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 
Annette Kristiansen, MD; Linn Brandt, MD; Thomas Agoritsas, MD; Elie A. Akl, MD, MPH, PhD; Eivind Berge, MD, PhD; Anne Flem Jacobsen, MD, PhD; Lars-Petter Granan, MD, PhD; Sigrun Halvorsen, MD, PhD; Gordon Guyatt, MD, FCCP; Per Olav Vandvik, MD, PhD
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Background:  The Antithrombotic Therapy and the Prevention of Thrombosis, 9th Edition: American College of Chest Physicians Evidence-based Guidelines (AT9) represent trustworthy international guidelines for antithrombotic treatment and thromboprophylaxis. Here, we describe major changes to the format and content resulting from applying new strategies for guideline adaptation and dissemination.

Methods:  A Norwegian guideline panel of 46 experts completed a structured and systematic adaptation process, updating the recommendations based on new evidence, and rewrote the recommendations in an electronic multilayered presentation format. We published the adapted guideline using a web-based authoring and publication platform (MAGICapp at www.magicapp.org/public).

Results:  We applied a novel presentation format to 333 recommendations from 11 of the 15 management chapters in AT9, condensed and restructured into 249 recommendations in a multilayered format. We added additional relevant information, such as 29 best practice statements about new oral anticoagulants and practical information sections for 121 recommendations. Common reasons for modifications included feasibility of the recommendations in a national context, disagreement with applied baseline risk estimates and re-evaluating the balance between the benefits and harms of interventions in relation to assumed typical patient preferences and values. The adapted guideline was published and disseminated online in November 2013.

Conclusion:  New strategies for adapting, updating and disseminating trustworthy guidelines proved feasible and will provide Norwegian health care professionals and patients with up to date guidance tailored to national circumstances.

original research 
Jinbo Liu, M.D.; Peter J. Mazzone, M.D.; Juan P. Cata, M.D.; Andrea Kurz, M.D.; Maria Bauer, M.D.; Edward J. Mascha, Ph.D.; Daniel I. Sessler, M.D.
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Background:  Lung cancer is the leading cause of cancer-related mortality. Surgical removal of the tumor at an early stage can be curative. However, lung cancer diagnosis at an early stage remains challenging. There is evidence that free fatty acids play a role in cancer development.

Methods:  Serum samples from 55 patients with lung cancer were propensity matched with samples from 165 similar pulmonary patients without known cancer. Patients were propensity-matched on age, gender, smoking history, family history of lung cancer, and chronic diseases that might affect free fatty acid levels.

Results:  Free fatty acids arachidonic acid and linoleic acid, and their metabolites hydroxyeicosatetraenoic acids (5-HETE, 11-HETE, 12-HETE, and 15-HETE) were an estimated 1.8 to 3.3-fold greater in 37 patients with adenocarcinoma versus 111 patients without cancer (all P<0.001). Areas under the receiver operating characteristics (ROC) curve were significantly greater than 0.50 discriminating lung cancer patients and controls for 6 of 8 biomarkers and 2 of 7 phospholipids tested, and ranged between 0.69 and 0.82 (all P<0.001) for lung cancer patients versus controls. Arachidonic acid, linoleic acid, and 15-HETE had observed sensitivity and specificity >0.70 at the best cutpoint. Concentrations of free fatty acids and their metabolites were similar in 18 squamous-cell carcinoma patients and 54 non-cancer controls.

Conclusions:  Serum fatty acids and their metabolites demonstrate good sensitivity and specificity for the identification of adenocarcinoma of the lung.

original research 
Annette Kristiansen, MD; Linn Brandt, MD; Thomas Agoritsas, MD; Elie A. Akl, MD, MPH, PhD; Eivind Berge, MD, PhD; Johan Bondi, MD, PhD; Anders E. Dahm, MD, PhD; Lars-Petter Granan, MD, PhD; Sigrun Halvorsen, MD, PhD; Pål-Andre Holme, MD, PhD; Anne Flem Jacobsen, MD, PhD; Eva-Marie Jacobsen, MD, PhD; Ignacio Neumann, MD; Per Morten Sandset, MD, PhD; Torunn Saetre, MD, PhD; Arnljot Tveit, MD, PhD; Trond Vartdal, MD, PhD; Gordon Guyatt, MD, FCCP; Per Olav Vandvik, MD, PhD
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Background:  Adaptation of guidelines for use at the national or local level can facilitate their implementation. We developed and evaluated an adaptation process in adherence with standards for trustworthy guidelines and the GRADE methodology aiming for efficiency and transparency. This is the first in a series of four articles describing our adaptation of the 9th iteration of the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis for a Norwegian setting.

Methods:  Informed by the ADAPTE framework, we developed a 5-step adaptation process customized to guidelines developed with GRADE: 1) planning, 2) initial assessment of the recommendations, 3) modification, 4) publication, and 5) evaluation. We developed a taxonomy for describing how and why recommendations from the parent guideline were modified. We applied a mixed-methods, case-study design for evaluation of the process.

Results:  We published the adapted guideline November 2013 in a novel multilayered format. The taxonomy for adaptation facilitated transparency of the modification process for both the guideline developers and end-users. We excluded 30 and modified 131 of the 333 original recommendations according to the taxonomy and developed 8 new recommendations. Unforeseen obstacles related to acquiring a licensing agreement and procuring a publisher resulted in a 9-month delay. We propose modifications of the adaptation process to overcome these obstacles in the future.

Conclusions:  This case study demonstrates the feasibility of our novel adaptation process. Replication is needed to further validate the usefulness of the process in increasing the organizational and methodological efficiency of guideline adaptation.

original research 
Rodrigo P. Pedrosa, MD, PhD; Isly M. L. Barros, MD; Luciano F. Drager, MD, PhD; Marcio S. Bittencourt, MD, MPH; Ana Kelley L. Medeiros, RN; Liana L. Carvalho, RN; Thais C. Lustosa, RpT; Martinha M. B. Carvalho, RpT; Moacir N. L. Ferreira, MD, PhD; Geraldo Lorenzi-Filho, MD, PhD; Laura O. B. F. Costa, MD, PhD
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Background:  Perimenopause is associated with increased cardiovascular risk. Obstructive sleep apnea (OSA) is an emerging risk factor for cardiovascular disease particularly among men. However, the independent contribution of OSA to cardiovascular risk in climacteric women is not clear.

Methods:  We evaluated 277 consecutive women [age: 56(52-61) years; body mass index: 28(25-32) kg/m2], without manifest cardiovascular disease (heart failure, coronary disease, and stroke). All women performed 24-hour ambulatory blood pressure monitoring, arterial stiffness evaluation (pulse wave velocity) and portable sleep study.

Results:  OSA (apnea-hypopnea index: ≥5 events/hour) and moderate/severe OSA (apnea-hypopnea index: ≥15 events/h) were diagnosed in 111 (40.1%) and 31 (11.1%) of women, respectively. None of the participants had a previous OSA diagnosis. Women with moderate/severe OSA had a higher prevalence of hypertension, were prescribed more medications for hypertension, had higher awake blood pressure (systolic: 133 [125-142] vs 126 [119-134] mmHg, p<0.01, diastolic: 82 [78 -88] vs 79 [74-85], p=0.07), nocturnal blood pressure (systolic: 125 [118-135] vs 115 [109-124] mmHg, p <0.01, diastolic blood pressure: 73 [69-79] vs 69 [62-75] mmHg, p<0.01) as well as higher arterial stiffness (pulse wave velocity: 11.5 [10.1 to 12.3] vs 9.5 [8.6 to 10.8] m/s, p<0.001) than women without OSA, respectively. Oxygen desaturation index during the night was independently associated with 24h arterial blood pressure and with arterial stiffness (per 5 unit increase in oxygen desaturation index: β=1.30, CI 95%:0.02-2.54; p=0.04 and β=0.22, CI 95%:0.03-0.40; p=0.02; respectively).

Conclusions:  OSA is common, underdiagnosed and independently associated with high blood pressure and increased arterial stiffness in the perimenopause.

original research 
Daiana Stolz, MD; Wim Boersma, MD; Francesco Blasi, MD; Renaud Louis, MD; Branislava Milenkovic, MD; Kostantinos Kostikas, MD; Joachim G. Aerts, MD; Gernot Rohde, MD; Alicia Lacoma, PhD; Janko Rakic, MD; Lucas Boeck, MD; Paola Castellotti; Andreas Scherr, MD; Alicia Marin, MD; Sabine Hertel, PhD; Sven Giersdorf, PhD; Antoni Torres, MD; Tobias Welte, MD; Michael Tamm, MD
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Background:  The prevalence of exertional hypoxemia in unselected COPD patients is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) up regulation through the HIF-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD.

Methods:  1233 6-minute walking tests and circulating proadrenomedullin levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed-up for 2 years were concomitantly analyzed.

Results:  The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multi-state model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related QoL, higher severe exacerbation and death annual rates. In the logistic linear and conditional Cox-regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (p<0.001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation-rate did not influence results. Relative to using FEV1% pred alone, adding proADM resulted in a significant improvement of the predictive properties (p=0.018). Based on the suggested non-linear nomogram, patients with moderate COPD (FEV1 predicted=50%) but high proADM levels (>2nmol/l) presented increased risk (>30%) for exertional desaturation.

Conclusions:  Exertional desaturation is common and associated with poorer clinical outcomes in COPD. Adrenomedullin improves prediction of exertional desaturation as compared to the use of FEV1%pred alone.

original research 
Craig M. Lilly, M.D.; Xinggang Liu, M.D., Ph.D.; Omar Badawi, Pharm.D. MPH.; Christine S. Franey, MPH; Ilene H. Zuckerman, Pharm. D, Ph.D.
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Background:  The optimal approach for managing increased risk of venous thromboembolism (VTE) among critically ill adults is unknown.

Methods:  An observational study of 294,896 episodes of critical illness among adults was conducted in 271 geographically dispersed United States adult intensive care units. The primary outcomes were all cause ICU and in-hospital mortality after adjustment for acuity and other factors among groups of patients assigned, based on clinical judgment, to prophylactic anticoagulation, mechanical devices, both or neither. Outcomes of those managed with prophylactic anticoagulation or mechanical devices were compared in a separate paired propensity matched cohort.

Results:  After adjustment for propensity to receive VTE prophylaxis, APACHE IV scores and management with mechanical ventilation, the group treated with prophylactic anticoagulation was the only one with significantly lower risk of dying than those not provided VTE prophylaxis (ICU; 0.81 (0.79 to 0.84), p<.0001; hospital; 0.84 (0.82 to 0.86), p<.0001). The mortality risk of those receiving mechanical devices was not lower than that of patients without VTE prophylaxis. A study of 87,107 pairs of patients matched for propensity to receive VTE prophylaxis found that those managed with prophylactic anticoagulation had significantly lower risk of death (ICU sub-hazard ratio 0.82 [95% CI, 0.78 to 0.85]; p < .001 hospital sub-hazard ratio 0.82 [95% CI, 0.79 to 0.85]; p < .001) than those receiving only mechanical device prophylaxis.

Conclusions:  These findings support a recommendation for prophylactic anticoagulation in preference to mechanical device prophylaxis for critically ill adults that do not have a contraindication to anticoagulation.

original research 
Lucas Boeck, MD; Mikael Gencay, PhD; Michael Roth, PhD; Hans H. Hirsch, MD; Mirjam Christ-Crain, MD; Beat Mueller, MD; Michael Tamm, MD; Daiana Stolz, MD
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Background:  B-cells in airways and lung parenchyma may be involved in COPD evolution. However, whether their pathogenic role is beneficial or harmful remains controversial. The objective of this study was to investigate the maturation of adenovirus-specific immunoglobulins in COPD patients in respect to clinical outcome.

Methods:  The presence of adenovirus-specific immunoglobulins during acutely exacerbated COPD (AECOPD) was analyzed at exacerbation and 2-3 weeks later. Patients with detectable adenovirus-specific IgM and low IgG avidity were grouped into fast and delayed IgG maturation. The clinical outcome of both groups was evaluated.

Results:  Out of 208 patients, 43 patients (20.7%) had serologic evidence of recent adenovirus infection and were grouped into 26 patients with fast IgG maturation and 17 patients with delayed IgG maturation. Baseline characteristics, AECOPD therapy, and duration of hospitalization were similar in both groups. However, the AECOPD recurrence rate within six months was higher (p = 0.003) and there was a trend for earlier AECOPD related re-hospitalizations (p = 0.061) in patients with delayed IgG maturation. The time to re-hospitalization or death within two years was shorter in patients with delayed IgG maturation (p = 0.003). Adenovirus-specific IgG maturation was an independent predictor of both, the number of recurrent AECOPDs within six months (p = 0.001) and the occurrence of hospitalization or death within two years (p = 0.005).

Conclusions:  Delayed immunoglobulin avidity maturation, following COPD exacerbation, is associated with worse outcome.

original research 
Ellen L. Burnham, MD; Robert C. Hyzy, MD; Robert Paine, III, MD; Aine M. Kelly, MD; Leslie E. Quint, MD; David Lynch, MB; Douglas Curran-Everett, PhD; Marc Moss, MD; Theodore J. Standiford, MD
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Background.  In the acute respiratory distress syndrome (ARDS), the extent of fibroproliferative activity on chest HRCT has been reported to correlate with poorer short-term outcomes and pulmonary-associated quality of life. However, clinical factors associated with HRCT fibroproliferation are incompletely characterized. We questioned if lung compliance assessed at the bedside would be associated with fibroproliferation on HRCT obtained during the resolution phase of ARDS.

Methods.  We utilized data from a published randomized, controlled clinical trial in ARDS. All patients were cared for using a low tidal volume strategy. Demographic data and ventilator parameters were examined in association with radiologic scores from chest HRCTs obtained 14 days after diagnosis.

Results.  Data from 82 ARDS patients were analyzed. Average static respiratory compliance over the first 14 days after diagnosis was inversely associated with chest HRCT reticulation (rho=-0.46); this relationship persisted in multivariable analysis including APACHE II scores, initial PaO2/FiO2, pneumonia diagnosis and ventilator days. Average static respiratory compliance was also lower among patients with bronchiectasis at day 14 (p=0.007). Initial static respiratory compliance obtained within the first day after ARDS diagnosis was correlated inversely with the presence of HRCT reticulation (rho=-0.38), and was lower among patients who demonstrated bronchiectasis on the day 14 HRCT (p=0.008).

Conclusions.  In patients with ARDS, diminished lung compliance measured bedside was associated with radiologic fibroproliferation 14 days post diagnosis. Establishing factors that predispose to development of excessive fibroproliferation with subsequent confirmation by chest HRCT represents a promising strategy to identify ARDS patients at risk for poorer clinical outcomes.

original research 
Gregory Y. H. Lip, MD; Ken Haguenoer, MD; Christophe Saint-Etienne, MD; Laurent Fauchier, MD, PhD
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Background  The efficacy and safety of anticoagulation with use of the Vitamin K antagonists(VKA) is highly dependent on the quality of anticoagulation control, as reflected by the average time in therapeutic range(TTR) in keeping within a therapeutic range of 2.0-3.0. A clinical dilemma is trying to predict which anticoagulation-naïve patients with atrial fibrillation(AF) would do well on a VKA(with a TTR>70%) whist those less likely to do well on VKA could be managed with novel oral anticoagulants.

Methods  In our cohort of 4637 patients, we investigated whether the SAME-TT2R2 score could discriminate between patients with AF who were likely to have a labile INR during followup, as well as stroke/thromboembolism(TE), clinically relevant bleeding(defined as ‘severe bleeding’ and also as BARC-defined major bleeding) and mortality, whilst being treated with a VKA.

Results  During a mean follow-up of 1016±1108 days, there was a significant increase in risk of severe bleeding events [RR(95%CI): 1.38(1.12-2.68), p=0.002] and a significant increase in risk of major BARC bleeding [RR 1.77(1.29-2.44), p=0.0005] in AF patients with a high (>2) SAME-TT2R2 score. Increasing SAME-TT2R2 score was associated with an increasing risk of labile INR(p=0.004), stroke/TE at followup(p=0.007), severe bleeding(p<0.0001), major BARC bleeding (p<0.0001) and death (p=0.002).Amongst the patients on VKA, the SAME-TT2R2 score was predictive of labile INR(c-statistic ∼0.58) as well as for stroke/TE, severe bleeding, major BARC bleeding and death(c-statistics ∼0.54 to 0.57 for events), reflecting the suboptimal TTR in such patients. This was not the case for those patients who were not on VKA.

Conclusion  We demonstrate that the SAME-TT2R2 score was predictive for an increasing risk of stroke/TE, severe bleeding, major BARC bleeding and death, reflecting poor anticoagulation control (and labile INRs) on VKA amongst our patients with AF.

original research 
Allan J. Walkey, MD, MSc; Bradley G. Hammill, MS; Lesley H. Curtis, PhD; Emelia J. Benjamin, MD, ScM
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Background:  New-onset atrial fibrillation (AF) is associated with adverse outcomes during a sepsis hospitalization; however, long-term outcomes following hospitalization with sepsis-associated new-onset AF are unclear.

Methods:  We used a Medicare 5% sample to identify patients who survived hospitalization with sepsis from 1999-2010. AF was defined as ‘no AF’, ‘prior AF’, or ‘new-onset AF’ based on AF claims during and prior to a sepsis hospitalization. We used competing risk models to determine five-year risks for AF occurrence, heart failure, ischemic stroke, and mortality after the sepsis hospitalization, according to AF status during the sepsis admission.

Results:  We identified 138,722 sepsis survivors of whom 95,536 (69%) had no AF during sepsis, 33,646 (24%) had prior AF, and 9540 (7%) had new-onset AF during sepsis. AF occurrence following the sepsis hospitalization was more common among patients with new-onset AF during sepsis (54.9%) than patients with no AF during sepsis (15.5%). Compared to patients with no AF during sepsis, those with new-onset AF during sepsis had greater five-year risks of hospitalization for heart failure [11.2% vs 8.2%; multivariable-adjusted hazard ratio (HR) 1.25, (95% CI 1.16-1.34)], ischemic stroke [5.3% vs 4.7%; HR 1.22 (1.10-1.36)] and death (74.8% vs 72.1%; HR 1.04 (1.01-1.07)].

Conclusions:  Most sepsis survivors with new-onset AF during sepsis have AF occur after discharge from the sepsis hospitalization, and have increased long-term risks for heart failure, ischemic stroke and death. Our findings may have implications for post-hospitalization surveillance of patients with new-onset AF during a sepsis hospitalization.

special features  OPEN ACCESS
Mary G. George, MD; Linda J. Schieb, MSPH; Carma Ayala, PhD; Anjali Talwalkar, MD; Shaleah Levant, MPH
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Background:  Pulmonary hypertension (PH) is an uncommon but progressive condition. Much of what we know about PH comes from specialized disease registries. With expanding research into the diagnosis and treatment of PH, it is important to provide updated surveillance on the impact of this disease on hospitalizations and mortality. This study builds on previous PH surveillance of mortality and hospitalization.

Methods:  This study analyzed mortality data from the National Vital Statistics System and data from the National Hospital Discharge Survey between 2001 and 2010. Pulmonary hypertension deaths were identified using ICD-10 codes I27.0, I27.2, I27.8, or I27.9 as any contributing cause of death on the death certificate. Hospital discharges associated with PH were identified using ICD-9-CM codes 416.0, 416.8, or 416.9 as one of up to seven listed medical diagnoses.

Results:  The decline in death rates associated with pulmonary hypertension among males from 1980 to 2005 has reversed and now shows a significant increasing trend. Similarly, the death rates for women with pulmonary hypertension have continued to significantly increase during the past decade. Pulmonary hypertension-associated mortality rates for those aged 85 and older have accelerated compared to rates for younger age groups. There have been significant declines in pulmonary hypertension-associated mortality rates for those with pulmonary embolism and emphysema. Rates of hospitalization for pulmonary hypertension have significantly increased for both men and women during the past decade. For those aged 85 and older, hospitalization rates have nearly doubled.

Conclusions:  Continued surveillance helps us understand and address evolving trends in hospitalization and mortality associated with pulmonary hypertension and for pulmonary hypertension-associated conditions, especially for sex, age, and race/ethnicity disparities.

original research 
Michael R Baria, MD; Leili S Shahgholi Ghahfarokhi, MD; Eric J Sorenson, MD; Caitlin J Harper; Kaiser G Lim, MD; Jeffrey A Strommen, MD; Carl D Mottram, RRT; Andrea J Boon, MBChB
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Background:  Electromyographic evaluation of diaphragmatic neuromuscular disease in COPD patients is technically difficult and potentially high risk. Defining standard values for diaphragm thickness and thickening ratio using B mode ultrasound may provide a simpler, safer means of evaluating these patients.

Materials and Methods:  Fifty patients with a diagnosis of COPD and FEV1 < 70% underwent B mode ultrasound. Three images were captured both at end-expiration (TMIN) and at maximal inspiration (TMAX). The thickening ratio was calculated as (TMAX / TMIN) and each set of values were averaged. Findings were compared to a database of 150 healthy controls.

Results:  There was no significant difference in diaphragm thickness or thickening ratio between sides within groups (controls or COPD) or between groups, with the exception of the subgroup with severe air trapping (residual volume > 200%), in which the only difference was that the thickening ratio was higher on the left (p=.0045).

Conclusion:  In patients with COPD presenting for evaluation of co-existing neuromuscular respiratory weakness, the same values established for healthy controls serve as the baseline for comparison. This knowledge expands the role of ultrasound in evaluating neuromuscular disease in COPD patients.

original research 
Matthew J. Strand, PhD; David Sprunger, MD; Gregory P. Cosgrove, MD; Evans R. Fernandez-Perez, MD, MPH; Stephen K. Frankel, MD; Tristan J. Huie, MD; Amy L. Olson, MD, MSPH; Joshua Solomon, MD; Kevin K. Brown, MD; Jeffrey J. Swigris, DO, MS
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Background:  The usual interstitial pneumonia pattern of lung injury (UIP) may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF).

Objective:  To observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF.

Methods:  We used longitudinal data analytic models to compare groups (IPF N=321 and CTD-UIP N=56) on percent predicted forced vital capacity (FVC%) or diffusing capacity (DLCO%), and we used both unadjusted and multivariable techniques to compare survival between these groups.

Results:  There were no significant differences between groups in longitudinal changes in FVC% or DLCO% up to diagnosis, or from diagnosis to ten years beyond (over which time, the mean decrease in FVC% per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, p=0.49 for difference; and the mean decrease in DLCO% per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, p=0.60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log rank p=0.003) and certain multivariable analyses.

Conclusion:  Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF—an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.

original research 
Peter J Mazzone, MD, MPH, FCCP; Anil Vachani, MD, FCCP; Andrew Chang, MD, FCCP; Frank Detterbeck, MD, FCCP; David Cooke, MD, FCCP; John Howington, MD, FCCP; Amos Dodi, MD; Douglas Arenberg, MD, FCCP
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Background:  Ideally, quality indicators are developed with the input of professional groups involved in the care of patients. This project, led by the Thoracic Oncology Network and Quality Improvement Committee of the American College of Chest Physicians, had the goal of developing quality indicators related to the evaluation and staging of lung cancer patients.

Methods:  Evidence based guidelines were used to generate a list of process of care quality indicators. Project members revised the content and wording of this list. A survey of the Steering Committee of the Thoracic Oncology Network was performed to rate the validity, feasibility, and relevance of the indicators. Predefined thresholds were used to select indicators from this list. This process was repeated for the selected indicators, through a survey available to all members of the Thoracic Oncology Network. Three academic medical centers determined if the surviving indicators were feasible and relevant within their practices.

Results:  18 quality indicators were drafted. Eleven survived the first round of voting, and 7 survived the second round of voting. One was related to tissue acquisition for molecular testing, 4 were related to staging and stage documentation, 1 to smoking cessation counseling, and one to documentation of a performance status measure. The indicators were feasible and relevant within the practices assessed.

Conclusions:  We have defined 7 process of care quality indicators related to the evaluation and staging of lung cancer patients, felt to be valid, feasible, and relevant, by lung cancer specialists.

original research 
Maxine Boudreau; Simon L. Bacon, PhD; Karine Ouellet; Ariane Jacob; Kim L. Lavoie, PhD
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Background:  Obesity has been associated with worse asthma control. Depression has also been shown to be disproportionally prevalent among both asthma patients and among the obese. However, no studies have examined the mediating effect of depression on the obesity-asthma relationship. This study examined the extent to which depressive symptoms may mediate the obesity-asthma relationship in a sample of adult asthmatics.

Methods:  A total of 798 patients with physician-diagnosed asthma were recruited from the outpatient asthma clinic at Hôpital du Sacré-Coeur de Montréal. Patients provided demographic and medical history information, and completed a battery of questionnaires including the Beck Depression Inventory-II (BDI-II) and the Asthma Control Questionnaire (ACQ). BMI was calculated from patient’s self-reported height and weight.

Results:  Analyses, adjusted for age, sex, years of education, cohabitation, and ICS dose revealed an association between BMI and ACQ (β = .017, p = .026), between BMI and BDI-II (β = .189, p = .002), and between BDI-II and ACQ (β = .044, p < .001). However, when both BDI-II and BMI were entered into the same model, only BDI-II (β = .044, p < .001), and not BMI (β = .009, p = .226), remained significantly associated with ACQ.

Conclusions:  Results indicate that having high depressive symptoms and high BMI are both associated with worse asthma control. However, consistent with our hypotheses, the relationship between BMI and worse asthma control was mediated by depressive symptoms. Future studies should examine the precise role of depressive symptoms in both weight control and asthma control.

original research 
Chi-Hsien Chen; H. Jasmine Chao; Chang-Chuan Chan; Bing-Yu Chen; Yue Leon Guo
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Background:  The presence of visible mold in households is associated with asthma. However, the role of “classroom fungus” in the development of childhood asthma, as well as the fungal species that may lead to asthma, remains controversial. This nationwide school survey was conducted to investigate the correlation between fungal spores in classrooms and asthma in schoolchildren.

Methods:  From April to May 2011, a cross-sectional survey was conducted to assess allergic/asthmatic conditions in schoolchildren aged 6∼15 years old in 44 schools across Taiwan. Personal histories and current asthmatic conditions were collected using a modified International Study of Asthma and Allergies in Childhood questionnaire. Fungal spores in classroom were collected using a Burkard Personal Air Sampler and counted under light microscopy. Three-level hierarchical modeling was used to determine the complex correlation between fungal spores in classrooms and childhood asthma.

Results:  The survey was completed by 6346 out of 7154 parents (88.7%). The prevalences of physician-diagnosed asthma, current asthma, and asthma with symptoms reduced on holidays or weekend (ASROH) were 11.7%, 7.5%, and 3.1%, respectively. The geometric mean spore concentrations of total fungi, Aspergillus/Penicillium, and basidiospores were 2181, 49, and 318 spores/m3. Aspergillus/Penicillium and basidiospores were significantly correlated with current asthma and ASROH after adjusting for personal and school factors. Of those with current asthma, 41% reported relief of symptoms during weekends.

Conclusions:  Classroom Aspergillus/Penicillium and basidiospores are significantly associated with childhood asthma and ASROH. Government health policy should explore environmental interventions for the elimination of fungal spores in classrooms to reduce the prevalence of childhood asthma.

original research 
Yuhui Zhang, MD, PhD; Yuanhua Yang, MD, PhD; Wenhui Chen, MD; Lijuan Guo, MD, PhD; Lirong Liang, MD, PhD; Zhenguo Zhai, MD, PhD; Chen Wang, MD, PhD; for the China Venous Thromboembolism (VTE) Study Group*
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Background:  The risk of venous thromboembolism (VTE) before anticancer therapy in lung cancer patients is not well-defined.

Methods:  A total of 673 hospitalized patients with newly diagnosed lung cancer were examined for VTE within one week after admission at five hospitals between January, 2009 and January, 2011. Additionally, VTE diagnoses within the last three months were reviewed. All VTE events were confirmed with imaging studies. Blood cell count and serum carcinoembryonic antigen (CEA) levels were measured before initial treatment.

Results:  VTE events occurred in 89 (13.2%) of the 673 patients enrolled in this study. Forty-two (6.2%) patients developed lower extremity deep vein thrombosis (DVT) alone, 33 (4.9%) patients developed pulmonary embolism (PE) alone, and 14 (2.1%) patients developed both DVT and PE. By multivariate logistic regression analysis, distant metastasis (odds ratio [OR] 2.2; 95% CI 1.2-3.9) and leukocytosis (OR 2.8; 95% CI 1.5-5.4) were significantly associated with DVT; adenocarcinoma (OR 2.1; 95% CI 1.1-4.4) and anemia (OR 4.6; 95% CI 1.4-14.5) were significantly associated with PE; and an elevated CEA level in tertiles was linearly associated with PE (P for trend=0.06). The area under the receiver-operator-characteristic curve for the prognostic or diagnostic CEA values was 0.68 (95% CI 0.59-0.76, P <0.001).

Conclusions:  The prevalence of VTE was high in patients with newly diagnosed lung cancer. In lung cancer patients, the factors associated with DVT might be different from those associated with PE. An elevated CEA level might facilitate the identification of patients at a higher risk of developing PE.

original research 
Audrey Mansuet-Lupo, MD; Antonio Bobbio, MD, PhD; Hélène Blons, PharmD, PhD; Etienne Becht; Hanane Ouakrim; Audrey Didelot; Marie-Christine Charpentier, MD; Serge Bain; Béatrice Marmey; Patricia Bonjour; Jérôme Biton, PhD; Isabelle Cremer, PhD; Marie-Caroline Dieu-Nosjean, PhD; Catherine Sautès-Fridman, PhD; Jean-François Régnard, MD; Pierre Laurent-Puig, MD, PhD; Marco Alifano, MD, PhD, FCCP; Diane Damotte, MD, PhD
Topics: , , , ,

Background:  Histological classification of lung adenocarcinoma subtype has a prognostic value in most studies. However, lung adenocarcinoma characteristics differ across countries. Here, we aimed at validating the prognostic value of this classification in a large French series of lung adenocarcinoma.

Methods:  We reviewed 407 consecutive lung adenocarcinomas operated on between 2001 and 2005 and reclassified them according to the IASLC/ATS/ERS classification and subsequently graded into low, intermediate and high grade. We analysed the relevance of this classification according to clinical, pathological, and molecular analysis.

Results:  Patients (median age: 61, 288 men) underwent lobectomy (n=378) or pneumonectomy (n=29). Patients overall survival at 5 and 10-year was 53.2% and 32.6%, respectively. UICC stage distribution was 189 stage I, 104 stage II, 107 stage III and 7 stage IV. Low grade tumor was found in 1 patient, intermediate grade in 275 patients and high grade in 131 patients. KRAS and EGFR mutations, were detected in 34% and 9.6% respectively. Histological grade was significantly correlated with extent of resection (P=0.01), TTF-1 expression (P=10-8), vascular emboli (P=0.03) and EGFR mutations (P=0.01). Mucinous adenocarcinomas were associated with KRAS mutations (P=0.003). At univariate analysis, age, extent of resection, histological grade, pleural invasion, vascular emboli, pathological T and N, and stage, were predictive of survival. At multivariate analysis, age (P=10-4), histological grade (P=0.03) and stage (P=3.10-6) were independent prognostic factors.

Conclusions:  IASLC/ATS/ERS classification of lung adenocarcinomas predicts survival in French population. Histological grade correlates with clinical, pathological and molecular parameters suggesting different oncogenic pathways.

original research 
Rajesh Thomas, FRACP; Charley A. Budgeon, BSc (Hons); Yi Jin Kuok, MBBS, FRANZCR; Catherine Read, BSc (Hons); Edward T. H. Fysh, MBBS; Sean Bydder, MBChB, FRANZCR; Y. C. Gary Lee, PhD, FRACP, FRCP, FCCP
Topics: , , ,

Indwelling pleural catheters (IPC) are commonly used to manage malignant effusions. Tumor spread along the catheter tract remains a clinical concern for which limited data exist. We report the largest series of IPC-related catheter tract metastases (CTM) to date.

Methods:  Single center, retrospective review of IPC inserted over a 44-month period. CTM was defined as a new, solid chest wall lesion over the IPC insertion site and/or the tunneled subcutaneous tract and clinically compatible with a malignant track metastasis.

Results:  110 IPCs were placed in 107 patients (76.6% male; 60% mesothelioma). CTM developed in 11 (10%) cases: nine with MPM and two with metastatic adenocarcinoma. CTM often developed late (median 280 days; range 56-693) post-IPC insertion. Seven cases had chest wall pain and six received palliative radiotherapy to the CTM. Radiotherapy was well tolerated with no major complications and causing no damage to the catheters. Longer interval after IPC insertion was the sole significant risk factor for development of CTM (OR, 2.495; 95%CI 1.247-4.993; p=0.0098) in the multivariate analyses.

Conclusion:  IPC-related CTM is uncommon but can complicate both mesothelioma and metastatic carcinomas. The duration of interval after IPC insertion is the key risk factor identified for development of CTM. Symptoms are generally mild and respond well to radiotherapy that can be administered safely without removal of the catheter.

original research 
Luke S.G.E. Howard, DPhil, FRCP; Vatshalan Santhirapala, MBChB; Kevin Murphy, PhD; Bhashkar Mukherjee, PhD, MRCP; Mark Busbridge, PhD; Hannah C. Tighe, BSc; James E. Jackson, FRCR, FRCP; J. Michael B. Hughes, DM, FRCP; Claire L. Shovlin, PhD, FRCP
Topics: , , ,

BACKGROUND:  Patients with pulmonary arteriovenous malformations are unusual because hypoxemia results from right-to-left shunting, and not airway/alveolar disease. Their surprisingly well-preserved exercise capacity is not generally appreciated.

METHODS:  To examine why exercise tolerance is preserved, cardiopulmonaryexercise tests were performed on air in 21 patients with radiologically-proven pulmonary arteriovenous malformations, including five restudied 3-12 months after embolization, when PAVMs had regressed. Where physiological matching was demonstrable, comparisons were made to 12 healthy controls.

RESULTS:  The majority of patients achieved their predicted work rate despite resting oxygen saturations (SaO2) of 80%-96%. Peak work rate and oxygen consumption were no lower in more hypoxemic patients. Despite higher SaO2 following embolization (medians 96%/90%, p=0.009), patients achieved similar work rates and similar peak oxygen consumption. Strikingly, treated patients reset to virtually identical peak oxygen pulses (oxygen consumption per heart beat), and in many cases to the same point on the peak oxygen pulse/work-rate plot. The 21 patients had increased minute ventilation (V(dot)E) for given increases in CO2 production (V(dot)E/ V(dot)CO2 slope), but perceived dyspnea was no greater than in controls, nor in the same patients before compared to after embolization. Overall, work rate and peak V(dot)O2 were associated not with oxygenation parameters, but with V(dot)E/ V(dot)CO2 slope, body mass index, and anerobic threshold.

CONCLUSIONS:  Hypoxemic patients with pulmonary arteriovenous malformations can maintain normal oxygen delivery/consumption during peak exercise. Following improvement of SaO2 by embolization, patients appeared to reset compensatory mechanisms, and as a result, achieved similar peak oxygen consumption per heart beat, and peak work rates.

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