Publications by authors named "Charlie Strange"

154 Publications

PRIMUS - Prompt Initiation of Maintenance Therapy in the US: A Real-World Analysis of Clinical and Economic Outcomes Among Patients Initiating Triple Therapy Following a COPD Exacerbation.

Int J Chron Obstruct Pulmon Dis 2022;17:329-342. Epub 2022 Feb 10.

BioPharmaceuticals, US Medical Affairs, AstraZeneca, Wilmington, DE, USA.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) may experience moderate (requiring outpatient care) or severe (requiring hospitalization) disease exacerbations. Guidelines recommend escalation from dual to triple therapy (inhaled corticosteroid + long-acting beta agonist + long-acting muscarinic antagonist) after two moderate or one severe exacerbation in a year. This study examined whether prompt initiation of triple therapy lowers risk of future exacerbations and reduces healthcare costs, compared to delayed/very delayed triple therapy after an exacerbation.

Patients And Methods: This retrospective observational study of US healthcare claims included patients ≥40 years old with COPD who initiated triple therapy (1/1/2011-3/31/2020) after ≥2 moderate or ≥1 severe exacerbation in the prior year. The earliest of the second moderate or first severe exacerbation was the index date. Patients were stratified by triple therapy timing: prompt (≤30 days post-index), delayed (31-180 days), very delayed (181-365 days). COPD exacerbations, all-cause and COPD-related healthcare utilization and costs were assessed during 12 months post-index (follow-up). Multivariable regression estimated the effect of each 30-day delay in triple therapy on the odds of exacerbations, number of exacerbations, and costs during follow-up, controlling for patient characteristics.

Results: A total of 24,770 patients were included: 7577 prompt, 9676 delayed, 7517 very delayed. Each 30-day delay of triple therapy was associated with 11% and 7% increases in the odds of any exacerbation and a severe exacerbation, respectively (odds ratio [95% CI]: 1.11 [1.10-1.13] and 1.07 [1.05-1.08]), a 4.3% (95% CI: 3.9-4.6%) increase in the number of exacerbations, a 1.8% (95% CI: 1.3-2.3%) increase in all-cause costs, and a 2.1% (95% CI: 1.6-2.6%) increase in COPD-related costs during follow-up.

Conclusion: Promptly initiating triple therapy after two moderate or one severe exacerbation is associated with decreased morbidity and economic burden in COPD. Proactive disease management may be warranted to prevent future exacerbations and lower costs among patients with COPD.
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http://dx.doi.org/10.2147/COPD.S347735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843423PMC
March 2022

Proteomic Analysis of Exosomes Secreted from Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells.

Biology (Basel) 2021 Dec 21;11(1). Epub 2021 Dec 21.

Departments of Surgery, Medical University of South Carolina, CRI 410, 173 Ashley Avenue, Charleston, SC 29425, USA.

Extracellular vesicles (EVs) mediate many therapeutic effects of stem cells during cellular therapies. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) were manufactured to overexpress the human antiprotease alpha-1 antitrypsin (hAAT) and studied to compare the EV production compared to lentivirus treated control MSCs. The goal of this study was to compare protein profiles in the EVs/exosomes of control and hAAT-MSCs using unbiased, high resolution liquid chromatography and mass spectrometry to explore differences. Nanoparticle tracking analysis (NTA) showed that the particle size of the EVs from control MSCs or hAAT-MSCs ranged from 30 to 200 nm. Both MSCs and hAAT-MSCs expressed exosome-associated proteins, including CD63, CD81, and CD9. hAAT-MSCs also expressed high levels of hAAT. We next performed proteomic analysis of EVs from three healthy donor cell lines. Exosomes collected from cell supernatant were classified by GO analysis which showed proteins important to cell adhesion and extracellular matrix organization. However, there were differences between exosomes from control MSCs and hAAT-MSCs in cytokine signaling of the immune system, stem cell differentiation, and carbohydrate metabolism ( < 0.05). These results show that hAAT-MSC exosomes contain a different profile of paracrine effectors with altered immune function, impacts on MSC stemness, differentiation, and prevention of cell apoptosis and survival that could contribute to improved therapeutic functions.
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http://dx.doi.org/10.3390/biology11010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773149PMC
December 2021

Feasibility of RESP-FIT: Technology-Enhanced Self-Management Intervention for Adults with COPD.

Int J Chron Obstruct Pulmon Dis 2021;16:3263-3273. Epub 2021 Dec 3.

College of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with substantial functional morbidity, including activity-limiting symptoms such as dyspnea and fatigue. Self-management interventions aid in symptomatic management of COPD and have been shown to produce positive outcomes on quality of life (QOL) and reduce hospital admissions.

Purpose: The purpose of this randomized controlled longitudinal pilot study was to assess feasibility of the combined Respiratory Fitness (RESP-FIT) + Smartphone Airway Management System (SAMS) program, a 6-week, self-management, technology-enhanced respiratory muscle strength training (RMST) mHealth intervention.

Patients And Methods: Feasibility was assessed by evaluating recruitment, retention, acceptability, adherence, and safety data. Data were collected from 30 participants (15 in intervention group, 15 in control) at 3 time points (baseline, 6 weeks, and 14 weeks). The intervention group was requested to perform RMST at regular intervals during the week (5 breaths, 5 times a day, 5 days a week). Bluetooth enabled tracking was used to track training sessions. Data were analyzed using descriptive statistics.

Results: Recruitment was staggered for device usage and was completed in 57 weeks, with near 90% retention from baseline to end-of-intervention. Mobile application rating scale scores and interview data indicated moderate satisfaction. Participants completed 14,388 actions in the app. The most commonly used features were recording of daily symptoms via ecological momentary assessment (EMA) and tracking RMST if assigned to training sessions. Training days were successfully captured using EMA, but Bluetooth enabled training tracking was found to be not feasible. Overall, participants reported satisfaction with the RESP-FIT + SAMS mHealth intervention and found it acceptable.

Conclusion: RESP-FIT is feasible and enables real-time COPD symptom assessment in the home environment, but additional work is needed to integrate Bluetooth technology into the platform. Ongoing investigations focus on the accuracy of symptom perception, self-efficacy, and momentary factors that impact adherence behaviors.
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http://dx.doi.org/10.2147/COPD.S326675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650775PMC
March 2022

A Novel Cellular Therapy to Treat Pancreatic Pain in Experimental Chronic Pancreatitis Using Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells.

Biomedicines 2021 Nov 16;9(11). Epub 2021 Nov 16.

Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.

Chronic pancreatitis (CP) is characterized by pancreatic inflammation, fibrosis, and abdominal pain that is challenging to treat. Mesenchymal stromal cells (MSCs) overexpressing human alpha-1 antitrypsin (hAAT-MSCs) showed improved mobility and protective functions over native MSCs in nonobese diabetic mice. We investigated whether hAAT-MSCs could mitigate CP and its associated pain using trinitrobenzene sulfonic acid (TNBS)-induced CP mouse models. CP mice were given native human MSCs or hAAT-MSCs (0.5 × 10 cells/mouse, i.v., = 6-8/group). The index of visceral pain was measured by graduated von Frey filaments. Pancreatic morphology and pancreatic mast cell count were analyzed by morphological stains. Nociceptor transient receptor potential vanilloid 1 (TRPV1) expression in dorsal root ganglia (DRG) was determined by immunohistochemistry. hAAT-MSC-treated CP mice best preserved pancreatic morphology and histology. MSC or hAAT-MSC infusion reduced abdominal pain sensitivities. hAAT-MSC therapy also suppressed TRPV1 expression in DRG and reduced pancreatic mast cell density induced by TNBS. Overall, hAAT-MSCs reduced pain and mitigated pancreatic inflammation in CP equal to MSCs with a trend toward a higher pancreatic weight and better pain relief in the hAAT-MSC group compared to the MSC group. Both MSCs and hAAT-MSCs might be used as a novel therapeutic tool for CP-related pain.
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http://dx.doi.org/10.3390/biomedicines9111695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615652PMC
November 2021

A Novel Detection Method to Identify Individuals with Alpha-1 Antitrypsin Deficiency: Linking Prescription of COPD Medications with the Patient-Facing Electronic Medical Record.

Chronic Obstr Pulm Dis 2022 Jan;9(1):26-33

Education and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States.

Background: Alpha-1 antitrypsin deficiency (AATD) is under-recognized, prompting the need for enhanced detection strategies. The primary aim of this study is to determine the feasibility of using the electronic medical record (EMR) and linked electronic patient messages (EPM) to encourage AATD testing by patients with chronic obstructive pulmonary disease (COPD).

Methods: Study participants were eligible, untested adult patients who were prescribed an inhaled medication which is exclusively Food and Drug Administration-approved for treating COPD. Eligible patients received a message with basic information about AATD and availability of free, home-based AATD testing. Through a collaboration with the Alpha-1 Foundation's Alpha-1 Coded Testing (ACT) study, patients referred to home-based testing through EPM were flagged. The effectiveness of the electronic message was evaluated by the proportion of patients who underwent testing, and the rate of detecting individuals with severe deficiency of AAT among those tested.

Results: A total of 12,369 patients on eligible inhalers were screened; 5430 patients met all criteria and received an EPM. During the study, 396 patients (7.3%) fully requested an ACT kit. Of these, 209 patients (52.8%) returned the test sample and received genotyping results; 65.5%, had a normal AAT genotype (PI*MM), 31.6% were heterozygotes for a deficient allele (PI*MS, PI*MZ and PI*M/Null rare), and 2.9% had severe deficiency of alpha-1 antitrypsin (PI*SZ, PI*ZZ, PI*S/Null rare).

Conclusions: While the response rate and test return rate were low, the rate of detecting individuals with AATD using this detection strategy exceeds that of many prior strategies. As such, while requiring independent validation in other populations, this detection strategy holds promise.
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http://dx.doi.org/10.15326/jcopdf.2021.0260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893965PMC
January 2022

Relationship between alpha-1 antitrypsin deficiency and obstructive sleep apnea.

Sleep Breath 2021 12 30;25(4):2091-2097. Epub 2021 Apr 30.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA.

Purpose: This study aimed to identify if individuals with mild to severe alpha-1 antitrypsin deficiency (AATD) are at higher risk for developing obstructive sleep apnea (OSA) than the general population.

Methods: A seven-question sleep apnea risk assessment questionnaire, STOP-BAG, was applied to 2338 participant responses from the Alpha-1 Coded Testing Study (ACT) and 4638 participant responses from the Kentucky Behavioral Risk Factor Survey (KyBRFS). Propensity scores were generated from a logistic regression model using continuous variables of age and body mass index (BMI). STOP-BAG scores were analyzed using chi-square analysis on this matched cohort to assess OSA risk in AATD.

Results: Self-reported OSA was higher in the KyBRFS cohort (14.5%) than in individuals with mild or severe AATD (11.2%) (p = 0.012). However, a higher percentage of the AATD cohort met clinically meaningful thresholds for STOP-BAG scores ≥ 5 (22.7%) than the KyBRFS cohort (13.0%) (p = 0.001). These differences persisted despite 1:1 propensity score matching on age and BMI to account for differences in baseline characteristics. No statistically significant difference in OSA risk between AATD genotypes was found.

Conclusion: AATD appears to have higher risk for OSA than the general population. The 11.2% prevalence of diagnosed OSA in the AATD population is much lower than symptom scores would predict. Further studies are needed to validate the possibility that elastin loss is involved in OSA pathogenesis.
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http://dx.doi.org/10.1007/s11325-021-02386-0DOI Listing
December 2021

Improving the Lives of Patients with Alpha-1 Antitrypsin Deficiency.

Int J Chron Obstruct Pulmon Dis 2020 10;15:3313-3322. Epub 2020 Dec 10.

University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition that predisposes patients to lung and liver disease and is often underdiagnosed due to incomplete diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Improvements in physician awareness have been made, but better strategies for both diagnosis and management are still required. The only current disease-modifying therapy for AATD is the infusion of the missing Alpha-1 Antitrypsin (AAT) protein, which can slow progression of emphysema. However, AAT treatment can impact patient freedom and quality of life due to the need for weekly intravenous infusions. A symposium was held to discuss patient-centric aspects of care that have impact on the lives of patients with AATD, including exacerbations of their lung disease, self-administration of intravenous AAT therapy and pulmonary rehabilitation. Intravenous self-infusion of drugs is an established treatment strategy for patients with a variety of conditions and can improve patient quality of life, freedom and mental well-being. Experience from these areas show that patients typically manage their treatment well and without complications. When applied to AATD, training patients to self-infuse therapy can be successful, but formal guidelines would be beneficial. In addition to pharmacological intervention, individualized pulmonary rehabilitation, exercise and educational programs can encourage health-enhancing patient behavior and further improve patient quality of life. However, differences in skeletal muscle adaptations to pulmonary rehabilitation exercise regimens have been observed between patients with AATD and non-AATD COPD, highlighting the need to develop training programs specifically designed for patients with AATD.
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http://dx.doi.org/10.2147/COPD.S276773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735792PMC
June 2021

Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency.

Thorax 2021 02 10;76(2):134-143. Epub 2020 Dec 10.

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.

Methods: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.

Result: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.

Conclusions: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214301DOI Listing
February 2021

Alpha-1 Antitrypsin Augmentation Therapy Improves Survival in Severely Deficient Patients with Predicted FEV1 Between 10% and 60%: A Retrospective Analysis of the NHLBI Alpha-1 Antitrypsin Deficiency Registry.

Int J Chron Obstruct Pulmon Dis 2020 3;15:3193-3199. Epub 2020 Dec 3.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA.

Purpose: The extent of the survival benefit of augmentation therapy for alpha-1 antitrypsin deficiency (AATD) in individuals with advanced COPD is difficult to define. We performed a retrospective analysis using all available data from the observational registry of individuals with severe deficiency of alpha-1 antitrypsin (AAT) conducted by the NHLBI investigators.

Patients And Methods: Individuals (N=1129) with severe deficiency of AAT were evaluated for mortality using all data sources and stratified by 10% increments of baseline forced expiratory volume in 1 second (FEV1) percent predicted and by augmentation therapy status (ever receiving versus never receiving). Kaplan-Meier survival curves were constructed for each of the deciles comparing survival in treated vs non-treated groups. A multivariable model was performed to define the correlates of survival in individuals with FEV1 <30% predicted.

Results: Amongst all subjects, augmentation was associated with improved survival (p<0.0001). Among the individuals ever receiving augmentation therapy, survival was better than for those not receiving augmentation at all 10% increments of FEV1% predicted from 10% to 60% (P values <0.05 in all deciles). In subgroups of participants with hyperinflation defined as residual volume (RV)>120% predicted and in subgroups of participants with reduced diffusing capacity for carbon monoxide (DLCO) <70% predicted, there was significantly better survival for those ever receiving augmentation therapy than for those who never received augmentation (p<0.001). A multivariable analysis showed that mortality benefit is influenced by age, DLCO % predicted, and augmentation therapy.

Conclusion: There is a survival benefit from augmentation therapy in AATD between FEV1 values in the 10-60% predicted range. Screening and treatment of AATD patients should therefore not be limited by the severity of illness as defined by FEV1.
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http://dx.doi.org/10.2147/COPD.S263725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721109PMC
June 2021

Comorbidity Associations with AATD Among Commercially Insured and Medicare Beneficiaries with COPD in the US.

Int J Chron Obstruct Pulmon Dis 2020 5;15:2389-2397. Epub 2020 Oct 5.

Department of Kinesiology, College of Health and Human Services, University of North Carolina at Charlotte, Charlotte, NC, USA.

Introduction: Alpha-1 antitrypsin deficiency (AATD) is often not identified in patients with chronic obstructive pulmonary disease (COPD) until advanced stages of disease, despite the availability of genetic testing. While clinical practice guidelines provide recommendations on patients who should be tested, more refined algorithms are needed to identify COPD patients who are likely candidates for AATD testing and to prevent delays in diagnosis and treatment. The objective of this study was to identify comorbid associations with AATD among patients diagnosed with COPD in the United States.

Methods: Using data from the 2012-2017 PharMetrics Plus Administrative Claims Database and 2011-2014 Medicare Fee for Service 5% Sample, patients with COPD (ICD-9-CM: 491.xx, 492.xx, or 496, ICD-10-CM J41, J42, J43, J44) and AATD (ICD-9-CM: 273.4, ICD-10-CM: E88.01) were identified. Patient demographic and diagnostic characteristics were assessed. Logistic regression models were developed to identify significant predictors of AATD.

Results: A cohort of 344,528 Medicare beneficiaries with COPD (of which 302 (0.09%) also had two diagnoses of AATD) and a cohort of 340,259 commercially insured patients with COPD (of which 1076 (0.3%) also had a diagnosis of AATD) were constructed. Associations with AATD identified in both models included ICD-9-CM and ICD-10-CM codes for chronic pulmonary heart disease, chronic liver disease and cirrhosis, and liver transplant.

Discussion: Significant associations with a diagnosis of AATD among patients with COPD were consistently represented in each of the datasets evaluated, which suggests meaningful comorbidity implications in AATD patients. These findings reinforce the need to test individuals with COPD for AATD as early as possible to help reduce the development of associated comorbid conditions.
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http://dx.doi.org/10.2147/COPD.S263297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547287PMC
June 2021

A population-based estimate of the health care burden of obstructive sleep apnea using a STOP-BAG questionnaire in South Carolina.

J Clin Sleep Med 2021 03;17(3):367-374

Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Study Objectives: Population based estimates of obstructive sleep apnea (OSA) frequency and health impact are incomplete. The aim of this study was to determine the prevalence of risk factors for physician and sleep study diagnosed OSA among individuals in a state-based surveillance program.

Methods: Using questions inserted into the 2016 (n = 5,564) and 2017 (n = 10,884) South Carolina Behavioral Risk Factor Surveillance System of the Centers for Disease Control and Prevention, we analyzed the prevalence of physician diagnosed OSA and associated comorbidities. The validated STOP-BANG questionnaire without neck circumference (STOP-BAG) defined populations at moderate risk (score 3-4) and high risk (score 5-7). Statistical analysis using weighted prevalence and means and their 95% confidence intervals (CI) thus reflect population estimates of disease burden.

Results: The population-based prevalence of physician diagnosed OSA in South Carolina was 9.7% (95% CI: 9.0-10.4). However, the populations with moderate risk (18.5%, 95% CI: 17.3-19.8) and high risk (25.5%, 95% CI: 23.9-27.1) for OSA, as determined by the STOP-BAG questionnaire, were much higher. Compared to those at low risk for OSA, those at high risk were more often diagnosed with coronary heart disease, stroke, asthma, skin cancer, other cancers, chronic obstructive pulmonary disease, arthritis, depression, kidney disease, and diabetes (all P < .001).

Conclusions: OSA is common and strongly associated with major comorbidities. As such, this public health crisis warrants more diagnostic and therapeutic attention. The STOP-BAG questionnaire provides a public health platform to monitor this disease.
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http://dx.doi.org/10.5664/jcsm.8860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927332PMC
March 2021

Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation.

Am J Transplant 2021 05 16;21(5):1713-1724. Epub 2020 Nov 16.

Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.

Alpha-1 antitrypsin (AAT) has protective functions in animal islet transplantation models. While the therapeutic effect of AAT therapy is currently being tested in clinical trials, we investigated the mechanism of AAT protection in a clinically relevant marginal intrahepatic human islet transplantation model. In recipients receiving islets and AAT, 68.9% (20/29) reached normoglycemia, compared to 35.7% (10/28) in those receiving islets only, at 60 days posttransplant (PT). AAT-treated mice had lower serum levels of inflammatory cytokines immediately PT. Reduced M1 macrophages were observed in livers of AAT-treated recipients compared to controls as evidenced by flow cytometry and RNA-seq transcriptional profiling analysis. In vitro AAT suppressed IFN-γ-induced M1 macrophage activation/polarization via suppression of STAT1 phosphorylation and iNOS production. AAT inhibits macrophage activation induced by cytokines or dying islets, and consequently leads to islet cell survival. In a macrophage depletion mouse model, the presence of M1 macrophages in the liver contributed to graft death. AAT, through suppressing macrophage activation, protected transplanted islets from death and dysfunction in the human islet and NOD-SCID mouse model. The protective effect of AAT was confirmed in a major mismatch allogeneic islet transplantation model. Taken together, AAT suppresses liver macrophage activation that contributes to graft survival after transplantation.
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http://dx.doi.org/10.1111/ajt.16342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082666PMC
May 2021

Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).

Eur Respir Rev 2020 Sep 5;29(157). Epub 2020 Oct 5.

Dept of Medicine, Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven CT, USA.

Background: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research.

Methods: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion.

Results: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder.

Conclusions: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.
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http://dx.doi.org/10.1183/16000617.0287-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537943PMC
September 2020

Community-acquired Pneumonia Guideline Recommendations-Impact of a Consensus-based Process versus Systematic Reviews.

Clin Infect Dis 2021 10;73(7):e1467-e1475

Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Background: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews.

Purpose: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines.

Methods: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline's systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined.

Results: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64-1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%).

Conclusions: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action.
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http://dx.doi.org/10.1093/cid/ciaa1428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677595PMC
October 2021

Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.

Stem Cells Transl Med 2021 02 18;10(2):320-331. Epub 2020 Sep 18.

Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.

Islet/β cell dysfunction and death caused by autoimmune-mediated injuries are major features of type 1 diabetes (T1D). Mesenchymal stromal cells (MSCs) have been used for the treatment of T1D in animal models and clinical trials. Based on the anti-inflammatory effects of alpha-1 antitrypsin (AAT), we generated human AAT engineered MSCs (hAAT-MSCs) by infecting human bone marrow-derived MSCs with the pHAGE CMV-a1aT-UBC-GFP-W lentiviral vector. We compared the colony forming, differentiation, and migration capacity of empty virus-treated MSCs (hMSC) and hAAT-MSCs and tested their protective effects in the prevention of onset of T1D in nonobese diabetic (NOD) mice. hAAT-MSCs showed increased self-renewal, better migration and multilineage differentiation abilities compared to hMSCs. In addition, polymerase chain reaction array for 84 MSC-related genes showed that 23 genes were upregulated, and 3 genes were downregulated in hAAT-MSCs compared to hMSCs. Upregulated genes include those critical for the stemness (ie, Wnt family member 3A [WNT3A], kinase insert domain receptor [KDR]), migration (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion protein 1 [VICAM-1], matrix metalloproteinase-2 [MMP2]), and survival (insulin-like growth factor 1 [IGF-1]) of MSCs. Pathway analysis showed that changed genes were related to growth factor activity, positive regulation of cell migration, and positive regulation of transcription. In vivo, a single intravenous infusion of hAAT-MSCs significantly limited inflammatory infiltration into islets and delayed diabetes onset in the NOD mice compared with those receiving vehicle or hMSCs. Taken together, overexpression of hAAT in MSCs improved intrinsic biological properties of MSCs needed for cellular therapy for the treatment of T1D.
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http://dx.doi.org/10.1002/sctm.20-0122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848369PMC
February 2021

Alpha-1 Antitrypsin Deficiency Associated COPD.

Authors:
Charlie Strange

Clin Chest Med 2020 09;41(3):339-345

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, MSC630, Charleston, SC 29425, USA. Electronic address:

Alpha-1 antitrypsin deficiency (AATD) was the first genetic risk factor for chronic obstructive pulmonary disease (COPD) described. In the more than 50 years since its description, the disease continues to provide insights into more common forms of COPD. Although AATD is caused by a single genetic variant, the clinical manifestations of disease include panacinar emphysema, airway hyperresponsiveness, and bronchiectasis. With improved molecular understanding of the mechanisms of disease pathogenesis and progression, new therapies in addition to intravenous augmentation therapy are on the horizon.
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http://dx.doi.org/10.1016/j.ccm.2020.05.003DOI Listing
September 2020

Detection of alpha-1 antitrypsin deficiency: the past, present and future.

Orphanet J Rare Dis 2020 04 19;15(1):96. Epub 2020 Apr 19.

University of Miami School of Medicine, Miami, USA.

Background: Most patients with alpha-1 antitrypsin deficiency remain undiagnosed and therefore do not benefit from current therapies or become eligible for research studies of new treatments under development. Improving the detection rate for AATD is therefore a high priority for the Alpha-1 Foundation. A workshop was held on June 23, 2019 in Orlando, Florida during which stakeholders from the research, pharmaceutical, and patient communities focused on the topic of alpha-1 antitrypsin deficiency detection.

Results: A variety of detection strategies have been explored in the past and new approaches are emerging as technology advances. Targeted detection includes patients with chronic obstructive pulmonary disease, unexplained chronic liver disease, and family members of affected individuals. Newborn screening, electronic medical record data mining, and direct-to-consumer testing remain options for future detection strategies.

Conclusion: These meeting proceedings can serve as a basis for innovative approaches to the detection of alpha-1 antitrypsin deficiency.
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http://dx.doi.org/10.1186/s13023-020-01352-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168939PMC
April 2020

Clinical And Economic Burden Of Eosinophilic COPD In A Large Retrospective US Cohort.

Int J Chron Obstruct Pulmon Dis 2019 26;14:2625-2637. Epub 2019 Nov 26.

Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Purpose: We sought to describe clinical and economic outcomes for COPD patients by blood eosinophil (EOS) count.

Methods: This retrospective cohort study of COPD patients used data from the Practice Fusion electronic medical records (EMR) database linked to Symphony Health Solutions transactional pharmacy, medical, outpatient, and inpatient claims data to evaluate COPD-related and all-cause health care resource utilization and cost in the 12-month period following the date of each patient's greatest recorded blood eosinophil count during the 27-month period from January 2014 to March 2016. A post-index moderate exacerbation was defined as an outpatient or emergency care visit for COPD and a prescription for oral corticosteroid and/or antibiotics within 10 days of the visit. Severe exacerbation was defined as an inpatient hospitalization with COPD as primary diagnosis.

Results: Of 48,090 EMR patients, 39,939 (83.1%) had a charge in the claims data both pre- and post-index (mean age 67.2 years, 58.3% female), 17,397 (43.6%) had EOS ≥220 cells/µL. Moderate and severe exacerbations were more frequent for patients with EOS≥220 cells/µL compared with those with EOS <220 cells/µL (moderate: 6.8% vs 6.1%, p<0.05; severe: 3.1% vs 2.5%, p<0.001). After adjustment for baseline clinical characteristics, each 100-unit increase in EOS count was associated with a significant 2.24% increase in total all-cause costs and 4.54% increase in total COPD-related costs (p<0.001 for both). COPD-related costs were significantly greater for patients with an EOS count of ≥220 cells/µL compared with those with EOS <220 cells/µL (p<0.001). These costs appear to have been driven by a greater percentage of patients in the ≥220 cells/µL cohort with COPD-related resource use including hospitalization, office visits, ambulatory procedures and pharmacy prescriptions.

Conclusion: COPD patients with EOS counts ≥220 cells/µL were more likely to have had moderate or severe exacerbations and greater cost of care than those with EOS <220 cells/µL.
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http://dx.doi.org/10.2147/COPD.S220009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884975PMC
August 2020

Islet Harvest in Carbon Monoxide-Saturated Medium for Chronic Pancreatitis Patients Undergoing Islet Autotransplantation.

Cell Transplant 2019 Dec 30;28(1_suppl):25S-36S. Epub 2019 Dec 30.

Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.

Stresses encountered during human islet isolation lead to unavoidable β-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, β-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less β-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.
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http://dx.doi.org/10.1177/0963689719890596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016471PMC
December 2019

Anxiety and depression in patients with alpha-1 antitrypsin deficiency: current insights and impact on quality of life.

Ther Clin Risk Manag 2019 31;15:959-964. Epub 2019 Jul 31.

Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA.

Chronic physical illness is associated with significant vulnerability for emotional disorders. Some studies suggest anxiety and depression are common comorbidities in individuals with alpha-1 antitrypsin deficiency (AATD). Many aspects of AATD contribute to quality of life impairment. Delays in diagnosis, high costs of disease treatment, and inherited genetic risk add to the symptom burden of lung or liver disease to alter quality of life. Whether anxiety and depression independently contribute to quality of life impairment remains unproven. In this article, we aim to review current literature examining the impact of anxiety and depression on the quality of life of AATD-affected individuals. Multifaceted approaches may best meet the needs of a heterogeneous population and are the best future strategies to minimize these emotional impacts and assure highest quality of life possible. More research studies are needed to achieve this ambitious goal and make life of AATD-affected individuals better by minimizing the effects of anxiety and depression.
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http://dx.doi.org/10.2147/TCRM.S175369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682319PMC
July 2019

Prevalence of self-reported sleep problems amongst adults with obstructive airway disease in the NHANES cohort in the United States.

Sleep Breath 2020 Sep 13;24(3):985-993. Epub 2019 Sep 13.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 816, MSC 630, Charleston, SC, 29425, USA.

Rationale: Sleep and respiratory problems are common in adults in the USA. However, sleep problems often remain undiagnosed in patients with obstructive airway diseases (OADs). This study was designed to examine the association between sleep problems and different categories of OAD amongst US adults.

Methods: We conducted an observational, cross-sectional study using a nationally representative sample of the US civilian non-institutionalized population from 2007 to 2008 National Health and Nutritional Examination Survey (NHANES). A total of 3204 study participants aged ≥35 years were stratified into four groups, using a self-reported history of asthma and data from spirometry: asthma-COPD overlap (ACO) (n = 70, 2.2%), asthma (n = 168, 5.2%), chronic obstructive pulmonary disease (COPD) (n = 412, 12.8%), and those without any OAD (normal) (n = 2554, 79.7%). After characterizing the baseline demographics and health status of the four groups, multivariate logistic regression analysis was performed to estimate the likelihood of sleep problems in adults after adjusting for age, gender, body mass index, smoking, alcohol, obstructive sleep apnea syndrome (OSAS), depression, and diabetes. The index sample was the normal group. Sleep problems were defined as any complaints which affect or involve sleep.

Results: The participants with COPD were older (62.0 ± 11.7 years) as compared to ACO (59.1 ± 11.3 years), asthma (53.6 ± 11.3), and normal groups (53.8 ± 12.1) (p < 0.0001). Comparing baseline characteristics between the four groups, there were significant associations between OAD status and sleep problems including inadequate sleep, sleep-onset insomnia, snoring, frequent trouble sleeping, nocturnal arousals, early morning awakenings, fatigue, daytime sleepiness, use of prescription medication for sleep, leg jerks, leg cramps, difficulty in concentration, and difficulty in remembering things when tired. The multivariate logistic regression models evaluating the prevalence of sleep problems in individual OADs showed a stronger association between asthma and sleep problems as compared to COPD and ACO and sleep disorders.

Conclusion: All OADs are associated with a higher prevalence of sleep problems. There is a stronger association between asthma and sleep problems as compared to COPD and ACO. We speculate that the nocturnal burden of asthma contributes to sleep problems. Our results suggest that adults with OAD should be aggressively screened for sleep problems.
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http://dx.doi.org/10.1007/s11325-019-01941-0DOI Listing
September 2020

A Retrospective Claims Analysis of Dual Bronchodilator Fixed-Dose Combination Versus Bronchodilator Monotherapy in Patients with Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2019 Jul;6(3):221-232

AstraZeneca, Wilmington, Delaware.

Introduction: Patients with chronic obstructive pulmonary disease (COPD) increasingly receive combination bronchodilator therapies. Real world evidence for the benefits of combination therapy compared to monotherapy is lacking.

Methods: COPD patients aged ≥ 40 years initiating monotherapy (MT) with either a long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) or dual therapy (DT) with a LAMA/LABA fixed dose combination (FDC) between January 1, 2016 and December 31, 2016 were identified from a large U.S. administrative claims database. Patients diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma were excluded. Cohorts were propensity score matched 1:1 using baseline measures (e.g., exacerbations, hospitalizations) as proxies for COPD severity to create balanced cohorts.

Results: Following propensity score matching (PSM), 1286 patients remained in each cohort for analysis. Patients were followed for approximately 1 year. Patients in the DT versus MT cohort had lower rates of exacerbations leading to hospitalization (incidence rate ratio 0.7886; =0.019), lower mean COPD-related pharmacy costs per patient per month (PPPM) ($300 versus $379, respectively; <0.001) and total costs PPPM ($990 versus $1203, respectively; =0.003). This occurred despite lower mean COPD-related pharmacy fills PPPM in the DT versus MT cohorts (1.41 versus 1.51, respectively; =0.038). Patients in the DT cohort had lower rates of switching (<0.001) and augmentation (<0.001), and higher rates of non-persistence (<0.001) versus the MT cohort. Rates of discontinuation were similar.

Conclusions: Patients in the DT cohort had lower rates of exacerbations leading to hospitalization, lower COPD-related pharmacy and total costs PPPM, and lower rates of switching and augmentation compared to patients in the MT cohort.
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http://dx.doi.org/10.15326/jcopdf.6.3.2018.0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872213PMC
July 2019

Patient-reported outcomes of dual bronchodilator fixed-dose combination versus bronchodilator monotherapy in individuals with COPD.

Int J Chron Obstruct Pulmon Dis 2019 28;14:1377-1388. Epub 2019 Jun 28.

Health Economics and Outcomes Research, AstraZeneca, Wilmington, DE, USA.

This study compared real-world patient-reported outcomes (PROs) measured by the Clinical COPD Questionnaire (CCQ), the London Chest Activities of Daily Living (LCADL) scale, and the Work Productivity and Activity Impairment (WPAI) questionnaire between individuals with COPD initiating LAMA/LABA fixed-dose combination (FDC) dual therapy versus either long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) monotherapy. Individuals with COPD aged ≥40 years initiating a LAMA/LABA FDC dual therapy or a LAMA or LABA monotherapy (index date = first prescription date) between January 1, 2016 and December 31, 2016 were identified from a large US administrative claims database. Individuals were excluded if they were prescribed an inhaled corticosteroid (ICS) or ICS/LABA two months prior to the index date or were diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma. The cohorts were propensity score matched (PSM) 1:1 for COPD severity using baseline measures. Each participant completed a survey. Surveys were completed by 399 participants in the dual therapy cohort, and 718 participants in the monotherapy cohort. Following PSM, 379 participants remained in each cohort for analysis (monotherapy: 369 LAMA and 10 LABA). The dual therapy cohort reported fewer COPD-related symptoms (CCQ symptom score 2.75 vs 2.97, respectively, =0.023), and, fewer limitations in leisure activities (LCADL leisure score 4.78 vs 5.17, respectively, =0.021) versus the monotherapy cohort. No significant differences were found in the WPAI. A greater percentage of participants in the dual therapy cohort stayed on index therapy (63.1%) when compared with the monotherapy cohort (30.3%, <0.0001). Only 30% of the participants prescribed monotherapy, usually with a LAMA, remained on index therapy alone at the time of survey administration. In the dual therapy cohort, 63% of the participants remained on the index medication and had fewer COPD-related symptoms and fewer limitations in leisure activities compared with participants in the monotherapy cohort.
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http://dx.doi.org/10.2147/COPD.S194856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612016PMC
February 2020

Clathrin-mediated Endocytosis of Alpha-1 Antitrypsin is Essential for its Protective Function in Islet Cell Survival.

Theranostics 2019 31;9(13):3940-3951. Epub 2019 May 31.

Department of Surgery, Medical University of South Carolina, Charleston, 29425.

Cytokine-induced pancreatic β cell death plays a pivotal role in both type 1 and type 2 diabetes. Our previous study showed that alpha-1 antitrypsin (AAT) inhibits β cell death through the suppression of cytokine-induced c-Jun N-terminal kinase (JNK) activation in an islet transplantation model. The aim of this study was to further understand how AAT impacts β cells by studying AAT endocytosis in human islets and a βTC3 murine insulinoma cell line. : In vitro, human islets and βTC3 cells were stimulated with cytokines in the presence or absence of chlorpromazine (CPZ), a drug that disrupts clathrin-mediated endocytosis. Western blot, real-time PCR and cell death ELISA were performed to investigate β cell death. The oxygen consumption rate (OCR) was measured on human islets. , islets were harvested from C57BL/6 donor mice treated with saline or human AAT and transplanted into the livers of syngeneic mice that had been rendered diabetic by streptozotocin (STZ). Islet graft survival and function were analyzed. : AAT was internalized by β cells in a time- and dose-dependent manner. AAT internalization was mediated by clathrin as treatment with CPZ, profoundly decreased AAT internalization, cytokine-induced JNK activation and the downstream upregulation of c-Jun mRNA expression. Similarly, addition of CPZ attenuated cytokine-induced caspase 9 cleavage (c-casp 9) and DNA fragmentation, which was suppressed by AAT. Treatment of donor mice with AAT produced AAT internalization in islets, and resulted in a higher percentage of recipients reaching normoglycemia after syngeneic intraportal islet transplantation. : Our results suggest that AAT is internalized by β cells through clathrin-mediated endocytosis that leads to the suppression of caspase 9 activation. This process is required for the protective function of AAT in islets when challenged with proinflammatory cytokines or after islet transplantation.
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http://dx.doi.org/10.7150/thno.31647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587339PMC
September 2020

Evidence-Based Medicine and the American Thoracic Society Guidelines.

JAMA Intern Med 2019 07;179(7):1003-1004

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamainternmed.2019.1867DOI Listing
July 2019

Rare Disease Registries: Steps Forward.

Authors:
Charlie Strange

Chronic Obstr Pulm Dis 2019 Apr;6(2):126-128

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston.

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http://dx.doi.org/10.15326/jcopdf.6.2.2019.0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596431PMC
April 2019

Evaluating fluticasone furoate + vilanterol for the treatment of chronic obstructive pulmonary disease (COPD).

Expert Opin Pharmacother 2019 Jun 14;20(9):1075-1085. Epub 2019 Apr 14.

a Pulmonary, Critical Care, Allergy and Sleep Medicine , Medical University of South Carolina , Charleston , SC , USA.

Introduction: Inhaled corticosteroid/long-acting β-2 agonists (ICS/LABA) combination inhalers have been a lifeline for a generation of chronic obstructive pulmonary disease (COPD) and asthma patients. Fluticasone furoate and Vilanterol (FF/VI) as a once-daily ICS/LABA combination have an extensive clinical trial and real-world data to support its use in COPD patients. Areas covered: The authors provide pharmacological profiles of fluticasone furoate, vilanterol and the FF/VI fixed dose combination. Salient clinical trials evaluating efficacy and safety of the FF/VI combination, and studies demonstrating the impact on COPD exacerbation risk and mortality are also discussed. Expert opinion: ICS/LABA combinations provide bronchodilation and decrease the frequency of COPD exacerbations. Individualizing treatment of each COPD patient based on unique phenotypes will maximize chances of therapeutic responsiveness. Asthma-COPD overlap (ACO), patients with sputum and/or blood eosinophilia, patients with a brisk bronchodilator response, and patients with frequent exacerbations are more likely to show a therapeutic response to ICS than populations who have none of these features. FF/VI will likely remain a popular ICS/LBA combination to treat COPD, as a once-daily inhaled therapy delivered via the Ellipta device popular with COPD patients, with extensive clinical trial and real-world data to support its use.
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http://dx.doi.org/10.1080/14656566.2019.1603292DOI Listing
June 2019

Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

Eur Respir J 2019 04 4;53(4). Epub 2019 Apr 4.

University of Cincinnati, Cincinnati, OH, USA.

Introduction: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM.

Methods: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV; 51-70% ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum.

Results: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV slope -17±3 -3±3 mL·month; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 -1±2 mL·month; p<0.0001) and post-menopausal patients (-3±3 6±3 mL·month; p=0.04) exhibited a beneficial response in mean±se FEV slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus.

Conclusions: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.
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http://dx.doi.org/10.1183/13993003.02066-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394189PMC
April 2019

Predictors of Response to Endobronchial Coil Therapy in Patients With Advanced Emphysema.

Chest 2019 05 21;155(5):928-937. Epub 2019 Feb 21.

Royal Brompton Hospital and Chelsea and Westminster Hospital, London, UK; National Heart and Lung Institute, Imperial College London, London, UK.

Background: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment.

Objectives: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy.

Methods: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response.

Results: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L).

Discussion: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes.

Trial Registry: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2019.02.012DOI Listing
May 2019

Use of a Cross-Sectional Survey in the Adult Population to Characterize Persons at High-Risk for Chronic Obstructive Pulmonary Disease.

Healthcare (Basel) 2019 Jan 18;7(1). Epub 2019 Jan 18.

Division of Pulmonary, Critical Care and Sleep Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Rationale/Objective: The Behavioral Risk Factor Surveillance System (BRFSS) health survey has been used to describe the epidemiology of chronic obstructive pulmonary disease (COPD) in the US. Through addressing respiratory symptoms and tobacco use, it could also be used to characterize COPD risk.

Methods: Four US states added questions to the 2015 BRFSS regarding productive cough, shortness of breath, dyspnea on exertion, and tobacco duration. We determined COPD risk categories: provider-diagnosed COPD as self-report, high-risk for COPD as ≥10 years tobacco smoking and at least one significant respiratory symptom, and low risk was neither diagnosed COPD nor high risk. Disease burden was defined by respiratory symptoms and health impairments. Data were analyzed using multiple logistic regression models with age as a covariate.

Results: Among 35,722 adults ≥18 years, the overall prevalence of COPD and high-risk for COPD were 6.6% and 5.1%. Differences among COPD risk groups were evident based on gender, race, age, geography, tobacco use, health impairments, and respiratory symptoms. Risk for disease was seen early where 3.75% of 25⁻34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly >20 years. Seventy-nine percent of persons ≥45 years-old with frequent shortness of breath (SOB) reported having or being at risk of COPD, reflecting disease burden.

Conclusion: These data, representing nearly 18% of US adults, indicates those at high risk for COPD share many, but not all of the characteristics of persons diagnosed with the disease and demonstrates the value of the BRFSS as a tool to define lung health at a population level.
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http://dx.doi.org/10.3390/healthcare7010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473439PMC
January 2019
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