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 
Allison A. Lambert, MD MHS; Nirupama Putcha, MD MHS; M. Bradley Drummond, MD MHS; Aladin M. Boriek, PhD; Nicola A. Hanania, MS MD; Victor Kim, MD; Gregory L. Kinney, MPH PhD; Merry-Lynn N. McDonald, PhD; Emily P. Brigham, MD MHS; Robert A. Wise, MD; Meredith C. McCormack, MD MHS; Nadia N. Hansel
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Background  Obesity is prevalent in the United States; however the impact of obesity upon COPD morbidity is unclear. We hypothesized that obesity is associated with worse outcomes in COPD.

Methods  We examined 3631 participants from the multicenter prospective cohort study COPDGene who had spirometry confirmed COPD, a post-bronchodilator FEV1 <80% predicted and a body mass index (BMI) ≥18.5kg/m2. 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 18.5-29.9kg/m2).

Results  Overall, 35% of participants were obese, with 21% class I (BMI 30-34.9kg/m2), 9% class II (BMI 35-39.9kg/m2) and 5% class III (BMI ≥ 40kg/m2). The number of comorbidities increased with increasing obesity class (p<0.001). 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 v2, respectively), reduced 6 minute walk distance (6MWD), increased dyspnea (modified Medical Research Council score of ≥2) and greater odds of a 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.

original research 
Ying Zhou; Elyse E. Lower; Hui-ping Li; Alexandru Costea; Mehran Attari; Robert P. Baughman
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Objective  To assess the clinical characteristics, diagnosis, and outcome of cardiac sarcoidosis in a single institution sarcoidosis clinic.

Methods  Patients with cardiac sarcoidosis were identified using refined WASOG criteria of highly probable and probable. Patient demographics, local and systemic treatments and clinical outcome were collected.

Results  Of the 1815 patients evaluated over a six year period, 73 patients met the WASOG criteria for cardiac sarcoidosis. The median age at diagnosis was 46 years with a median follow up of 8.8 years. Reduced left ventricular ejection fraction (LVEF) was the most common manifestation (54.8%). Patients with arrhythmias experienced ventricular tachycardia (VT) or severe heart block, (35.6% and 19.2%, respectively) with or without reduced LVEF. A total of 45 (61.6%) patients underwent cardiac PET and/or MRI, with 41 (91.1%) having a positive study. During follow up, 10 patients (13.7%) either underwent transplant (3 patients) or died (7 patients) from sarcoidosis. Kaplan-Meier survival curves revealed five and ten year survival rates of 95.5% and 93.4%, respectively. Univariate factors of age at diagnosis < 46, implantation of pacemaker or defibrillator, mycophenolate treatment, or LVEF>40% were associated with improved survival. Cox regression analysis demonstrated that age ≥ 46 years and lack of an implanted pacemaker or defibrillator were the only independent predictors of mortality.

Conclusion  The new WASOG criteria were able to characterize cardiac involvement in our sarcoidosis clinic. Age and lack of pacemaker or defibrillator were the significant predictors of mortality for cardiac sarcoidosis, and reduced LVEF <40% was associated with worse prognosis.

translating basic research into clinical practice 
Kimberly J. Dunham-Snary, PhD; , MD, PhD; Edward A. Sykes, PhD; Amar Thakrar, MD; Leah RG. Parlow; Jeffrey D. Mewburn; Joel L. Parlow, MD; Stephen L. Archer, MD

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation-perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in PASMC. This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and HIF-1α, leading to adverse pulmonary vascular remodelling and pulmonary hypertension (PH). In the non-ventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis that optimizes systemic PO2 without altering pulmonary artery pressure. In single-lung anesthesia, HPV reduces blood flow to the non-ventilated lung thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PA pressure and initiates PH. Exaggerated or heterogeneous HPV contributes to high altitude pulmonary edema. Conversely, impaired HPV, whether due to diseases (COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudo-hypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen-sensing are important in human health and disease.

original research 
Kamonpun Ussavarungsi, MD; Ryan M. Kern, MD; Anja C. Roden, MD; Jay H. Ryu, MD; Eric S. Edell, MD

Background  Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiologic, and pathologic features. Surgical lung biopsies remain the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD.

Methods  We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic, Rochester, Minnesota in June 2013-September 2015.

Results  Seventy-four patients (33 female, 45%) with a mean age of 63 years (SD 13.8) were included. Mean maximal diameter of samples was 9.2 mm (range 2-20, SD 3.9). The median number of samples per procedure was 3 (range 1-7). Diagnostic yield was 51% (38/74). The most frequent histopathologic patterns were granulomatous inflammation (12) and organizing pneumonia (OP) (11), resulting in the final diagnoses of hypersensitivity pneumonitis (6), cryptogenic OP (6), connective tissue disease-associated OP (3), drug toxicity (3), infection-related OP (2), sarcoidosis (2), and aspiration (1). Other histopathologic patterns included respiratory bronchiolitis (3), acute fibrinous and organizing pneumonia (2), desquamative interstitial pneumonia (1), diffuse alveolar damage (1), pulmonary alveolar proteinosis (1), amyloidosis (1), eosinophilic pneumonia (1), necrotizing vasculitis (1), bronchiolitis with food particle (1), and malignancy (3). Pneumothorax developed in one patient (1.4%), bleeding occurred in 16 (22%).

Conclusions  Our single center cohort demonstrated 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. Optimal use of TBC needs to be determined.

original research  OPEN ACCESS
Rik T. Gerritsen, MD; Matty Koopmans, RN MSc; José G.M. Hofhuis, RN PhD; J. Randall Curtis, MD MPH; Hanne Irene Jensen, RN PhD; Jan G. Zijlstra, MD PhD; Ruth A. Engelberg, PhD; Peter E. Spronk, MD PhD
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Background  The Quality of Dying and Death (QODD) questionnaire is used as a self-reported measure to allow families and clinicians to assess patients’ quality of dying and death. We evaluated end-of-life (EOL) experiences as measured by the QODD completed by families and nurses in the United States (US) and the Netherlands (NL) to explore similarities and differences in these experiences and identify opportunities for improving EOL care.

Methods  Questionnaire data were gathered from family members of patients dying in the ICU and nurses caring for these patients. In NL, data were gathered in three teaching hospitals; in the US from 12 sites participating in a randomized trial. The QODD is consists of 25 items and has been validated in the US.

Result  Data from 446 patients were analysed, (346 in US; 100 in NL). Dutch patients were older than those in the US (72 +10.2 vs. 65 +16.0, p<0.0025). The family-assessed overall QODD score (medians [IQR]) was the same in both countries: NL 9 [8-10], US 8[5-10]. US family members rated the quality of two items higher than NL families: “time spent with loved ones” and “time spent alone”. Nurse-assessed QODD ratings varied: the single-item QODD summary score was significantly higher in NL (NL 9 [8-10] vs US 7 [5-8]; p<0.0025), while the QODD total score was higher in the US (NL 6.9 [5.5-7.6] vs US.7.1 [5.8-8.4]; p=0.014), although not meeting our criteria for statistical significance. Of the 22 nurse-assessed items, 10 were significantly different between NL and US with 8 higher in the US and 2 higher in NL.

Conclusion  The QODD was rated similarly by family members in the US and the Netherlands but varied when assessed by nurses. These differences may be due to organizational or cultural differences between the two countries or to expectations of respondents.

original research 
Bethany T. Samuelson, MD; Adam Cuker, MD; Deborah M. Siegal, MD; Mark Crowther, MD; David A. Garcia, MD
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Background  The direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or non-cancer associated venous thromboembolic disease. While routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this study was to systematically review and summarize current evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban and edoxaban.

Methods  Pubmed, Embase, and Web of Science were searched for studies reporting a relationship between drug levels and coagulation assay results.

Results  One hundred and twelve eligible studies were identified, including 35 for dabigatran, 50 for rivaroxaban, nine for apixaban and 13 for edoxaban. The performance of standard anticoagulation tests, including APTT and PT/INR, varied across both DOACs as well as reagents. For most assays, standard anticoagulation tests showed insufficient correlation to provide a reliable assessment of DOAC effects, including exclusion of clinically relevant drug levels. Dilute thrombin time assays demonstrated a high degree of linear correlation (r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated a high degree of linear correlation (r2 = 0.78-1.0) across a wide range of drug concentrations for rivaroxaban, apixaban and edoxaban.

Conclusions  Unfortunately, an ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend the use of a dilute thrombin time assay or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for assessment of the anticoagulant effects of direct Xa inhibitors. In the absence of these tests, thrombin time or APTT are recommended over PT/INR for assessment of dabigatran and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.

original research 
Yonatan Y. Greenstein, MD; Ross Littauer, MD; Mangala Narasimhan, DO, FCCP; Paul H. Mayo, MD, FCCP; Seth J. Koenig, MD, FCCP
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Background  Widespread use of critical care ultrasonography (CCUS) for the management of patients in the intensive care unit requires an effective training program. The effectiveness of national and regional CCUS training courses is not known. This study describes a national level, simulation-based, three day CCUS training program and evaluates its effectiveness.

Methods  Five consecutive CCUS courses, with a total of 363 people, were studied. The three day CCUS training program consisted of didactic lectures, ultrasonography interpretation sessions, and hands-on modules with live models. Thoracic, vascular, and abdominal ultrasonography were taught in addition to goal-directed echocardiography. Learners rotated between hands-on training and interpretation sessions. The teacher to learner ratio was 1:3 during hands-on training. Interpretation sessions were composed of interactive small groups that reviewed normal and abnormal ultrasonography images. Learners completed a video-based examination before and after the courses completion. Hands-on image acquisition skills were tested at the completion of the course.

Results  Average scores on the pre and post-test were 57% and 90%, respectively (p < 0.001). The average score on the hands-on test was 86%. Learners ages 20-39 compared to learners ≥ 40 years old scored better on the pre-test (64% vs. 51%, p < 0.001), post-test (91% vs. 88%, p < 0.010), and hands-on test (90% vs. 82%, p < 0.001).

Conclusions  Learners demonstrated a significant improvement in written test scores which assessed cognitive and image interpretation abilities. Additionally, they demonstrated acquisition of practical skills as evidenced by high scores during hands-on testing. Further studies are needed to determine if a simulation-based CCUS course will translate into effective clinical practice and to measure the durability of training.

Clinical Implications  This three day course is an effective method to train large groups of critical care clinicians in the skills requisite for CCUS: image acquisition and image interpretation.

original research 
Robert A. Balk, MD; Sameer S. Kadri, MD, MS; Zhun Cao, PhD; Scott B. Robinson, MA, MPH; Craig Lipkin, MS; Samuel A. Bozzette, MD, PhD
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Background  There is a growing use of Procalcitonin (PCT) to facilitate the diagnosis and management of severe sepsis. We investigated the impact of 1-2 PCT determinations on ICU day 1 on healthcare utilization and cost in a large research database.

Methods  A retrospective, propensity score matched multivariable analysis was performed on the Premier Healthcare Database for patients admitted to the ICU with 1-2 PCT evaluations on day 1 of ICU admission versus patients who did not have PCT testing.

Results  33,569 PCT managed patients were compared to 98,543 propensity-matched non-PCT patients. In multivariable regression analysis, PCT utilization was associated with significantly decreased total [11.6 days (95% CI 11.4-11.7 days) vs 12.7 days (95% CI 12.6-12.8 days); (95% CI for difference 1-1.3) p<0.001] and ICU length of stay [5.1 days (95% CI 5.1-5.2 days) vs 5.3 days (95% CI 5.3-5.4 days); (95% CI for difference 0.1- 0.3) p<0.03], and lower hospital costs [$30,454 (95% CI $29,968-$31,033) vs $33,213 (95% CI $32,964-$33,556); (95% CI for difference $2,159 - $3,321) p<0.001]. There was significantly less total antibiotic exposure [16.2 days (95% CI 16.1 -16.5 days) vs 16.9 days (95% CI 16.8-17.1 days) (95% CI for differences -0.9- -0.4 days) p=0.006] in PCT managed patients. Patients in the PCT group were more likely to be discharged to home [44.1% (95% CI 43.7%-44.6%) vs 41.3% (95% CI 41%-41.6%); 95% CI for difference 2.3 - 3.3) p=0.006]. Mortality was not different in an analysis including the 96% of patients that had an independent measure of mortality risk available [19.1% (95% CI 18.7%-19.4%) vs 19.1% (95% CI 18.9%-19.3%); 95% CI for difference -0.5%-0.4%) p=0.93].

Conclusions  Use of PCT testing on the first day of ICU admission was associated with significantly lower hospital and ICU length of stay, as well as decreased total, ICU, and pharmacy cost of care. Further elucidation of clinical outcomes requires additional data.

evidence-based medicine 
Peter J. Kahrilas, MD; Kenneth W. Altman, MD PhD; Anne B. Chang, FRACP PhD; Stephen K. Field, MD FCCP; Susan M. Harding, MD FCCP; Andrew P. Lane, MD; Kaiser Lim, MD FCCP FAAAAI; Lorcan McGarvey, MD FRCP; Jaclyn Smith, PhD FRCP; Richard S. Irwin, MD Master FCCP
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Background  We updated the 2006 ACCP clinical practice guidelines for management of reflux-cough syndrome.

Methods  Two PICO questions were addressed by systematic review: 1) can therapy for gastroesophageal reflux improve or eliminate cough in adults with chronic and persistently troublesome cough? and 2) are there minimal clinical criteria to guide practice in determining that chronic cough is likely to respond to therapy for gastroesophageal reflux?

Results  We found no high quality studies pertinent to either question. From available RCTs addressing question #1, we concluded that: 1) there was a strong placebo effect for cough improvement; 2) studies including diet modification and weight loss had better cough outcomes; 3) while lifestyle modifications and weight reduction may be beneficial in suspected reflux-cough syndrome, PPIs demonstrated no benefit when used in isolation; and 4) because of potential carryover effect, crossover studies using PPIs should be avoided. For question #2, we concluded from the available observational trials that: 1) an algorithmic approach to management resolved chronic cough in 82-100% of instances; 2) cough variant asthma and upper airway cough syndrome (UACS) from rhinosinus conditions were the most commonly reported etiologies; and 3) the reported prevalence of reflux-cough syndrome varied widely.

Conclusions  The panelists: 1) endorsed use of a diagnostic/therapeutic algorithm addressing common cough etiologies including symptomatic reflux, 2) advised that while lifestyle modifications and weight reduction may be beneficial in suspected reflux-cough syndrome, PPIs demonstrated no benefit when used in isolation, and 3) suggested that physiological testing be reserved for refractory patients being considered for anti-reflux surgery or in whom there is strong clinical suspicion warranting diagnostic testing.

original research 
Shipra Gupta, MBBS FAAP; Ankit Sakhuja, MBBS FACP FASN; Gagan Kumar, MBBS; Eric McGrath, MD; Rahul S. Nanchal, MBBS; Kianoush B. Kashani, MD FASN FCCP
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Background  Though 28-49% of severe sepsis hospitalizations have been described to be culture negative, there is very limited data on epidemiology and outcomes of those with culture negative severe sepsis (CNSS). The objectives of this study were to investigate the proportion and trends of CNSS, and its association with mortality.

Methods  Using Nationwide Inpatient Sample database from 2000-2010 we identified adults hospitalized with severe sepsis. Those without any specific organism codes were identified as with CNSS. We examined the proportion of CNSS hospitalizations and rates of mortality associated with it. We also assessed the independent effect of CNSS on mortality.

Results  Of 6,843,279 admissions with severe sepsis 3,226,406 (47.1% ) were culture negative. The age-adjusted proportion of CNSS has increased from 33.9% in 2000 to 43.5% in 2010 (p<0.001). Those with CNSS had more co-morbidities, acute organ dysfunctions (respiratory, cardiac, hepatic and renal) and in-hospital mortality (34.6% vs. 22.7%; p<0.001) though acute kidney injury requiring dialysis is less (5.3% vs. 6.1%; p<0.001). CNSS was an independent predictor of mortality in those with severe sepsis (OR 1.75; 95% CI: 1.72-1.77).

Conclusions  CNSS among hospitalized patients is common, and its proportion is on the rise. CNSS is associated with greater acute organ dysfunctions and mortality. Being culture negative is an independent predictor of death.

original research 
Snigdha Jain, M.D; Rohan Khera, M.D; Saket Girotra, M.D., S.M; David Badesch, M.D; Zhen Wang, Ph.D; Mohammad Hassan Murad, M.D; Amy Blevins, M.A.L.S; Gregory A. Schmidt, M.D; Siddharth Singh, M.D; Alicia K. Gerke, M.D
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Background  We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension (PAH).

Methods  MEDLINE, Cochrane register, EMBASE, CINAHL and clinicaltrials.gov were searched (January 1, 1990 - March 3, 2016). Randomized controlled trials (RCTs) of approved pharmacological agents - endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), oral/inhaled and intravenous/subcutaneous prostanoids, riociguat, and selexipag, alone or in combination for pulmonary arterial hypertension (PAH) reporting at least one efficacy outcome were selected.

Results  31 RCTs with 6,565 patients were selected. In network meta-analysis, compared to a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR] 0.19, 95% CI 0.05,0.76), 3.9% with ERA+PDE5i (RR 0.27, 95% CI 0.14,0.52) and 5.7% with PDE5i (RR 0.39, 95% CI 0.24,0.62). For improvement in functional status, compared to 16.2% in the placebo group, improvement in at least 1 NYHA/WHO functional class was estimated at 81.8% with intravenous/subcutaneous prostanoids (RR 5.06, 95% CI 2.32,11.04), 28.3% with ERA+PDE5i (RR 1.75, 95% CI 1.05,2.92) and 25.2% with ERA (RR 1.56, 95% CI 1.22,2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with oral/inhaled prostanoids (RR 2.92, 95% CI 1.68,5.06) and selexipag (RR 2.06, 95% CI 1.04,3.88) compared to placebo.

Conclusions  Currently approved pharmacological agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on patient-centered approach to therapy.

Adam T. Hill, Professor
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Long-term macrolide therapy offers an evidence-based treatment to reduce frequent exacerbations in stable adult patients with bronchiectasis. There is limited evidence that they also attenuate the decline in lung function and improve health-related quality of life. The benefits and risks of long-term macrolides need to be clearly explored for individual patients. Further work is needed to understand the optimal drug, dose and regimen, the mechanisms behind these benefits, appropriate patient selection, sustainability of efficacy, potential long-term risk on the lung microbiome, and their placement with or without inhaled antibiotic treatment. We reviewed the current evidence on long term macrolides in adults with bronchiectasis.

Mangala Narasimhan, DO, FCCP; Seth J. Koenig; Paul H. Mayo

Ultrasonography is an essential imaging modality in the ICU used to diagnose and guide the treatment of cardiopulmonary failure. Critical care ultrasonography requires that all image acquisition, image interpretation, and clinical applications of ultrasonography are personally performed by the critical care clinician at the point of care and that the information obtained is combined with the history, physical, and laboratory information. Point-of-care ultrasonography is often compartmentalized such that the clinician will focus on one body system while performing the critical care ultrasonography examination. We suggest a change from this compartmentalized approach to a systematic whole-body ultrasonography approach. The standard whole-body ultrasonography examination includes thoracic, cardiac, limited abdominal, and an evaluation for DVT. Other elements of ultrasonography are used when clinically indicated. Each of these elements is reviewed in this article and are accompanied by a link to pertinent cases from the Ultrasound Corner section of CHEST.

original research 
Ikenna C. Okereke, M.D.; Maria F. Bates, M.D.; Matthew D. Jankowich, M.D.; Sharon I. Rounds, M.D.; Brian A. Kimble, M.D.; Janelle V. Baptiste, M.D.; Thomas T. Ng, M.D.; Linda L. Nici, M.D.
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Background  Lung cancer screening recommendations have been developed, but none has focused on veterans. We report the results of the lung cancer screening program at our Veterans Affairs Medical Center and compare them to historic results.

Methods  All veterans between 55 and 74 years who were current smokers or quit within the past 15 years and had at least a 30 pack year smoking history were invited to receive an annual low-dose chest computerized tomography (CT) scan beginning in December 2013. Demographics, CT results, and pathologic data of screened patients were recorded retrospectively. Overall results during the screening period were compared to results in veterans diagnosed from January 2011 to December 2013 (pre-screening period).

Results  From December 2013 through December 2014 (screening period) 1,832 patients obtained a screening CT scan. Mean age was 65. A lung nodule was present in 24% (439/1832) of patients. Lung cancer was diagnosed in 3.0% (55/1832) of screened patients. During the pre-screening period, 37% (30/82) of every lung cancer detected at our center was Stage I or Stage II. After implementation of the screening program that percentage rose to 60% (52/87, p <0.01). During the screening period 63% (55/87) of all diagnosed lung cancers were detected through the screening program. The number of lung cancers detected per month rose from 2.4 to 6.7 after implementation of the screening program (p <0.01).

Conclusions  Implementation of lung cancer screening in the veteran population leads to detection of increased number and proportion of early stage lung cancers. Lung cancer screening in veterans may also increase the rate of lung cancer diagnoses in the immediate post-implementation period.

original research 
Isaac Almendros, PhD; Abdelnaby Khalyfa, PhD; Wojciech Trzepizur, MD, PhD; Alex Gileles-Hillel, MD; Lei Huang, PhD; Mahzad Akbarpour, DVM, PhD; Jorge Andrade, PhD; Ramon Farré, PhD; David Gozal, MD, MBA, FCCP
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Background  Obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. Exosomes are vesicles secreted by most cells, are released into the bloodstream, and play a role in tumor progression and metastasis. Here, we evaluated whether the chronic intermittent hypoxia (IH) that characterizes OSA leads to release of tumor-promoting exosomes in circulation.

Methods  C57/B6 male mice were randomized to 6 weeks of IH or room air (RA). A subgroup of the mice was injected with TC1 lung carcinoma cells in the left flank after 2 weeks of IH. Exosomes from mouse plasma and from 10 adult human patients with OSA before (Pre) and after adherent treatment for 6 wks (Post) were co-cultured with mouse TC1 and human adenocarcinoma cells lines. Malignant tumor properties such as proliferation, migration, invasion and endothelial monolayer disruption were assessed, as well as miRNA exosomal content and transcriptomic effects of exosomes on TC1 cells in vitro to identify target genes.

Results  Application of IH-induced exosomes from either IH-exposed tumor bearing (IH (+) or non-bearing mice IH (-) significantly promoted TC1 malignant properties. Similarly, Pre exosomes from OSA patients significantly enhanced proliferation and migration of human adenocarcinoma cells compared to Post. 11 distinct miRNAs emerged in IH (-) mice and their gene targets in TC1 cells were identified.

Conclusion  Circulating exosomes released under IH conditions in vivo selectively enhance specific properties of lung tumor cell cultures. Thus, plasma exosomes participate in the increased tumor aggressiveness observed in OSA patients.

original research 
Michele D’Alto, MD, PhD; Emanuele Romeo, MD, PhD; Paola Argiento, MD, PhD; Yoshiki Motoji, MD, PhD; Anna Correra, MD; Giovanni Maria Di Marco, MD; Agostino Mattera Iacono, MD; Rosaria Barracano, MD; Antonello D’Andrea, MD, PhD; Gaetano Rea, MD; Berardo Sarubbi, MD, PhD; Maria Giovanna Russo, MD; Robert Naeije, MD, PhD
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Background  A fluid challenge may help to the differential diagnosis between pre- and post-capillary pulmonary hypertension (PH). However the test is still in need of standardization and better defined clinical relevance.

Methods and Results  Two-hundred-twelve patients referred for PH underwent a right heart catheterization with measurements before and after rapid infusion of 7 ml/kg of saline. PH was defined by a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and post-capillary PH by a wedged PAP (PAWP) > 15 mmHg. An increase in PAWP ≥ 18 mmHg was considered diagnostic for post-capillary PH. At baseline, 66 patients were diagnosed with no PH, 22 with post-capillary PH and 124 with pre-capillary PH (mostly pulmonary arterial hypertension, PAH). After fluid challenge 5/66 patients with no PH (8%) and 8/124 with pre-capillary PH (6%) were reclassified as post-capillary PH. Fluid challenge was associated with an increase in PAWP by 7±2 mmHg in post-capillary PH, and 3±1 mmHg in both pre-capillary PH and no-PH patients. Between group differences were significant, but there was overlap. There were no adverse events related to fluid challenge. Prediction bands calculated from quadratic fits of the PAWP responses in pooled no-PH control and pre-capillary PH patients confirmed 18 mmHg as cut-off for the diagnosis of post-capillary PH.

Conclusions  Fluid challenge with 7 ml/kg saline increases PAWP, more in post-capillary PH than in pre-capillary PH or no-PH controls. A cut-off value of 18 mmHg allows to re-classify 6-8% of patients with pre-capillary PH or normal hemodynamics at baseline.

original research 
Daiana Stolz, Prof.; Diana Julie Leeming, PhD; Jacob Hull Edfort Kristensen, PhD; Morten A. Karsdal, PhD; Wim Boersma, MD; Renaud Louis, MD; Branislava Milenkovic, MD; Konstantinos Kostikas, MD; Francesco Blasi, MD; Joachim Aerts, MD; Jannie M.B. Sand, PhD; Emiel FM. Wouters, MD; Gernot Rohde, MD; Cristina Prat, MD; Antoni Torres, MD; Tobias Welte, MD; Michael Roth, PhD; Eleni Papakonstantinou, MD, PhD; Michael Tamm, MD
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Background  Extracellular matrix remodeling (ECM) of the lung tissue releases protein fragments into the blood, where they may be detected as serological surrogate markers of disease activity in chronic obstructive pulmonary disease (COPD). We aimed to assess the association of ECM turnover with severity and outcome of COPD.

Methods  In a prospective, observational, multicenter study including 506 patients with COPD, GOLD grades II-IV, we analyzed serum samples at stable state, exacerbation and 4 weeks after exacerbation, for a panel of 5 novel neo-epitopes including fragments of collagen type-III (C3M) and type-VI (C6M), pro-forms of collagen type-III (Pro-C3) and type-VI (Pro-C6) and neutrophil elastase-generated fragments of elastin (EL-NE) by ELISA. These neo-epitopes were also measured at stable state in a derivation cohort including 100 COPD patients.

Results  Serum levels of C3M, C6M, Pro-C3, Pro-C6 and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. Degradation of collagen type-III and -VI was associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation as compared to stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (HR 0.72[0.59-0.89] p=0.002) and Pro-C6 with survival (HR 2.09[1.18-3.71], p=0.011).

Conclusions  Serum biomarkers of ECM turnover are significantly associated with disease severity and clinically relevant outcomes in COPD.

original research 
Danielle F. Wurzel, PhD; Julie M. Marchant, PhD; Stephanie T. Yerkovich, PhD; John W. Upham, PhD; Helen L. Petsky, PhD; Heidi Smith-Vaughan, PhD; Brent Masters, PhD; Helen Buntain, PhD; Anne B. Chang, PhD
Topics: ,

Background  Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diagnostic entities that share common clinical and laboratory features. It is postulated, but remains unproven, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children. In a cohort of children with PBB, our objectives were to: (a) determine the medium-term risk of bronchiectasis and (b) identify risk factors for bronchiectasis and recurrent episodes of PBB.

Methods  161 children with PBB and 25 controls were prospectively recruited to this cohort study. A subset of 106 children was followed for 2 years. Flexible bronchoscopy, BAL and basic immune function tests were performed. CT chest was undertaken if clinical features were suggestive of bronchiectasis.

Results  Of 161 children with PBB (66% male), 13 (8.1%) were diagnosed with bronchiectasis over the study period. Almost half (43.5%) with PBB had recurrent episodes (>3/year). Major risk factors for bronchiectasis included: H. influenzae lower airway infection (in BAL) (p=0.013) and recurrent episodes of PBB (p=0.003). H. influenzae infection conferred >7 times higher risk of bronchiectasis [HR 7.55 (95%CI 1.66 - 34.28), p=0.009] compared to absence of H. influenzae. The majority of isolates (82%) were nontypeable H. influenzae. No risk factors for recurrent PBB were identified.

Conclusions  PBB is associated with a future diagnosis of bronchiectasis in a subgroup of children. H. influenzae lower airway infection and recurrent PBB are significant predictors. Clinicians should be cognisant of the relationship between PBB and bronchiectasis and appropriate follow-up measures should be taken in those with risk factors.

original research 
Anja Frei, PhD; Lara Siebeling, PhD; Callista Wolters, MD; Leonhard Held, Prof; Patrick Muggensturm, MD; Alexandra Strassmann, MSc; Marco Zoller, MD; Gerben ter Riet, PhD; Milo A. Puhan, Prof
Topics: ,

Background  COPD exacerbation incidence rates are often ascertained retrospectively, through patient recall and self-reports. We compared exacerbation ascertainment through patient self-reports and single physician chart review to central adjudication by a committee and explored determinants and consequences of misclassification.

Methods  Self-reported exacerbations (event-based definition) in 409 primary care COPD patients participating in the ICE COLD ERIC cohort were ascertained 6-monthly over 3 years. Exacerbations were adjudicated by single experienced physicians and an adjudication committee who had information from patient charts. We assessed the accuracy (sensitivities and specificities) of self-reports and single physician chart review against a central adjudication committee (reference standard). We used multinomial logistic regression and bootstrap stability analyses to explore determinants of misclassifications.

Results  The adjudication committee identified 648 exacerbations, corresponding with an incidence rate of 0.60±0.83 exacerbations/patient-year and a cumulative incidence proportion of 58.9%. Patients self-reported 841 exacerbations (incidence rate 0.75±1·01, incidence proportion 59.7%). Sensitivity/specificity of self-reports were 84%/76%, those of single physician chart review between 89-96% and 87-99%. The multinomial regression model and bootstrap selection showed that having experienced more exacerbations was the only factor consistently associated with under- and over-reporting of exacerbations (under-reporters: relative risk ratio 2.16, 95% CI 1.76-2.65; over-reporters: relative risk ratio 1.67, 95% CI 1.39-2.00).

Conclusions  Patient 6-month recall of exacerbation events are inaccurate. This may lead to inaccurate estimates of incidence measures and underestimation of treatment effects. The use of multiple data sources combined with event adjudication could substantially reduce sample size requirements and possibly cost of studies.

translating basic research into clinical practice 
Amir Pelleg, Ph.D.; Edward S. Schulman, MD; Peter J. Barnes, DM, Master FCCP
Topics: ,

In recent years numerous studies have generated data supporting the hypothesis that extracellular adenosine 5’-triphosphate (ATP) plays a major role in obstructive airway diseases. Studies in animal models and human subjects have shown that increased amounts of extracellular ATP are found in the lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma, and that ATP has effects on multiple cell types in the lungs resulting in increased inflammation, induction of bronchoconstriction and cough. These effects of ATP are mediated by cell surface P2 purinergic receptors (P2R) and involve other endogenous inflammatory agents. Recent clinical trials showed promise of treatment with P2X3R antagonists for alleviation of chronic cough.

The purpose of this review is to describe these studies and outline some of the remaining questions as well as the potential clinical implications associated with the pharmacologic manipulation of ATP signaling in the lungs.

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