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 
Richard J. Schwab, MD; Sarah E. Leinwand, MPH; Cary B. Bearn, MS; Greg Maislin, MS; Ramya Bhat Rao, DMD; Adithya Nagaraja, BA; Stephen Wang, BS; Brendan T. Keenan, MS
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Background  Obstructive sleep apnea (OSA) is associated with changes in pharyngeal anatomy. The goal of this study was to objectively and reproducibly quantify pharyngeal anatomy using digital morphometrics based on a laser ruler, and to assess differences between apneics and controls and associations with AHI (apnea-hypopnea index). This is the first study to use digital morphometrics to quantify intraoral risk factors for OSA.

Methods  Digital photographs were obtained using an intraoral laser ruler and digital camera in 311 controls (mean AHI=4.2 events/hour) and 533 apneics (mean AHI=39.2 events/hour).

Results  The digital morphometric paradigm was validated and reproducible over time and camera distances. A larger modified Mallampati score and having a non-visible airway were associated with a higher AHI both unadjusted (p<0.001) and controlling for age, gender, race and BMI (p=0.015 and p=0.018, respectively). Measures of tongue size were larger in apneics versus controls in unadjusted models and controlling for age, gender and race, but non-significant controlling for BMI; similar results were observed with AHI severity. Multivariate regression suggests photography-based variables capture independent associations with OSA.

Conclusions  Measures of tongue size, airway visibility and Mallampati scores were associated with increased OSA risk and severity. This study shows that digital morphometrics is an accurate, high-throughput and non-invasive technique to identify anatomic OSA risk factors. Morphometrics may also provide a more reproducible and standardized measurement of the Mallampati score. Digital morphometrics represent an efficient and cost-effective method of examining intraoral crowding and tongue size when examining large populations, genetics or screening for OSA.

original research 
Elizabeth Moore; Roger Newson, Dr; Miland Joshi, Dr; Thomas Palmer; Kieran J. Rothnie, Dr; Sally Singh, Professor; Azeem Majeed; Michael Soljak, Dr; Jennifer K. Quint, Dr
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Background  In previous systematic reviews, predominantly of randomised controlled trials, pulmonary rehabilitation (PR) has been shown to reduce hospital admissions for acute exacerbations of COPD (AECOPD). However, findings have been less consistent for cohort studies. We aimed to compare rates of hospitalized and general practice (GP) treated AECOPD before and after PR.

Methods  Using anonymised data from the Clinical Practice Research Datalink and Hospital Episode Statistics, hospital admissions and GP visits for AECOPD were compared one year before and after PR in patients referred for PR. Exacerbation rates were also compared between individuals eligible and referred for PR with those eligible and not referred.

Results  69,089 (64%) of the COPD patients in the cohort were eligible for PR. Of these, only 6,436 (9.3%) were recorded as having been referred for rehabilitation. 62, 019 (89.8%) were not referred and 634 (0.98%) declined referral. When combining GP and hospital exacerbations, people who were eligible and were referred for PR had a slightly higher but not statistically significant exacerbation rate (2.83 exacerbations/patient-year 95% CI: 2.66, 3.00) than those who were eligible but not referred (2.17 exacerbations/patient-year 95% CI: 2.11, 2.24).

Conclusions  This study found that less than 10% of patients who were eligible for PR were actually referred. Patients who were eligible and referred for (but not necessarily completed) PR did not have fewer GP visits and hospitalizations for AECOPD in the year after PR compared to those not referred or compared to the year before PR.

original research 
Takahiro Ando, MD.; Masahiro Kawashima, MD.; Kimihiko Masuda, MD, PhD.; Keita Takeda, MD.; Kenichi Okuda, MD.; Junko Suzuki, MD.; Nobuharu Ohshima, MD, PhD.; Hirotoshi Matsui, MD, PhD.; Atsuhisa Tamura, MD, PhD.; Hideaki Nagai, MD, PhD.; Shinobu Akagawa, MD, PhD.; Ken Ohta, MD, PhD.
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Background  Hemoptysis can cause a life threatening condition and often need to be treated urgently. Nearly 20% of hemoptysis cases were diagnosed as cryptogenic after clinical investigation. The purpose of this study was to clarify clinical and angiographic characteristics of cryptogenic hemoptysis.

Methods  We retrospectively reviewed medical records of 35 patients admitted to our hospital with cryptogenic hemoptysis from October 2010 to September 2014.

Results  In the 35 cases, bronchial artery embolization was successfully performed in 33 patients (94.3%) while bronchoscopic hemostatic therapy was added in one patient (2.8%) and embolization was not done in one patient (2.8%) because the bronchial artery was too narrow. In successful embolization group, non-rebleeding rate was 97.0% for 20 months. The angiographic findings revealed that the diameter of bronchial arteries was less than 2 mm in 13 patients, 2 to 3 mm in 17 and more than 3 mm in five. Hypervascularization was detected in 29 patients (82.9%), small bronchial aneurysms in eight (22.9%). The amount of hemoptysis was slight (< 50 mL / day) in 12, mild (50 - 100 mL / day) in 11, moderate (100 - 200 mL / day) in 8 and massive (> 200 mL / day) in 4 patients. No obvious relationship was found between the diameter of bronchial arteries and the amount of hemoptysis.

Conclusion  BAE was highly effective for the management of cryptogenic hemoptysis. Most cases of cryptogenic hemoptysis have angiographic abnormalities, including small or micro aneurysms which were suspected as the cause in some cases.

original research 
Arun Jose, MD; Christopher S. King, MD; Oksana A. Shlobin, MD; Joseph M. Kiernan, MD; Nicolas A. Cossa, MD; A.Whitney Brown; Steven D. Nathan, MD
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Background  Pulmonary hypertension (PH) is diagnosed and classified through right heart catheterization (RHC), with a number of hemodynamic markers used to help guide treatment decisions. These markers may not reflect the complex remodeling of the right ventricle or the interplay between ventricles, and struggle to predict treatment response. This study investigates the use of a novel marker; the ratio of left to right ventricular end-diastolic pressures (LVEDP/RVEDP), in predicting treatment outcomes in a cohort of PH patients.

Methods  We performed a retrospective analysis of PH patients at INOVA Fairfax Hospital Advanced Lung Disease Program with simultaneous left- and right-heart catheterization. The primary endpoint was the time to clinical improvement, defined by an improvement in distance walked on the 6MWT of greater than 35 meters in a year without interceding hospitalization for worsening PH or need for additional PH therapy.

Results  A total of 51 patients were included in the final analysis, of which 21 (41.2%) had a salutary treatment effect with a mean improvement in the 6MWT of 75 meters. Treatment responders were more likely to have a lower LVEDP/RVEDP ratio (1.08 vs 1.62, p=0.051). This association persisted in the final multivariate regression model after adjustment for age, gender, and controlling for severity of pulmonary hypertension (OR 0.17, 95% confidence interval 0.03-0.65, p=0.024).

Conclusion  The LVEDP/RVEDP ratio is a novel marker for therapeutic response in PH patients treated with pulmonary vasodilator medications, and may offer robust predictive value independent of existing markers of disease severity.

contemporary reviews in sleep medicine 
Sirimon Reutrakul, MD; Babak Mokhlesi, MD, M.Sc.
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Obstructive sleep apnea (OSA) is a chronic treatable sleep disorder and a frequent comorbidity in patients with type 2 diabetes. Cardinal features of OSA, including intermittent hypoxemia and sleep fragmentation, have been linked to abnormal glucose metabolism in laboratory-based experiments. OSA has also been linked to the development of incident type 2 diabetes. The relationship between OSA and type 2 diabetes may be bidirectional in nature given that diabetic neuropathy can affect central control of respiration and upper airway neural reflexes promoting sleep-disordered breathing. Despite the strong association between OSA and type 2 diabetes, the effect of treatment with continuous positive airway pressure (CPAP) on markers of glucose metabolism has been conflicting. Variability with CPAP adherence may be one of the key factors behind these conflicting results. Lastly, accumulated data suggests an association between OSA and type 1 diabetes as well as gestational diabetes. This review will explore the role of OSA in the pathogenesis of type 2 diabetes, glucose metabolism dysregulation and complications of type 2 diabetes. The association between OSA and diabetic complications as well as gestational diabetes will also be reviewed in the online supplement.

original research  OPEN ACCESS
Kui Jin, MD; Raghavan Murugan, MD, MS; Florentina E. Sileanu, MS; Emily Foldes, MS; Priyanka Priyanka, MS; Gilles Clermont, MD, MS; John A. Kellum, MD
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Background  Urine output (UO) is a vital sign for critical ill patients but standards for monitoring and reporting vary widely between ICUs. Careful monitoring of UO could lead to earlier recognition of acute kidney injury (AKI) and better fluid management. We sought to determine if intensity of UO monitoring is associated with outcomes in patients with and without AKI.

Methods  Retrospective cohort study including 15,724 adults admitted to ICUs from 2000-2008. Intensive UO monitoring was defined as hourly recordings and no gaps >3 hours for the first 48 hours after ICU admission.

Results  4,049 (26%) patients underwent intensive monitoring for UO and we found significantly higher rates of AKI (OR 1.22 p<0.001) in these patients. After adjustment of age and severity of illness, intensive UO monitoring was associated with improved survival, but only among patients developing AKI. With or without AKI, patients with intensive monitoring also had less cumulative fluid volume (2.98L vs. 3.78L, p<0.001) and less fluid overload (2.49% vs. 5.68%, p <0.001) over the first 72 hours of ICU stay.

Conclusion  In this large ICU population, intensive monitoring of UO was associated with improved detection of AKI and reduced 30-day mortality in patients developing AKI; as well as less fluid overload for all patients. Our results should help inform clinical decisions and ICU policy around frequency of monitoring of UO especially for patients at high risk of AKI and/or fluid overload.

original research 
Angelo M. Taveira-DaSilva, M.D., Ph.D.; Amanda M. Jones, C.R.N.P.; Patricia Julien-Williams, C.R.N.P.; Mario Stylianou, Ph.D.; Joel Moss, M.D., Ph.D.
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Background  Sirolimus reduces serum levels of VEGF-D, size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas, and stabilizes lung function in patients with lymphangioleiomyomatosis.

Methods  To determine whether reductions in VEGF-D levels are sustained over time, and parallel changes in lung function and lymphatic disease, we evaluated 25 patients with lymphangioleiomyomatosis and measured VEGF-D levels, lung function and extent of lymphatic disease before and during sirolimus therapy

Results  Treatment with sirolimus stabilized FEV1 and DLCO over a period of 4.5±1.6 years, caused resolution of lymphatic disease, and reduced angiomyolipomas size and VEGF-D levels (3,720±3,020 to 945±591 pg/ml, p<0.0001).. Yearly changes in % predicted FEV1 and DLCO were reduced from -7.4±1.4 to -0.3±0.5 % (p<0.001) and -6.4±0.9 to -0.4±0.5 % (p<0.001), respectively. Lower VEGF-D levels correlated with sirolimus therapy (p<0.001), but no significant relationship was observed between reduction in VEGF-D levels and FEV1 and DLCO during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy, than those without lymphatic disease.

Conclusions  Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated pre-therapy levels. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.

original research 
Galit Aviram, MD; Zach Rozenbaum, MD; Tomer Ziv-Baran, PhD; Shlomo Berliner, MD, PhD; Yan Topilsky, MD; Dominik Fleischmann, MD; Yon K. Sung, MD; Roham T. Zamanian, MD; Haiwei Henry Guo, MD, PhD
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Background  Evaluations of patients with pulmonary hypertension (PH) commonly include chest computed tomography (CT). We hypothesized that cardiac chamber volumes calculated from the same CT scans can yield additional information to distinguish left heart disease-related PH (WHO Group 2) from other PH subtypes.

Methods  Patients with right heart catheterization (RHC)-confirmed PH and contrast-enhanced chest CT studies were enrolled in this retrospective multicenter study. Cardiac chamber volumes were calculated using automated segmentation software and compared between Group 2 and non-Group 2 PH patients.

Results  This study included 114 PH patients, of whom 27 (24%) were classified as Group 2 based on their pulmonary capillary wedge pressure. Group 2 PH patients exhibited significantly larger median left atrial (LA) volumes (118 vs. 63 mL, P < 0.001), larger median left ventricular (LV) volumes (90 vs. 76 mL, P = 0.02), and smaller median right ventricular (RV) volumes (173 vs. 210 mL, P = 0.005) than non-Group 2 patients. On multivariate analysis adjusted to age, gender, and mean pulmonary arterial pressure, Group 2 PH was significantly associated with larger median LA and LV volumes (P < 0.001 and P = 0.008, respectively), and decreased volume ratios of RA/LA, RV/LV and RV/LA (P = 0.001, P = 0.004, and P < 0.001, respectively). Enlarged LA volumes demonstrated high discriminatory ability for Group 2 PH (AUC=0.92; 95%CI, 0.870-0.968).

Conclusions  Volumetric analysis of the cardiac chambers from non-gated chest CTs, particularly with findings of an enlarged LA, exhibited high discriminatory ability for identifying patients with PH due to left heart disease.

original research 
Samuel Y. Ash, MD; Rola Harmouche, PhD; Rachel K. Putman, MD MPH; James C. Ross, PhD; Alejandro A. Diaz, MD MPH; Gary M. Hunninghake, MD MPH; Jorge Onieva Onieva, MSc; Fernando J. Martinez, MD MS; Augustine M. Choi, MD; David A. Lynch, MD; Hiroto Hatabu, MD PhD; Ivan O. Rosas, MD; Raul San Jose Estepar, PhD; George R. Washko, MD
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Background  Smoking related lung injury may manifest on computed tomography (CT) as both emphysema and interstitial changes. We have developed an automated method to quantify interstitial changes and hypothesized that this measurement would be associated with lung function, quality of life, mortality, and a MUC5B polymorphism.

Methods  Using CT scans from the COPDGene study, lung parenchyma was objectively labeled as a tissue subtype and the percentage of the lung occupied by interstitial subtypes was calculated.

Findings  8345 participants had clinical and CT data available. A 5% absolute increase in interstitial changes was associated with an absolute increase in percent predicted forced vital capacity of 2.47% (p<0.001) and a 1.36 point higher St. George’s Respiratory Questionnaire score (p<0.001). Among the 6827 participants with mortality data, a 5% increase in interstitial changes was associated with a 29% increased risk of death (p<0.001). These associations were present in a subgroup without visually defined interstitial lung abnormalities, as well as in those with normal spirometry, and in those without chronic respiratory symptoms. In non-Hispanic whites, for each copy of the minor allele of the MUC5B promoter polymorphism there was a 0.63% (p=1x10-7) absolute increase in the percentage of lung with interstitial changes.

Conclusions  Objective interstitial changes on CT were associated with impaired lung function, worse quality of life, increased mortality, and more copies of a MUC5B promoter polymorphism, suggesting that these changes may be a marker of susceptibility to smoking related lung injury, detectable even in those who are normal by other measures.

original research 
Abigail Moore, BM BCh; Helen F. Ashdown, MRCP MRCGP; Bethany Shinkins, DPhil; Nia W. Roberts, MSc (Econ); Cameron C. Grant, PhD; Daniel S. Lasserson, MD; Anthony Harnden, FRCGP
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Background  Pertussis (whooping cough) is a highly infective cause of cough that causes significant morbidity and mortality. Existing case definitions include paroxysmal cough, whooping and post-tussive vomiting but diagnosis can be difficult. We determined the diagnostic accuracy of clinical characteristics of pertussis-associated cough.

Methods  We systematically searched CINAHL, Embase, Medline and SCI-EXPANDED/CPCI-S up to June 2016. Eligible studies compared clinical characteristics in those positive and negative for Bordetella pertussis infection, confirmed by laboratory investigations. Two authors independently completed screening, data extraction and quality and bias assessments. For each characteristic RevMan was used to produce descriptive forest plots. We used the bivariate meta-analysis method to generate pooled estimates of sensitivity and specificity.

Results  Of 1969 identified papers, 53 were included. Forty-one clinical characteristics were assessed for diagnostic accuracy. In adult patients, paroxysmal cough and absence of fever had a high sensitivity (93.2%, CI 83.2-97.4 and 81.8%, CI 72.2-88.7 respectively) and low specificity (20.6%, CI 14.7-28.1 and 18.8%, CI 8.1-37.9 respectively), whereas post-tussive vomiting and whooping had low sensitivity (32.5%, CI 24.5-41.6 and 29.8%, CI 8.0-45.2 respectively) and high specificity (77.7%, CI 73.1-81.7 and 79.5%, CI 69.4-86.9 respectively). Post-tussive vomiting in children is moderately sensitive (60.0%, CI 40.3-77.0) and specific 66.0%, CI 52.5-77.3).

Conclusions  In adult patients the presence of whooping or post-tussive vomiting should rule in a possible diagnosis of pertussis, whereas the lack of a paroxysmal cough or the presence of fever should rule it out. In children, post-tussive vomiting is much less helpful as a clinical diagnostic test.

original research 
Theodore J. Dubinsky, MD, FSRU, FSAR; Hardik Shah, MD; Rachelle Sonneborn, BA; Daniel S. Hippe, MS
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Background  We prospectively identified B-lines in patients undergoing ultrasound examinations following liver transplants who also had a chest x-ray (CXR) and/or chest CT scan on the same day to determine if an association between the presence of B-lines s from the thorax on ultrasound images correlates with the presence of pulmonary abnormalities on chest radiographs.

Materials and Methods  Following IRB approval, patients undergoing routine postoperative liver transplant ultrasound examinations and a CXR and/or CT scan on the same day between 1/1/2015 through 7/1/2016 were prospectively identified.Two readers blinded to CXR and CT images and reports independently reviewed the US. Inter-reader agreement for presence/absence of the B-lines was evaluated for the presence or absence of diffuse parenchymal lung disease on CXR and CT, as well as on clinical evaluation. Receiver operating characteristic (ROC) curves were constructed.

Results  There was good agreement between the two readers on the presence/absence of B-lines (kappa: 0.94) The area under the ROC curve (AUC) for discriminating between DPLD+ and DPLD- for both readers was 0.79 (95% CI: 0.71-0.87.

Conclusion  There is an association between the presence of extensive B-lines to the point of confluence and “dirty shadowing” on ultrasound examinations of the chest and associated findings on chest radiographs and CT scans of diffuse parenchymal lung disease. Conversely, isolated B-lines do not always correlate with abnormalities on chest X-ray or and in fact appear sometimes to be a normal variant.

original research  OPEN ACCESS
Satoru Yanagisawa, Ph.D.; Andriana I. Papaioannou, Ph.D.; Anastasia Papaporfyriou, Ph.D.; Jonathan Baker, Ph.D.; Chaitanya Vuppusetty, M.Sc.; Stelios Loukides, Ph.D.; Peter J. Barnes, FRS; Kazuhiro Ito, Ph.D.
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Background  The protein deacetylase sirtuin-1 (SIRT1) is an anti-aging molecule that is decreased in the lung from patients with chronic obstructive pulmonary disease (COPD). Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 levels have not yet been reported in patients with COPD.

Methods  Serum SIRT1 was measured by Western blotting, and relative ratio of band density in samples against that of a positive control were calculated.

Results  Several molecular sizes of SIRT1, including 120kDa (actual size) and fragments (102, 75kDa) were quantified by Western blotting. Among them, only the 120kDa serum SIRT1 (s120S) was significantly decreased in the patients with COPD compared to the control subjects without COPD (s120S ratio in healthy: 0.90±0.34, vs COPD: 0.68±0.24; p=0.014), and was positively correlated with airway obstruction (FEV1/ FVC; r=0.31; p=0.020) and its severity measured by FEV1 % predicted (r=0.29; p=0.029). Serum s120S also showed a positive correlation with body mass index (BMI; r=0.36; p=0.0077) and diffusing capacity of the lung per unit volume (KCO%; r=0.32; p=0.025). It was also significantly decreased with increasing severity of lung emphysema (r=-0.40, p=0.027) and with a clinical history of frequent COPD exacerbations (infrequent: 0.76±0.20 vs frequent: 0.56±0.26; p=0.027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture condition.

Conclusions  Serum SIRT1 (s120S) was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarkers for certain disease characteristics of COPD.

original research 
Matthew W. Semler, MD, MSc; David R. Janz, MD, MSc; Derek W. Russell, MD; Jonathan D. Casey, MD; Robert J. Lentz, MD; Aline N. Zouk, MD; Bennett P. deBoisblanc, MD; Jairo I. Santanilla, MD; Yasin A. Khan, MD; Aaron M. Joffe, DO; William S. Stigler, MD; Todd W. Rice, MD, MSc
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Background  Hypoxemia is the most common complication during endotracheal intubation of critically ill adults. Intubation in the ramped position has been hypothesized to prevent hypoxemia by increasing functional residual capacity and decreasing the duration of intubation, but has never been studied outside of the operating room.

Methods  Multicenter, randomized trial comparing ramped position (head of the bed elevated to 25 degrees) to sniffing position (torso supine, neck flexed, head extended) among 260 adults undergoing endotracheal intubation by Pulmonary and Critical Care Medicine fellows in four intensive care units between July 22, 2015 and July 19, 2016. The primary outcome was lowest arterial oxygen saturation between induction and two minutes after intubation. Secondary outcomes included Cormack-Lehane grade of glottic view, difficulty of intubation, and number of laryngoscopy attempts.

Results  The median lowest arterial oxygen saturation was 93% [IQR 84-99%] with ramped position versus 92% [IQR 79-98%] with sniffing position (P = .27). Ramped position appeared to increase the incidence of grade III or IV view (25.4% vs 11.5%, P = .01), increase the incidence of difficult intubation (12.3% vs 4.6%, P = .04), and decrease the rate of intubation on the first attempt (76.2% vs 85.4%, P = .02).

Conclusions  In this multicenter trial, ramped position did not improve oxygenation during endotracheal intubation of critically ill adults compared to sniffing position. Ramped position may worsen glottic view and increase the number of laryngoscopy attempts required for successful intubation.

original research 
E. Henkle; T.R. Aksamit; A.F. Barker; J.R. Curtis; C.L. Daley; M.L. Daniels; A. DiMango; E. Eden; K. Fennelly; D.E. Griffith; M. Johnson; M.R. Knowles; A. Leitman; P. Leitman; E. Malanga; M.L. Metersky; P.G. Noone; A.E. O'Donnell; K.N. Olivier; D. Prieto; M. Salathe; B. Thomashow; G. Tino; G. Turino; S. Wisclenny; K.L. Winthrop
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Purpose  Non-cystic fibrosis bronchiectasis (“bronchiectasis”) is a chronic inflammatory lung disease often associated with nontuberculous mycobacterium (NTM) infection. Very little data exist to guide bronchiectasis management decisions. We sought to describe patterns of inhaled corticosteroid (ICS) and antibiotic therapy in the U.S.

Methods  We invited 2,000 patients through NTM Info & Research (NTMir) to complete an anonymous electronic survey. We separately queried baseline clinical and laboratory data from the U.S. Bronchiectasis and NTM Research Registry (BRR).

Results  Among 511 NTMir survey responders with bronchiectasis, median age was 67, 85 (17%) reported asthma, and 99 (19%) reported chronic obstructive pulmonary disease (COPD). History of ICS use was reported by 282 (55%), of whom 171 (61%) were treated >1 year and 150 (53%) were currently taking ICS. Fewer reported ever taking azithromycin for non-NTM bronchiectasis (203, 40%) or inhaled tobramycin (78, 15%). Median age of 1912 BRR patients was 69, 528 (28%) had asthma, and 360 (19%) had COPD. Among 740 lacking NTM, 314 (42%) were taking ICS at baseline. Among non-NTM patients taking ICS, only 178 (57%) had a concurrent diagnosis of COPD or asthma that could explain ICS use. Fewer were taking suppressive macrolides (96, 13%) and of the 70 (10%) taking inhaled suppressive antibiotics, 48 (68%) had chronic Pseudomonas aeruginosa infection.

Conclusions  In two national samples of bronchiectasis patients ICS use is common, with relatively few patients taking suppressive antibiotic therapies. Further research is needed to clarify the safety and effectiveness of these therapies in bronchiectasis patients.

original research 
Vincent Yi-Fong Su, MD; Wei-Juin Su, MSc; Yung-Feng Yen, MD, MPH, PhD; Sheng-Wei Pan, MD; Pei-Hung Chuang, PhD; Jia-Yih Feng, MD; Kun-Ta Chou, MD; Kuang-Yao Yang, MD, PhD; Yu-Chin Lee, MD; Tzeng-Ji Chen, MD, PhD
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Background  Statins are widely used to lower cholesterol levels and cardiovascular risk. Further, studies have shown that statins may decrease the risks of infectious diseases and infection-related mortality. However, the association between statin use and active tuberculosis (TB) disease remains unclear.

Methods  Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients taking statins during 2000–2013, without antecedent TB disease, were included. Data from 102,424 statin users and 202,718 age-, sex-, and enrollment date-matched subjects were analyzed. The two cohorts were monitored until December 31, 2013 for incident TB disease. The definition of TB disease was validated using the claims database of Taipei Veterans General Hospital.

Results  The statin and matched cohorts were observed for 571,568 and 1,027,385 person-years, respectively. Of the total 305,142 subjects, 1,264 (0.41%) developed subsequent TB disease. Validation study confirmed the accuracy of the definition of TB disease (sensitivity, 96.3%), with excellent interobserver agreement (κ=1.00). Multivariate analysis revealed a reduced risk of TB disease among the statin cohort (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.47-0.61; p<0.001). Compared with the matched group, statin use showed a dose-response relationship with the incident TB disease risk (<180 cumulative defined daily doses [cDDDs]: HR 1.06, 95% CI 0.91-1.24, p=0.477; 180-365 cDDDs: HR 0.57, 95% CI 0.45-0.72, p<0.001; >365 cDDDs: HR 0.27, 95% CI 0.22-0.33, p<0.001).

Conclusions  Statin use associates with a lower risk of incident TB disease.

translating basic research into clinical practice 
Marius Alexander Möbius, MD; Bernard Thébaud, MD, PhD
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Celebrating its 50th anniversary in 2017, bronchopulmonary dysplasia (BPD) - the chronic lung disease of prematurity that follows ventilator and O2 therapy for acute respiratory failure - remains the most frequent complication of extreme prematurity. Survival of premature infants born at increasingly earlier stages of gestation has made the prevention of lung injury increasingly challenging. BPD is postulated to be a misdirection of many functions in the developing lung including growth factor signalling and matrix as well as cellular composition, resulting in impaired alveolar and lung vascular growth. Despite improvements in understanding the mechanisms that regulate normal lung development, BPD remains without therapies. Recent insights into stem cell biology have identified the repair potential of stem cells. Promising preclinical studies demonstrated the lung protective effects of stem cell-based therapies in animal models mimicking BPD, leading to early phase clinical trials. While the time is ripe to conduct well-designed early phase clinical trials, much more needs to be learned about the biology of these cells in order to develop safe, efficient, high quality, clinical-grade cell products. Stem cells are essential for normal organ development, maintenance and repair. It is therefore biologically plausible that exhaustion/dysfunction of resident lung stem cells contributes to the inability of the immature lung to repair itself. Understanding how normal lung stem cells function and how these cells are perturbed in BPD may prove useful in designing superior cell products with enhanced repair capabilities to ensure the successful translation of basic research into clinical practice.

original research 
Alexander D. Zider, MD; Xiaoyan Wang, PhD; Russell G. Buhr, MD; Worawan Sirichana, MD; Igor Z. Barjaktarevic, MD; Christopher B. Cooper, MD

Background  The mechanism by which various classes of medication reduce COPD exacerbation risk remains unknown. We hypothesized a correlation between reduced exacerbation risk and improvement in airway patency as measured by the forced expiratory volume in 1 second (FEV1).

Methods  By systematic review, we identified COPD trials that reported therapeutic changes in pre-dose FEV1 (dFEV1) and occurrence of moderate to severe exacerbations. Using meta-regression analysis, we generated a model with dFEV1 as moderator variable, and absolute difference in exacerbation rate (RD), ratio of exacerbation rates (RR), or hazard ratio (HR) as dependent variables.

Results  The analysis of RD and RR included 119,227 patients, and that of HR 73,475 patients. For every 100 mL change in pre-dose FEV1, the HR decreased by 21% (95% CI: 17-26%, P<0.001, R2 = 0.85) and the absolute exacerbation rate decreased by 0.06 per patient per year (95% CI: 0.02-0.11, P=0.009, R2 = 0.05), which corresponded to a RR of 0.86 (95% CI: 0.81-0.91, P<0.001, R2 = 0.20). The relationship with exacerbation risk remained statistically significant across multiple subgroup analyses.

Conclusions  A significant correlation between increased FEV1 and lower COPD exacerbation risk suggests airway patency is an important mechanism responsible for this effect.

original research 
Stacey L. Martiniano, MD, MCSC; Brandie D. Wagner, PhD; Adrah Levin, MPH; Jerry A. Nick, MD; Scott D. Sagel, MD, PhD; Charles L. Daley, MD.
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Background  Clofazimine is an antimicrobial agent that has activity in vitro against mycobacteria. Increasingly, it has been used for the treatment of nontuberculous mycobacteria (NTM), despite limited data supporting use in this setting. The objective of this study was to evaluate safety, tolerability, and clinical outcomes associated with clofazimine in patients with NTM infection.

Methods  Observational-cohort study of clofazimine used for pediatric and adult cystic fibrosis (CF) and non-CF patients with pulmonary and extrapulmonary NTM infection as part of a multidrug regimen from 2006-2014. Treatment regimens and adverse drug reactions (ADRs) were captured.

Results  One hundred twelve subjects were included (median age 62 years); 24 subjects (21%) had CF. Eighty-seven (78%) had refractory disease with failure of prior therapy. Fifty-four subjects (48%) had M. abscessus complex, 41 (37%) had M. avium complex, and 16 (14%) had two NTM species. The median duration of clofazimine use was 383 days (range 3 – 2,419 days). Sixteen subjects (14%) stopped clofazimine due to an ADR after a median of 101 days (95% CI, 63-119 days). Forty-one of 82 subjects (50%) with pulmonary disease converted to negative NTM cultures within 12 months.

Conclusions  Clofazimine is a safe, reasonably tolerated, and active oral drug for NTM infection in our heterogeneous population of pediatric and adult CF and non-CF patients. It should be considered as an alternative drug for treatment of NTM disease.

original research 
Suzana M. Lobo, MD; Flávio Henrique Barros de Simoni, MD; Stephan M. Jakob, MD PhD; Angel Estella, MD; Sonali Vadi, MD; Andreas Bluethgen, MD; Ignacio Martin-Loeches, MD; Yasser Sakr, MD PhD; Jean-Louis Vincent, MD PhD FCCP
Topics: , ,

Background  Many critically ill patients who die will do so after a decision has been made to withhold/withdraw life-sustaining therapy. Our objective was to document the characteristics of intensive care unit (ICU) patients with a decision to withhold/withdraw life-sustaining treatment, including the types of supportive treatments used, patterns of organ dysfunction, and international differences, including gross national income (GNI).

Methods  In this observational cohort study conducted in 730 ICUs in 84 countries, all adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance, were included.

Results  The analysis included 9,524 patients, with a hospital mortality of 24%. A decision to withhold/withdraw life-sustaining treatment was reported during the ICU stay in 1,259 patients (13%), including 820 (40%) non-survivors and 439 (5%) survivors. Hospital mortality in patients with a decision to withhold/withdraw life-sustaining treatment was 69%. The proportion of deaths in patients with a decision to withhold/withdraw life-sustaining treatment ranged from 10% in South Asia to 67% in Oceania. Decisions to withhold/withdraw life-sustaining treatment were less frequent in low/lower-middle GNI countries than in high GNI countries (6% vs 14%, p<0.001). Greater disease severity, presence of >two organ failures, severe comorbidities, medical and trauma admissions and admission from the emergency room or hospital floor were independent predictors of a decision to withhold/withdraw life-sustaining treatment.

Conclusions  There is considerable worldwide variability in decisions to withhold/withdraw life-sustaining treatments. Interestingly, almost one-third of patients with a decision to withhold/withdraw life-sustaining treatment left the hospital alive.

original research 
Monica Khunger, MD; Sagar Rakshit, MD; Vinay Pasupuleti, MD, PhD; Adrian V. Hernandez, MD, MSc, PhD; Peter Mazzone, MD, MPH, FCCP; James Stevenson, MD; Nathan A. Pennell, MD PhD; Vamsidhar Velcheti, MD, FACP
Topics: , ,

Background  PD-1/PD-L1 inhibitors show significant clinical activity in non-small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD-1 and PD-L1 inhibitors. We sought to determine the overall incidence of pneumonitis, and differences according to type of inhibitors and prior chemotherapy use.

Methods  Medline, Embase and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade 3 or higher from all clinical trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors, as well as between treatment naive and previously treated patients.

Results  19 trials (12 with PD-1 inhibitors [n=3232] and 7 with PD-L1 inhibitors [n=1806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis as compared to PD-L1 inhibitors (3.6%, 95%CI 2.4%-4.9% vs 1.3%, 95%CI 0.8%-1.9%, respectively; p=0.001). PD-1 inhibitors were also associated with higher incidence of grade 3-4 pneumonitis (1.1%, 95%CI 0.6%-1.7% vs 0.4%, 95%CI 0%-0.8%, p=0.02). Treatment naïve patients had higher incidence of grade 1-4 pneumonitis as compared to previously treated patients (4.3%, 95%CI 2.4%-6.3% vs 2.8%, 95%CI 1.7%- 4%, p=0.03).

Conclusion  There was a higher incidence of pneumonitis with use of PD-1 inhibitors as compared to PD-L1 inhibitors. Higher rate of pneumonitis was more common in treatment naïve patients.

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