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 
Timothy R. Aksamit, MD; Anne E. O’Donnell, MD; Alan Barker, MD; Kenneth N. Olivier, MD; Kevin L. Winthrop, MD; M. Leigh Anne Daniels, MD MPH; Margaret Johnson, MD; Edward Eden; David Griffith, MD; Michael Knowles, MD; Mark Metersky, MD; Matthias Salathe, MD; Byron Thomashow, MD; Gregory Tino, MD; Gerard Turino, MD; Betsy Carretta, MPH; Charles L. Daley, MD

Objective  We sought to describe the characteristics of adult bronchiectasis patients enrolled in the United States Bronchiectasis Research Registry (BRR).

Methods  The BRR is a database of non-cystic fibrosis bronchiectasis (NCFB) patients enrolled at 13 sites within the United States. Baseline demographic, spirometric, imaging, microbiologic, and therapeutic data were entered into a central web-based database. Patients were subsequently analyzed by the presence NTM.

Results  We enrolled 1826 patients between 2008 and 2014. Patients were predominantly female (79%), white (89%), and never smokers (60%) with a mean age 64±14 years. Sixty-three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation into the BRR. NTM patients were older, predominantly female, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux (GERD) was more common in those with NTM whereas asthma, primary immunodeficiency and primary ciliary dyskinesia were more common in those without NTM. Fifty-one percent of patients had spirometric evidence of airflow obstruction. NTM patients were more likely to have diffusely dilated airways and tree-in-bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were less commonly cultured among patients with NTM. Bronchial hygiene measures were used more often in those with NTM; whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM.

Conclusion  Adult bronchiectasis patients enrolled in the US BRR are described with differences noted in demographic, radiographic, microbiologic, and treatment variables based on stratification of the presence of NTM.

original research 
Marilyn K. Glassberg, M.D.; Julia Minkiewicz, Ph.D.; Rebecca L. Toonkel, M.D.; Emmanuelle S. Simonet, M.A.; Gustavo A. Rubio, M.D.; Darcy Difede, R.N., B.S.N.; Shirin Shafazand, M.D.; Aisha Khan, Ph.D.; Marietsy V. Pujol, M.B.A.; Vincent F. LaRussa, Ph.D.; Lisa H. Lancaster, M.D.; Glenn D. Rosen, M.D.; Joel Fishman, M.D., Ph.D.; Yolanda N. Mageto, M.D., M.P.H.; Adam Mendizabal, Ph.D.; Joshua M. Hare, M.D.
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Background  Despite recent FDA approval of two new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Pre-clinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The AETHER trial was the first study designed to evaluate the safety of a single infusion of bone marrow-derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis.

Methods  Nine patients with mild to moderate IPF were sequentially assigned to one of three cohorts and dosed with a single intravenous infusion of 20, 100, or 200 x 106 human bone marrow-derived mesenchymal stem cells per infusion from young, unrelated, male donors. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary endpoint was the incidence (at week four post infusion) of treatment emergent serious adverse events, defined as the composite of: death, non-fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60, and additionally 28 days thereafter. Secondary efficacy endpoints were exploratory and measured disease progression.

Results  No treatment-emergent serious adverse events were reported. Two non-treatment related deaths occurred due to progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks post-infusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted DLCO.

Conclusions  Data from this trial support the safety of a single infusion of hMSC in patients with mild-moderate IPF.

point and counterpoint 
Richard G. Wunderink, MD, FCCP
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No abstract is available for this article
point and counterpoint 
Marin H. Kollef, MD, FCCP
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No abstract is available for this article
point and counterpoint 
Richard G. Wunderink, MD, FCCP
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Routine use of aerosolized antibiotics is the most rational approach to the current treatment dilemmas for severe hospital-acquired pneumonia (HAP) requiring endotracheal intubation or ventilator-associated pneumonia (VAP). The two main issues for HAP/VAP are inappropriate initial therapy and ineffective therapy for multidrug resistant (MDR) pathogens, particularly gram negative bacilli such as Pseudomonas aeruginosa and Acinetobacter species. The emergence of extended spectrum beta-lactamases (ESBL) and carbapenem resistance in Enterobacteriaceae (CRE) have made even common pathogens such as Escherichia coli difficult to treat.

point and counterpoint 
Marin H. Kollef, MD, FCCP
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No abstract is available for this article
original research 
Ivan FN. Hung, MD; Kelvin KW. To, MD; Jasper FW. Chan, MBBS; Vincent CC. Cheng, MD; Kevin SH. Liu, MBChB; Anthony Tam, MBBS; Tuen-Ching Chan, MD; Anna Jinxia Zhang, PhD; Patrick Li, MSc; Tin-Lun Wong, BSc; Ricky Zhang, MSc; Michael KS. Cheung; William Leung, MBBS; Johnson YN. Lau, MD; Manson Fok, MD; Honglin Chen, PhD; Kwok-Hung Chan, PhD; Kwok-Yung Yuen, MD
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Background  Influenza causes excessive hospitalizations and deaths. Single agent treatment with oseltamivir in severe influenza might be insufficient. The study assessed the efficacy and safety of oseltamivir-clarithromycin-naproxen combination for treatment of serious influenza.

Methods  From February to April 2015, we conducted a prospective open-label randomized-controlled trial. Adult patients hospitalized for A(H3N2) influenza were randomly assigned to a 2-day combination of clarithromycin 500mg, naproxen 200mg and oseltamivir 75mg twice daily, followed by 3 days of oseltamivir; or oseltamivir 75mg twice daily without placebos for 5 days as control (1:1). The primary end-point was 30-day mortality. The secondary end-points were 90-day mortality, serial nasopharyngeal-aspirate (NPA) virus titer, percentage of neuraminidase inhibitor resistant A(H3N2) virus (NIRV) quasispecies by pyrosequencing, pneumonia-severity-index (PSI), and duration of hospital-stay.

Results  Among the 217 influenza A(H3N2) patients enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years and 56% were men. Adverse events were uncommon. Ten patients succumbed during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P=0.01), less frequent ICU/HDU admission (P<0.001), and shorter hospital-stay (P<0.0001). The virus titer, PSI (day 1-3;P<0.01), and NPA specimens with NIRV quasispecies ≥5% (day 1-2;P<0.01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (odds-ratio:0.06; 95%,confidence-interval, 0.004-0.94;P=0.04).

Conclusions  Combination treatment reduced both 30- and 90-day mortality and length of hospital-stay. Further study on the antiviral and immunomodulatory effects of this combination treatment for severe influenza is warranted.

original research 
Giovanna E. Carpagnano; Maria P. Foschino-Barbaro; Corrado Crocetta; Donato Lacedonia; Valerio Saliani; Luigi Davide Zoppo; Peter J. Barnes
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Background  Exhaled breath temperature (EBT) is a new non-invasive method for the study of inflammatory respiratory diseases with a potential to reach clinical practice. However, few studies, and mainly derived from small, paediatric populations, are available on the validation of the method and the range of normal values is not well established.The aim of this study was to measure EBT values in an Italian population of 298 (45.2±15.5 yrs, 143 male, FEV1 97.2±5.8%, FVC 98.4±3.9%) selected from 867 adult volunteers, in order to define reference values in healthy subjects and to analyse the influence of individual and external variables on this parameter.

Methods  We measured EBT with a X-halo PRO device to different ambient temperature that ranged from 0 to 38°C

Findings  We report reference value of EBT in healthy Caucasian never smoker subjects. EBT values are strongly influenced by the external temperature and to a lesser extent by gender.

Interpretation  These data provide reference values in a large population of healthy never smokers subjects for measuring EBT as a basis for future studies. Our results are a contribution to the promotion of the EBT from bench to bed side.

Fundings  No funding was provided for this review.

original research 
D. Hunter Best, PhD; Kelli L. Sumner, BS; Benjamin P. Smith, MD; Kristy Damjanovich-Colmenares, BS; Ikue Nakayama, MD; Lynette M. Brown, MD, PhD; Youna Ha, BS; Eleri Paul, MLS (ASCP); Ashley Morris, MLS (ASCP); Mohamed A. Jama, MS, MB (ASCP); Mark W. Dodson, MD, PhD; Pinar Bayrak-Toydemir, MD, PhD; C. Gregory Elliott, MD, MACP, FCCP
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Background  Differentiating pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic or heritable pulmonary arterial hypertension (IPAH and HPAH) is important clinically. Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) cause heritable PVOD and PCH whereas mutations in other genes cause HPAH. The aim of this study is to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH.

Methods  We performed Sanger sequencing and deletion/duplication analysis to detect mutations in the BMPR2 gene on 81 patients diagnosed at 30 North American medical centers with IPAH (n=72) or HPAH (n=9). BMPR2 mutation negative patients (n=67) were sequenced for mutations in four other genes (ACVRL1, ENG, CAV1, KCNK3) known to cause HPAH. Patients negative for mutations in all known PAH genes (n=66) were then sequenced for mutations in EIF2AK4. We assessed the pathogenicity of EIF2AK4 mutations and reviewed clinical characteristics of patients with pathogenic EIF2AK4 mutations.

Results  Pathogenic BMPR2 mutations were identified in 8 of 72 (11.1%) IPAH patients and 6 of 9 (66.7%) HPAH patients. We identified a novel homozygous EIF2AK4 mutation (c.257+4A>C) in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 IPAH patients had bi-allelic EIF2AK4 mutations.

Conclusions  Pathogenic bi-allelic EIF2AK4 mutations are identified rarely in patients diagnosed with HPAH. Identification of pathogenic bi-allelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.

original research 
Alejandro A. Diaz, M.D., M.P.H.; Thomas P. Young, B.Sc.; Diego J. Maselli, M.D.; Carlos H. Martinez, M.D., M.P.H.; Ritu Gill, M.D., M.P.H.; Pietro Nardelli, Ph.D.; Wei Wang, Ph.D.; Gregory L. Kinney, Ph.D.; John E. Hokanson, Ph.D.; George R. Washko, M.D.; Raul San Jose Estepar, Ph.D.
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Background  Bronchiectasis is frequent in smokers with COPD, however there is only limited data on objective assessments of this process.

Objective  To objectively assess bronchovascular morphology, calculate the ratio of the diameters of bronchial lumen and adjacent artery (BA ratio), and identify those measurements able to discriminate bronchiectasis.

Methods  We collected quantitative computed tomography (QCT) measures of BA ratios, peak wall attenuation, wall thickness (WT), wall area, and wall area percent (WA%) at matched 4th-6th airway generations in 21 ever smokers with bronchiectasis (cases) and 21 never-smoking controls (control airways). In cases, measurements were collected at both bronchiectatic and non-bronchiectatic airways. Logistic analysis and the area under receiver operating characteristic curve (AUC) were used to assess the predictive ability of QCT measurements for bronchiectasis.

Results  The whole-lung and 4th-6th airway generations BA ratio, WT, and WA% were significantly greater in bronchiectasis cases than controls. The AUCs for the BA ratio to predict bronchiectasis ranged from 0.90 (whole-lung) to 0.79 (4th-generation). AUCs for WT and WA% ranged from 0.72 to 0.75 and from 0.71 to 0.75. The artery diameters but not bronchial diameters were smaller in bronchiectatic than both non-bronchiectatic and control airways (P<0.01 for both).

Conclusions  Smoking related increases in the BA ratio appear to be driven by reductions in vascular caliber. QCT measures of BA ratio, WT, and WA% may be useful to objectively identify and quantify bronchiectasis in smokers.

original research 
Marin H. Kollef, MD; Jean-Damien Ricard, MD; Damien Roux, MD; Bruno Francois, MD; Eleni Ischaki, MD; Zsolt Rozgonyi, MD; Thierry Boulain, MD; Zsolt Ivanyi, MD; Gál János, MD; Denis Garot, MD; Firas Koura, MD; Epaminondas Zakynthinos, MD; George Dimopoulos, MD; Antonio Torres, MD; Wayne Danker, MD; A. Bruce Montgomery, MD
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Background  Clinical failures in ventilator-associated pneumonia (VAP) caused by Gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.

Methods  We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of Gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if <10 days) via the investigational eFlow Inline System (PARI GmbH, Germany). The primary efficacy endpoint was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with Gram-negative bacteria.

Results  143 patients were randomized, 71 to AFIS, 72 to placebo. Comparison of CPIS change from baseline between treatment groups was not different (P=0.70). The secondary hierarchical endpoint of no mortality and clinical cure at Day 14 or earlier was also not significant (P=0.68) nor the hierarchical endpoint of no mortality and ventilator free days (P=0.06). Mortality was 17 (24%) in AFIS, 12 (17%) in placebo P=0.32. The AFIS group had significantly fewer positive tracheal cultures on Days 3 and 7 compared to placebo.

Conclusions  In this trial of adjunctive aerosol therapy compared to standard of care intravenous antibiotics in patients with Gram-negative VAP, AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.

evidence-based medicine  FREE TO VIEW
Louis-Philippe Boulet, MD, FCCP; Julie Turmel, PhD; Richard S. Irwin, MD, Master FCCP
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Background  Cough is a common symptom experienced by athletes, particularly after exercise. We performed a systematic review to assess in this population: 1) the main etiologies of acute and recurrent cough, either exercise-induced or not; 2) how it is assessed; and 3) how cough is treated in this population. From the systematic review, suggestions for management were developed.

Method  ology: This review was done according to the CHEST methodological guidelines and GRADE framework up to April 2015. To be included, studies had to meet the following criteria: participants had to be athletes, adults and adolescents aged ≥ 12 years, and complaining of cough, regardless of its duration or relation with exercise. The Expert Cough Panel based their suggestions on the data extracted from the review and final grading by consensus according to a Delphi process.

Results  Only 60 reports fulfilled the inclusion criteria and the results of our analysis revealed only low quality evidence on cough etiology and to support how to assess and treat cough specifically in athletes. Although there was no formal evaluation of causes of cough in the athlete population, the most common etiologies reported were asthma, exercise-induced bronchoconstriction, respiratory tract infections, upper airway cough syndrome (mostly from rhinitis) and environmental exposures. Cough was also reported to be related to exercise-induced vocal cord dysfunction among a variety of less common etiologies. Although gastroesophageal reflux disease (GERD) is frequent in athletes, we found no publication on cough and GERD in this population. Assessment of cough etiologies was mainly done with bronchoprovocation tests and suspected disease-specific investigations. The evidence to guide treatment of cough in the athlete was weak or non-existent, depending on the etiology. As data on cough in athletes were hidden in a set of other data (respiratory symptoms), evidence tables were difficult to produce, and were done only for cough treatment in athletes.

Conclusions  Etiology of cough in the athlete appears to differ slightly from the general population. It is often related to environmental exposures related to the sport training environment and occurs predominantly following intense exercise. Clinical history and specific investigations should allow identification of the etiology of cough and targeting the treatment. Until management studies have been performed in the athlete, current guidelines that exist for the general population should be applied for the evaluation and treatment of cough in the athlete taking into account specific training context and anti-doping regulations.

original research 
Bobby Gouin, MD; Marc Blondon, MD; David Jiménez, PhD; Carmen Fernández-Capitán, PhD; Henri Bounameaux, MD; Silvia Soler, MD; Rita Duce, MD; Joan Carles Sahuquillo, PhD; Nuria Ruiz-Giménez, PhD; Manuel Monreal, PhD

Background  Whether the localization of non-massive pulmonary embolism (PE) is associated with the short and long-term prognosis of patients remains unknown. Our aim is to characterize associations of non-massive PE localization with risks of recurrent venous thromboembolism (VTE), major bleeding and mortality during and after anticoagulation.

Methods  Among participants of the RIETE registry with an incident symptomatic non-massive PE diagnosed by computerized tomography (CT), we compared risks of recurrent VTE, major bleeding and mortality during and after anticoagulation period between central PE (main pulmonary artery) and non-central PE (more peripheral arteries), using Cox proportional hazard adjusted models.

Results  Of the 6674 participants, patients with central PE (40.5%) had similar age (mean 66 years), sex (46.9% male) and proportion of idiopathic (45.0%) and cancer-related (22.3%) PE as patients with non-central PE. During anticoagulation (5256.1 patient-years), the risk of recurrent VTE was similar between the two groups (2.5 vs. 2.1 per 100 patient-years; adjusted HR 1.32, 95%CI 0.91-1.90), as were risks of major bleeding and mortality. After anticoagulation was discontinued (2175.4 patient-years), participants with central PE had a borderline greater risk of recurrent VTE than participants with non-central PE (11.0 vs. 8.0 per 100 patient-years; adjusted HR 1.34, CI 95% 1.01-1.78), but not when restricting to participants after unprovoked PE (13.8 vs. 11.9 per 100 patient-years, HR 1.15, 95%CI 0.79-1.68, p= 0.48). Risks of major bleeding and mortality were similar.

Conclusions  Among non-massive PE, central localization of PE is associated with greater risk of recurrent VTE after anticoagulation cessation. However, the low magnitude of this association and the absence of association after unprovoked PE suggest that the clinical relevance of this finding is limited and that the duration of anticoagulation should not be tailored to PE localization after non-massive unprovoked PE.

original research 
Julian M. Williams, MBBS; Jaimi H. Greenslade, PhD; Juliet V. McKenzie, MBBS; Kevin Chu, MS; Anthony FT. Brown, MBChB; Jeffrey Lipman, MD (research)
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Objective  A proposed revision of sepsis definitions has abandoned SIRS, defined organ dysfunction as an increase in total SOFA score of ≥2, and conceived “qSOFA” as a bedside indicator of organ dysfunction. We aimed to (1) determine the prognostic impact of SIRS, (2) compare diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis-2) and revised (Sepsis-3) definitions for organ dysfunction in emergency department patients with infection.

Methods  Consecutive ED patients admitted with presumed infection were prospectively enrolled over three years. Observational data were collected sufficient to calculate SIRS, qSOFA, SOFA, comorbidity and mortality.

Results  8871 patients were enrolled, 4176 (47.1%) with SIRS. SIRS was associated with increased risk of organ dysfunction (RR 3.5), and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showed similar discrimination for organ dysfunction (AUROC 0.72 vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1%, 29.7% respectively). Mortality for patients with organ dysfunction was similar for Sepsis-2 and Sepsis-3 (12.5%, 11.4%) although 29% of patients with Sepsis-3 organ dysfunction did not meet Sepsis-2 criteria. Increasing number of Sepsis-2 organ dysfunctions was associated with greater mortality.

Conclusions  SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature. Although qSOFA≥2 showed high specificity, poor sensitivity may limit utility as a bedside screen. Although mortality for organ dysfunction was comparable between Sepsis-2 and Sepsis-3, more prognostic and clinical information is conveyed using Sepsis-2 regarding number of organ dysfunctions. ​The SOFA score may require recalibration.

original research  OPEN ACCESS
Lucy Yang, MBChB; Joseph Cheriyan, FRCP; David D. Gutterman, MD; Ruth J. Mayer, PhD; Zsuzsanna Ament, PhD; Jules L. Griffin, PhD; Aili L. Lazaar, MD; David E. Newby, FRCP; Ruth Tal-Singer, PhD; Ian B. Wilkinson, FRCP
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Background  Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD, and a novel sEH inhibitor GSK2256294 attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.

Methods  Endogenous and stimulated endothelial release of EETs was assessed in 12 COPD patients, 11 overweight smokers, and 2 matched control groups, using forearm plethysmography with intra-arterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilatation in human resistance arteries were assessed in vitro and in vivo in a Phase 1 clinical trial in healthy overweight smokers.

Results  Compared to controls, there was reduced vasodilatation to bradykinin (p=0.005), blunted effect of fluconazole on bradykinin-induced vasodilatation (p=0.03), and a trend towards reduced basal EET/DHETs ratio in COPD patients (p=0.08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilatation compared to vehicle (90±4.2% vs. 72.6±6.2% maximal dilatation), and shifted the bradykinin EC50 (-8.33±0.172 vs. -8.10±0.118 logM; p=0.001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338±46% pre-dose to 566±110% post single dose (p=0.02), and to 503±123% post chronic dose (p=0.003).

Conclusion  GSK2256294 attenuates smoking related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.

original research 
Karen C. Patterson; Rupal J. Shah; Mary K. Porteous; Jason D. Christie; Carly D’Errico; Matthew Chadwick; Matthew Triano; Charuhas Deshpande; Milton D. Rossman; Leslie A. Litzky; Maryl E. Kreider; Wallace T. Miller, Jr.
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Background  Despite the relationship of idiopathic pulmonary fibrosis (IPF) with advancing age, little is known about the epidemiology of interstitial lung diseases (ILD) in the elderly. Here we describe the diagnoses, clinical characteristics, and outcomes of patients who were elderly at the time of ILD diagnosis.

Methods  Among subjects from a prospective cohort study of ILD, elderly was defined as age > 70. Diagnoses were derived from a multi-disciplinary review. Differences between elderly and non-elderly groups were determined using chi-square and ANOVA testing.

Results  Of the 327 subjects enrolled, 80 (24%) were elderly. The majority of elderly subjects were white and male. The most common diagnoses were unclassifiable ILD (45%), IPF (34%), hypersensitivity pneumonitis (8%), and connective tissue disease ILD (11%). Most elderly subjects (74%) with unclassifiable ILD had an imaging pattern inconsistent with usual interstitial pneumonia (UIP). There were no significant differences in pulmonary function or three-year mortality between non-elderly and elderly subjects combined, or in a subgroup analysis of those with IPF.

Conclusions  While IPF was the single most common diagnosis, the majority of elderly subjects had non-IPF ILD. Our findings highlight the need for every patient with new-onset ILD, regardless of age, to be surveyed for exposures and findings of connective tissue disease. Unclassifiable ILD was common among the elderly, but for most the radiographic pattern was inconsistent with UIP. While the effect of ILD may be more pronounced in the elderly due to reduced global functionality, ILD was not more severe or aggressive in this group.

special features 
Leah R. Reznikov
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Cystic Fibrosis (CF) is a life-shortening autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is an anion channel that conducts bicarbonate and chloride across cell membranes. While defective anion transport across epithelial cells is accepted as the basic defect in CF, many of the features observed in people with CF and organs affected in CF are modulated by the nervous system. This is of interest because CFTR expression has been reported in both the peripheral and central nervous systems, and it is well known that the transport of anions, such as chloride, greatly modulates neuronal excitability. Thus, it is predicted that in CF, lack of CFTR in the nervous system affects neuronal function. Consistent with this prediction, several nervous system abnormalities and nervous system disorders have been described in people with CF and animal models of CF. The goal of this special feature article is to highlight the expression and function of CFTR in the nervous system. Special emphasis is placed on nervous system abnormalities described in people with and animal models of CF. Lastly, features of CF that may be modulated by or attributed to faulty nervous system function are discussed.

original research 
Niloofar Taghizadeh, PhD; Marc Fortin, MD; Alain Tremblay, MDCM
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Background  Malignant pleural effusions (MPE) are a common complication of advanced malignancy, but little is known regarding their prevalence and overall burden on a population level.

Methods  We conducted a retrospective analysis of MPE associated hospitalizations using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample, Agency for Healthcare Research and Quality (HCUP-NIS 2012). Cases were included if MPE was coded as a primary or secondary diagnosis or if an unspecified pleural effusion was coded in addition to a diagnosis of cancer with either of these being the primary diagnosis.

Results  A weighted sample of 126,825 (0.35 %) admissions for MPE was identified among the 36,484,846 weighted admissions included in the database in 2012. Of these admissions, 70,750 (55.8 %) were for female patients. The median (interquartile range (IQR)) age at admission was 68.0 (58.4-77.2). Lung (37.8%), breast (15.2%), hematologic (11.2%), GI tract (11.0%), and gynecologic (9.0%) cancers were the most common primary malignancies associated with MPE. The median (IQR) length of stay was 5.5 (2.7-10.1) days and the inpatient mortality rate was 11.6%. Median (IQR) hospitalization total charges were $42,376 (21,618-84,679). In the multivariate analyses, female gender, large fringe counties residential area, Medicare insurance and Elective type of admission were independently associated with a lower risk of inpatient mortality.

Conclusions  There is a considerable inpatient burden and high inpatient mortality associated with MPE in the United States with potential demographic, geographic and socioeconomic disparities.

original research 
Ana B. Alcaide, MD; Pablo Sanchez-Salcedo, MD; Gorka Bastarrika, MD; Arantza Campo, MD; Juan Berto, MD; Maria del Mar Ocon, RN; Bartolome R. Celli, MD; Javier J. Zulueta, MD; Juan P. de-Torres, MD
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Rationale  The clinical characteristics of patients with emphysema but without airway limitation remain unknown.

Objective  To compare the clinical features of current and former smokers without airflow limitation who have radiological emphysema on chest CT with a control group of current and ex-smokers without emphysema.

Methods  Subjects enrolled had anthropometrics, medical history and a low dose chest computed tomography (LDCT). The following parameters were also evaluated: pulmonary function tests (PFT) including diffusion capacity for carbon monoxide (DLCO), modified MRC dyspnea score, COPD assessment test (CAT) and 6-min walk distance (6MWD). A comparison was conducted between those with and those without CT emphysema.

Results  Of the 203 subjects, 154 had emphysema (78%) while 49 did not. Adjusted group comparisons revealed that a higher proportion of patients with emphysema on LDCT had an abnormal DLCO (<80%) (46% vs 19%, p=0.02), a fall of SpO2% >4% during the 6MWD (8,5% vs 0%, p= 0,04) and an altered quality of life (CAT score ≥ 10) (32% vs 14%, p=0.01). A detailed analysis of the CAT questionnaire items revealed that more patients with emphysema had a score≥1 in the “chest tightness” (p=0.05), and “limitation when doing activities at home” items (p<0.01) compared with no emphysema. They also had significantly more exacerbations in the previous year (0.19 vs 0.04, p=0.02).

Conclusions  A significant proportion of smokers with emphysema on LDCT but without airway limitation have alterations in their quality of life, number of exacerbations, diffusion capacity and oxygen saturation during the 6MWD test.

original research 
Monali Patil, MD; Samjot Singh Dhillon, MD; Kristopher Attwood, PhD; Marwan Saoud, MD; Abdul H. Alraiyes, MD; Kassem Harris, MD
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Introduction  Indwelling pleural catheter (IPC), which was initially introduced for the management of recurrent malignant effusions, could be a valuable management option for recurrent benign pleural effusions (BPE) in place of chemical pleurodesis. The purpose of this study is to analyze the efficacy and safety of IPC in the management of refractory non-malignant effusions.

Methods  We conducted a systematic review and meta-analysis on the published literature. Retrospective cohort studies, case series, and reports that used indwelling pleural catheter for the management of pleural effusion were included in the study.

Results  Thirteen studies were included in the analysis with a total of 325 patients. Congestive heart failure (49.8%) was the most common etiology of BPE requiring IPC placement. The estimated average rate of spontaneous pleurodesis was 51.3% (95% C.I. 37.1%-65.6%). The estimated average rate of all complications was 17.2% (95% C.I 9.8-24.5%) for the entire group. The estimated average rate of major complications was empyema 2.3% (95% C.I 0.0-4.7%), loculation 2.0% (95% C.I 0.0-4.7%), dislodgement 1.3% (95% C.I 0.0-3.7%), leak 1.3% (95% C.I 0.0-3.5%) and pneumothorax 1.2% (95% C.I 0.0- 4.1%). The estimated average rate of minor complications was skin infection 2.7% (95% C.I 0.6- 4.9%), blockage and drainage failure 1.1% (95% C.I 0.0-3.5%), subcutaneous emphysema 1.1% (95% C.I 0.0-4.0%) and others 2.5 %( 95% C.I 0.0-5.2%). One death was directly related to IPC use.

Conclusions  IPC is effective and a viable option in the management of patients with refractory benign pleural effusion. The quality of evidence to support the IPC use for BPE remains low, and high-quality studies such as randomized control trials are needed.

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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543