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Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals., Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections., Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds)., Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months., Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Background: Home-based testing for COVID-19 has potential to reduce existing health care disparities among underserved populations in the United States. However, implementation of home-based tests in these communities may face significant barriers. This study evaluates the acceptability, feasibility, and success of home-based testing and the potential added benefit of active support from trusted community health workers for Native Americans and Hispanic/Latino adults living in rural Montana and Washington states., Methods/design: The academic-community research team designed the trial to be responsive to community needs for understanding barriers and supports to home-based COVID-19 testing. The "Protecting Our Community" study is a two-arm pragmatic randomized controlled trial in which a total of 400 participants are randomized to active or passive arms. Participants of both study arms receive a commercially available home collection COVID-19 test kit, which is completed by mailing a self-collected nasal swab to a central laboratory. The primary study outcome is return of the kit to the central lab within 14 days. The cultural, social, behavioral, and economic barriers to home-based COVID-19 testing are also assessed by qualitative research methods. A survey and semi-structured interviews are conducted after the trial to evaluate perceptions and experience of home-based testing., Discussion: Implementing home-based testing in underserved populations, including among Native American and Hispanic/Latino communities, may require additional support to be successful. The Protecting Our Community trial examines the effect of trusted community health workers on use of home-based testing, which may be adaptable for community-driven models of home-based testing in other underserved populations., (Copyright © 2022. Published by Elsevier Inc.)

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19., Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475., Findings: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group., Interpretation: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo., Funding: The National Institute of Allergy and Infectious Diseases (USA)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The differences in the respiratory system between women and men begin in utero. Biologic sex plays a critical role in fetal development, airway anatomy, inhalational exposures, and inhaled particle deposition of the respiratory system, thus leading to differences in risk for disease, as well as clinical manifestations, morbidity, and mortality. In this article, we focus on those respiratory diseases unique to females: lymphangioleiomyomatosis and thoracic endometriosis syndrome., Competing Interests: Disclosure R.N. Criner, A. Al-abcha, A.A. Lambert have nothing to disclose. MeiLan Han receives funding from the NHLBI K24HL138188. Dr. Han has also received research funding from Novartis, Sunovion, Sanofi and Nuvaira. She has consulted for AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Cipla, Chiesi, DevPro Pharma, Merck, Sanofi, Teva, Mylan and Verona., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Wildland fires are diminishing air quality on a seasonal and regional basis, raising concerns about respiratory health risks to the public and occupational groups. This American Thoracic Society (ATS) workshop was convened in 2019 to meet the growing health threat of wildland fire smoke. The workshop brought together a multidisciplinary group of 19 experts, including wildland fire managers, public health officials, epidemiologists, toxicologists, and pediatric and adult pulmonologists. The workshop examined the following four major topics: 1 ) the science of wildland fire incidence and fire management, 2 ) the respiratory and cardiovascular health effects of wildland fire smoke exposure, 3 ) communication strategies to address these health risks, and 4 ) actions to address wildland fire health impacts. Through formal presentations followed by group discussion, workshop participants identified top priorities for fire management, research, communication, and public policy to address health risks of wildland fires. The workshop concluded that short-term exposure to wildland smoke causes acute respiratory health effects, especially among those with asthma and chronic obstructive pulmonary disease. Research is needed to understand long-term health effects of repeated smoke exposures across fire seasons for children, adults, and highly exposed occupational groups (especially firefighters). Other research priorities include fire data collection and modeling, toxicology of different fire fuel sources, and the efficacy of health protective measures to prevent respiratory effects of smoke exposure. The workshop committee recommends a unified federal response to the growing problem of wildland fires, including investment in fire behavior and smoke air quality modeling, research on the health impacts of smoke, and development of robust clinical and public health communication tools.

Background: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials., Methods: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol., Results: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV 1 ) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group., Conclusions: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose of Review: Current respiratory society guidelines recommend confirming the diagnosis of chronic obstructive pulmonary disease (COPD) with demonstration of airflow obstruction on spirometry. However, multiple recent studies have demonstrated that smokers without overt airflow obstruction on spirometry, termed symptomatic smokers, have evidence of structural lung disease on imaging, have a substantial symptom burden, and also suffer respiratory exacerbations. In this review, we provide an overview of the epidemiology of symptomatic smokers, and address issues of screening and diagnosis, evaluation, and management considerations., Recent Findings: Two large prospective cohorts of adults with and at risk for COPD quantified the respiratory morbidity of symptomatic smokers. These studies demonstrated that approximately half of smokers without spirometrically defined airflow obstruction have increased respiratory symptoms, poor quality of life, low functional capacity, and suffer from respiratory exacerbations. Symptomatic smokers also have evidence of structural lung disease on imaging, and are at risk for faster lung function decline compared with those without respiratory symptoms. Several methods have been proposed to detect smoking-related lung damage among symptomatic smokers with normal forced expired volume in 1 second (FEV1)/forced vital capacity (FVC) ratio. Novel spirometry measures have been reported to diagnose disease before detection using traditional spirometry thresholds. Small airway involvement can be detected earlier using impulse oscillometry and metrics on multiple breath nitrogen washout tests. Imaging biomarkers have been developed that are associated with respiratory morbidity and lung function decline in symptomatic smokers. The translation of novel methods for COPD disease detection into more timely introduction of therapeutics and a consequent reduction in long-term morbidity and mortality has not yet been observed., Summary: A better understanding of the pathobiologic basis of disease in smokers without overt airflow limitation, and earlier recognition of lung disease, while also appropriately evaluating for comorbidities that may account for the symptoms, will enhance the management of symptomatic smokers with preserved lung function.

Introduction: Cathelicidin (also known as LL-37 in humans) is an antimicrobial peptide secreted by epithelial and immune cells and regulated by vitamin D. The immunological roles of cathelicidin make it a putative biomarker to identify individuals at risk for reduced lung function. The objective of this study is to determine potential independent associations between low plasma cathelicidin and longitudinal lung function in current or former smokers without COPD., Methods: In a nested analysis of 308 participants from an observational cohort study, plasma cathelicidin and serum 25-hydroxy-vitamin D measurements were obtained at baseline, years three and five. The independent association between lowest quartile cathelicidin (<35 ng/ml) and forced-expiratory-volume-in-1-second (FEV1) at baseline, six and 18 months from each cathelicidin measurement was assessed with generalized estimating equations after adjusting for age, sex, race, smoking status and intensity. The long-term stability of cathelicidin and relationship with vitamin D was evaluated., Results: The cohort was 91% African-American, mean age 48.6 years, 32% female, and 81% current smokers. Participants with low cathelicidin were more likely to be female and have lower FEV1. Low cathelicidin was not independently associated with baseline FEV1. There was an independent association between low cathelicidin and reduced FEV1 at six months [-72 ml (95% CI, -140 to -8ml); p = 0.027] and 18 months [-103 ml (95% CI, -180 to -27 ml); p = 0.007]. Cathelicidin was stable over time and not correlated with vitamin D level., Conclusion: In current and former smokers with preserved lung function, low cathelicidin is associated with sustained lung function reductions at six and 18 months, suggesting that cathelicidin may be an informative biomarker to predict persistent lung function disparities among at-risk individuals., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear. Objectives: In this work, we sought to determine the independent association between rural residence and COPD-related outcomes, including COPD exacerbations, airflow obstruction, and symptom burden. Methods: A total of 1,684 SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) participants with forced expiratory volume in 1 second/forced vital capacity < 0.70 had geocoding-defined rural-urban residence status determined ( N = 204 rural and N = 1,480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes, including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of the home address to the block level at the time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures. The primary outcome measures were exacerbations determined over a 1-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. The odds ratio (OR) and incidence rate ratio (IRR) of exacerbations that required treatment with medications, including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates. Results: Rural residence was independently associated with a 70% increase in the odds of total exacerbations (OR, 1.70 [95% confidence interval (CI), 1.13-2.56]; P = 0.012) and a 46% higher incidence rate of total exacerbations (IRR 1.46 [95% CI, 1.02-2.10]; P = 0.039). There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation in the analysis attenuated the association between rural residence and the odds and incidence rate of total exacerbations (OR, 1.52 [95% CI, 1.00-2.32]; P = 0.05 and IRR 1.39 [95% CI, 0.97-1.99]; P = 0.07). There was no difference in symptoms or airflow obstruction between rural and urban participants. Conclusions: Rural residence is independently associated with increased odds and incidence of total, but not severe, COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of the increased risk of COPD exacerbations in the rural population.

Rationale: Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and associated with a significant burden of comorbidities. Although anemia is associated with adverse outcomes in COPD, its contribution to outcomes in individuals with other comorbid chronic diseases is not well understood., Objectives: This study examines the association of anemia with outcomes in a large, well-characterized COPD cohort, and attempts to understand the contribution of anemia to outcomes and phenotypes in individuals with other comorbidities., Methods: Participants with COPD from SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study) were analyzed in adjusted models to determine the associations of normocytic anemia with clinical outcomes, computed tomographic measures, and biomarkers. Analysis was additionally performed to understand the independence and possible interactions related to cardiac and metabolic comorbidities., Results: A total of 1,789 individuals with COPD from SPIROMICS had data on hemoglobin, and of these 7.5% (n = 135) were found to have normocytic anemia. Anemic participants were older with worse airflow obstruction, a higher proportion of them were African Americans, and they had a higher burden of cardiac and metabolic comorbidities. Anemia was strongly associated with 6-minute walk distance (β, -61.43; 95% confidence interval [CI], -85.11 to -37.75), modified Medical Research Council dyspnea questionnaire (β, 0.27; 95% CI, 0.11-0.44), and St. George's Respiratory Questionnaire (β, 3.90; 95% CI, 1.09-6.71), and these adjusted associations were stronger among those with two or more cardiac and metabolic comorbidities. Anemia was associated with higher levels of serum C-reactive protein, soluble receptor for advanced glycosylation end-products, and epithelial cadherin-1, findings that persisted when in those with a high burden of comorbidities., Conclusions: Anemia is associated with worse exercise capacity, greater dyspnea, and greater disease severity among adults with COPD, particularly among those with comorbid chronic cardiac and metabolic diseases. The biomarkers found in anemic individuals suggest inflammation, lung tissue injury, and oxidative stress as possible pathways for the adverse correlations of anemia with outcomes in COPD; however, substantial further study is required to better understand these potential mechanisms. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Background: Decreased but measurable serum IgA levels (≤70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD., Methods: Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions were performed., Results: Mean IgA was 269.1 mg/dL (SD 150.9). One individual had deficient levels of serum IgA (<7 mg/dL) and 25 (2.4%) had IgA level ≤70 mg/dL. Participants with IgA ≤70 mg/dL were younger (62 vs. 66 years, p = 0.01) but otherwise similar to those with higher IgA. In adjusted models, IgA ≤70 mg/dL was associated with higher exacerbation incidence rates (IRR 1.71, 95% CI 1.01-2.87, p = 0.044) and greater risk for any severe exacerbation (OR 2.99, 95% CI 1.30-6.94, p = 0.010). In adjusted models among those in the lowest decile (<120 mg/dL), each 10 mg/dL decrement in IgA (analyzed continuously) was associated with more exacerbations during follow-up (β 0.24, 95% CI 0.017-0.46, p = 0.035)., Conclusions: Subnormal serum IgA levels were associated with increased risk for acute exacerbations, supporting mildly impaired IgA levels as a contributing factor in COPD morbidity. Additionally, a dose-response relationship between lower serum IgA and number of exacerbations was found among individuals with serum IgA in the lowest decile, further supporting the link between serum IgA and exacerbation risk. Future COPD studies should more comprehensively characterize immune status to define the clinical relevance of these findings and their potential for therapeutic correction.

Rationale and Objectives: Noninfectious pulmonary complications are common among HIV-infected individuals and may be detected early by quantitative computed tomography (CT) scanning. The association of HIV disease markers with CT lung density measurement remains poorly understood., Materials and Methods: One hundred twenty-five participants free of spirometry-defined lung disease were recruited from a longitudinal cohort study of HIV-infected and HIV-uninfected individuals to undergo standardized CT scan of the chest. Parenchymal density for the entire lung volume was calculated using computerized software. Qualitative assessment of CT scans was conducted by two radiologists masked to HIV status. Linear regression models were developed to determine the independent association of markers of HIV infection on inspiratory scan mean lung density (MLD)., Results: HIV-infected participants had a significantly higher MLD (denser lung) compared to HIV-uninfected participants (-815 Hounsfield unit [HU] vs -837 HU; P = 0.002). After adjusting for relevant covariates, HIV infection was independently associated with 19.9 HU higher MLD (95% CI 6.04 to 33.7 HU; P = 0.005). In qualitative assessment, only ground glass attenuation and cysts were noted more commonly among HIV-infected individuals compared to HIV-uninfected individuals (34% vs 17% [P = 0.045] and 27% vs 10% [P = 0.03], respectively). No qualitative radiographic abnormalities attenuated the association between HIV infection and increased MLD., Conclusions: HIV infection is independently associated with increased lung density. Although qualitative CT abnormalities were common in this cohort, only ground glass attenuation and cysts were noted more frequently in HIV-infected participants, suggesting that the increased lung density observed among HIV-infected individuals may be associated with subclinical inflammatory lung changes., Competing Interests: The authors declare that there are no conflicts of interest for any author as it pertains to this manuscript., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is prevalent in the United States; however, the impact of obesity on COPD morbidity is unclear. We hypothesized that obesity is associated with worse outcomes in COPD., Methods: We examined 3,631 participants from the multicenter prospective cohort study Genetic Epidemiology of COPD (COPDGene) who had spirometry-confirmed COPD, a postbronchodilator FEV 1  < 80% predicted, and a BMI ≥ 18.5 kg/m 2 . We conducted logistic and linear regression analyses to determine the association between COPD outcomes and obesity class, adjusting for relevant confounders. The referent for obesity classes included normal/overweight individuals (BMI range, 18.5-29.9 kg/m 2 )., Results: Overall, 35% of participants were obese, with 21% class I (BMI range, 30-34.9 kg/m 2 ), 9% class II (BMI range, 35-39.9 kg/m 2 ), and 5% class III (BMI ≥ 40 kg/m 2 ). The number of comorbidities increased with increasing obesity class (P < .001). Increasing obesity class was independently associated with worse respiratory-specific and general quality of life (QOL) (St. George's Respiratory Questionnaire score and Short Form-36 score version 2, respectively), reduced 6-min walk distance (6MWD), increased dyspnea (Modified Medical Research Council score ≥ 2), and greater odds of severe acute exacerbation of COPD (AECOPD). The associations between obesity and worse outcomes were independent of the presence of comorbidities, except in the case of SF-36 and severe exacerbations., Conclusions: Obesity is prevalent among individuals with COPD and associated with worse COPD-related outcomes, ranging from QOL and dyspnea to 6MWD and severe AECOPD. These associations were strengthened when obesity was analyzed as a dose-dependent response. Obesity in patients with COPD may contribute to a worse COPD-related course., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Human immunodeficiency virus (HIV) is associated with increased risk for chronic obstructive pulmonary disease (COPD); yet substantial under-recognition of COPD exists. We administered a patient-completed, physician-reviewed COPD screening tool in an outpatient HIV clinic to determine whether screening is feasible or possible. Patients attending nonacute, routine HIV care visits were provided a brief COPD screening tool, which included three questions focused on age, respiratory symptoms, and smoking history. Providers were given completed forms for review and ordered spirometry at their discretion. Forms and medical records were subsequently reviewed to determine completion and results of spirometry testing. Of the 1,510 patients screened during the study period, 968 (64%) forms were completed. After excluding 79 incomplete forms, 889 (92%) unique patient forms were included in this analysis. Among these, 204 (23%) met criteria for spirometry referral, among whom physicians ordered spirometry in 64 (31%). At 6 months following study completion, 19 (30%) of the patients referred for spirometry had the test completed, with 5 (26%) demonstrating airflow obstruction. Nearly one out of four HIV patients met indication for screening spirometry and roughly one out of four undergoing spirometry had COPD. Critical drop-offs in the screening and diagnostic process occurred at questionnaire completion and spirometry ordering. Interventions tailored to these critical steps could improve the yield from COPD screening and help to optimize the identification of COPD in high-risk HIV-infected populations. COPD screening in a clinic focused on longitudinal HIV care can effectively identify COPD among those completing the screening continuum.

Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway epithelial cells and alter their function by impairing cell-cell adhesion and increasing the expression of inflammatory mediators. These observed changes may contribute local inflammation, which can lead to lung function decline and increased susceptibility to COPD in HIV patients.

This article serves as a CME-available, enduring material summary of the following COPD9 USA presentations: "COPD and Asthma" Presenter: Prescott Woodruff, MD, MPH "COPD and Lung Cancer" Presenter: William Bulman, MD "COPD and Bronchiectasis" Presenter: Jeremy Clain, MD "COPD and Interstitial Lung Disease" Presenter GeorgeWashko, MD., Competing Interests: Dr. Lambert has served as a consultant for GLG Consulting and has received grants from the National Institutes of Health. Dr. Dransfield has received grants from GlaxoSmithKline and Forest and has been a contracted researcher for Boehringer Ingelheim, GlaxoSmithKline, Pulmonx, PheumRx, Otsuka, Pearl, Forest and AstraZeneca. Dr. Woodruff has served as an advisor for Janssen, Neostem and Genentech. He has been a consultant for Roche, Novartis and AstraZeneca and has received a grant from Genentech. Dr. Washko has served as a consultant for GlaxoSmithKline and his spouse is employed by Merck.

Exosomes are extracellular vesicles (EVs) that play a role in intercellular communication. Stimulation of dendritic cells by the HIV-1 virus triggers their release. HIV-1 binds to dendritic cells via dendritic cell immunoreceptor (DCIR). This study shows that inhibiting the binding to DCIR significantly decreases exosome release by HIV-1-pulsed dendritic cells. In addition, exosome release from Raji-CD4 expressing DCIR cells stimulated by anti-DCIR or HIV-1 is decreased when the immunoreceptor tyrosine-based inhibition motif (ITIM) signaling motif of DCIR is mutated. Unlike the EVs released from Raji-CD4-DCIR cells after antibody stimulation, those released from HIV-1-infected cells contain the pro-apoptotic protein DAP-3. Furthermore, EVs from HIV-1 pulsed dendritic cells increase spontaneous apoptosis in uninfected CD4 T lymphocytes while they decrease it in neutrophils. This study describes for the first time that DCIR plays a role in the release of exosomes strengthening the importance of this receptor and EVs/exosomes in HIV-1 pathogenesis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults., Methods: We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy., Results: Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31)., Discussion: Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.

Background: Poorly controlled HIV infection is associated with increased risk for chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are major contributors to morbidity and mortality. Little is known about the association between HIV infection and AECOPD., Methods: We identified 167 individuals with spirometry-confirmed COPD from a longitudinal study of current or former injection drug users at risk or with HIV infection. AECOPD, defined as self-report of worsening breathing requiring treatment with antibiotics or steroids, was assessed at 6-month study visits. Multivariable logistic regression identified factors associated with AECOPD., Results: Of 167 participants, the mean age was 52 years; 89% were black, 30% female, and 32% HIV infected (median CD4 count: 312 cells per milliliter, 46% with detectable HIV RNA). After adjusting for age, gender, smoking history, comorbidity treatment, and airflow obstruction severity, HIV was independently associated with a 2.47 increased odds of AECOPD [95% confidence interval (CI): 1.22 to 5.00]. Compared with HIV-uninfected persons, HIV-infected persons with undetectable (<50 copies/mL) HIV RNA levels and those with a CD4 count ≥350 cells per cubic millimeter demonstrated increased AECOPD (odds ratio, 2.91; 95% CI: 1.26 to 6.71; odds ratio, 4.16; 95% CI: 1.87 to 9.27, respectively). Higher AECOPD risk was observed with higher CD4 counts irrespective of treatment for comorbid diseases., Conclusions: HIV infection is independently associated with increased odds of AECOPD, potentially due to differences in treatment access and to variable disease manifestation by immune status. Providers should be aware that HIV infection may increase risk for AECOPD and that symptom may be more discernible with intact immune function.

Background: Even after quitting illicit drugs, tobacco abuse remains a major cause of morbidity and mortality in former injection drug users. An important unmet need in this population is to have effective interventions that can be used in the context of community based care. Contingency management, where a patient receives a monetary incentive for healthy behavior choices, and incorporation of individual counseling regarding spirometric "lung age" (the age of an average healthy individual with similar spirometry) have been shown to improve cessation rates in some populations. The efficacy of these interventions on improving smoking cessation rates has not been studied among current and former injection drug users., Methods: In a randomized, factorial design study, we recruited 100 active smokers from an ongoing cohort study of current and former injection drug users to assess the impact of contingency management and spirometric lung age on smoking cessation. The primary outcome was 6-month biologically-confirmed smoking cessation comparing contingency management, spirometric lung age or both to usual care. Secondary outcomes included differences in self-reported and biologically-confirmed cessation at interim visits, number of visits attended and quit attempts, smoking rates at interim visits, and changes in Fagerstrom score and self-efficacy., Results: Six-month biologically-confirmed smoking cessations rates were 4% usual care, 0% lung age, 14% contingency management and 0% for combined lung age and contingency management (p = 0.13). There were no differences in secondary endpoints comparing the four interventions or when pooling the lung age groups. Comparing contingency management to non-contingency management, 6-month cessation rates were not different (7% vs. 2%; p = 0.36), but total number of visits with exhaled carbon monoxide-confirmed abstinence were higher for contingency management than non-contingency management participants (0.38 vs. 0.06; p = 0.03), and more contingency management participants showed reduction in their Fagerstrom score from baseline to follow-up (39% vs. 18%; p = 0.03)., Conclusions: While lung age appeared ineffective, contingency management was associated with more short-term abstinence and lowered nicotine addiction. Contingency management may be a useful tool in development of effective tobacco cessation strategies among current and former injection drug users., Trial Registration: Clinicaltrials.gov NCT01334736 (April 12, 2011).

Introduction: Vitamin D deficiency is highly prevalent and is associated with bone disease, cardiovascular disease, metabolic syndrome and malignancy. Injection drug users (IDUs), with or without HIV infection, are at risk for these conditions; however, limited data on vitamin D deficiency exist in this population. We determined the prevalence and correlates of vitamin D deficiency among urban IDUs in the AIDS Linked to the IntraVenous Experience (ALIVE) Study cohort., Methods: For this cross-sectional sub-study, vitamin D deficiency was defined as a serum 25(OH)-vitamin D level <20 ng/mL. Multivariable logistic regression was used to identify factors independently associated with vitamin D deficiency., Results: Of 950 individuals analyzed, 29% were HIV-infected. The median age was 49 years; 65% were male, and 91% were black. The median vitamin D level was 13.5 ng/mL (IQR, 9.0-20.3); 74% were deficient (68% in HIV-infected vs. 76% in HIV-uninfected, p = 0.01). Non-black race, fall/winter season, multivitamin intake, higher serum albumin, HCV seropositivity and HIV-infection were associated with significantly lower odds of vitamin D deficiency., Conclusions: Vitamin D deficiency is prevalent among IDUs. Notably, HIV-infected IDUs were less likely to be vitamin D deficient. Higher vitamin D levels were associated with multivitamin intake and with higher albumin levels, suggesting that nutritional status contributes substantially to deficiency. The association between HCV serostatus and vitamin D level remains unclear. Further investigation is needed to define the clinical implications of the heavy burden of vitamin D deficiency in this high-risk, aging population with significant co-morbidities.

Background: Vitamin D deficiency is associated with reduced lung function. Cathelicidin, an antimicrobial peptide regulated by vitamin D, plays a role within the innate immune system. The association of cathelicidin with lung function decrement and respiratory infection is undefined. We determined the independent relationship of cathelicidin with lung function., Methods: In a cross-sectional analysis of 650 participants in an urban observational cohort with high smoking prevalence, plasma 25(OH)-vitamin D and cathelicidin levels were measured from stored samples obtained within 6 months of spirometry study visits. Multivariable linear regression was used to determine the independent association between low cathelicidin (defined as the lowest quartile of the cohort) and absolute forced expiratory volume in 1 second (FEV1)., Results: The mean age of the cohort was 49 years; 91% were black, 35% female and 41% HIV-infected. Participants with low cathelicidin had a 183 mL lower FEV1 compared to higher cathelicidin (p = 0.009); this relationship was maintained (115 ml lower; p = 0.035) after adjusting for demographics, BMI, and smoking. Neither HIV serostatus, heavy smoking history, nor 25(OH)-vitamin D levels were associated with cathelicidin levels. Participants with low cathelicidin had a greater prevalence of prior bacterial pneumonia (21% versus 14%; p = 0.047). Inclusion of pneumonia in adjusted models did not substantially reduce the FEV1 decrement observed with low cathelicidin (104 mL lower FEV1; p = 0.05). Lung function decrements associated with low cathelicidin were greatest among individuals with lower 25(OH)-vitamin D levels., Conclusions: In a cohort at risk for airflow obstruction, low cathelicidin was independently associated with lower FEV1. These clinical data support a mechanistic link between 25(OH)-vitamin D deficiency and lung function impairment, independent of pneumonia risk.

The HIV-1 pandemic continues to expand while no effective vaccine or cure is yet available. Existing therapies have managed to limit mortality and control viral proliferation, but are associated with side effects, do not cure the disease and are subject to development of resistance. Finding new therapeutic targets and drugs is therefore crucial. We have previously shown that the dendritic cell immunoreceptor (DCIR), a C-type lectin receptor expressed on dendritic cells (DCs), acts as an attachment factor for HIV-1 to DCs and contributes to HIV-1 transmission to CD4(+) T lymphocytes (CD4TL). Directly involved in HIV-1 infection, DCIR is expressed in apoptotic or infected CD4TL and promotes trans-infection to bystander cells. Here we report the 3D modelling of the extracellular domain of DCIR. Based on this structure, two surface accessible pockets containing the carbohydrate recognition domain and the EPS binding motif, respectively, were targeted for screening of chemicals that will disrupt normal interaction with HIV-1 particle. Preliminary screening using Raji-CD4-DCIR cells allowed identification of two inhibitors that decreased HIV-1 attachment and propagation. The impact of these inhibitors on infection of DCs and CD4TL was evaluated as well. The results of this study thus identify novel molecules capable of blocking HIV-1 transmission by DCs and CD4TL.

This review of lung malignancies in human immunodeficiency virus (HIV) briefly highlights key epidemiologic and clinical features in the pulmonary involvement of AIDS-defining malignancies of Kaposi sarcoma and non-Hodgkin lymphoma. Then, focusing on non-AIDS defining lung cancer, the epidemiology and mechanisms, clinical presentation, pathology, treatment and outcomes, and prevention of HIV-associated lung cancer are discussed. Finally, the important knowledge gaps and future directions for research related to HIV-associated lung malignancies are highlighted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed at high levels on dendritic cells (DCs). This surface molecule acts as an attachment factor for HIV-1 on DCs and contributes to trans- and cis-infection pathways. Moreover, DICR is induced by HIV-1 in CD4(+) T cells and promotes virus replication in this cell type. Nothing is known hitherto about the DCIR-dependent signaling, which is induced following HIV-1 ligation. First, specific pharmacologic inhibitors were tested on HIV-1 binding/entry and, second, specific antisense oligonucleotides targeted, more specifically kinases and phosphatases, were used. Our results show that SHP-1, SHP-2, Syk, and Src kinases (ie, Src, Fyn, and Hck) as well as PKC-α and MAP kinases (ie, Erk1/2 and p38) are all involved in the DCIR-mediated signal transduction pathway triggered by HIV-1. By mutagenesis and through the use of intracellular phosphorylated peptides, we show as well a pivotal role for the tyrosine and threonine residues of the DCIR immunoreceptor tyrosine-based inhibitory motif (ITIM). Our data suggest for the first time an involvement of ITIM domain in HIV-1-mediated signaling events and a relationship between phosphorylation events and DCIR function with respect to HIV-1 biology.

The C-type lectin receptor DCIR, which has been shown very recently to act as an attachment factor for HIV-1 in dendritic cells, is expressed predominantly on antigen-presenting cells. However, this concept was recently challenged by the discovery that DCIR can also be detected in CD4(+) T cells found in the synovial tissue from rheumatoid arthritis (RA) patients. Given that RA and HIV-1 infections share common features such as a chronic inflammatory condition and polyclonal immune hyperactivation status, we hypothesized that HIV-1 could promote DCIR expression in CD4(+) T cells. We report here that HIV-1 drives DCIR expression in human primary CD4(+) T cells isolated from patients (from both aviremic/treated and viremic/treatment naive persons) and cells acutely infected in vitro (seen in both virus-infected and uninfected cells). Soluble factors produced by virus-infected cells are responsible for the noticed DCIR up-regulation on uninfected cells. Infection studies with Vpr- or Nef-deleted viruses revealed that these two viral genes are not contributing to the mechanism of DCIR induction that is seen following acute infection of CD4(+) T cells with HIV-1. Moreover, we report that DCIR is linked to caspase-dependent (induced by a mitochondria-mediated generation of free radicals) and -independent intrinsic apoptotic pathways (involving the death effector AIF). Finally, we demonstrate that the higher surface expression of DCIR in CD4(+) T cells is accompanied by an enhancement of virus attachment/entry, replication and transfer. This study shows for the first time that HIV-1 induces DCIR membrane expression in CD4(+) T cells, a process that might promote virus dissemination throughout the infected organism.

Introduction: Histone acetylation/deacetylation represents a central mechanism for the control of gene expression. Histone deacetylases (HDACs) deacetylate histones and transcription factors, causing transcriptional repression critical to the maintenance of the normal adult cardiac myocyte phenotype. Export of HDAC5 from the nucleus is associated with derepression of the fetal gene program and induction of hypertrophy in the cardiac myocyte. Prior studies of HDAC5 localization in adult cardiomyocytes have employed rabbit cells., Methods: Because many laboratories are restricted from working with USDA-regulated species such as rabbits, we sought to develop a quantitative assay to monitor signal-dependent nuclear export of HDAC5 in adult rat ventricular myocytes (ARVMs)., Results: We demonstrate that GFP-tagged HDAC5 expressed from an adenoviral vector appropriately localizes in nuclei of cultured ARVMs within 24 h post infection. Nuclear localized GFP-HDAC5 undergoes quantitative nuclear export (approximately 20-30% within 2 h) in response to hypertrophic agonists such as endothelin-1 (ET-1) and prostaglandin-F2alpha (PGF2alpha), as well as the direct protein kinase C (PKC) activator and phorbol myristate acetate (PMA). Nuclear export of HDAC5 in ARVMs is blocked by Gö6976, a small molecule inhibitor of PKC and protein kinase D (PKD)., Discussion: These data suggest that GFP-HDAC5 is appropriately functional in ARVMs 24 h post infection, and that translocation events can be quantitated for the study of hypertrophy or the identification of antihypertrophic agents in adult cardiac myocytes.

The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4(+) T cells with HIV-1 can also occur through DC-SIGN-independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DC immunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4(+) T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.

We show that Arf3p, a member of the ADP ribosylation family, is involved in the organization of actin cables and cortical patches in Saccharomyces cerevisiae. Profilin-deficient cells (pfy1Delta) have severe growth defects and lack actin cables. Overexpression of ARF3 restores actin cables and corrects growth defects in these cells. Cells deficient for the cortical patch proteins Las17p and Vrp1p have growth defects and a random cortical patch distribution. Overexpression of ARF3 in las17Delta and in vrp1Delta cells partially corrects growth defects and restores the polarized distribution of cortical patches. The N-terminal glycine, a myristoylation site in Arf3p, is necessary for its suppressor activity. arf3Delta cells show a random budding pattern. Overexpression of BNI1, GEA2 or SYP1, three genes involved in actin cytoskeleton formation, restores the normal axial budding pattern of arf3Delta cells. BUD6 is a polarity gene and GEA2 is involved in retrograde transport and the organization of the actin cytoskeleton. We have identified genetic interactions between ARF3 and BUD6, and between ARF3 and GEA2. Both double mutant strains have actin cytoskeleton defects. Our results support a role for ARF3 in cell polarity and the organization of the actin cytoskeleton.

The global entropy generation rate in the zero-mean oscillatory flow of a Maxwell fluid in a pipe is analyzed with the aim of determining its behavior at resonant flow conditions. This quantity is calculated explicitly using the analytic expression for the velocity field and assuming isothermal conditions. The global entropy generation rate shows well-defined peaks at the resonant frequencies where the flow displays maximum velocities. It was found that resonant frequencies can be considered optimal in the sense that they maximize the power transmitted to the pulsating flow at the expense of maximum dissipation.