carbon monoxide (DLco) % predicted, composite physiologic index (CPI), GAP (gender, age, lung physiology) stage, use of anti-acid therapy and use of disease-modifying antirheumatic drugs (DMARDs) at baseline.
RESULTS
The effect of nintedanib versus placebo on reducing the rate of decline in FVC over 52 weeks was consistent across the subgroups by baseline characteristics analysed. Interaction p values did not indicate heterogeneity in the treatment effect between these subgroups (p > 0.05). Over the whole trial (median follow-up time ∼19 months), progression of ILD or death occurred in similar or lower proportions of patients treated with nintedanib than placebo across the subgroups analysed, with no heterogeneity detected between the subgroups.
CONCLUSIONS
In the INBUILD trial, no heterogeneity was detected in the effect of nintedanib on reducing the rate of ILD progression across subgroups based on demographics, ILD severity or use of anti-acid therapy or DMARDs. These data support the use of nintedanib as a treatment for progressive pulmonary fibrosis.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Identifier: NCT02999178.
Topics: Humans; Lung; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Vital Capacity; Treatment Outcome; Antirheumatic Agents; Disease Progression
PubMed: 37751022
DOI: 10.1007/s12325-023-02668-x -
Seminars in Arthritis and Rheumatism Feb 2024Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung...
OBJECTIVE
Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD).
METHODS
In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality.
RESULTS
We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68).
CONCLUSION
In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.
Topics: Humans; Male; Aged; Female; Retrospective Studies; Lung Diseases, Interstitial; Arthritis, Rheumatoid; Lung; Lung Transplantation
PubMed: 38056314
DOI: 10.1016/j.semarthrit.2023.152312 -
Scientific Reports Oct 2023Studies considering the relationship between non-obesity-related body composition and lung function are few; therefore, this study aimed to explore these correlations...
Studies considering the relationship between non-obesity-related body composition and lung function are few; therefore, this study aimed to explore these correlations and effects. This cross-sectional study conducted in rural Qingtongxia City and Pingluo County, Ningxia, China, included 776 participants aged 30-75 years. Body composition and lung function were measured using direct segmental multifrequency bioelectrical impedance analysis and a digital spirometer, respectively. Their correlation was assessed using partial correlation analysis, controlling for age and smoking status, and the body composition effect on lung function was analyzed using binomial logistic regression analysis. The body components total body water content, protein content, mineral content, muscle mass, fat-free mass (FFM), skeletal muscle mass, basal metabolic volume, and chest circumference (CC) positively correlated with pulmonary function (forced vital capacity and forced expiratory volume in one second) in both sexes. Neck circumference and hip circumference positively correlated with pulmonary function in women. Additionally, lung function declines more slowly in women (odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.44-0.98, p = 0.04); CC (OR = 0.92, 95% CI = 0.86-0.98, p = 0.01) increased as a protective factor for decreased lung function. Increased waist circumference (OR = 1.04, 95% CI = 1.00-1.09, p = 0.04) was a risk factor for reduced lung function. FFM contains body composition indicators positively correlating with lung function, excluding fat-related body composition. Abdominal obesity increases the risk of decreased lung function.
Topics: Male; Humans; Female; Cross-Sectional Studies; Body Mass Index; Body Composition; Lung; Obesity
PubMed: 37857639
DOI: 10.1038/s41598-023-44486-9