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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 
Lonny Yarmus, DO; Roy Semaan, MD; Sixto Arias, MD; David Feller-Kopman, MD; Ricardo Ortiz; Hans Bösmüller, MD; Peter Illei, MD; Bernice Frimpong; Karen Oakjones-Burgess; Hans Lee, MD
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Introduction  Transbronchial forceps biopsy (FBx) has been the preferred method for obtaining bronchoscopic lung biopsy. Cryoprobe biopsy (CBx) has been shown to obtain larger and higher quality samples but has been limited by the inability to retrieve the sample through the working channel of the bronchoscope requiring the bronchoscope to leave the airway for sample retrieval. We evaluate a novel device using a sheath cryobiopsy (SCBx) allowing for specimen retrieval through the working channel of the bronchoscope with the scope remaining inside the airway.

Methods  Prospective, randomized, controlled, single blinded porcine study comparing a 1.1 mm SCBx probe, 1.9 mm CBx probe and 2.0 mm FBx forceps. Assessment of histological assessability, sample quantity and quality, number of attempts to acquire and retrieve samples, cryoprobe activation time, fluoroscopy activation time, technical feasibility and complications were compared.

Results  Specimens adequate for standard pathologic processing were retrieved with 82.1% of the SCBx specimens, 82.9%% of the CBx and 30% of the FBx. The histologic assessability of both, SCBx (p =0.0002) and CBx (p=0.0003) was superior over FBx. Procedure time for FBx was faster than both SCBx and CBx, but SCBx was significantly faster than CBx (p<0.0001). Fluoroscopy time was lower for both SCBx and CBx as compared to FBx. There were no significant bleeding events.

Conclusion  SCBx is a feasible technique providing a higher quality lung biopsy compared to FBx and can successfully be retrieved through the working channel. Human studies are needed to further assess this technique with additional safety data.

original research 
Hongbo Liu, MD, PhD; Divya Patel, MD; Alison Welch, CIH; Carla Wilson, MS; Margaret Mroz, MSPH; Li Li, MD, PhD; Cecile Rose, MD, MPH; Michael VanDyke, PhD, CIH; Jeffrey Swigris, DO, MS; Nabeel Hamzeh, MD; Lisa A. Maier, MD, MSPH
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No abstract is available for this article
original research 
Samuel M. Brown, MD MS; Colin K. Grissom, MD; Marc Moss, MD; Todd W. Rice, MD MSc; David Schoenfeld, PhD; Peter Hou, MD; B. Taylor Thompson, MD; Roy G. Brower, MD
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Background  Acute Respiratory Distress Syndrome (ARDS) is an important clinical problem. The definition of ARDS requires an arterial blood gas to define the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FIO2 ratio). However, many patients with ARDS do not have a blood gas measured, which may result in under-diagnosis of the condition. As a consequence, a method for estimating PaO2 from noninvasive measurements is desirable.

Methods  Using data from three ARDS Network studies, we analyzed the enrollment arterial blood gas to compare non-linear to linear and log-linear imputation methods of estimating PaO2 from hemoglobin percent saturation with oxygen measured by a pulse oximeter (SpO2). We compared mortality on the basis of various measured and imputed PaO2/FIO2 ratio cutoffs to assure clinical equivalence.

Results  We studied 1184 patients, of whom 707 had SpO2≤96%. Non-linear imputation from an SpO2/FIO2 ratio resulted in lower error than linear or log-linear imputation (p<0.001) for patients with SpO2≤96% but was equivalent to log-linear imputation in all patients. 90-day hospital mortality was 26-30%, depending on the PaO2/FIO2 ratio, whether non-linearly imputed or measured. On multivariate regression, the association between imputed and measured PaO2 varied by use of vasopressors and SpO2.

Conclusions  A non-linear equation more accurately imputes PaO2/FIO2 from SpO2/FIO2 than linear or log-linear equations, with similar observed hospital mortality of SpO2/FIO2 ratio versus measured PaO2/FIO2 ratios. While further refinement through prospective validation is indicated, a non-linear imputation appears superior to prior approaches to imputation.

original research 
Alice Huertas, MD, PhD; Carole Phan, MSc; Jennifer Bordenave, MSc; Ly Tu, PhD; Raphaël Thuillet; Morane Le Hiress, PhD; Jérôme Avouac, MD, PhD; Yuichi Tamura, MD, PhD; Yannick Allanore, MD, PhD; Roland Jovan, MD; Olivier Sitbon, MD, PhD; Christophe Guignabert, PhD; Marc Humbert, MD, PhD
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Pulmonary arterial hypertension (PAH) encompasses a group of conditions with distinct causes. Dysimmunity is a common feature of all forms of PAH and contributes to both disease susceptibility and/or progression. Regulatory T lymphocytes (Treg) are dysfunctional in idiopathic PAH (iPAH) patients in a leptin-dependent manner. However, it is not known whether these abnormalities are specific to iPAH. Hence, we hypothesized that (1) Treg dysfunction is also present in heritable (hPAH) and connective tissue disease-associated PAH (CTD-PAH); (2) defective leptin-dependent signaling is present in hPAH and CTD-PAH and could contribute to Treg dysfunction; (3) modulating leptin axis in vivo could protect against Treg dysfunction; (4) restoration of Treg activity could limit and/or reverse experimental chronic hypoxia (Hx)-induced pulmonary hypertension (PH) in vivo. We analysed 62 patients with PAH (30 iPAH, 18 hPAH and 14 CTD-PAH), 10 CTD patients without PAH and 20 healthy controls. Our results indicate that Treg are dysfunctional in all PAH forms tested, as well as in CTD patients without PAH. Importantly, leptin axis is crucial in Treg dysfunction in iPAH and CTD patients (with or without PAH), whereas in hPAH, Treg are altered in a leptin independent manner. Using leptin receptor (ObR)-deficient rats which develop less severe Hx-PH, we found that ObR-deficient rats are protected against decreased Treg function after Hx exposure. Taken altogether, our results suggest that Treg dysfunction is common to all forms of PAH and may contribute to the development and/or the progression of the disease.

original research 
Fang Yi, MD; Ruchong Chen, MD, PhD; Wei Luo, MSc; Danyuan Xu, MD; Lina Han, MD; Baojuan Liu, MD; Siqi Jiang, MD; Qiaoli Chen, BSc; Kefang Lai, MD, PhD
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Background  Whether FeNO measurement alone, or combining with sputum eosinophil and atopy is useful in predicting of corticosteroids responsive cough (CRC) and non-corticosteroids responsive cough (NCRC) is not clear.

Methods  A total of 244 patients with chronic cough and 59 healthy subjects as control were enrolled. The causes of chronic cough were confirmed according to a well established diagnostic algorithm. FeNO measurement and induced sputum for differential cell were performed in all subjects.

Results  CRC occurred in 139 (57.0%) patients and NCRC occurred in 105 patients. The FeNO level in CRC significantly correlated with sputum eosinophils (rs=0.583, P<0.01). The median (quarter) of FeNO level in CRC was significantly higher than NCRC [32.0 ppb (19.0-65.0 ppb) vs 15.0 ppb (11.0-22.0 ppb), P<0.01]. FeNO of 31.5 ppb had a sensitivity and specificity of 54.0% and 91.4% in predicting CRC from chronic cough, with a positive predictive value of 89.3% and a negative predictive value of 60.0%. If the patients had a combination of low level of FeNO (<22.5 ppb), normal sputum eosinophil (<2.5%) and absence of atopy, the sensitivity and specificity would be 30.3% and 93.5% for predicting NCRC.

Conclusions  In our cohort, a high level (≥31.5 ppb) of FeNO indicates more likelihood of CRC, but the sensitivity is insufficient to rule out the diagnosis of CRC. A combination of low level of FeNO, normal sputum eosinophil and absence of atopy suggests less likelihood of CRC.

recent advances in chest medicine 
Rachel K. Hopper, MD; Steven H. Abman, MD; D. Dunbar Ivy, MD
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Pulmonary hypertension (PH) and related pulmonary vascular diseases cause significant morbidities and high mortality and present many unique challenges towards improving outcomes in neonates, infants and children. Differences between pediatric and adult disease are reflected in controversies regarding etiologies, classification, epidemiology, diagnostic evaluations and therapeutic interventions. This brief review highlights several key topics reflecting recent advances in the field and identifies persistent gaps in our understanding of clinical pediatric PH.

original research 
Federico Lavorini, MD; Elisa Chellini, MD; Francesca Bigazzi, MD; Elisabetta Surrenti, MD; Giovanni A. Fontana, MD
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Background  Patients with deflation cough (DC), i.e. the cough-like expulsive effort(s) evoked by maximal lung emptying during a slow vital capacity (SVC) maneuver, also present symptoms of gastro-esophageal reflux (GER). Deflation cough can be inhibited by prior intake of antacids. We wished to assess DC prevalence and association between DC and chemical characteristics of refluxate in patients with GER symptoms.

Methods  157 consecutive outpatients underwent DC assessment and 24-hour multichannel intraluminal impedance pH (MII-pH) monitoring; 93/157 also had chronic cough. Patients performed 2-4 SVC maneuvers and DC was detected aurally. Subsequently, they underwent 24-hour MII-pH monitoring, the outcomes of which were defined as abnormal when acid or non-acid reflux events were >73.

Results  Deflation cough occurred in 46/157 patients, 18 of whom had abnormal MII-pH outcomes; 28 of the remaining 111 patients without DC also had abnormal MII-pH findings. Thus, in the patients as a group, there was no association between DC and MII-pH outcomes. DC occurred in 40/93 of the chronic coughers; 15 of whom had acid reflux. All but 2 of the 53 patients without DC had normal MII-pH outcomes (P<0.001), and the negative predictive value of DC for excluding acid reflux was 96.2%. At follow up, 65% of coughers showed significant improvement after treatment.

Conclusions  The overall prevalence of DC was 29%, increasing to 43% in chronic coughers in whom the absence of DC virtually excludes acid reflux. Therefore, DC assessment may represent a useful screening test for excluding acid reflux in chronic coughers with reflux symptoms.

original research 
Neomi Shah, MD MPH; David B. Hanna, PhD; Yanping Teng, MD MSPH; Daniela Sotres-Alvarez, PhD; Martica Hall, PhD; Jose S. Loredo, MD MS MPH; Phyllis Zee, MD PhD; Mimi Kim, ScD; H. Klar Yaggi, MD; Susan Redline, MD MPH; Robert C. Kaplan, PhD
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Background  We developed and validated the first ever sleep apnea (SA) risk calculator in a large population-based cohort of Hispanics/Latinos.

Methods  We analyzed cross-sectional data on adults from the Hispanic Community Health Study/Study of Latinos (2008-2011). Subjective and objective sleep measurements were obtained. Clinically significant SA was defined as an apnea-hypopnea index (AHI) ≥ 15 events per hour. Using logistic regression we created 4 prediction models: 3 sex-specific models (female-only, male-only, and a sex*covariate interaction model to allow differential predictor effects) and 1 overall model with sex included as a main effect only. Models underwent 10-fold cross-validation and were assessed using the C-statistic. SA and its predictive variables; a total of 17 variables were considered.

Results  12,158 participants had complete sleep data; 7,363 (61%) were females. The population-weighted prevalence of SA (AHI ≥15) was 6.1% in females and 13.5% in males. We found that both male-only (C-statistic 0.808) and female-only prediction models (C-statistic 0.836) had the same predictor variables, i.e. age, BMI and self-reported snoring. The sex-interaction model (C-statistic 0.836) contained sex, age, age*sex, BMI, BMI*sex and self-reported snoring. Our final overall model (C-statistic 0.832) contained age, BMI, snoring, and sex. We developed two websites for our SA risk calculator: one in English (https://www.montefiore.org/sleepapneariskcalc.html) and another in Spanish (http://www.montefiore.org/sleepapneariskcalc-es.html).

Conclusions  We created an internally validated, highly discriminating, well-calibrated and parsimonious prediction model for SA. Contrary to our hypothesis, the variables did not have different predictive magnitudes in males and females.

original research 
Takahiro Nakajima, MD, PhD, FCCP; Masato Shingyoji, MD, PhD; Takashi Anayama, MD, PhD; Hideki Kimura, MD, PhD; Kazuhiro Yasufuku, MD, PhD, FCCP; Ichiro Yoshino, MD, PhD
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Background  The aim of this study is to analyze the spectral features of the radiofrequency of lymph nodes during endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) and its diagnostic value for detecting metastatic nodes in patients with lung cancer.

Methods  Ultrasound spectrums of lymph nodes during EBUS-TBNA were retrospectively analyzed. A linear regression of frequency spectrum and the ultrasonic spectral parameters midband-fit, slope, and intercept were calculated. Mean values for these parameters within lymph nodes were computed, and the cut-off values for each parameter for distinguishing metastatic versus benign lymph nodes were first determined within the training set. Then, these cut-off values were applied to the testing set for validation.

Results  Overall, 362 lymph nodes (112 metastatic, 250 benign) were analyzed as the training set and 284 lymph nodes (74 metastatic, 210 benign) were evaluated as the testing set. In the training set, all of the parameters showed a significant difference between metastatic and benign lymph nodes (p<0.001). The metastatic nodes tended to show low midband-fit, high slope, and low intercept. When we combined midband-fit and intercept, the diagnostic accuracy was maximized in the training set. In the testing set, the combination of intercept and slope showed the highest diagnostic accuracy with sensitivity, 79.7%; specificity, 84.3%; PPV, 64.1%; NPV, 92.2%; and diagnostic accuracy, 83.1%.

Conclusions  Metastatic lymph nodes possess unique ultrasonic spectrum features, and spectrum analysis may be used as a novel diagnostic tool for differentiating between benign and malignant nodes in patients with lung cancer.

recent advances in chest medicine 
Cynthia W. Baffi; Lisa Wood; Daniel Winnica; Patrick J. Strollo; Mark T. Gladwin; Loretta G. Que; Fernando Holguin
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A link between metabolic syndrome (MetS) and lung diseases has been observed in several cross sectional and longitudinal studies. This syndrome has been identified as an independent risk factor for worsening respiratory symptoms, greater lung function impairment, pulmonary hypertension and asthma. This review will discuss several potential mechanisms to explain these associations, including dietary factors and the effect of adiposity and fat-induced inflammation on the lungs, and the role of other co-morbidities that frequently co-exist with MetS, such as obstructive sleep apnea (OSA) and obesity. In contrast to the well-known association between asthma and obesity, the recognition that MetS affects the lung is relatively new. Although some controversy remains as to whether MetS is a unique disease entity, its individual components have independently been associated with changes in pulmonary function or lung disease; there is however, uncertainty as to the relative contribution that each metabolic factor has in adversely affecting the respiratory system; also, it is unclear how much of the MetS – lung effects occur independently of obesity. In spite of these epidemiological limitations, the proposed mechanistic pathways strongly suggest that this association is likely to be causal. Given the wide prevalence of MetS in the general population, it is imperative that we continue to further understand how this metabolic disorder impacts the lung and how to prevent its complications.

original research 
David Hodgson, PhD; John Anderson, PhD; Catherine Reynolds; Janet Oborne; Garry Meakin; Helen Bailey; Dominick Shaw, MD; Kevin Mortimer, PhD; Tim Harrison, MD
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Background  Chronic cough is a common clinical problem worldwide. Although many patients have underlying precipitating conditions such as asthma, gastro-oesophageal reflux or rhinitis, many remain symptomatic despite treating these conditions. New approaches are needed for the treatment of this group of patients.

Methods  We conducted a randomised, double blind, placebo controlled trial to determine whether 250mg azithromycin three times a week for 8 weeks would affect the Leicester Cough Questionnaire (LCQ) score in 44 patients with treatment resistant cough. Cough severity on a visual analogue scale and bronchial exhaled nitric oxide were measured as secondary outcomes.

Results  There was a clinically important improvement in LCQ score with azithromycin (mean change 2.4; 95% CI 0.5 to 4.2) but not placebo (mean change 0.7; 95% CI -0.6 to 1.9) but the between group difference was not statistically significant (p=0.12). There were no significant between group differences for any of the secondary outcome measures. Looking at subgroups of responders, there was a large and significant improvement in LCQ score in patients with chronic cough and a concurrent diagnosis of asthma treated with azithromycin (mean 6.19; 95% CI 4.06 to 8.32).

Conclusions  Treatment with low-dose azithromycin for 8 weeks did not significantly improve LCQ score compared to placebo. The use of macrolides for the treatment of resistant cough cannot be recommended from this study but they may have a place in the treatment of chronic cough associated with asthma and this is worthy of further investigation.

original research 
Kohei Hasegawa, MD, MPH; Koichiro Gibo, MD; Yusuke Tsugawa, MD, MPH; Yuichi J. Shimada, MD, MPH; Carlos A. Camargo, Jr., MD, DrPH
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Background  Reducing hospital readmissions has attracted attention from many stakeholders. However, the characteristics of 30-day readmissions after asthma-related hospital admissions in adults are not known. It is also unclear whether older adults are at higher risk of 30-day readmission.

Objectives  To investigate the rate, timing, and principal diagnosis of 30-day readmissions in adults with asthma and to determine age-related differences.

Methods  Retrospective cohort study of adults hospitalized for asthma exacerbation using the population-based inpatient samples of 3 states (California, Florida, and Nebraska) from 2005 through 2011. Patients were categorized into 3 age groups: younger (18-39 years), middle-age (40-64 years) and older (≥65 years) adults. Outcomes were 30-day all-cause readmission rate, timing, and principal diagnosis of readmission.

Results  Of 301,164 asthma-related admissions at risk for 30-day readmission, readmission rate was 14.5%. Compared to younger adults, older adults had significantly higher readmission rates (10.1% vs. 16.5%; OR, 2.15 [95%CI, 2.07-2.23]; P<0.001). The higher rate attenuated with adjustment (OR, 1.19 [95%CI, 1.13-1.26]; P<0.001), indicating that most of the age-related difference is explained by sociodemographics and comorbidities. For all age groups, readmission rate was highest in the first week after discharge and declined thereafter. Overall, only 47.1% of readmissions were assigned respiratory diagnoses (asthma, COPD, pneumonia, and respiratory failure). Older adults were more likely to present with non-respiratory diagnoses (41.7% vs. 53.8%; P<0.001).

Conclusions  After asthma-related admission, 14.5% had 30-day readmission with wide range of principal diagnoses. Compared to younger adults, older adults had higher 30-day readmission rates and proportions of non-respiratory diagnoses.

original research 
Rajesh Thomas, MBBS, FRACP; Hui Min Cheah, BSc; Jenette Creaney, PhD; Berwin A. Turlach, PhD; Y C Gary Lee, MBChB PhD FRCP FCCP FRACP
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Background  Malignant pleural effusion (MPE) is common. Existing literature on pleural fluid compositions are restricted to cross-sectional sampling with little information on longitudinal changes of fluid biochemistry and cytokines with disease progression. Indwelling pleural catheters (IPC) provide the unique opportunity for repeated sampling and longitudinal evaluation of MPE, which may provide insight on tumor pathobiology.

Methods  638 MPE samples were collected from 103 patients managed with IPC over 95 (median, range 0-735) days and analyzed for protein, pH, LDH and glucose levels. Peripheral blood was quantified for hematocrit, platelets, leukocytes, protein and albumin. Cytokine levels (monocyte chemotactic protein (MCP)-1, vascular endothelial growth factor, interleukin (IL)-6, -8, -10, tumor necrosis factor-α and interferon-γ) were determined in 298 samples from 35 mesothelioma patients. Longitudinal changes of all parameters were analyzed using a linear mixed model.

Results  Significant decreases were observed over time in pleural fluid protein by 8g/L/100days (SE 1.32; p<0.0001) and pH (0.04/100days, SE 0.02; p=0.0203), accompanied by a non-significant rise of LDH. The pleural fluid to serum protein ratio decreased by 0.06/100days (SE 0.02; p=0.04). MPEs from mesothelioma (n=63) had lower pleural fluid glucose (p=0.0104) at baseline and a faster rate of decline in glucose (p=0.0423) when compared with non-mesothelioma effusions (n=38). A progressive rise in mesothelioma pleural fluid concentration of [log] MCP-1 ([log] 0.37pg/ml/100days, SE 0.13; p=0.0046), but not of other cytokines, was observed.

Conclusion  MPE fluids become less exudative and more acidic over the disease course. The rise in MCP-1 levels may suggest a patho-biological role in MPE.

contemporary reviews in critical care medicine 
Emmanuel Canet, MD; Lara Zafrani, MD PhD; Élie Azoulay, MD PhD
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Kidney transplantation is the most common solid organ transplantation performed worldwide. Up to 6% of kidney transplant recipients experience a life-threatening complication that requires ICU admission, chiefly in the late post-transplant period (≥6 months). Acute respiratory failure and septic shock are the main reasons for ICU admission. Cardiac pulmonary edema, bacterial pneumonia, acute graft pyelonephritis, and bloodstream infections account for the vast majority of the diagnoses in the ICU. Pneumocystis jirovecii pneumonia is the most common opportunistic infection and requires mechanical ventilation in half the cases. Incidence of cytomegalovirus visceral infections in the era of preemptive therapy has dramatically decreased. Drug-related neutropenia, sirolimus-related pneumonitis, and posterior reversible encephalopathy syndrome are among the most common immunosuppressive associated toxic effects. Importantly, the impact of critical illness on graft function is worrisome. Throughout the ICU stay, acute kidney injury is common, and about 40% of the recipients require renal replacement therapy. Half of the patients are discharged alive and free from dialysis. Hospital mortality can reach 30% and correlates with acute illness severity and reason for ICU admission. Transplant characteristics are not predictors of short term survival. Graft survival depends on pre-ICU graft function, disease severity and renal toxicity of ICU investigations and treatments.

original research 
Thomas K. Aldrich, MD; Madeline Vossbrinck, MS; Rachel Zeig-Owens, DrPH; Charles B. Hall, PhD; Theresa M. Schwartz, MS; William Moir, MPH; Mayris P. Webber, DrPH; Hillel W. Cohen, DrPH; Anna Nolan, MD; Michael D. Weiden, MD; Vasilios Christodoulou, BA; Kerry J. Kelly, MD; David J. Prezant, MD.
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Background  World Trade Center (WTC)-exposed Fire Department of the City of New York (FDNY) firefighters lost, on average, 10% of lung function after 9/11, and >10% developed new obstructive airways disease. There was little recovery (on average) over the first 6 years. Follow-up into the next decade allowed us to determine the longer-term exposure effects and the roles of cigarette-smoking and cessation on lung function trajectories.

Methods  We examined serial measurements of FEV1 from 3/11/2000 to 9/10/2014 among 10,641 WTC-exposed FDNY firefighters with known smoking and body weight histories.

Results  The median number of FEV1’s during follow-up was 9; 15% arrived at the WTC during the morning of 9/11/2001; and 65% never smoked. Firefighters arriving the morning of 9/11/2001 averaged lower lung function than did lesser-exposed firefighters; this difference remained significant during most of follow-up (P<0.05). Never-smokers had significantly better lung function than current-smokers; former-smokers fell in-between, depending upon their cessation date. Those arriving the morning of 9/11/2001 were more likely to have an FEV1<LLN compared with those arriving between 9/13/2001-9/24/2001 (odds ratio [OR]=1.70, P<0.01). Current-smokers were more likely to have an FEV1<LLN compared with: never-smokers (OR=2.06, P<0.01), former-smokers who quit before 9/11/2001 (OR=1.96, P<0.01); or, those who quit between 9/11/2001-3/10/2008 (OR=1.49, P<0.01).

Conclusions  13-years after 9/11/2001, most firefighters continued to show a lack of lung function recovery, with the trajectory of decline differing by WTC-exposure and smoking-status. Unlike the immutable effect of WTC exposure, we demonstrated the benefit on lung function of smoking cessation in this unique occupational/environmental cohort.

original research 
Tom van der Hulle, MD; Paul L. den Exter, MD; Pim van den Hoven, MD; Jacobus J. van der Hoeven, MD PhD; Felix J.M. van der Meer, MD PhD; Jeroen Eikenboom, MD PhD; Menno V. Huisman, MD PhD; Frederikus A. Klok, MD PhD
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Introduction  After diagnosis of cancer-associated venous thromboembolism (VTE), guidelines recommend to consider continuing anticoagulant treatment until patients are cured from cancer, although the safety of stopping anticoagulant treatment after cancer is cured has never been evaluated.

Methods  Cohort study in consecutive patients diagnosed with cancer-associated VTE at the Leiden University Medical Center between January 2001 and January 2010 followed for the effect of cancer treatment, occurrence of recurrent VTE, major haemorrhage and death.

Results  Of the 358 patients diagnosed with cancer-associated VTE, anticoagulant treatment was continued until death in 207 patients. In another 12 patients anticoagulant treatment was continued because of an alternative indication despite cure from cancer. Anticoagulant treatment was stopped in 50 patients for reasons other than major haemorrhage despite active cancer, in 21 patients after major haemorrhage, and in 68 patients after cure from cancer. Among these 68 patients, 10 patients were diagnosed with symptomatic recurrent VTE during a cumulative follow-up of 311 years resulting in an incidence rate (IR) of 3.2/100 PY (95%CI 1.5-5.9). Seven out of these 10 patients with recurrent VTE were also diagnosed with a cancer relapse during follow-up. In the 50 patients who stopped anticoagulant treatment despite active cancer the recurrent VTE IR was 19 per 100 PY (11 events during 59 years of follow-up; 95%CI 9.3-33).

Conclusions  Our data support the recommendation to stop anticoagulant treatment for cancer-associated VTE in patients cured from cancer. A cancer relapse seems to be a strong risk factor for recurrent symptomatic VTE.

original research 
Amélie Seguin, MD; Lionel Galicier, MD; David Boutboul, MD, PhD; Virginie Lemiale, MD; Elie Azoulay, MD, PhD
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Background  Acquired hemophagocytic lymphohistiocytosis [HLH] is a life-threatening event that usually occurs as a complication of immune deficiency. Lung involvement in HLH has received little attention. We described lung involvement in HLH and assessed whether it affected the prognosis.

Methods  We retrospectively studied 219 patients with HLH admitted to a national reference centre over a 14-year period, including 118 [54%] with lung involvement.

Results  Dyspnoea and cough were the most common onset symptoms. Radiographs showed interstitial infiltrates with centrilobular nodules, ill-defined consolidation, or localised ground-glass opacities. Pleural effusions and mediastinal lymphadenopathies were found in about half the patients. One or more causes of lung involvement were documented in 91/118 [77.1%] and included infection [n=52], pulmonary oedema [n=34], and malignancies [n=22, mostly lymphoma]. HLH-specific treatment combined with treatment of the cause of lung involvement improved respiratory function in only 67/118 [56.7%] patients. Hospital mortality was higher in patients with lung involvement [52.5% vs. 20%]. Infection as the cause of lung involvement was the only determinant of death [56% vs. 30%, p=0.004].

Conclusion  Lung involvement is common and of poor prognosis in patients with HLH. Studies should assess whether specific diagnostic and therapeutic strategies are warranted in HLH patients with lung involvement.

original research 
Robert C. Bourge, MD; Aaron B. Waxman, MD, PhD; Mardi Gomberg-Maitland, MD, MSc; Shelley M. Shapiro, MD, PhD; James H. Tarver, III, MD; Dianne L. Zwicke, MD; Jeremy P. Feldman, MD; Murali M. Chakinala, MD; Robert P. Frantz, MD; Fernando Torres, MD; Jeffrey Cerkvenik; Marty Morris; Melissa Thalin; Leigh Peterson; Lewis J. Rubin, MD
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Background  The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH), is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include intravenous catheter-related bloodstream infections and subcutaneous infusion site pain. Thus, we investigated a fully-implantable intravascular delivery system for treprostinil infusion.

Methods  A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted utilizing an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary endpoint was the rate of catheter-related complications using the new Model 10642 catheter compared with a pre-defined objective performance criterion of 2.5/1000 patient days based on literature.

Results  Patients (n=60) with severe PAH (WHO Group 1) receiving a stable dose of intravenous treprostinil for at least 4 weeks, were implanted and followed for 12.1±4.4 months. There were 6 catheter-related complications, corresponding to a complication rate of 0.27/1000 patient days. The 97.5% upper one-sided confidence bound of 0.59 was less than the pre-defined criterion of 2.5/1000 patient days (p<0.0001). Plasma treprostinil levels at one week post-implant were highly correlated with baseline levels (r=0.91, p<0.0001). The delivery-system management time as reported by the patients was 2.5±1.7 hours/week pre-implant and decreased to 0.6±0.8 hours/week at 6 months post-implant (p<0.0001). All patients rated overall satisfaction with the implantable system as good, very good or excellent at 6 and 26 weeks. There were no catheter-related bloodstream infections or catheter occlusions.

Conclusion  The implantable intravascular delivery system delivered treprostinil to PAH patients, with a low rate of catheter-related complications and high rate of patient satisfaction.

original research 
Jonathan A. Rose, MS; Jody M. Cleveland, MS; Youlan Rao, PhD; Omar A. Minai, MD; Adriano R. Tonelli, MD, MS
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Background  In recent years, the pulmonary arterial hypertension (PAH) patient population has changed dramatically including more advanced age at diagnosis. We hypothesized that older patients have a distinct clinical profile with different disease characteristics and response to intervention.

Methods  All previously-published treatment studies for PAH conducted by United Therapeutics including seven randomized, placebo-controlled trials and one extension study were included and analyzed to assess the association of age with various demographic, functional, hemodynamic, and outcome variables.

Results  A total of 2,627 patients across three age groups were included: ≤ 50 (n=1,438, 54.7%), 51–64 (n=780, 29.7%) and ≥ 65 years (n=409, 15.6%). In comparison with the youngest group, the oldest age group had higher proportions of connective tissue disease-associated etiology (27-49% vs 13-21%), higher proportions of New York Heart Association Functional Classes III and IV (74-91% vs 57-84%), shorter baseline 6-minute walk distance (6MWD) (261-316 vs 335-371 m), better hemodynamic measurements including lower baseline mean pulmonary artery pressure (48-51 vs 58-63 mmHg), and smaller changes in 6MWD from baseline to endpoint (-5.6-24 vs 14-43 m). Age remained associated with change in 6MWD when adjusting for covariates in multivariate analyses.

Conclusions  For the first time using data from large randomized controlled trials, this study characterizes the different phenotype and outcomes of older PAH patients, which includes different disease etiology, diminished functional status, and decreased response to intervention. This may have significant implications for the management of this patient population and design of future therapy trials.

original research 
Jonathan H. Chung, MD; Anna L. Peljto, Phd; Ashish Chawla, MD; Janet L. Talbert, MS; David F. McKean, MS; Byung-Hak Rho, MD; Tasha E. Fingerlin, PhD; Marvin I. Schwarz, MD; David A. Schwartz, MD; David A. Lynch, MBBS
Topics: , ,

Background  To determine the effect of the MUC5B promoter polymorphism (rs35705950) on the CT appearance of pulmonary fibrosis.

Methods  HRCT scans of 1,764 subjects were scored as part of an IRB-approved, genome-wide association study; 1,491 of these had pulmonary fibrosis on CT and were included in the study. Two thoracic radiologists independently systematically scored CT scans. Discrepancies were resolved by a third thoracic radiologist. All patients were genotyped specifically for the rs35705950 SNP. Two-tailed Fisher’s exact or Chi-square tests and t-test or Mann-Whitney U test were used to compare proportions and means, respectively.

Results  The major and minor alleles at the rs35705950 SNP are guanine (G) and thymine (T), respectively: 514 were homozygous for the major allele (G group) and 977 were heterozygous or homozygous for the minor allele (T group). The G group had a higher proportion with ground-glass opacity than the T group (62.1% versus 54.2%, p-value 0.04). There was no significant difference between the G and T groups in regard to presence of honeycombing. The T group showed a significantly higher subpleural axial distribution of fibrosis than that of the G group (62.3% versus 42.2%, p-value<0.0001). The T group showed a higher proportion of high confidence UIP diagnoses (43.8% [395/902] versus 32.6% [155/475]) and lower proportion of inconsistent with UIP diagnoses (20.3% [258/902] versus 30.5% [184/475]) [p-value <0.0001].

Conclusions  The MUC5B promoter polymorphism identifies a pattern of fibrosis that is different from other causes of fibrosis and may respond differently to potential therapies.

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