CHEST publishes select peer-reviewed, accepted manuscripts Online First each week. The media embargo is lifted on the date of Online First publication. Final, edited versions will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication.

original research 
Roberto Badagliacca, MD, PhD; Silvia Papa, MD; Gabriele Valli, MD; Beatrice Pezzuto, MD; Roberto Poscia, MD, PhD; Giovanna Manzi, MD; Elisa Giannetta, MD, PhD; Susanna Sciomer, MD; Paolo Palange, MD; Robert Naeije, MD; Francesco Fedele, MD, FESC; Carmine Dario Vizza, MD
Topics: , , ,

Background  Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to evaluate the incremental prognostic value of echocardiography of the RV and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients.

Methods  One hundred-thirty treatment-naïve IPAH patients were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-minute walk distance plus an increase in functional class, or non elective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done.

Results  During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (Model-1). With addition of echocardiographic and CPET variables (Model-2), peak O2 pulse (peak VO2/heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (AUC: 0.81 vs 0.66, respectively; p=0.005). Patients with low RVFAC and low O2 pulse (low RVFAC + low O2 pulse) and high RVFAC+low O2 pulse showed 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk -RR- of 41.1 and 25.3, respectively), compared with high RVFAC+high O2 pulse (p=0.0001).

Conclusions  Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O2 pulse identifies patients at a particularly high risk of clinical deterioration.

original research 
Samy Suissa; Sophie Dellaniello; Pierre Ernst
Topics: , , ,

Background  Long-acting bronchodilators, including long-acting beta2-agonists (LABA) and the anticholinergic tiotropium, are recommended as initial maintenance therapy in COPD. Studies to date have been limited in size and reported ambivalent results on the comparative risk of cardiovascular, cerebrovascular and pulmonary adverse events between these two long-acting bronchodilators. Moreover, little information is available for the period when treatment is first initiated, a time when subjects may be especially at risk.

Methods  We identified a cohort of new users of long-acting bronchodilators during 2002-2012, age 55 or older, from the United Kingdom’s Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high-dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for one year for the occurrence of acute myocardial infarction (AMI), stroke, heart failure, arrhythmia and pneumonia.

Results  26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio (HR) of AMI associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI: 0.88-1.38), while for stroke it was 1.02 (95% CI: 0.78-1.34), for arrhythmia 0.81 (95% CI: 0.60-1.09), and heart failure 0.90 (95% CI: 0.79-1.02). The incidence of pneumonia was significantly less with tiotropium (HR 0.81; 95% CI: 0.72-0.92).

Conclusion  COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

recent advances in chest medicine 
Oksana A. Shlobin, MD; A. Whitney Brown, MD; Steven D. Nathan, MD
Topics: ,

Pulmonary hypertension (PH) can be triggered by any number of disease processes that result in increased pulmonary vascular resistance. Although historically associated with idiopathic pulmonary arterial hypertension (iPAH), the majority of patients with PH do not have the idiopathic subtype, but rather PH associated with another underlying diagnosis, such as left heart or lung disease. The World Health Organization (WHO) classification of PH helps conceptualize the different categories based on presumed etiology. WHO group 3 is PH associated with lung disease. This review focuses on PH in diffuse parenchymal lung diseases (DPLD) such as the idiopathic interstitial pneumonias and other more rare forms of DPLD. Although there are clear associations of PH with DPLD, the exact pathophysiologic mechanisms and full clinical significance remain uncertain. Treatment of PH related to DPLD remains investigational, but an area of great interest given the negative prognostic implications and the growing number of available pulmonary vasoactive agents.

recent advances in chest medicine  OPEN ACCESS
Ayodeji Adegunsoye, MD; Mary E. Strek, MD

Among the interstitial lung diseases (ILD), idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis and fibrotic connective tissue disease related ILD are associated with a worse prognosis with death occurring both from respiratory failure and serious associated co-morbidities. The recent development and approval of the antifibrotic agents nintedanib and pirfenidone, both of which reduced the rate of decline in lung function in patients with IPF in clinical trials, offer hope that it may be possible to alter the increased mortality associated with IPF. Although chronic hypersensitivity pneumonitis and connective tissue disease related-ILD may be associated with an inflammatory component, the evidence for the use of immunosuppressive agents in their treatment is largely limited to retrospective studies. The lack of benefit of immunosuppressive therapy in advanced fibrosis argues for rigorous clinical trials using anti-fibrotic therapies in these types of ILD as well. Patients with fibrotic ILD may benefit from identification and management of associated co-morbid conditions such as pulmonary hypertension, gastroesophageal reflux and obstructive sleep apnea, which may improve the quality of life, and in some cases, survival in affected individuals. Lung transplant evaluation should occur early in patients with IPF and those with other forms of fibrotic ILD as early evaluation may optimize post- transplantation outcomes.

Hiren J. Mehta, MD; Tan-Lucien Mohammed; Michael A. Jantz, MD
Topics: ,

Lung cancer screening using low dose CT scan reduces lung cancer specific and overall mortality in high risk patients. A significant limitation of lung cancer screening is the false positive rates. The American College of Radiology Lung Imaging Reporting and Data System (Lung-RADS)was designed to standardize reporting of low dose lung cancer screening scans and also to decrease the false positive rates without significantly compromising on the sensitivity. Implementing Lung-RADS can also improve cost effectiveness. Lung-RADS, however, has never been studied in a prospective fashion. Lung-RADS does not have a specific reporting category for patients with isolated hilar and mediastinal adenopathy or pleural effusion in the absence of lung nodules. We report four such cases in our lung cancer screening program. We believe that this is a significant limitation of Lung-RADS and should be revised in its new version.

evidence-based medicine 
Susan M. Tarlo, MB BS, FCCP; Kenneth W. Altman, MD, PhD; John Oppenheimer, MD; Kaiser Lim, MD; Anne Vertigan, PhD, MBA, BAppSc (Sp Path); David Prezant, MD; Richard S. Irwin, MD, Master FCCP

Background  In response to occupational and environmental exposures, cough can be an isolated symptom reflecting exposure to an irritant with little physiological consequence, or can be a manifestation of more significant disease. This document reviews occupational and environmental contributions to chronic cough in adults, focusing on aspects not previously covered in the 2006 ACCP Cough Guideline or our more recent systematic review, and suggests an approach to investigation of these factors when suspected.

Methods  Medline and Toxline literature searches were supplemented by articles identified by the cough panel occupational and environmental subgroup members, to identify occupational and environmental aspects of chronic cough not previously covered in the 2006 ACCP Cough Guideline. Based on the literature reviews and the Delphi methodology, the cough panel occupational and environmental subgroup developed guideline suggestions that were approved after review and voting by the full cough panel.

Results  The literature review identified relevant articles regarding: mechanisms; allergic environmental causes; chronic cough and the recreational and involuntary inhalation of tobacco and marijuana smoke; non-allergic environmental triggers; laryngeal syndromes; and occupational diseases and exposures. Consensus-based statements were developed for the approach to diagnosis, due to a lack of strong evidence from published literature.

Conclusions  Despite increased understanding of cough related to occupational and environmental triggers, there remains a gap between the recommended assessment of occupational and environmental causes of cough and the reported systematic assessment of these factors, and a need for further documentation of this in the future.

translating basic research into clinical practice 
Y C Gary Lee, PhD; Steven Idell, MD; Georgios T. Stathopoulos, MD
Topics: ,

The incidence of pleural infection has been rising in recent years. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has significantly reduced the need of surgery and its impact on clinical care is rising worldwide. Efforts are underway to optimize the delivery regime and establish the short and longer term effects of this therapy. The complex interactions of bacterial infection within the pleura with inflammatory responses and clinical interventions (antibiotics and tPA/DNase) require further studies to improve future treatment options. Intrapleural instillation of tPA potently induces pleural fluid formation, principally via a monocyte chemotactic protein (MCP)-1 dependent mechanism. Activation of transcriptional programs in pleural resident cells and infiltrating cells during pleural infection and malignancy results in the local secretion of a cocktail of pro-inflammatory signalling molecules (including MCP-1) within the pleural confines that contributes to effusion formation. Understanding the biology of these molecules and their interaction may provide novel targets for pleural fluid control.

original research 
Ming Ding, M.D; Yu Chen, Ph.D; Wei-jie Guan, Ph.D; Chang-hao Zhong, M.D; Mei Jiang, M.D; Wei-zhan Luo, M.D; Xiao-bo Chen, M.D; Chun-li Tang, M.D; Yan Tang, M.D; Qi-ming Jian, M.D; Wei Wang, M.D; Shi-yue Li, M.D; Nan-shan Zhong, M.D.
Topics: , ,

Background  Although forced expiratory volume in one second (FEV1) remains the gold standard for staging COPD, the association between airway remodeling and airflow limitation remains unclear.

Objective  Endobronchial optical coherence tomography (EB-OCT) was performed to assess the association between disorders of large- and medium-to-small-sized airways and COPD staging. We also evaluated small-airway architecture in heavy-smokers with normal FEV1 (SNL) and healthy never-smokers.

Methods  We recruited 48 COPD patients (stage Ⅰ, n=14; stage Ⅱ, n=15; stage Ⅲ-Ⅳ, n=19), 21 SNL, and 17 healthy never-smokers. Smoking history inquiry, spirometry, chest computed tomography, bronchoscopy and EB-OCT were performed. Mean luminal diameter (Dmean), inner luminal area (Ai), and airway wall area (Aw) of generation 3∼9 bronchi were measured using EB-OCT.

Results  Patients with more advanced COPD demonstrated greater abnormality of airway architecture in both large- and medium-to-small-sized airways, followed by SNL and never-smokers. Abnormality of airway architecture and EB-OCT parameters in SNL were comparable to those with stage I COPD. FEV1% predicted correlated with D and Ai of generation 7∼9 in COPD; however, neither D nor Ai of generation 3∼6 correlated with FEV1% in stage Ⅰ and Ⅱ COPD and SNL.

Conclusions  FEV1-based COPD staging partially correlates with small-airway disorders in stage Ⅱ-Ⅳ COPD. EB-OCT-detected small airway abnormalities correlate with FEV1-based staging in COPD and identify early pathology in healthy heavy-smokers.

original research 
F.E. Aleva, MD, PhD student; L.W.L.M. Voets, Bsc; S.O. Simons, MD, PhD; Q. de Mast, MD, PhD; A.J.A.M. van der Ven, MD, PhD; Y.F. Heijdra, MD, Phd
Topics: ,

Background  COPD patients encounter episodes of increased inflammation, so-called acute exacerbations of COPD (AE-COPD). In 30% of AE-COPD no clear etiology is found. Since there is a well-known crosstalk between inflammation and thrombosis, the objectives of this study were to determine the prevalence, embolus localization and clinical relevance, and clinical markers of pulmonary embolism (PE) in unexplained AE-COPD.

Methods  A systematic search was performed using MEDLINE and EMBASE platforms from 1974 – October 2015. Prospective- and cross-sectional studies that included patients with an AE-COPD and used pulmonary CT-angiography for diagnosis of PE were included.

Results  The systematic search resulted in 1650 records. Main reports of 22 articles were reviewed and 7 studies were included. The pooled prevalence of PE in unexplained AE-COPD was 16.1% (95% confidence-interval 8.3%-25.8%) in a total of 880 patients. Sixty-eight percent of the emboli found were located in the main pulmonary arteries, lobar arteries or inter-lobar arteries. Mortality and length of hospital admission seem to be increased in patients with unexplained AE-COPD and PE. Pleuritic chest pain and cardiac failure were more frequently reported in patients with unexplained AE-COPD and PE. In contrast, signs of respiratory tract infection was less frequently related to PE.

Conclusions  PE is frequently seen in unexplained AE-COPD. Two-thirds of emboli are found at localizations that have a clear indication for anticoagulant treatment. These findings merit clinical attention. PE should receive increased awareness in patients with unexplained AE-COPD, especially when pleuritic chest pain and signs of cardiac failure are present and no clear infectious origin can be identified.

recent advances in chest medicine 
Federico Lavorini, Ph.D; Søren Pedersen, Ph.D; Omar S. Usmani, Ph.D
Topics: ,

Over the last decade, there is increasing evidence that the small airways, i. e. airways <2 mm in internal diameter, contribute significantly to the pathophysiology and clinical expression of asthma and chronic obstructive pulmonary disease (COPD). The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiological methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and side effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery. The availability of small-particle aerosols of corticosteroid, bronchodilator or their combination, enables a higher total lung deposition, better peripheral lung penetration, and provides added clinical benefit, compared to large-particle aerosol treatment. However, a number of questions remain unanswered on the pragmatic approach relevant in order for clinicians to consider the role of small airways directed therapy in the day-to-day management of their patients with asthma and COPD. We have thus tried to clarify the dilemmas, confusion, and misconceptions related to small airways directed therapy. To this end, we have systematically reviewed all studies on small-particle aerosol therapy in order to address the dilemmas, confusion, and misconceptions related to small airways directed therapy.

original research 
Philip S. Wells, MD; Martin H. Prins, MD, PhD; Bennett Levitan, MD, PhD; Jan Beyer-Westendorf, MD; Timothy A. Brighton, MD; Henri Bounameaux, MD; Alexander T. Cohen, MD, FRACP; Bruce L. Davidson, MD, MPH; Paolo Prandoni, MD, PhD; Gary E. Raskob, PhD; Zhong Yuan, MD, PhD; Eva G. Katz, PhD, MPH; Martin Gebel, PhD; Anthonie WA. Lensing, MD, PhD
Topics: , , , , ,

Background  Short-term anticoagulant treatment for acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) effectively reduces the risk of recurrent disease during the first 6 to 12 months of therapy. Continued anticoagulation is often not instituted because of the perception among physicians that the risk of major bleeding will outweigh the risk of new venous thrombotic episodes.

Methods  Benefit-risk analysis using the randomized EINSTEIN-EXTENSION trial, which compared continued rivaroxaban versus placebo in 1197 patients with symptomatic DVT or PE who had completed 6-12 months of anticoagulation and in whom physicians had equipoise with respect to the need for continued anticoagulation. One-year Kaplan-Meier rates and rate differences of recurrent venous thromboembolism (VTE) and major bleeding were calculated. Benefits and risks were assessed using rate differences scaled to a population size of 10000 patients treated for 1 year.

Results  Recurrent VTE occurred in 8 (3.0%) rivaroxaban recipients and 42 (9.6%) placebo patients. In a population of 10000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI 246-1084) fewer recurrent VTEs than placebo (number needed to treat=15). Major bleeding occurred in 4 (0.7%) and 0 patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI 2-134) more major bleeding events than placebo (number needed to harm=147). Kaplan–Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at ±100 days.

Conclusions  A clinically important benefit and a favorable benefit–risk profile of continued rivaroxaban anticoagulation was observed.

original research 
Elizabeth Moore, MSc; Thomas Palmer, MSc; Dr Roger Newson, PhD; Prof Azeem Majeed; Dr Jennifer K Quint, MRCP, PhD; Dr Michael A Soljak, PhD
Topics: , ,

Background  Acute exacerbations of COPD (AECOPD) have a significant impact on healthcare utilization, including physician visits and hospitalizations. Previous studies and reviews have shown that pulmonary rehabilitation has many benefits but the effect on hospitalizations for AECOPD is inconclusive.

Methods  A literature search was carried out to find studies that might help determine, using a meta-analysis, the impact of pulmonary rehabilitation on AECOPD, defined as unscheduled or emergency hospitalizations and emergency room (ER) visits. Cohort studies and randomised controlled trials (RCTs) reporting hospitalizations for AECOPD as an outcome were included. Meta-analyses compared hospitalization rates between eligible pulmonary rehabilitation recipients and non-recipients, before and after rehabilitation.

Results  18 studies were included in the meta-analysis. Results from ten RCTs showed that the control groups had a higher overall rate of hospitalizations than the pulmonary rehabilitation groups (0.97 hospitalizations/patient-year, 95% Confidence Intervals (CIs) 0.67, 1.40; 0.62 hospitalizations/patient-year, 95% CI 0.33, 1.16 respectively). Five studies compared admission numbers in the 12 months before and after rehabilitation, finding a significantly higher admission rate before compared to after (1.24 hospitalizations/patient-year, 95% CIs 0.66, 2.34; 0.47 hospitalizations/patient-year, 95% CIs 0.28, 0.79 respectively). The pooled result of three cohort studies found the reference group had a lower admission rate compared to the pulmonary rehabilitation group (0.18 hospitalizations/patient-year, 95% CI 0.11, 0.32 for reference group versus 0.28 hospitalizations/patient-year, 95% CI 0.25, 0.32 for pulmonary rehabilitation).

Conclusions  Although results from RCTs suggested that pulmonary rehabilitation reduces subsequent admissions, pooled results from the cohort studies did not, likely reflecting the heterogeneous nature of individuals included in observational research and the varying standard of pulmonary rehabilitation programmes.

recent advances in chest medicine 
Rishi Raj, MD; Kirtee Raparia, MD; David A. Lynch, MD; Kevin K. Brown, MD
Topics: , ,

This review addresses common questions regarding the role of surgical lung biopsy in the diagnosis and treatment of interstitial lung disease (ILD). We specifically address when a surgical lung biopsy (SLB) can be diagnostic as well as when it may be avoided, e.g., when the combination of the clinical context and the imaging pattern seen on high resolution CT (HRCT) chest can provide a confident diagnosis. Existing studies on the diagnostic utility as well as the complications associated with SLB are reviewed; as are the performance characteristics and reliability of HRCT scan of the chest in predicting the underlying histopathology of the lung. The review is formatted in the form of answers to questions that clinicians regularly ask when considering SLB in a patient with ILD.

translating basic research in clinical practice 
G.F. Curley, MB, PhD; J.G. Laffey, MD, MA; H. Zhang, MD, PhD; A.S. Slutsky, MD

The pathophysiological mechanisms by which mechanical ventilation can contribute to lung injury – termed ventilator induced lung injury (VILI) – is increasingly well understood. “Biotrauma” describes release of mediators by injurious ventilatory strategies, which can lead to lung and distal organ injury. Insights from preclinical models demonstrating that traditional high tidal volumes drove the inflammatory response helped lead to clinical trials demonstrating lower mortality in patients ventilated with a lower tidal volume strategy. Other approaches that minimize VILI, such as higher PEEP, prone positioning and neuromuscular blockade have each been demonstrated to decrease indices of activation of the inflammatory response. This review examines the evolution of our understanding of the mechanisms underlying VILI, particularly with regard to biotrauma. We will assess evidence that ventilatory and other ‘adjunctive’ strategies that decrease biotrauma offer great potential to minimize the adverse consequences of VILI, and to improve the outcomes of patients with respiratory failure.

original research 
Asli Gorek Dilektasli, MD; Janos Porszasz, MD, PhD; Richard Casaburi, PhD, MD; William W. Stringer, MD; Surya P. Bhatt, MD; Youngju Pak, PhD; Harry B. Rossiter, PhD; George Washko, MD; Peter J. Castaldi, MD; Raul San Jose Estepar, PhD; James E. Hansen, MD

Rationale  In chronic obstructive pulmonary disease both smaller and larger airways are affected. Forced expiratory volume in one second (FEV1) mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow.

Objective  To evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6), and small airway measures and gas trapping in quantitative chest computed tomography (CT), and clinical outcomes in the COPDGene cohort.

Methods  7,853 current and ex-smokers were evaluated for airflow obstruction using recently-defined linear iteratively-derived equations of Hansen et al.1 to determine lower limits of normal equations for pre-bronchodilator FEV1/FVC, FEV1/FEV6, FEV3/FEV6 and FEV3/FVC. General linear and ordinal regression models were applied to the relation between pre-bronchodilator spirometry and radiologic and clinical data.

Main Results  Of the 10,311 participants included in the COPDGene Phase 1 study, participants with incomplete quantitative CT or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with ratio of FEV1 to forced vital capacity (FEV1/FVC) greater than lower limit of normal, 15.4% had abnormal FEV3/FEV6. Compared to participants with normal FEV3/FEV6 and FEV1/FVC, abnormal FEV3/FEV6 was associated with significantly greater gas trapping, St. George Respiratory Questionnaire score, mMRC dyspnea score, BODE index, and shorter six-minute walking distance (all P < 0.0001), but not CT-evidence of emphysema.

Conclusions  Current and ex-smokers with pre-bronchodilator FEV3/FEV6 < lower limit of normal as the sole abnormality identifies a distinct population with evidence of small airway disease in quantitative CT, impaired indices of physical function and quality of life otherwise deemed normal by current spirometric definition.

special features 
Tanmay S. Panchabhai, MD, FACP, FCCP; Sanjay Mukhopadhyay, MD; Sameep Sehgal, MD; Debabrata Bandyopadhyay, MD, MRCP, FACP; Serpil C. Erzurum, MD; Atul C. Mehta, MD, FACP, FCCP
Topics: , , , , , , , , , , , , , , , , , , , , , ,

Although mucus is a normal product of the tracheobronchial tree, some diseases of the respiratory tract are characterized by unusually thick (inspissated) forms of mucus that accumulate within the airways. These are known as mucus plugs. The pathologic composition of these plugs is surprisingly diverse and, in many cases, correlates with distinctive clinical, radiologic, and bronchoscopic findings. The best-known conditions that involve mucus plugs are allergic bronchopulmonary aspergillosis, plastic bronchitis, and asthma. Other lung diseases occasionally associated with plugs within the airways include Aspergillus tracheobronchitis, hyper-immunoglobulin E syndromes, exogenous lipoid pneumonia, pulmonary alveolar proteinosis, and chronic eosinophilic pneumonia. In this review, we describe and illustrate the bronchoscopic, pathologic, and imaging findings in respiratory disorders characterized by mucus plugs or plugs composed of other similar materials. Recognition of the characteristic appearance and differential diagnosis of mucus plugs will hopefully facilitate diagnosis and management of these diseases.

original research 
Andrew J. Goodwin, MD, MSCR; Nandita R. Nadig, MD; James T. McElligott, MD, MSCR; Kit N. Simpson, DrPh; Dee W. Ford, MD, MSCR
Topics: ,

Background  Medically underserved areas are comprised of vulnerable populations with reduced access to ambulatory care services. Our goal was to determine the association between residence in a medically underserved area and severe sepsis incidence and mortality.

Methods  Using administrative data, we identified adults admitted with severe sepsis to non-federal hospitals in South Carolina. We determined whether each resident lived in a medically underserved area or non-medically underserved area from US census and Department of Health and Human Services data. Age-adjusted severe sepsis incidence and mortality rates were calculated and compared between both residential classifications. Multivariate logistic regression measured the association between residence in a medically underserved area and mortality while adjusting for confounders.

Results  In 2010, 24,395 adults were admitted with severe sepsis and 1,446,987 (43%) adults lived in a medically underserved area. Residents of medically underserved areas were admitted more frequently with severe sepsis (8.6 vs. 6.8 cases/1,000 people, p<0.01) and were more likely to die (15.5 vs 11.9 deaths/10,000 people, p<0.01) with increased odds of severe sepsis-related death (OR 1.12) after adjustment for age, race, and severity of illness. ZIP Code-based surrogates of socioeconomic status including median income, proportion below poverty level, and educational attainment, however, had minimal association with sepsis mortality.

Conclusions  Residence in a medically underserved area is associated with higher incidence and mortality rates of severe sepsis and represents a novel method of access-to-care adjustment. Traditional access-to-care surrogates, however, are poorly associated with sepsis mortality.

original research 
Thomas K. Aldrich, MD; Jessica Weakley, MPH; Sean Dhar, MD; Charles B. Hall, PhD; Tesha Crosse, MS; Gisela I. Banauch, MD; Michael D. Weiden, MD; Gabriel Izbicki, MD; Hillel W. Cohen, DrPH; Aanchal Gupta, MD; Camille King, RRT; Vasilios Christodoulou, BA; Mayris P. Webber, DrPH; Rachel Zeig-Owens, DrPH; William Moir, MPH; Anna Nolan, MD; Kerry J. Kelly, MD; David J. Prezant, MD

Background  World Trade Center (WTC)-exposed rescue/recovery workers endured massive respiratory insult from inhalation of particulate matter and gases, resulting in respiratory symptoms, loss of lung function, and, for many, bronchial hyperreactivity (BHR). The persistence of respiratory symptoms and lung function abnormalities has been well-documented, while persistence of BHR has not been investigated.

Methods  173 WTC-exposed firefighters with bronchial reactivity measured within 2 years after 9/11/2001 (9/11), (baseline methacholine challenge test [MCT]), were re-evaluated in 2013-2014 (follow-up-MCT). FEV1 measurements were obtained from the late pre-9/11, early post-9/11 and late post-9/11 periods. Respiratory symptoms and corticosteroid treatment were recorded.

Results  Bronchial reactivity remained stable (within 1 doubling dilution) for most (n=101, 58%). 16 of 28 (57%) with BHR (PC20<8mg/ml) at baseline had BHR at follow up, and an additional 27 of the 145 (19%) without BHR at baseline had BHR at follow-up. In multivariable models, we found that BHR baseline was strongly associated with BHR follow-up (OR=6.46) and that BHR at follow-up was associated with an estimated 15.4 ml/year greater FEV1 decline than experienced by those without BHR at follow-up. Annual FEV1 decline was moderated by corticosteroid use.

Conclusions  Persistent BHR and its deleterious influence on lung function suggest a role for airway inflammation in perpetuation of WTC-associated airway disease. In future massive occupational exposure to inorganic dust/gases, we recommend early and serial pulmonary function testing, including measurements of bronchial reactivity, when possible, and inhaled corticosteroid therapy for those with symptoms or pulmonary function tests consistent with airway disease.

original research 
Simeon Gotzev, BMSc; Joshua C. Lipszyc, HBA; Dale Connor, MMath; Susan M. Tarlo, MB BS FRCPC
Topics: ,

Background  Work-related asthma (WRA) is the most common chronic occupational lung disease in the developed world. Several factors including socio-demographic status, and occupation / industry, increase the risks of developing WRA. In this study, we sought to identify changes in patterns and characteristics among WRA patients over a fifteen-year period in an occupational lung disease clinic.

Methods  We performed a retrospective analysis of WRA patient charts at the Occupational Lung Disease Clinic of a University Hospital in Toronto, Canada. Patients were divided into two periods classified by first attendance at the clinic 2000-2007 and 2008-2015. Comparisons between the two periods included: socio-demographic characteristics, smoking status, occupations, exposures, and submitted workers’ compensation claims.

Results  Fewer occupational asthma cases were seen in the more recent period versus the earlier period (40 vs. 74 cases), with a smaller reduction in work-exacerbated asthma cases (40 vs. 58). The recent period included a significantly smaller proportion employed in the manufacturing industry and isocyanate-induced cases compared with the earlier period. An increased proportion were employed in health care and education industries (primarily cleaners and teachers) in the recent period, consistent with a corresponding increased frequency of cleaning agents and dust exposures.

Conclusions  The changes observed in work sectors in our work-related asthma patients in this clinic in Toronto are consistent with reductions reported in Ontario workers’ compensation claims for occupational asthma, and may relate to preventive measures. Cleaners and teachers should be a focus of further intervention measures for work-related asthma.

original research 
Sameer S. Kadri, MD, MS; Chanu Rhee, MD, MPH; Jeffrey R. Strich, MD; Megan K. Morales, MD; Samuel Hohmann, PhD; Jonathan Menchaca, BA; Anthony F. Suffredini, MD; Robert L. Danner, MD; Michael Klompas, MD, MPH
Topics: , , ,

Background  Reports that septic shock incidence is rising and mortality rates declining may be confounded by improving recognition of sepsis and changing coding practices. We compared trends in septic shock incidence and mortality in academic hospitals using clinical versus claims data.

Methods  We identified all patients with concurrent blood cultures, antibiotics, and ≥2 consecutive days of vasopressors and all patients with ICD-9 codes for septic shock at 27 academic hospitals from 2005-2014. We compared annual incidence and mortality trends. We reviewed 967 records from 3 hospitals to estimate the accuracy of each method.

Results  Of 6.5 million adult hospitalizations, 99,312 (1.5%) were flagged by clinical criteria, 82,350 (1.3%) by ICD-9 codes, and 44,651 (0.7%) by both. Sensitivity for clinical criteria was higher than claims (74.8% vs. 48.3%, p<0.01), whereas positive predictive value was comparable (83% vs. 89%, p=0.23). Septic shock incidence using clinical criteria rose from 12.8 to 18.6 cases per 1000 hospitalizations (average 4.9% increase/year, 95% CI 4.0%-5.9%), while mortality declined from 54.9% to 50.7% (average 0.6% decline/year, 95% CI 0.4%-0.8%). In contrast, septic shock incidence using I0CD-9 codes increased from 6.7 to 19.3 per 1000 hospitalizations (19.8% increase/year, 95% CI 16.6%-20.9%), while mortality decreased from 48.3% to 39.3% (1.2% decline/year, 95% CI 0.9%-1.6%).

Conclusions  A clinical surveillance definition based on concurrent vasopressors, blood cultures, and antibiotics accurately identifies septic shock hospitalizations and suggests that the incidence of patients receiving treatment for septic shock has risen and mortality rates have fallen, but less dramatically than estimated using ICD-9 codes.

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    Print ISSN: 0012-3692
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