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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 
Marilyn L. Moy, MD; Riley J. Collins, BS; Carlos H. Martinez, MD; Reema Kadri, MLIS; Pia Roman, MA; Robert G. Holleman, MPH; Hyungjin Myra Kim, ScD; Huong Q. Nguyen, PhD; Miriam D. Cohen, MSN; David E. Goodrich, EdD; Nicholas D. Giardino, PhD; Caroline R. Richardson, MD
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Background:  Low levels of physical activity (PA) are associated with poor outcomes in persons with COPD. Interventions to increase PA could improve outcomes.

Methods:  We tested the efficacy of a novel Internet-mediated, pedometer-based exercise intervention. Veterans with COPD (n=239) were randomized in a 2:1 ratio to: (1) intervention group (Omron HJ-720 ITC pedometer and Internet-mediated program) or (2) wait-list control group (pedometer). The primary outcome was health-related quality of life (HRQL), assessed by the St. George’s Respiratory Questionnaire (SGRQ), at 4 months. We examined the SGRQ Total Score (SGRQ-TS) and three domain scores: Symptoms, Activities, and Impact. The secondary outcome was daily step counts. Linear regression models assessed the effect of intervention on outcomes.

Results:  Participants had mean age 67±9 years and were 94% male. There was no significant between-group difference in mean 4-month SGRQ-TS (2.3 units, P=0.14). Nevertheless, a significantly greater proportion of intervention participants than controls had at least a 4-unit improvement in SGRQ-TS, the minimum clinically important difference, (53% versus 39% respectively, P=0.05). For domain scores, the intervention group had a lower (reflecting better HRQL) mean than the control group by 4.6 units for Symptoms (P=0.046) and by 3.3 units for Impact (P=0.049). There was no significant difference in Activities score between the two groups. Compared to the controls, intervention participants walked 779 more steps per day at 4 months (P=0.005).

Conclusions:  An Internet-mediated, pedometer-based walking program can improve domains of HRQL and daily step counts at 4 months in persons with COPD.

Trial registration:  Clinical Trials.gov NCT01102777

original research 
Justin M. Oldham, M.D.; Disha Kumar, M.D.; Cathryn Lee, M.D.; Shruti Patel, M.D.; Stephenie Takahashi Manns, M.D.; Carley Demchuk, B.S.; Mary E. Strek, M.D.; Imre Noth, M.D.
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Background:  A significant minority of patients with Idiopathic Pulmonary Fibrosis (IPF) display features of autoimmunity without meeting criteria for overt connective tissue disease. A link between IPF and other immune-mediated processes, such as hypothyroidism, has not been reported. In this investigation we aim to determine whether hypothyroidism is associated with IPF and if outcomes differ between IPF patients with and without hypothyroidism.

Methods:  A retrospective case-control analysis was conducted. Of 311 patients referred to the University of Chicago Interstitial Lung Disease Center with an initial diagnosis of IPF, 196 met inclusion criteria and were included in the final analysis. Each case was matched 1:1 by age, gender and race to a control with chronic obstructive pulmonary disease.

Results:  Hypothyroidism was identified in 16.8% of cases and 7.1% of controls (OR 2.7; 95% CI 1.31-5.54; p=0.01). Among patients with IPF, hypothyroidism was associated with reduced survival time (p<0.001) and was found to be an independent predictor of mortality in multivariable Cox regression analysis (HR 2.12; 95% CI 1.31-3.43; p=0.002). A secondary analysis of two IPF clinical trial datasets supports these findings.

Conclusions:  Hypothyroidism is common among patients with IPF, with a higher prevalence than in those with COPD and that of the general population. The presence of hypothyroidism also predicts mortality in IPF, a finding that may improve future prognostication models. More research is needed to determine the biologic link between IPF and hypothyroidism, and how the presence of thyroid disease may influence disease progression.

original research 
Kensuke Kataoka; Hiroyuki Taniguchi; Yasuhiro Kondoh; Osamu Nishiyama; Tomoki Kimura; Toshiaki Matsuda; Toshiki Yokoyama; Koji Sakamoto; Masahiko Ando
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Background:  Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening closely associated with endothelial damage and disordered coagulopathy. Recombinant human soluble thrombomodulin (rhTM) regulates the coagulation pathway mainly by reducing thrombin-mediated clotting and enhancing protein C activation. We investigated the efficacy of rhTM for the treatment of patients with AE-IPF.

Methods:  This historical control study comprised 40 patients with AE-IPF. Twenty patients treated with rhTM (0.06mg/kg/day) for about 6 days (rhTM group) and 20 patients treated without rhTM (control group) were evaluated. The predictors of 3-month mortality (logistic regression model) were evaluated.

Results:  There was no difference in baseline characteristics between the control group and the rhTM group. Three-month mortality of the rhTM group and control group was 30.0% and 65.0%, respectively. In univariate analysis, respiratory rate, C-reactive protein (CRP), and rhTM therapy were significant determinants for 3-month survival. In multivariate analysis, rhTM therapy (odds ratio, 0.219; 95% CI 0.049-0.978; p=0.047) was an independent significant determinant for 3-month survival.

Conclusions:  We found that rhTM therapy improved 3-month survival of AE-IPF. The results observed here warrant further investigation of rhTM in randomized control trials.

original research 
Ronald D. Chervin, M.D, M.S.; Susan S. Ellenberg, Ph.D.; Xiaoling Hou, M.S.; Carole L. Marcus, M.B B.Ch.; Susan L. Garetz, M.D.; Eliot S. Katz, M.D.; Elise K. Hodges, Ph.D.; Ron B. Mitchell, M.D.; Dwight T. Jones, M.D.; Raanan Arens, M.D.; Raouf Amin, M.D.; Susan Redline, M.D.; Carol L. Rosen, M.D.

Background:  Adenotonsillectomy (AT) is commonly performed for childhood obstructive sleep apnea syndrome (OSAS), but little is known about prognosis without treatment.

Methods:  The Childhood Adenotonsillectomy Trial (CHAT) randomized 50% of eligible children with OSAS to a control arm (watchful waiting), with 7-month follow-up symptom inventories, physical examinations, and polysomnography. Polysomnographic and symptomatic resolution were defined respectively by an apnea/hypopnea index (AHI) <2 and obstructive apnea index (OAI) <1, and by an OSAS symptom score (Pediatric Sleep Questionnaire, PSQ) <0.33 with ≥25% improvement from baseline.

Results:  After 194 children aged 5-9 years underwent 7 months of watchful waiting, 82 (42%) no longer met polysomnographic criteria for OSAS. Baseline predictors of resolution included lower AHI, better oxygen saturation, smaller waist circumference or percentile, higher-positioned soft palate, smaller neck circumference, and non-African-American race (each p<.05). Among these, the independent predictors were lower AHI and waist circumference percentile <90%. Among 167 children with baseline PSQ scores ≥0.33, only 25 (15%) experienced symptomatic resolution. Baseline predictors were low PSQ and PSQ snoring subscale scores; absence of habitual snoring, loud snoring, observed apneas, or a household smoker; higher quality of life; fewer Attention-Deficit/Hyperactivity Disorder symptoms; and female gender. Only lower PSQ and snoring scores were independent predictors.

Conclusions:  Many candidates for AT no longer have OSAS on polysomnography after 7 months of watchful waiting, whereas meaningful improvement in symptoms is not common. In practice, a baseline low AHI and normal waist circumference, or low PSQ and snoring score, may help identify an opportunity to avoid adenotonsillectomy.

Clinical Trials Registration:  Childhood Adenotonsillectomy Study for Children with OSAS (CHAT). ClinicalTRials.gov Identifier #NCT00560859

original research 
Khagendra Dahal, MD; Sharan P. Sharma, MD; Erik Fung, MD, PhD; Juyong Lee, MD, PhD; Jason H. Moore, PhD; John N. Unterborn, MD; Scott M. Williams, PhD
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Introduction:  Warfarin is widely prescribed anticoagulant and its effect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotype-guided dosing (GD) of warfarin with standard dosing (SD) have shown mixed efficacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD versus SD in adult patients with various indications of warfarin use.

Methods:  We searched MEDLINE, EMBASE, Cochrane CENTRAL and relevant references for English language RCTs (inception through March 2014). We performed the meta-analysis using random effects model.

Results:  10 RCTs with a total of 2505 patients were included in the meta-analysis. GD compared to SD resulted in similar % time in therapeutic range (TTR) at ≤1 month follow-up [44% vs. 44.5%, mean difference (MD): -0.52, 95% confidence interval (CI): (-3.15-2.10), P=0.70] and higher %TTR [62.9% vs. 56.6%, MD: 6.35 (1.76-10.95), p= 0.007] at >1 month follow up, a trend towards lower risk of major bleeding [risk ratio (RR): 0.46 (0.19-0.1.11) , p= 0.08] at ≤1 month follow-up and lower risks of major bleeding [0.34 (0.16-0.74), p= 0.006] at >1-month follow-up, and shorter time to maintenance dose (TMD) [23 days vs. 33 days, MD: -9.54 days (-18.10, -0.98), P=0.03] at follow-up but had no effects on INR > 4.0, non-major bleeding, thrombotic outcomes or overall mortality.

Conclusion:  In the first month of genotype-guided warfarin therapy, compared to standard dosing, there were no improvements in %TTR, INR > 4.0, major or minor bleeding, thromboembolism, or all-cause mortality. There was shorter TMD, and after one month, improved %TTR and major bleeding incidence, making this a cost-effective strategy in patients requiring longer anticoagulation.

original research 
Denis Angoulvant, MD; Olivier Villejoubert, MD; Theodora Bejan Angoulvant, MD; Fabrice Ivanes, MD; Christophe Saint Etienne, MD; Gregory Y.H. Lip, MD; Laurent Fauchier, MD
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Background  Active smoking is associated with elevated thrombotic risk. Smoking status has recently been incorporated into the SAMe-TT2R2 score that can help predict poor INR control in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKA). The clinical benefit of antiplatelet therapy (APT) has been seen primarily in smokers. We hypothesised that active smoking may differently influence the risks of stroke and bleeding in AF patients treated with VKA or with APT.

Methods  We examined the clinical course of 7809 consecutive patients with AF seen between 2000-2010. Outcomes in patients with active smoking were compared with those in other patients.

Results  Among 7809 patients with AF, 1034(13%) were actively smoking. APT was prescribed on an individual basis for 2761 patients (35%) and VKA in 4534 (57%). After a follow-up of 929±1082 days (median=463 days, interquartile range=1564 days), smoking was not independently associated with a higher risk of stroke/TE in AF patients (hazard ratio (HR) 0.95, 95%CI 0.78-1.22, p=0.66). On multivariate analysis, smoking was independently associated with a worse prognosis for the risk of severe bleeding (HR 1.23, 95%CI 1.01-1.49, p=0.04) and for the risk of major BARC bleeding (HR 1.40, 95%CI 1.02-1.90, p=0.03). Smoking was independently associated with a higher risk of bleeding in patients treated with VKA (HR 1.32, 95%CI 1.04-1.67; p=0.02) whilst the risk was non- significant in patients treated with APT (HR 1.28, 95%CI 0.94-1.74; p=0.11).

Conclusion  In AF, there was a higher risk of severe bleeding in smokers, mainly in those treated with VKA.

original research 
Umut Özbek, PhD; Jashvant Poeran, MD, PhD; Madhu Mazumdar, PhD; Stavros G. Memtsoudis, MD, PhD
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Background:  Despite literature suggesting benefits of the regional anesthesia use, the impact of neuraxial anesthesia on perioperative outcomes in patients undergoing lung surgery remains unstudied. We therefore studied the effect of combined neuraxial/general anesthesia (versus general anesthesia) on perioperative outcome in a large national sample of open lung resection patients.

Methods:  We extracted data from the Premier Perspective database on open lung resection patients. The main effect of interest was anesthesia type: general and combined neuraxial/general anesthesia. Patient and healthcare variables, complications, and resource use were compared between groups. Multivariable analyses assessed the independent impact of choice of anesthetic technique on outcomes.

Results:  For 18,943 patients anesthesia type was known: 79% (n=14,912) general and 21% (n=4,031) neuraxial/general anesthesia. Comparing general versus neuraxial/general anesthesia, unadjusted incidences for the latter were lower for acute myocardial infarction (1.09% versus 0.67%, P=0.018), pulmonary complications (20.96% versus 18.98%, P=0.006), blood transfusion (14.15% versus 9.80%, P<0.0001), and mechanical ventilation (11.60% versus 8.81%, P<0.0001). Neuraxial/general anesthesia was associated with lower adjusted odds of blood transfusion (OR 0.82, CI 0.69-0.98) and mechanical ventilation (OR 0.81, CI 0.67-0.98), while higher odds were seen for deep vein thrombosis (OR 1.50, CI 1.01-2.23) and pulmonary embolism (OR 1.56, CI 1.02-2.38).

Conclusions:  This study illustrates the association between adding neuraxial to general anesthesia in open lung resections among cancer patients and perioperative outcomes. Neuraxial anesthesia use was associated with a decreased blood transfusion but increased thromboembolic risks. Additional studies are needed to elucidate mechanisms by which neuraxial anesthesia may affect these outcomes.

original research 
Elida Duenas-Meza, MD; María A. Bazurto, MD; David Gozal, MD; Mauricio González-García, MD; Joaquín Durán-Cantolla, MD, MBA; Carlos A. Torres-Duque, MD
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BACKGROUND:  Approximately 8% of the world population resides above 1,600 m, with about ten million people living above 2,500 m in Colombia. However, reference values for polysomnography (PSG) and oxygen saturation (SpO2) of children < 2 years old residing at high altitude are currently unavailable.

METHODS:  Healthy infants aged 1-18 months born and residing at high altitude (Bogotá: 2,640 m) underwent overnight PSG. Four age groups were defined: Group 1: <45 days; Group 2: 3-4 months; Group 3: 6-7 months; Group 4: 10-18 months. Of 122 children enrolled, 50 had three consecutive PSG and were analyzed as a longitudinal sub-cohort.

RESULTS:  A total of 281 PSG were performed in 122 infants (56% girls): Group 1: 106 PSG; Group 2: 89; Group 3: 61; Group 4: 25. Active sleep diminished and quiet sleep increased with maturation. Apnea-hypopnea indices: total, central and obstructive were higher in Group 1 (21.4, 12.4, and 6.8/hTST respectively) and diminished with age (p<0.001). Mean SpO2 during waking and sleep increased with age (p<0.001). Nadir SpO2 values during respiratory events were lower in younger infants. Longitudinal assessments of 50 infants confirmed the temporal trends described for the cross-sectional dataset.

CONCLUSIONS:  Healthy infants (≤ 18 months) born and residing at high altitude show preserved sleep architecture but higher apnea-hypopnea indices and more prominent desaturation with respiratory events than those described at low altitude. The current study findings can be used as reference values for infants at high altitude.

original research 
Harpreet Kaur, M.Sc; Sahajal Dhooria, MD, DM; Ashutosh N. Aggarwal, MD, DM, FCCP; Dheeraj Gupta, MD, DM, FCCP; Digamber Behera, MD, FCCP; Ritesh Agarwal, MD, DM, FCCP
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Background:  The optimal concentration of lignocaine to be used during flexible bronchoscopy (FB) remains unknown. This randomized controlled trial compared the efficacy and safety of 1% and 2% lignocaine solution for topical anesthesia during FB.

Methods:  Consecutive patients were randomized to receive either 1% or 2% lignocaine solution through the bronchoscope by “spray-as-you-go” technique. The primary outcome of the study was the assessment of cough by the operator and the patient, using the visual analogue scale (VAS) and pain assessment using the faces pain rating scale. The secondary outcomes included total lignocaine dose, oxygenation status, adverse reactions related to lignocaine and others.

Results:  Five hundred patients were randomized (median age 51 years, 71% men) 1:1 to either group. The median operator VAS score for cough was significantly higher (25 vs. 21; p=0.015) in the 1% group; however, the patient VAS score was not significantly different (32 vs. 27; p=0.065). The pain rating was similar between the two groups. The median cumulative dose of lignocaine was significantly higher in the 2% group (397 vs. 312 mg, p=0.0001; 7.1 vs. 5.7 mg/kg, p=0.0001). About 28% patients in the 2% group exceeded the maximum recommended dose (>8.2 mg/kg) of lignocaine. No adverse event related to lignocaine overdose was seen in either group.

Conclusion:  1% lignocaine was found to be as effective as 2% solution for topical anesthesia during FB, albeit at a significantly lower dose as the latter. Thus, 1% lignocaine should be the preferred concentration for topical anesthesia during FB.

  (clinicaltrials.gov: NCT01955824)

original research 
Il Ju Choi, MD, PhD; Young-Woo Kim, MD, PhD; Hee Seok Lee, MD; Keun-Won Ryu, MD, PhD; Hong Man Yoon, MD; Bang Wool Eom, MD; Chan Gyoo Kim, MD, PhD; Jong Yeul Lee, MD; Soo Jeong Cho, MD, PhD; Byung-Ho Nam, PhD
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Background:  Gastrectomy is known as one of the risk factors for tuberculosis (TB). However, there is no study about the association between TB development and gastrectomy performed in patients with early gastric cancer (EGC). The study is aimed at evaluating conventional risk factors including gastrectomy associated with TB development in patients with EGC.

Methods:  A retrospective cohort study was performed, using database of the Center for Gastric Cancer of National Cancer Center, Korea. The patients with EGC whose T1 lesions were pathologically confirmed by gastrectomy or endoscopic resection were included.

Results:  A total of 1,935 patients constituted the EGC cohort. Of these, 1,495 patients were confirmed by gastrectomy and the rest 440 by endoscopic resection. The median follow-up duration was 4.9 years and during this period, 31 cases of TB developed (TB incidence 334/100,000 person-year, 95% CI 227-475). Multivariate Cox regression analysis showed that old TB lesion on chest radiograph and gastrectomy were significant risk factors (HR 5.01, 95% CI 2.44-10.28, P<0.001, and HR 8.95, 95% CI 1.22-65.78, P=0.031, respectively). In the gastrectomy subgroup, old TB lesion, ≥15% reductions in weight and albumin level about one year after gastrectomy were significant risk factors (HR 4.80, 95% CI 2.26-10.18, P<0.001, HR 3.08, 95% CI 1.47-6.48, P=0.003, and HR 5.02, 95% CI 1.47-17.12, P=0.010, respectively).

Conclusions:  Old TB lesion and gastrectomy were significant risk factors in the EGC cohort. In addition, old TB lesion and ≥15% post-op reductions in weight and albumin level were significant risk factors in the gastrectomy subgroup

special features 
Atul C. Mehta, MD, FCCP; Tany Thaniyavarn, MD; Michael Ghobrial, MD; Danai Khemasuwan, MD, MBA
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The knowledge of airway anatomy is the most fundamental requirement of every bronchoscopist. There are numerous and frequent anatomical variations of the central airways making the examination unique for every individual. It is imperative for every bronchoscopist to be fully cognizant of the common congenital anomalies involving the central airways. Proper identification and reporting of these findings are a matter of the utmost importance, especially when surgical options in a lung cancer patient or a lung transplantation is under consideration. This article focuses on the congenital anomalies of central airway encountered among adults. Each of these anatomical variations has a characteristic appearance yet, requires bronchoscopic acumen for their identification. This review provides a comprehensive description of these anomalies and highlight their clinical implications.

contemporary reviews in critical care medicine 
Ali Al-Khafaji, MD, MPH; Mitra K. Nadim, MD; John A. Kellum, MD, MCCM
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Renal dysfunction is common in patients with end-stage liver disease (ESLD) and takes on many forms from acute to chronic renal injury and may involve a variety of mechanisms. Hepatorenal syndrome (HRS) is a specific type of hepatorenal disorders (HRD) with a unique pathophysiology. HRS is characterized by splanchnic arterial vasodilatation and decreased effective intravascular volume that leads to renal vasoconstriction and decreased renal blood flow. The incidence of HRS in relation to other forms of HRD is unknown, however, it is estimated that 35-40 % patients with ESLD and ascites eventually develop the condition. Two subtypes of HRS have been described. Type 1 HRS is rapidly progressive, whereas renal function in type 2 HRS deteriorates slowly over weeks or months. Type 1 HRS may be precipitated by sepsis or acute alcoholic hepatitis and occasionally develops in patients who already have type 2 HRS. Diagnosis of HRS is based on exclusion of other causes of renal dysfunction as there is no specific test available. Definitive treatment of HRS is liver transplantation. As a bridge to liver transplantation, medical management with volume expansion and use of vasoconstrictors is often implemented. Transjugular Intrahepatic Portosystemic Shunt (TIPS) has been attempted at treating hepatorenal syndrome, although there is little evidence of its efficacy compared to standard therapy. Renal replacement therapy (RRT) is often used if the patient is a liver transplant candidate. Artificial liver assist devices are in the research phase.

topics in practice management 
S.M. Kassutto, MD; R.J. Shah, MD, MSCE
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Patient satisfaction is an important factor for consideration in pulmonary practice management. Although evidence regarding the correlation of patient satisfaction with care quality remains mixed, there is an increasing national emphasis on the importance of patient experience in physician reimbursement, credentialing and public opinion. The introduction of the Affordable Care Act and Value Based Care Purchasing has tied a portion of reimbursement to patient experience surveys and other metrics related to care quality rather than quantity. Through nationally recognized assessments such as the Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys and easily accessible websites such as RateMD and Yelp, patient opinion of care quality is more widely available and more important to pulmonary practice than ever before. Physician credentialing may also be impacted by the American Board of Internal Medicine’s Maintenance of Certification program and potential future requirements for physicians to assess the patient experience in order to maintain certification. In the continually evolving health care delivery, credentialing and reimbursement climate, a thorough understanding of the increasing importance of patient satisfaction as well as strategies for successfully approaching this issue are essential to modern pulmonary inpatient and outpatient practice management.

original research 
David Gibeon, MBChB, MRCP; Liam G. Heaney, FRCP, MD; Chris E. Brightling, FRCP, PhD; Rob Niven, FRCP, MD; Adel Mansur, FRCP, PhD; Rekha Chaudhuri, MBBS, MD; Christine E. Bucknall, FRCP, MD; Andrew Menzies-Gow, FRCP, PhD on behalf of the British Thoracic Society Difficult Asthma Network
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Background:  Systematic assessment of severe asthma can be used to confirm the diagnosis, identify comorbidities and address adherence to therapy. However, the prospective utility of this approach is yet to be established.

Objective:  To establish whether the systematic assessment of severe asthma is associated with improved quality of life and health care utilisation. To compare relevant outcomes in patients referred with severe asthma to specialist centres across the UK using prospective data collection.

Methods:  Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between initial assessment and a median follow up of 286 days.

Results:  The study population consisted of 346 patients with severe asthma. At follow up there were significant reductions in healthcare utilisation in terms of primary care or emergency room visits (66.4% versus 87.8%, p<0.0001) and hospital admissions (38% versus 48%, p=0.0004). Although no difference was noted in terms of those requiring maintenance oral corticosteroids (OCS), there was a reduction in steroid dose (10mg [8 – 20] versus 15mg [10- 20], p=0.003) and fewer subjects required short burst steroids (77.4% versus 90.8%, p=0.01). Significant improvements were seen in quality of life and control using AQLQ and ACQ questionnaires.

Conclusions:  This is the first time that a prospective study has shown that a systematic assessment at a dedicated severe asthma centre is associated with improved QoL, asthma control, reduced healthcare utilisation and a reduction in oral steroid burden.

original research 
Renda Soylemez Wiener, MD, MPH; Christopher G. Slatore, MD, MS; Chris Gillespie, PhD; Jack A. Clark, PhD
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BACKGROUND:  Selecting a strategy (surveillance, biopsy, resection) for pulmonary nodule evaluation can be complex given the absence of high-quality data comparing strategies and the important trade-offs between strategies. Guidelines recommend a 3-step approach: 1) assess likelihood of malignancy; 2) evaluate whether the patient is a candidate for invasive intervention; 3) elicit patient's preferences and engage in shared decision-making. We sought to characterize how pulmonologists select a pulmonary nodule evaluation strategy and the extent to which they report following the guideline-recommended approach.

METHODS:  We conducted semi-structured qualitative interviews with 14 pulmonologists who manage patients with pulmonary nodules at 4 clinical sites. Transcripts of audiorecorded interviews were analyzed using principles of grounded theory.

RESULTS:  Pulmonologists reported consistently performing steps 1 and 2, but described diverse approaches to step 3 that ranged from always engaging the patient in decision-making to never doing so. Many described incorporating patients’ preferences only in particular circumstances, such as when the patient appeared particularly anxious or was aggressive in questioning management options. Indeed, other factors including convenience, physician preferences, physician anxiety, malpractice concerns, and physician experience, appeared to drive decision-making as much if not more than patient preferences.

CONCLUSION:  While pulmonologists appear to routinely personalize pulmonary nodule evaluation strategies based on the individual patient’s risk-benefit trade-offs, they may not consistently take patient preferences into account during the decision-making process. In the absence of high-quality evidence regarding optimal methods of pulmonary nodule evaluation, physicians should strive to ensure management decisions are consistent with patients’ values.

original research 
Sara E. Golden, MPH, CCRP; Renda Soylemez Wiener, MD, MPH; Donald Sullivan, MD, MA; Linda Ganzini, MD, MPH; Christopher Slatore, MD, MS
Topics: , ,

Purpose:  As lung cancer screening with low dose computed tomography (CT) is implemented, an increasing number of people will be diagnosed with pulmonary nodules. Primary care clinicians care for the vast majority of these patients but their experiences with communication and managing distress in this population are not well understood.

Methods:  We conducted qualitative interviews of 15 Primary Care Providers (PCPs) at two academic medical centers who care for patients with pulmonary nodules. We used qualitative description analysis, focusing on clinicians’ information exchange and other communication behaviors.

Results:  Most PCPs believed they had inadequate information to counsel patients regarding lung nodules, although this information is desired. PCPs were concerned patients could “fall through the cracks” but did not have access to a reliable system to ensure follow-up adherence . They were limited by time, knowledge, and resources in providing the preferred level of care. Most PCPs did not discuss the specific risk a nodule was lung cancer, in part because they did not have ready access to this information. PCPs believed most patients did not have substantial distress as a result of nodule detection. Most PCPs did not include patients when making decisions about the follow-up plan.

Conclusion:  PCPs often lack systemic resources to optimize patient-centered approaches when discussing incidental pulmonary nodules with patients. With the advent of lung cancer screening, pulmonologists can assist primary care colleagues by providing accurate information to counsel patients, and assisting in managing conversations about the risk of cancer. Pulmonologists should support efforts to implement reliable systems to ensure adherence to follow-up.

original research 
Joseph Footitt, PhD; Patrick Mallia, PhD; Andrew L. Durham, PhD; W. Eugene Ho, PhD; Maria-Belen Trujillo-Torralbo, BSc; Aurica G. Telcian, PhD; Ajerico Del Rosario, BSc; Cheng Chang, PhD; Hong-Yong Peh, MSc; Tatiana Kebadze, MD; Julia Aniscenko; Luminita Stanciu, PhD; Sarah Essilfie-Quaye, PhD; Kazuhiro Ito, PhD; Peter J. Barnes, FRS, FMedSci; Sarah L. Elkin, PhD; Onn M. Kon; W.S. Fred Wong, PhD; Ian M. Adcock, PhD; Sebastian L. Johnston, PhD
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Background  Respiratory virus infections are commonly associated with COPD exacerbations but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2) but their roles in COPD exacerbations is unknown. We investigated oxidative/nitrosative stress and HDAC2 in COPD exacerbations using experimental rhinovirus infection.

Methods  9 subjects with COPD (GOLD stage II), 10 smokers and 11 non-smokers were successfully infected with rhinovirus. Markers of oxidative and nitrosative-stress associated cellular damage, inflammatory mediators and proteases were measured in sputum, and HDAC2 activity measured in sputum and bronchoalveolar macrophages. In an in vitro model monocyte derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 measured.

Results  Rhinovirus infection induced significant increases in airways inflammation and markers of oxidative and nitrosative stress in COPD subjects. Oxidative/nitrosative stress markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory makers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity, inhibition of oxidative/nitrosative stress inhibited rhinovirus-induced inflammatory cytokines.

Conclusions  Oxidative and nitrosative stress, airways inflammation and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.

original research 
Gonzalo G. Alvarez, MD; Deborah D. Van Dyk, MScN; Marc Desjardins, PhD; Abdool S. Yasseen, III, MSc; Shawn D. Aaron, MD; D. William Cameron, MD; Natan Obed, BA; Maureen Baikie, MD; Smita Pakhale, MD; Claudia M. Denkinger, MD; Hojoon Sohn, MSc; Madhukar Pai, MD
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Background  Xpert MTB/RIF testing is being used extensively in countries with a high burden of TB. However recent evidence suggests that it may not have the same accuracy or impact in high-income, low-burden TB countries.

Methods  A prospective, pragmatic study was done between March 2012 and March 2014 to determine the feasibility, test accuracy, and impact on TB disease management provided by the Xpert test in a remote, medically underserved, predominantly Inuit population in Iqaluit, Nunavut, Canada.

Main Results  A total of 453 Xpert tests were run on sputum samples from 344 patients with suspected TB. Twenty seven patients were identified as having active TB disease by culture. There were no cases of drug resistant TB. Using culture as the gold standard, one Xpert test compared to 1,2 or 3 sputum samples cultured per patient, had a sensitivity of 85% (66-95, CI 95%) and a specificity = 99% (97-100, CI 95%) for detection of MTB. The indeterminate rate was 4.4% of all samples run. Treatment initiation was significantly shortened using Xpert versus the national standard of three smears (1.8 vs 7.7 days, p <0.007), and particularly shorter in smear-negative, culture-positive cases (1.8 vs 37.1 days, p value< 0.008).

Conclusions  In a predominantly Inuit population in a remote region of Canada where the burden of TB is high and no TB testing facilities are available, on-site Xpert was feasible, accurate and shortened time to TB treatment initiation.

original research 
Christopher R. Gilbert, D.O., M.S.; Hans J. Lee, M.D.; Joseph H. Skalski, M.D.; Fabien Maldonado, M.D.; Momen Wahidi, M.D., M.B.A.; Philip J. Choi, M.D.; Jamie Bessich, M.D.; Daniel Sterman, M.D.; A. Christine Argento, M.D.; Samira Shojaee, M.D.; Jed A. Gorden, M.D.; Candice L. Wilshire, M.D.; David Feller-Kopman, M.D.; Ricardo Ortiz, B.S.; Bareng Aletta Sanny Nonyane, Ph.D.; Lonny Yarmus, D.O.
Topics: , ,

BACKGROUND  Malignant pleural effusion remains a common complication of advanced malignancies. Indwelling tunneled pleural catheter placement provides effective palliation, but can be associated with complications, including infection. Hematologic malignancy in particular and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review the outcomes of hematological malignancy patients undergoing indwelling tunneled pleural catheter placement.

METHODS  A retrospective multicenter study of indwelling tunneled pleural catheters placed in hematologic malignancy patients from January 2009 to December 2013 was performed. Inclusion criteria included recurrent, symptomatic pleural effusion and underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, pathology, cytology, and microbiology reports.

RESULTS  A total of 91 patients were identified from eight institutions. The mean age was 65.4 years (SD +/- 15.4). The average in situ dwell time of all catheters was 89.9 days (SD +/- 127.1), with a total number of 8160 catheter days. A total of seven infectious complications were identified, all pleural space infections. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died from septic shock related to pleural infection.

CONCLUSION  We present the largest study examining clinical outcomes related to indwelling tunneled pleural catheter placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality was identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present within this population. Indwelling tunneled pleural catheter placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.

original research 
Arnold S. Kristof, M.D.; Pei Zhi Li, M.Sc; Philippe Major, M.D.; Jennifer S. Landry, M.D.
Topics: , , ,

Background:  Lymphangioleiomyomatosis (LAM) is a manifestation of Tuberous Sclerosis Complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health care utilization are lacking for TSC and LAM.

Methods:  Data on demographics, clinical outcomes, and health care utilization in the Quebec ministerial provincial health care database were analyzed for their association with TSC or LAM.

Results:  1004 subjects with TSC were identified using ICD-9 and 1CD-10 codes for a prevalence of 1/7,872 persons. There were 38 subjects with LAM, 9 of whom also had TSC. The mean ages, as well as the mean ages at death, were lower in LAM and TSC than those in the control group. Mortality rates were higher in LAM than in TSC or control subjects. Patients with LAM experienced more medical visits and hospitalizations than did TSC and control patients; these were associated with higher health care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mTOR inhibitors was uncommon.

Conclusion:  The prevalence of TSC in Quebec is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. The health care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Disorders of mental health may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

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