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RATIONALE: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals. OBJECTIVES: To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis. METHODS: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1, in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu366Lys, rs28929474). MEASUREMENTS AND MAIN RESULTS: We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p=0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p=0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p

BackgroundMillions of Americans are living in food deserts in the United States, however the role of the local food environment on COPD has not been studied. The aim of this study is to determine the association between food deserts and COPD-related outcomes.MethodIn this cross-sectional analysis we linked data collected from SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) between 2010 and 2015 and food desert data, defined as an underserved area that lacks access to affordable healthy foods, from the Food Access Research Atlas. COPD outcomes include percentage of predicted forced expiratory volume in one second (FEV1%), St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), 6-min walk distance test (6MWD), exacerbations, and air trapping. We used generalized linear mixed models to evaluate the association between living in food deserts and respiratory outcomes, adjusting for age, gender, race, education, income, marital status, BMI, smoking status, pack years, and urban status RESULTS: Among 2713 participants, 22% lived in food deserts. Participants living in food deserts were less likely to be white and more likely to have a lower income than those who did not live in food deserts. In the adjusted model controlling for demographics and individual income, living in food deserts was associated lower FEV1% (β = - 2.51, P = 0.046), higher air trapping (β = 2.47, P = 0.008), worse SGRQ (β = 3.48, P = 0.001) and CAT (β = 1.20, P = 0.003) scores, and 56% greater odds of severe exacerbations (P = 0.004). Results were consistent when looking at food access alone, regardless of whether participants lived in low income areas.ConclusionsFindings suggest an independent association between food desert and food access alone with COPD outcomes. Health program planning may benefit from addressing disparities in access to food.

BackgroundAttenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers.Research questionIs use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema?MethodsFormer and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume

OBJECTIVE: Insulin resistance (IR) may be a risk factor for lung disease, but objective evidence is limited. We sought to define the relationship of longitudinal IR with radiographic imaging outcomes and examiner-identified incident lung disease in the Framingham Offspring Study. RESEARCH DESIGN AND METHODS: Participants without baseline lung disease underwent repeated measurements of fasting insulin and glucose levels over an average period of 13.6 years, from which time-weighted average HOMA-IR was calculated. Each participant then underwent a cardiac gated whole-lung computed tomography scan, which was analyzed for the presence of emphysema, interstitial lung abnormalities (ILAs), and quantitative airway features. Incident lung disease was determined by a study examiner. The relationship of HOMA-IR to these outcomes was estimated in models adjusted for demographics, BMI, and lifetime smoking. RESULTS: A total of 875 participants with longitudinal IR data and outcomes were identified. Their mean age was 51.5 years, and BMI was 26.7 kg/m2. HOMA-IR was temporally unstable, with a within-person SD approximately two-thirds of the between-person SD. In adjusted models, a 1 SD increase in log(HOMA-IR) z score was associated with higher odds of qualitative emphysema (odds ratio [OR] 1.33; 95% CI 1.04–1.70), ILAs (OR 1.35; 95% CI 1.05–1.74), and modest increases in airway wall thickness and wall area percentage. These radiographic findings were corroborated by a positive association of HOMA-IR with incident lung disease. CONCLUSIONS: IR is associated with radiographic lung abnormalities and incident lung disease. Deeper phenotyping is necessary to define mechanisms of IR-associated lung injury. [ABSTRACT FROM AUTHOR]

The article offers information that Asthma is a diverse illness. Variable airflow restriction is a trait that airway hyperresponsiveness characteristics, and persistent airway irritation Management is intended to lessen symptom load, enhancing lung capacity and avoiding severe deteriorations. It also mentions the way to gauge nitric oxide is to use breathed air and is mostly produced from due to inducible NO synthase 2's activity a generated from epithelial enzyme.

Introduction: There is evidence that obesity, a risk factor for asthma severity and morbidity, has a unique asthma phenotype which is less atopic and less responsive to inhaled corticosteroids (ICS). Peripheral blood mononuclear cells (PBMC) are important to the immunologic pathways of obese asthma and steroid resistance. However, the cellular source associated with steroid resistance has remained elusive. We compared the lymphocyte landscape among obese children with asthma to matched normal weight children with asthma and assessed relationship to asthma control. Methods: High-dimensional flow cytometry of PBMC at baseline and after dexamethasone stimulation was performed to characterize lymphocyte subpopulations, T-lymphocyte polarization, proliferation (Ki-67+), and expression of the steroid-responsive protein FK506-binding protein 51 (FKBP51). T-lymphocyte populations were compared between obese and normal-weight participants, and an unbiased, unsupervised clustering analysis was performed. Differentially expressed clusters were compared with asthma control, adjusted for ICS and exhaled nitric oxide. Results: In the obese population, there was an increased cluster of CD4+ T-lymphocytes expressing Ki-67 and FKBP51 at baseline and CD4+ T-lymphocytes expressing FKBP51 after dexamethasone stimulation. CD4+ Ki-67 and FKBP51 expression at baseline showed no association with asthma control. Dexamethasone-induced CD4+ FKBP51 expression was associated with worse asthma control in obese participants with asthma. FKBP51 expression in CD8+ T cells and CD19+ B cells did not differ among groups, nor did polarization profiles for Th1, Th2, Th9, or Th17 percentage. Discussion: Dexamethasone-induced CD4+ FKBP51 expression is uniquely associated with worse asthma control in obese children with asthma and may underlie the corticosteroid resistance observed in this population. [ABSTRACT FROM AUTHOR]

Biologic therapies are emerging as an option to treat a subset of patients with severe asthma, however no direct comparison between these agents has been conducted. Furthermore, heterogeneity of outcomes in clinical trials makes it difficult to compare these agents and traditional therapies. The extent to which this heterogeneity exists has major implications for evidence-based decisions and is yet to be fully reported. We conducted a literature search to examine outcomes currently being used in clinical trials for asthma. The Cochrane Library and Clinicaltrials.gov were searched for clinical trials of asthma interventions. We limited our search to phase 2 through 4 clinical trials in adults, as early-phase trials tend to have pharmacodynamic and pharmacokinetic endpoints as primary outcomes. Interventions for acute exacerbations were excluded. We identified 117 studies and subsequently identified 111 outcomes. The most prevalent outcomes were asthma control and symptom severity, FEV1, and change in ACQ scale. Twenty patient-reported outcomes instruments were identified and de-facto standard asthma outcomes and PROs were under-reported in examined literature. Existing quality of life tools did not capture the day-to-day experience or the unique treatment burden from oral corticosteroids for patient with severe asthma. Compounding the absence of trials directly comparing therapies, the significant variation we identified in outcome definitions and measurement create hurdles to effectively compare traditional and biologic therapies. With the growing number of clinical trials evaluating advanced therapies such as biologics, a wide range of primary and secondary outcomes are evaluated. A core outcome set created by relevant stakeholders is needed to collectively evaluate pooled outcomes in order to allow more meaningful comparisons of asthma therapies and to incorporate the patient experience. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alpha-1 antitrypsin deficiency is frequently underrecognized. Individuals with symptoms often experience long diagnostic delays. Although a delayed diagnosis is logically presumed to be associated with adverse effects, confirmatory evidence that a delay in diagnosis confers harm is sparse. The current study characterized the association between a delayed diagnosis and the clinical status at the time of diagnosis. METHODS: Patients with newly diagnosed severe deficiency of alpha-1 antitrypsin received questionnaires that assessed self-reported diagnostic delay, the St George Respiratory Questionnaire (SGRQ) and COPD Assessment Test. Results of spirometry were retrieved and the relationship between the diagnostic delay interval and FEV1% predicted, SGRQ, and COPD Assessment Test were assessed. RESULTS: Forty subjects were recruited (31 with PI*ZZ, 9 with PI*SZ). Values for FEV1% predicted, SGRQ, and COPD Assessment Test were available for 17, 40, and 32 subjects, respectively. The relationship between the diagnostic delay interval and all outcomes was directionally consistent with an adverse impact of increasing diagnostic delay. For each additional year of diagnostic delay, the subject's FEV1%predicted decreased by 0.3% (P = .66), The SGRQ Total score increased by 1.6 points (P < .001), and the COPD Assessment Test score increased by 0.7 points (P = .004). CONCLUSIONS: The results of this analysis were consistent with a delayed diagnosis of alpha-1 antitrypsin deficiency being associated with worse COPD-related symptoms and functional status, and with a trend toward worsened air-flow obstruction. Given that alpha-1 antitrypsin deficiency is associated with accelerated emphysema progression, these findings underscore the importance of early detection of alpha-1 antitrypsin deficiency and reinforce guidelines that endorse alpha-1 antitrypsin deficiency testing in all adults with fixed air-flow obstruction and first-degree relatives of individuals with severe deficiency of alpha-1 antitrypsin. [ABSTRACT FROM AUTHOR]

Background: High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Objectives: We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH. Methods: We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort. Results: HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34–57 mg/dl; PAH: 35.3, 29–39 mg/dl; Control: 49, 40–60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity. Conclusions: HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH. [ABSTRACT FROM AUTHOR]

The article informs about the Airway Epithelial Genomic Signatures in Steroid-Resistant Chronic obstructive pulmonary disease (COPD); vascular Remodeling in Pulmonary Hypertension; and regulation of lung endothelial cell function. Topics discussed include Chronic airway inflammation contributes to airway remodeling and tissue destruction in COPD; and T cells use to recruit neutrophils and macrophages to promote inflammation.

Background. The study investigates the occurrence, severity, and outcomes of acute kidney injury (AKI) in octogenarians following heart valve surgery. Methods. All patients, age >80 years, not on dialysis and without kidney transplant, undergoing heart valve replacement at Mayo Clinic, Rochester, in the years 2002-2003 were enrolled. AKI was diagnosed based on AKIN criteria. Results. 209 octogenarians (88.0% aortic valve, 6.2% mitral valve, 1.0% tricuspid valve, and 4.8% multivalve) with (58.4%) and without CABG were studied. 34 (16.3%) had preexisting CKD. After surgery, 98 (46.8%) developed AKI. 76.5% of the AKI were in Stage 1, 9.2% in Stage 2, and 14.3% in Stage 3. 76.5% CKD patients developed AKI. Length of hospital stay was longer for AKI patients. More AKI patients were discharged to care facilities. Patient survival at 30 days and 1 year for AKI versus non-AKI was 88.8 versus 98.7%, p=0.003, and 76.5 versus 88.3%, p=0.025, respectively. With follow-up of 3.94±0.28 years, Kaplan-Meier analysis showed a reduced survival for AKI octogenarians. Preexisting CKD and large volume intraoperative fluid administration were independent AKI predictors. Conclusions. Nearly half of the octogenarians developed AKI after valve replacement surgery. AKI was associated with significant functional impairment and reduced survival. [ABSTRACT FROM AUTHOR]

End-of-life decision-making is a complex process that can be extremely challenging. We describe a 42-year-old woman in an irreversible coma without an advance directive. The case serves to illustrate the complications that can occur in end-of-life decision-making and challenges in resolving difficult futility disputes. We review the role of advance directives in planning end-of-life care, the responsibility and historical performance of patient surrogates, the genesis of futility disputes, and approaches to resolving disputes. [ABSTRACT FROM AUTHOR]

The article offers information on the study regarding the Acute respiratory distress syndrome, a severe inflammatory lung disease with high mortality. It discusses the pharmacotherapies designed to suppress inflammation have not succeded in improving the outcomes. It mentions the role of alveolar macrophages in the acute respiratory distress syndrome, along with its association with mechanical ventilation.

The article reports on survey findings on the prevalence of public speaking anxiety in the graduate medical education population in the U.S., as of February 2016.

Background: The prevalence of chronic respiratory diseases is increasing globally. There is evidence that those with spirometric impairment, and no evidence of obstruction, termed preserved ratio impaired spirometry (PRISm), have increased risk of morbidity and mortality, compared to those with normal lung function. There remain several gaps in characterizing PRISm., Research Questions: What is the prevalence, risk factors and clinical outcomes associated with PRISm globally?, Study Design and Methods: In this systematic review a comprehensive search using MEDLINE, Web of Science, CINHAL, and CENTRAL databases was conducted to include epidemiological studies with no language or data restrictions. Two reviewers independently screened citations and shortlisted full-text articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and data was extracted. Quality was assessed with the Effective Public Health Practice Project tool., Results: 52 studies met the inclusion criteria with 33 studies included in the meta-analysis. Pooled PRISm prevalence was 12% (95% CI: 0.10, 0.15) with greater prevalence in low-and middle-income countries (LMICs) compared to high-income countries (19% vs. 11%). Comorbid diabetes was a significant risk factor associated with PRISm but data for female sex and smoking were mixed. PRISm was associated with increased all-cause (OR 1.41, 95% CI:1.08, 1.83, p=0.02), cardiovascular (OR 1.84, 95% CI:1.31, 2.58, p<0.01), and respiratory mortality (OR 1.82, 95% CI:1.08, 3.05, p=0.03). PRISm was not associated with a reduced lung cancer diagnosis (p=0.46). Quality assessment analysis revealed 34.6% (n=18) studies were rated "strong," 42.3% (n=22) "moderate," and 23.1% (n=12) "weak." Studies conducted LMICs had lower quality ratings., Interpretation: Individuals with PRISm have increased risk of all-cause, cardiovascular, and respiratory mortality. Recognizing and targeting modifiable PRISm risk factors may reduce the growing burden of PRISm and transition to obstructive lung disease globally. Additional studies are needed in LMICs that have unique risk factors a disease trajectory., (Copyright © 2024. Published by Elsevier Inc.)

COPD is a heterogeneous condition, with tobacco smoking being the main environmental risk factor. The presence of type 2 (T2) inflammation is a well-recognised feature of asthma; however, it is now apparent that a subset of COPD patients also displays evidence of T2 inflammation with respect to elevated eosinophil counts and altered gene and protein expression of several T2 inflammatory mediators. T2 inflammatory mediators represent an attractive therapeutic target in both COPD and asthma; however, the efficacy of pharmaceutical interventions varies between diseases. Furthermore, the nature of some shared clinical features also differs. We provide a narrative review of differences in the nature of T2 inflammation between COPD and asthma, which may partly explain phenotypic differences between diseases. We focus on evidence from studies of pulmonary histopathology, sputum and epithelial gene and protein expression, and response to pharmacological interventions targeted at T2 inflammation., Competing Interests: Conflict of interest: D. Singh has received sponsorship to attend and speak at international meetings, honoraria for lecturing or attending advisory boards from the following companies: Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance and Verona. F. Trinkmann reports grants from AstraZeneca, Bayer Boehringer Ingelheim, Chiesi, Novartis, Roche, BMBF, DZL, Markedsmodningsfonden and E+H Knorr Stiftung, as well as consulting fees and honoraria from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Fisher & Paykel, GlaxoSmithKline, Janssen-Cilag, Merck Healthcare, Novartis, Omron, OM-Pharma, Roche, Sanofi, Aventis and Thorasys, and travel support from AstraZeneca, Actelion, Bayer, Berlin Chemie, Boehringer Ingelheim, Chiesi, Mundipharma, Novartis, Pfizer and TEVA. V. Tejwani reports grants from NIH NHLBI and payment or honoraria from Thermofisher. A. Beech, A. Higham and S. Booth have no conflicts of interest to declare., (Copyright ©ERS 2024.)

Background: The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive biomarker that potentially predicts acute exacerbations of chronic obstructive pulmonary disease (AECOPDs). We evaluated the association of baseline NLR and respiratory hospitalization risk within one year among chronic obstructive pulmonary disease (COPD) patients in Uganda, a low- and middle-income country., Methods: A total of 312 COPD patients were followed for one year. Clinical characteristics and exacerbation rates were collected. Poisson regression with robust variance estimators was used to measure the association between NLR and hospital admissions due to COPD exacerbations. Receiver-operator characteristic (ROC) curves and the area under the curve were used to assess the ability of NLR to predict AECOPDs., Results: The median (Q 1, Q 3) age was 64 years (53, 71). Females comprised 50.96% (n=159) of the cohort, and 71.2% (n=222) of participants had moderate or severe COPD. A total of 9.9% (n=31) of participants experienced a COPD exacerbation during the period of follow-up. At baseline, the median (Q 1, Q 3) NLR ratio among participants who experienced an exacerbation was 1.46 (0.92, 2.33) compared to 1.03 (0.72,1.42) among those who did not experience one during the follow-up period ( p =0.002). Using Youden and Liu's methods, the optimal NLR cutoff for predicting COPD exacerbation was 1.17. This cutoff resulted in a ROC curve area of 0.64 (95% confidence interval: 0.56, 0.73)., Conclusion: The NLR could be used as a risk predictor, in low- and middle-income countries, for hospital admissions due to COPD exacerbations. A cutoff of 1.17 was an independent predictor of hospitalization due to acute exacerbations of COPD within one year., (JCOPDF © 2024.)

Measuring the concentration of nitric oxide in the exhaled breath may have several roles in patients with suspected or confirmed asthma: as an adjunctive test for the disease, as a test to determine whether patients with asthma are likely to respond to inhaled corticosteroids, as a way to monitor and adjust this therapy, and as a way to estimate the likelihood of exacerbations. However, it is not very sensitive or specific and should not be used by itself, but rather in conjunction with clinical signs and symptoms. The authors address the role of measuring exhaled nitric oxide in the diagnosis and management of asthma and provide guidance for its appropriate use., (Copyright © 2023 The Cleveland Clinic Foundation. All Rights Reserved.)

Dynamic heterogeneity in lung ventilation is an important measure of pulmonary function and may be characteristic of early pulmonary disease. While standard indices like spirometry, body plethysmography, and blood gases have been utilized to assess lung function, they do not provide adequate information on regional ventilatory distribution nor function assessments of ventilation during the respiratory cycle. Emerging technologies such as xenon CT, volumetric CT, functional MRI and X-ray velocimetry can assess regional ventilation using non-invasive radiographic methods that may complement current methods of assessing lung function. As a supplement to current modalities of pulmonary function assessment, functional lung imaging has the potential to identify respiratory disease phenotypes with distinct natural histories. Moreover, these novel technologies may offer an optimal strategy to evaluate the effectiveness of novel therapies and therapies targeting localized small airways disease in preclinical and clinical research. In this review, we aim to discuss the features of functional lung imaging, as well as its potential application and limitations to adoption in research., Competing Interests: NE, TO, AF, and JK, are employed by 4D Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Karmali, Sowho, Bose, Pearce, Tejwani, Diamant, Yarlagadda, Ponce, Eikelis, Otvos, Khan, Lester, Fouras, Kirkness and Siddharthan.)

Background: Polymorphisms and products of the cyclooxygenase (COX) pathway have been associated with the development of chronic obstructive pulmonary disease (COPD) and adverse outcomes. COX-produced prostaglandin E2 (PGE-2) may play a role in the inflammation observed in COPD, potentially through deleterious airway macrophage polarization. A better understanding of the role of PGE-2 in COPD morbidity may inform trials for therapeutics targeting the COX pathway or PGE-2., Methods: Urine and induced sputum were collected from former smokers with moderate-severe COPD. The major urinary metabolite of PGE-2 (PGE-M) was measured, and ELISA was performed on sputum supernatant for PGE-2 airway measurement. Airway macrophages underwent flow cytometry phenotyping (surface CD64, CD80, CD163, CD206, and intracellular IL-1β, TGF-β1). Health information was obtained the same day as the biologic sample collection. Exacerbations were collected at baseline and then monthly telephone calls., Results: Among 30 former smokers with COPD (mean±SD age 66.4±8.88 years and forced expiratory volume in 1 second [FEV 1 ] 62.4±8.37 percent predicted), a 1 pg/mL increase in sputum PGE-2 was associated with higher odds of experiencing at least one exacerbation in the prior 12 months (odds ratio 3.3; 95% confidence interval: 1.3 to15.0), worse respiratory symptoms and health status. PGE-M was not associated with exacerbations or symptoms. Neither airway PGE-2 nor urinary PGE-M was uniformly associated with an M1 or M2 polarization., Conclusions: Elevated levels of sputum PGE-2, rather than systemic PGE-2, is associated with increased respiratory symptoms and history of exacerbation among individuals with COPD. Additional studies focused on mechanism of action are warranted., (JCOPDF © 2023.)

Introduction: There is evidence that obesity, a risk factor for asthma severity and morbidity, has a unique asthma phenotype which is less atopic and less responsive to inhaled corticosteroids (ICS). Peripheral blood mononuclear cells (PBMC) are important to the immunologic pathways of obese asthma and steroid resistance. However, the cellular source associated with steroid resistance has remained elusive. We compared the lymphocyte landscape among obese children with asthma to matched normal weight children with asthma and assessed relationship to asthma control., Methods: High-dimensional flow cytometry of PBMC at baseline and after dexamethasone stimulation was performed to characterize lymphocyte subpopulations, T-lymphocyte polarization, proliferation (Ki-67+), and expression of the steroid-responsive protein FK506-binding protein 51 (FKBP51). T-lymphocyte populations were compared between obese and normal-weight participants, and an unbiased, unsupervised clustering analysis was performed. Differentially expressed clusters were compared with asthma control, adjusted for ICS and exhaled nitric oxide., Results: In the obese population, there was an increased cluster of CD4 + T-lymphocytes expressing Ki-67 and FKBP51 at baseline and CD4 + T-lymphocytes expressing FKBP51 after dexamethasone stimulation. CD4 + Ki-67 and FKBP51 expression at baseline showed no association with asthma control. Dexamethasone-induced CD4 + FKBP51 expression was associated with worse asthma control in obese participants with asthma. FKBP51 expression in CD8 + T cells and CD19 + B cells did not differ among groups, nor did polarization profiles for Th1, Th2, Th9, or Th17 percentage., Discussion: Dexamethasone-induced CD4 + FKBP51 expression is uniquely associated with worse asthma control in obese children with asthma and may underlie the corticosteroid resistance observed in this population., Competing Interests: MM reports royalties from Uptodate, consulting fees from Glaxo Smith Kline and Celgene, outside the submitted work. NH reports grants from COPD Foundation, grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, and personal fees from Mylan during the conduct of the study, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tejwani, McCormack, Suresh, Woo, Xu, Davis, Brigham, Hansel, McCormack and D’Alessio.)

Background: Chronic obstructive pulmonary disease (COPD) is characterized by recurrent exacerbations. Macrophages play a critical role in immune response and tissue repair in COPD. Airway macrophages (AM) are exposed to environmental exposures which are retained in the cytoplasmic material. Both biomass and particulate matter have been linked to higher AM black carbon. It is unknown if AM black carbon is associated with COPD morbidity and macrophage phenotype., Methods: Former smokers with COPD were enrolled and sputum induction was performed to obtain airway macrophages. Macrophages underwent black carbon quantification and flow cytometry phenotyping. Health information was obtained the same day as sputum induction and prospective exacerbations were assessed by monthly telephone calls., Results: We studied 30 former smokers with COPD who had a mean age of 67 years and mean forced expiratory volume in 1 second (FEV 1 )% predicted of 60.8%. Higher AM black carbon content was associated with increased total exacerbations and severe exacerbations and reduced CD80 expression., Conclusion: AM black carbon association with respiratory morbidity is largely unexplored and this is the first study to identify association with prospective exacerbations. Macrophages expressed reduced CD80, a surface marker providing costimulatory signals required for development of antigen-specific immune responses. Our findings suggest that reduced CD80 expression is the pathophysiologic mechanism for the association of AM black carbon content and increased exacerbations. Therefore, beyond solely serving as a marker for increased exposures, AM black carbon content may be a predictor of future exacerbations given a macrophage less equipped to respond to an acute infectious exposure., Competing Interests: Drs. Tejwani, Suresh, Putcha, Alexis, Moughames, Tang, Romero, Woo, D’Alessio and Ms. Grammer have nothing to disclose. Dr. Hansel reports grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, grants from the COPD Foundation, and personal fees from Mylan, all outside the submitted work., (JCOPDF © 2021.)

Venous malformations have static venous lakes that predispose to spontaneous venous thrombosis within the malformation due to its low-flow static state. Thrombi of varying sizes can then embolize continually into the pulmonary arterial circulation, and occlude and narrow elastic pulmonary arteries causing chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboendarterectomy (PTE) is potentially curative in CTEPH, but has not been previously reported in the setting of mediastinal and chest wall venous malformations. We report the case of a 21-year-old female with such a large malformation treated successfully with PTE. The patient underwent complete endovascular reconstruction of her subclavian vein system from the axillary vein to the innominate vein stump with covered stent grafts to exclude the malformations from causing recurrent pulmonary emboli. This was followed by embolization of the malformation to allow for the surgical approach. The series of events in this case serves as a novel approach in managing such rare patients.

PI*ZZ alpha-1 antitrypsin (AAT) deficiency poses risk for lung disease through 2 different mechanisms: a toxic loss of function in which deficient AAT levels cause a depleted proteolytic screen and, separately, a proinflammatory effect of Z polymers produced both by alveolar macrophages and by the liver. Ample data support the first mechanism, while the possible contribution of the second 2 proinflammatory mechanisms is currently unknown. Experience with a 74 year-old PI*ZZ female who underwent single lung transplantation and subsequent orthotopic liver transplantation (OLT) may shed light on the relative contributions of each of the potential mechanisms. Availability of multiple pulmonary function tests (PFT) measurements uniquely permitted calculation of rates of lung function change before and after OLT. The rate of forced expiratory volume in 1 second (FEV 1 ) decline normalized post-OLT (from -60 to -21 ml/yr). Her course suggests that restoring the normal serum AAT levels or, alternately, eliminating liver-derived polymers, exerted a greater effect on preventing emphysema progression than local Z polymer production contributed to furthering emphysema., Competing Interests: Vickram Tejwani has no conflicts of interest to declare. Xiao-Feng Wang has no conflicts of interest to declare. James K. Stoller has served as a consultant to Grifols, Baxter, Kamada, Arrowhead Research, and CSL Behring and serves on the Board of Directors of the Alpha-1 Foundation.

The elderly chronic kidney disease (CKD) population is growing. Both aging and CKD can disrupt calcium (Ca2+) homeostasis and cause alterations of multiple Ca2+-regulatory mechanisms, including parathyroid hormone, vitamin D, fibroblast growth factor-23/Klotho, calcium-sensing receptor and Ca2+-phosphate product. These alterations can be deleterious to bone mineral metabolism and soft tissue health, leading to metabolic bone disease and vascular calcification and aging, termed CKD-mineral and bone disorder (MBD). CKD-MBD is associated with morbid clinical outcomes, including fracture, cardiovascular events and all-cause mortality. In this paper, we comprehensively review Ca2+ regulation and bone mineral metabolism, with a special emphasis on elderly CKD patients. We also present the current treatment-guidelines and management options for CKD-MBD.