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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 
So Hyeon Bak, MD; Ho Yun Lee, MD; Jae-Hun Kim, PhD; Sang-Won Um, MD; O. Jung Kwon, MD; Joungho Han, MD; Hong Kwan Kim, MD; Jhingook Kim, MD; Kyung Soo Lee, MD

Background:  We sought to determine if quantitative analysis of lung adenocarcinoma manifesting as a ground-glass opacity (GGO) nodule (GGN) on initial computed tomography (CT) can predict further CT change or rate of growth.

Methods:  This retrospective study included patients with lung adenocarcinoma manifesting as pure GGN on initial CT, who were followed up with interval CT until resection. All pure GGNs were classified based on CT interval change in three subgroups as follows: group A (development of solid component), group B (growth of GGO component), and group C (no change in size). Nodule size, volume, density, mass, and CT attenuation values were assessed from initial CT datasets.

Results:  Fifty-four pure GGNs were enrolled and classified into group A (n=9), group B (n=25), and group C (n=20). Nodule size, volume, mass, and density of the GGNs in each subgroup were not significantly different. The 97.5th percentile CT attenuation value and slope of CT attenuation values from 2.5th to 97.5th percentile were significantly different among the three subgroups (P = 0.02, P < 0.00). Three of nine (33%) pure GGNs showing a new solid component developed solid component within 6 months.

Conclusions:  The 97.5th percentile CT attenuation value and slope of CT attenuation values from 2.5th to 97.5th percentile could be helpful in predicting future CT change and rate of growth of pure GGNs. Pure GGNs showing higher 97.5th percentile CT attenuation values and steeper slopes of CT attenuation values may need more frequent follow-up than the usual interval of 6 months.

original research 
Joshua J. Shaw; Heena P. Santry
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Introduction:  While the benefits of early tracheostomy in ventilator dependent patients are well established, the reasons for variation in time from intubation to tracheostomy remain unclear. We identified clinical and demographic disparities in time-to-tracheostomy.

Methods:  We performed a level III retrospective prognostic study by querying the University HealthSystem Consortium (2007-2010) for adult patients receiving a tracheostomy after initial intubation. Time-to-tracheostomy was designated 'EARLY' <7 days or 'LATE' >10 days. Cohorts were stratified by time-to-tracheostomy and compared using univariate tests of association and multivariable adjusted models.

Results:  49,191 patients underwent tracheostomy after initial intubation: 42% EARLY (N= 21,029) and 58% LATE (N=28,162). On both univariate and multivariable analyses, females, blacks, Hispanics and Medicaid patients were less likely to receive an early tracheostomy. EARLY patients also experienced lower rates of mortality (OR 0.84; 95%CI 0.79–0.88).

Conclusions:  Early tracheostomy was associated with increased survival. Yet there were still significant disparities in time to tracheostomy according to sex, race and type of insurance. Application of evidence based algorithms for tracheostomy may reduce unequal treatment and improve overall mortality rates. Additional research into this apparent bias in referral/rendering of tracheostomy is needed.

original research 
Gillian L. Schauer, MPH; Anne G. Wheaton, PhD; Ann M. Malarcher, PhD; Janet B. Croft, PhD
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Background:  Cigarette smoking is the predominant cause of chronic obstructive pulmonary disease [COPD]. Quitting can prevent development of and complications from COPD. The gold standard in clinician delivery of smoking cessation treatments is the 5As (ask, advise, assess, assist, arrange). This study assessed prevalence and correlates of self-reported receipt of the 5A strategies among adult smokers with and without COPD.

Methods:  Data were analyzed from 20,021 adult past-year cigarette smokers in the 2009-2010 National Adult Tobacco Survey, a nationally-representative telephone survey of U.S. adults 18 years and older. Past year receipt of the 5As was self-reported by participants who saw a clinician in the past year. Logistic regression was used to estimate the likelihood of receipt of each of the 5As by COPD status, adjusted for sociodemographic and smoking characteristics.

Results:  Among smokers, those with COPD were more likely than those without COPD to report being asked about tobacco use (95.4% vs. 85.8%), advised to quit (87.5% vs. 59.4% ), assessed for readiness to quit (63.8% vs. 37.9%), offered any assistance to quit (58.6% vs. 34.0 %), and offered follow-up (14.9% vs. 5.2%). In adjusted logistic regression models, those with COPD were significantly more likely than those without COPD to receive each of the 5As.

Conclusion:  Health professionals should continue to prioritize tobacco cessation counseling and treatment to smokers with COPD. Increased system-level changes and insurance coverage for cessation treatments could be used to improve the delivery of brief tobacco cessation counseling to all smokers, regardless of COPD status.

original research 
Fabiola Schorr, MD; Fabiane Kayamori, PT; Raquel P. Hirata, PT; Naury J. Danzi-Soares, RN; Eloisa Gebrim, MD; Henrique T. Moriya, PhD; Atul Malhotra, MD; Geraldo Lorenzi-Filho, MD; Pedro R. Genta, MD
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Background:  Obstructive sleep apnea (OSA) pathogenesis is complex and may vary according to ethnicity. The anatomical component predisposing to OSA is the result of the interaction between bony structure and upper airway soft tissues and can be assessed using passive critical closing pressure (Pcrit). We hypothesized that Japanese-Brazilians and Caucasians present different predictors to upper airway collapsibility, suggesting different causal pathways to develop OSA in these two groups.

Methods:  Male Japanese-Brazilians (n=39) and Caucasians (n=39) matched for age and OSA severity were evaluated by full polysomnography, Pcrit and upper airway plus abdomen CT scans for determination of upper airway anatomy and abdominal fat, respectively.

Results:  Pcrit was similar between Japanese-Brazilians and Caucasians (-1.0 ± 3.3 vs -0.4 ± 3.1 cmH20, p=0.325). Japanese-Brazilians presented smaller upper airway bony dimensions (cranial base, maxillary and mandibular length) while Caucasians presented larger upper airway soft tissue (tongue length and volume) and greater imbalance between tongue and mandible (tongue/mandibular volume ratio). Cranial base angle was associated with Pcrit only among Japanese-Brazilians (r=-0.535, p<0.01). Tongue/mandibular volume ratio was associated with Pcrit only among Caucasians (r=0.460, p<0.01). Obesity-related variables (visceral fat, BMI, neck and waist circumferences) showed similar correlation with Pcrit in Japanese-Brazilians and Caucasians.

Conclusions:  Japanese-Brazilians and Caucasians present different predictors of upper airway collapsibility. While craniofacial bony restriction was determinant to Pcrit only in the Japanese-Brazilians, anatomical imbalance between tongue and mandible volume was important to Pcrit among Caucasians. These findings may have therapeutic implications regarding how to improve anatomical predisposition to OSA across ethnicities.

original research 
Christopher J. Lettieri, MD; Scott G. Williams, MD; Jacob F. Collen, MD
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Purpose:  We sought to determine the impact of OSAS on symptoms and quality of life (QoL) among patients with PTSD. In addition, we assessed adherence and response to positive airway pressure (PAP) therapy in this population.

Methods:  Case-controlled observational cohort at the Sleep Disorders Center of an academic military medical center. 200 consecutive patients with PTSD underwent sleep evaluations. PTSD patients with and without OSAS were compared to 50 consecutive age-matched OSAS patients without PTSD and 50 age-matched normal controls. Polysomnographic data, sleep-related symptoms and QoL measures, and objective PAP usage were obtained.

Results:  Among patients with PTSD over half (56.6%) were diagnosed with OSAS. Patients with PTSD+OSAS had lower QoL and more somnolence compared with the other groups. Patients with PTSD demonstrated significantly lower adherence and response to PAP therapy. Resolution of sleepiness occurred in 82% of patients with OSAS alone, compared with 62.5% of PAP adherent and 21.4% of non-adherent PTSD+OSAS patients (p<0.001). Similarly, post-treatment FOSQ≥17.9 was achieved in 72% of OSAS patients, compared to only 56.3% of PTSD+OSA patients who were PAP adherent and 26.2% who were non-adherent (p<0.03).

Conclusion:  In patients with PTSD, comorbid OSAS is associated with worsened symptoms, QoL, and adherence and response to PAP. Given the negative impact on outcomes, OSAS should be carefully considered in patients with PTSD. Close follow-up is needed to optimize PAP adherence and efficacy in this at-risk population.

original research 
Peter V. Dicpinigaitis, MD, FCCP; Alfredo Lee Chang, MD; Alis J. Dicpinigaitis; Abdissa Negassa, PhD
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Background:  Electronic cigarettes have attained widespread popularity, yet knowledge of their physiological effects remains minimal. The aim of this study was to evaluate the effect of a single exposure to electronic cigarette vapor on cough reflex sensitivity.

Methods:  30 healthy nonsmokers underwent cough reflex sensitivity measurement employing capsaicin cough challenge at baseline, 15 minutes, and 24 hours after electronic cigarette exposure (30 puffs 30 seconds apart). The endpoint of cough challenge is C5, the concentration of capsaicin inducing ≥5 coughs. The number of coughs induced by each electronic cigarette inhalation was counted. A subgroup of subjects (n=8) subsequently underwent an identical protocol with a non-nicotine-containing electronic cigarette.

Results:  Cough reflex sensitivity was significantly inhibited (C5 increased) 15 minutes after electronic cigarette use (-0.29, 95% CI (-0.43)-(-0.15), ( p<0.0001); 24 hours later C5 returned to baseline (0.24, 95% CI 0.10-0.38, p=0.0002 vs. post-15-minute value). A subgroup of 8 subjects demonstrating the largest degree of cough reflex inhibition had no suppression after exposure to a non-nicotine-containing electronic cigarette (p=0.0078 for comparison of ΔC5 after nicotine vs. non-nicotine device). Furthermore, more coughing was induced by the nicotine-containing vs.non-nicotine-containing device (p=0.0156).

Conclusions:  A single session of electronic cigarette use, approximating nicotine exposure of one tobacco cigarette, induces significant inhibition of cough reflex sensitivity. Exploratory analysis of a subgroup of subjects suggests that nicotine is responsible for this observation. Our data, consistent with previous studies of nicotine effect, suggest a dual action of nicotine: an immediate, peripheral protussive effect and a delayed central antitussive effect.

ClinicalTrials.gov identifier:  NCT02203162

original research 
Borja G. Cosio, MD; Joan B. Soriano, MD; Jose Luis López-Campos, MD; Myriam Calle-Rubio, MD; Juan José Soler-Cataluna, MD; Juan P. de-Torres, MD; Jose M. Marín, MD; Cristina Martínez-Gonzalez, MD; Pilar de Lucas, MD; Isabel Mir, MD; Germán Peces-Barba, MD; Nuria Feu-Collado, MD; Ingrid Solanes, MD; Inmaculada Alfageme, MD; Ciro Casanova, MD on behalf of the CHAIN study
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Background:  Asthma-COPD overlap syndrome (ACOS) has been recently described by international guidelines. A stepwise approach to diagnosis using usual features of both diseases is recommended although its clinical application is difficult.

Methods:  In order to identify patients with ACOS, a cohort of well-characterized patients with COPD and up to one-year follow-up was analyzed. We evaluated the presence of specific characteristics associated to asthma in this COPD cohort, divided in major criteria (bronchodilator test greater than 400 ml and 15% and past medical history of asthma) and minor criteria (blood eosinophils greater than 5%, IgE>100 UI/ml, or two separate bronchodilator tests greater than 200 ml and 12%). We defined ACOS by the presence of one major criterion or two minor criteria. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between patients with and without criteria for ACOS.

Results:  Out of 831 COPD patients included,125 (15%) fulfilled the criteria for ACOS, and 98.4% of them sustained these criteria after one year. Patients with ACOS were predominantly male (81.6%), with symptomatic mild to moderate disease (67%), and receiving inhaled corticosteroids (63.2%). There were no significant differences in baseline characteristics, and only survival was worse in non-ACOS COPD patients after one-year of follow-up (p <0.05).

Conclusions:  The proposed ACOS criteria are present in 15% of a cohort of COPD patients and these patients show better one-year prognosis than clinically similar COPD patients with no ACOS criteria.

ClinicalTrials.gov Identifier:  NCT01122758

original research 
Catherine Chen, MD; Marin H. Kollef, MD
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Background:  Intravenous fluid (IVF) represents a basic therapeutic intervention for septic shock. Unfortunately optimal administration of IVF to maximize patient outcomes and prevent complications is largely unknown.

Methods:  Patients with septic shock admitted to the medical ICUs of Barnes-Jewish Hospital (January - December 2014) requiring vasoactive agents for at least 12 hours following initial fluid resuscitation were randomized to usual care or to targeted fluid minimization (TFM) guided by daily assessments of fluid responsiveness.

Results:  82 patients were enrolled, 41 to usual care and 41 to TFM. For patients randomized to TFM the net median [interquartile range] fluid balance was less at the end of day 3 (1952 mL [48 mL - 5003 mL] versus 3124 mL [767 mL - 10103 mL]; P = 0.20) and at the end of day 5 (2641 mL [-1837 mL - 5075 mL] versus 3616 mL [ -1513 mL - 9746 mL]; P = 0.40). TFM appeared to be safe as indicated by similar clinical outcomes including in-hospital mortality (56.1% versus 48.8%; P = 0.51), ventilator days (8.0 days [3.25 days - 15.25 days] versus 5.0 days [3.0 days - 9.0 days]; P = 0.30), renal replacement therapy (41.5% versus 39.0%; P = 0.82), and vasopressor days (4.0 days [2.0 days - 8.0 days] versus 4.0 days [2.0 days - 6.0 days]; P = 0.84).

Conclusions:  This pilot study suggests that TFM in patients with septic shock can be performed using protocol-guided assessments of fluid responsiveness. Larger trials of TFM in septic shock are needed.

ClinicalTrials.gov Identifier:  NCT02473718

contemporary reviews in sleep medicine 
Amanda Piper, PhD

Obesity hypoventilation syndrome (OHS) is becoming an increasingly encountered condition both in respiratory outpatient clinics and in hospitalized patients. The health consequences and social disadvantages of OHS are significant. Unfortunately, the diagnosis and institution of appropriate therapy is commonly delayed when the syndrome is not recognised or misdiagnosed. Positive airway pressure (PAP) therapy remains the mainstay of treatment and is effective in controlling sleep-disordered breathing and improving awake blood gases in the majority of individuals. Evidence supporting one mode of therapy over another is limited. Both continuous and bilevel therapy modes can successfully improve daytime gas exchange, with adherence to therapy an important modifiable factor in the response to treatment. Despite adherence to therapy, these individuals continue to experience excess mortality primarily due to cardiovascular events compared to those with eucapnic sleep apnea using CPAP. This difference likely arises from ongoing systemic inflammation secondary to the morbidly obese state. The need for a comprehensive approach to managing nutrition, weight and physical activity in addition to reversal of sleep-disordered breathing is now widely recognised. Future studies need to evaluate the impact of a more aggressive and comprehensive treatment plan beyond managing sleep-disordered breathing. The impact of early identification and treatment of sleep-disordered breathing on the development and reversal of cardiometabolic dysfunction also requires further attention.

original research 
Wei Chen, M.D.; David R. Janz, M.D., M.S.C.I.; Ciara M. Shaver, M.D., Ph.D.; Gordon R. Bernard, M.D.; Julie A. Bastarache, M.D.; Lorraine B. Ware, M.D.
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BACKGROUND:  SpO2/FiO2 ratio (SF) is highly correlated with the PaO2/FiO2 ratio (PF) in patients with acute respiratory distress syndrome (ARDS). However, it remains uncertain whether SF can be substituted for PF for diagnosis of ARDS and whether SF might identify patients who are systemically different from patients diagnosed by PF.

METHODS:  We conducted a secondary analysis of a large observational prospective cohort study. Patients were eligible if they were admitted to the medical ICU and fulfilled the Berlin definition of ARDS which hypoxemia criteria using either the standard PF threshold (PF ratio ≤ 300) or a previously published SF threshold (SF ratio ≤ 315).

RESULTS:  Of 362 ARDS patients, 238 (66%) were diagnosed by PF and 124 (34%) by SF. In a small group of patients diagnosed with ARDS by SF ratio who had an ABG done on the same day (n=10), the PF ratio did not meet ARDS criteria. There were no major differences in clinical characteristics or comorbidities between groups with the exception of APACHE II scores, which were higher in the group diagnosed by PF. However, this difference was no longer apparent when arterial blood gas-dependent variables (pH, PaO2) were removed from the APACHE II score. There were also no differences in clinical outcomes including duration of mechanical ventilation (mean 7 days in both groups, p = 0.25), duration of ICU stay (mean 10 vs. 9 days in PF vs. SF, p = 0.26) or hospital mortality (36% in both groups, p = 0.9).

CONCLUSIONS:  ARDS patients diagnosed by SF have very similar clinical characteristics and outcomes compared with patients diagnosed by PF. These findings suggest that SF could be considered as a diagnostic tool for early enrollment into clinical trials.

original research 
Douglas J. Hsu, MD; Mengling Feng, PhD; Rishi Kothari, MD; Hufeng Zhou, PhD; Kenneth P. Chen, MD; Leo A. Celi, MD, MS, MPH
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Background:  Indwelling arterial catheters (IAC) are used extensively in the Intensive Care Unit (ICU) for hemodynamic monitoring and for blood gas analysis. IAC use also poses potentially serious risks, including blood stream infections and vascular complications. The purpose of this study was to assess whether IAC use was associated with mortality in mechanically ventilated patients who do not require vasopressor support.

Methods:  This study utilized the Multiparameter Intelligent Monitoring in Intensive Care II database, consisting of over 24,000 patients admitted to the Beth Israel Deaconess Medical Center ICU between 2001 – 2008. Patients requiring mechanical ventilation who did not require vasopressors or have a diagnosis of sepsis were identified, and the primary outcome was 28-day mortality. A model based on patient demographics, co-morbidities, vital signs, and laboratory results was developed to estimate the propensity for IAC placement. Patients were then propensity-matched, and McNemar’s test was used to evaluate the association of IAC with 28-day mortality.

Results:  We identified 1,776 mechanically ventilated patients that met inclusion criteria. There were no differences in the covariates included in the final propensity model between the IAC and non-IAC propensity-matched groups. For the matched cohort, there was no difference in 28-day mortality between the IAC group and the non-IAC group (14.7% vs 15.2%, OR 0.96, 95% CI [0.62, 1.47]).

Conclusions:  In hemodynamically stable mechanically ventilated patients, the presence of an IAC is not associated with a difference in 28-day mortality. Validation in other datasets, as well as further analyses in other subgroups is warranted.

original research 
Gillian S. Tomlinson, PhD; Niclas Thomas, PhD; Benjamin M. Chain, PhD; Katharine Best, MRes; Nandi Simpson, PhD; Georgia Hardavella, PhD; James Brown, MD; Angshu Bhowmik, MD; Neal Navani, PhD; Samuel M. Janes, PhD; Robert F. Miller, MBBS; Mahdad Noursadeghi, PhD
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Background  Endobronchial ultrasound (EBUS) guided biopsy is the mainstay for investigation of mediastinal lymphadenopathy for laboratory diagnosis of malignancy, sarcoidosis or tuberculosis. However, improved methods for discriminating between tuberculosis and sarcoidosis and excluding malignancy are still needed. We sought to evaluate the role of genome-wide transcriptional profiling to aid diagnostic processes in this setting.

Methods  Mediastinal lymph node samples from 88 individuals were obtained by EBUS guided aspiration for investigation of mediastinal lymphadenopathy and subjected to transcriptional profiling in addition to conventional laboratory assessments. Computational strategies were employed to evaluate the potential for using the transcriptome to distinguish between diagnostic categories.

Results  Molecular signatures associated with granulomas or neoplastic and metastatic processes were clearly discernible in granulomatous and malignant lymph node samples respectively. Support vector machine (SVM) learning using differentially expressed genes showed excellent sensitivity and specificity profiles in receiver operating characteristic curve analysis with area under curve values >0.9 for discriminating between granulomatous and non-granulomatous disease, tuberculosis and sarcoidosis, and between cancer and reactive lymphadenopathy. A two-step decision tree using SVM to distinguish granulomatous and non-granulomatous disease, then between tuberculosis and sarcoidosis in granulomatous cases and between cancer and reactive lymphadenopathy in non-granulomatous cases achieved >90% specificity for each diagnosis and afforded greater sensitivity than existing tests to detect tuberculosis and cancer. In some diagnostically ambiguous cases computational classification predicted granulomatous disease or cancer before pathological abnormalities were evident.

Conclusions  Machine learning analysis of transcriptional profiling in mediastinal lymphadenopathy may significantly improve the clinical utility of EBUS guided biopsies.

original research 
Abdelnaby Khalyfa, PhD; Leila Kheirandish-Gozal, MD, MSc; Rakesh Bhattacharjee, MD; Ahamed A. Khalyfa, BSc; David Gozal, MD, FCCP
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Background:  Cardiovascular disease (CVD) is a complex disease with multifactorial etiology. The presence of endothelial dysfunction (ED) constitutes an early risk factor for CVD in children. Circulating microRNAs (miRNAs) are short are small non-coding RNAs that regulate gene expression and represent a novel class of biomarkers and therapeutic targets; therefore, we examined whether the presence of ED is associated with differential expression of plasma miRNAs in otherwise healthy children.

Methods:  A total of 70 children (ages 5-10 years) were recruited and classified into two groups (NEF and ED). Time to peak post-occlusive reperfusion (Tmax) was considered as the indicator of either normal endothelial function (NEF; Tmax<45 sec) or ED (Tmax≥45 sec). Lipid profiles, high sensitivity C-reactive protein (hsCRP), fasting glucose and insulin were assayed using ELISA. miRNAs isolated from plasma were assayed with a custom human cardiovascular disease array, followed by quantitative PCR verification of candidates. In addition, bioinformatics approaches including combinatorial target prediction algorithms and Gene Ontology (GO) were applied.

Results:  Three miRNAs that have been previously linked to cardiomyopathy, hsa-miR-125a-5p, hsa-miR-342-3p, and hsa-miR-365b-3p, were identified as potential biomarkers of children with ED. The miRNA predicted gene targets revealed 31 common targets among all 3 putative candidate biomarker miRNAs, and encompass 3 biological pathways including TGF-β signaling, cytokine-cytokine receptor interactions, and activin receptor-like kinase (ALK) in cardiac myocytes.

Conclusion:  Plasma miRNAs may be useful as potential screening tools for the presence of ED in children, and may reveal ED-relevant target genes.

original research 
Allan J. Walkey, MD, MSc; Stephen R. Evans; Michael R. Winter, MPH; Emelia J. Benjamin, MD, ScM
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Background:  Atrial fibrillation (AF) during sepsis is associated with increased morbidity and mortality, but practice patterns and outcomes associated with rate- and rhythm-targeted treatments for AF during sepsis are unclear.

Methods:  Retrospective cohort study using enhanced billing data from approximately 20% of United States hospitals. We identified factors associated with intravenous AF treatments (beta-blockers, calcium channel-blockers, digoxin, or amiodarone) during sepsis. We used propensity score matching and instrumental variable approaches to compare mortality between AF treatments.

Results:  Among 39,693 patients with AF during sepsis, mean age was 77±11 years, 49% were women, and 76% were white. Calcium channel-blockers were the most commonly selected initial AF treatment during sepsis [14,202 (36%) patients], followed by beta-blockers [11,290 (28%)], digoxin [7,937 (20%)], and amiodarone [6,264 (16%)]. Initial AF treatment selection differed according to geographic location, hospital teaching status, and physician specialty. In propensity-matched analyses, beta-blockers were associated with lower hospital mortality when compared with calcium channel-blockers [N=18,720, RR 0.92 (95% CI, 0.86-0.97)], digoxin [N=13,994, 0.79 (0.75-0.85)], and amiodarone [N=5,378, 0.64 (0.61-0.69)]. Instrumental variable analysis showed similar results [adjusted RR 5th quintile vs. 1st quintile of hospital beta-blocker utilization rate: 0.67 (95% 0.58-0.79)]. Results were similar among subgroups with new-onset or pre-existing AF, heart failure, vasopressor-dependent shock or hypertension.

Conclusions:  Although calcium channel-blockers were the most frequently used intravenous medications for AF during sepsis, beta-blockers were associated with superior clinical outcomes in all subgroups analyzed. Our findings provide rationale for clinical trials comparing the effectiveness of AF rate- and rhythm-targeted treatments during sepsis.

contemporary reviews in sleep medicine 
Hui-Leng Tan, MBBS; Leila Kheirandish-Gozal, MD, MSc; David Gozal, MD, FCCP
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Purpose of review:  Pediatric obstructive sleep apnea (OSA) can result in significant neurocognitive, behavioral, cardiovascular and metabolic morbidities. Prompt diagnosis and treatment is therefore of paramount importance. The current gold standard for diagnosis of OSA in children is in-lab polysomnography (PSG). Home sleep apnea testing has been considered as an alternative as it is potentially more cost-effective, convenient and accessible. This review concentrates mainly on the use of type 2 and 3 portable monitoring devices. The current evidence on the feasibility and diagnostic accuracy of home testing in the diagnosis of pediatric OSA was examined.

Recent findings:  Overall, the evidence in children is limited. Feasibility studies that have been performed, have on the whole shown good results, with several reporting >90% of their home recordings as meeting pre-determined quality criteria with regards to signal artifact and minimum recording time. The limited data comparing Type 2 studies with in-lab PSG has shown no significant differences in respiratory parameters. The results pertaining to diagnostic accuracy of type 3 home sleep apnea testing devices are conflicting.

Conclusions:  While more research is needed, home testing with at least a type 3 portable monitor offers a viable alternative in the diagnosis of otherwise healthy children with moderate to severe OSA, particularly in settings where access to polysomnography is scarce or unavailable. Of note, since most studies have been performed in habitually snoring healthy children, home sleep apnea testing may not be applicable to children with other co-morbid conditions. In particular, CO2 monitoring is important in children in whom there is concern regarding nocturnal hypoventilation, such as children with neuromuscular disease, underlying lung disease or obesity hypoventilation and most home testing devices do not include a transcutaneous or end-tidal CO2 channel.

translating basic research into clinical practice 
Kyla C. Jamieson, BSc; Stephanie M. Warner, Ph.D.; Richard Leigh, MD, PhD; David Proud, Ph.D.
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In healthy individuals, human rhinovirus (HRV) infections are the major cause of the common cold. These are generally uncomplicated infections except for occasional cases of otitis media or sinusitis. In individuals with asthma, however, HRV infections can have a major impact on disease development and progression. HRV-induced wheezing illnesses in early life are a significant risk factor for subsequent development of asthma, and growing evidence supports a role of recurrent HRV infections in the development and progression of several aspects of airway remodelling in asthma. In addition, HRV infections are one of the most common triggers for acute exacerbations of asthma, which represent a major burden to health care systems around the world. None of our currently prescribed medications for asthma are effective in preventing or reversing asthma development and airway remodelling, nor are they ideal for treating HRV-induced exacerbations of asthma. Thus, it is important to better understand the role of HRV in asthma if we are to develop more effective therapies. In the past decade, we have gained new insights into the role of HRV infections in the development and progression of airway remodelling. We have also gained a new appreciation for the proinflammatory and host defense responses to HRV infections that may help to regulate the susceptibility to asthma exacerbations. In this article we review our current understanding of the role of HRV infections in the pathogenesis of asthma and identify possible avenues to new therapeutic strategies for limiting the effects of HRV infections in asthma.

editorials  FREE TO VIEW
Reena Mehra, MD, MS; Daniel J. Gottlieb, MD, MPH
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Periodic breathing with central sleep apnea (CSA), known as Hunter-Cheyne-Stokes Respiration (CSR), is among the first recognized sleep-related breathing disorders, described in the early 19th century and now recognized to be quite common in patients with chronic heart failure (HF). It remains uncertain whether CSA is simply a marker of underlying cardiac dysfunction or, alternatively, whether CSA exerts a detrimental effect on the failing heart (e.g. via hypoxia, arousal, and their associated sympathoexcitation) or is a beneficial compensatory mechanism (e.g., via increased end-expiratory lung volumes improving oxygenation or via promotion of cardioprotective alkalosis). Reports that CSA is associated with increased risk of mortality in heart failure (HF), along with preliminary findings of improved cardiac function and reduced mortality when CSA was treated with continuous positive airway pressure (CPAP), prompted a multicenter randomized controlled trial to investigate the effect of CPAP on transplant-free survival in HF with CSA. This trial was prematurely terminated due to low recruitment, reduced mortality due to secular trends in the medical treatment of heart failure, and early divergence of the survival curves in favor of the control group (hazard ratio in first 18 months 1.5, p=0.02). Beyond 18 months survival favored the CPAP arm, but the overall difference between treatment groups was not statistically significant, despite sustained improvement in intermediate measures (left ventricular ejection fraction [LVEF], plasma norepinephrine, 6-minute walk distance). As the power of this study was limited, CPAP had suboptimal effectiveness in reducing CSA burden, and secondary analysis suggested that survival was improved in those in whom CSA was suppressed, this led to the design and initiation of two larger, more adequately powered trials utilizing adaptive servoventilation (ASV), a bilevel positive airway pressure modality that is more effective in reversing CSA in HF patients. These include an ongoing trial enrolling patients with either obstructive or central sleep apnea (Effect of ASV on Survival and Hospital Admissions in HF, ADVENT-HF, NCT01128816) and a recently completed trial enrolling only patients with predominantly CSA (Treatment of Predominant CSA by ASV in Patients with HF, SERVE-HF, NCT00733343), with recently publicized results.

original research 
William W. Busse; Stephen T. Holgate; Sally W. Wenzel; Paul Klekotka; Yun Chon; JingYuan Feng; Edward Ingenito; Ajay Nirula
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Background:  High bronchodilator reversibility (HR) in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles and disease control in HR and low reversibility (LR) asthma patients.

Methods:  A retrospective analysis was performed with data from 2 completed clinical trials of similar design (NCT01018550 and NCT01199289). Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = ΔFEV1 post-bronchodilator ≥ +20%). Serum IgE, blood eosinophils, and exhaled nitric oxide (FeNO), biomarkers commonly used to stratify patients into Th2-high vs. Th2-low phenotypes, were measured in “not well controlled” (1.5 ≤ ACQ ≤ 2.143) and “very poorly controlled” (ACQ > 2.143) patients.

Results:  The majority of patients in HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarkers (40.1% vs. 29.4%; p=0.006), lower lung function (FEV1: 63.5±7.7% vs. 67.9±8.4% pred; p<0.001), and atopy (93.7% vs. 86.5%; p=0.005).

Conclusions:  HR is a physiological indicator of reduced lung function, and is more often associated with elevations in Th2 biomarkers than LR in moderate-to-severe asthma. However, the majority of HR and LR patients in this analysis displayed a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control.

original research 
Eleni Papakonstantinou; Ioannis Klagas; Michael Roth; Michael Tamm; Daiana Stolz
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Background:  Acute exacerbations in chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of glycosaminoglycans in bronchoalveolar lavage (BAL) in a large cohort of 97 COPD patients.

Methods:  COPD patients, undergoing diagnostic bronchoscopy, with either stable disease (n=53) or AE-COPD (n=44), matched for their demographics and lung function parameters were included in this study. Levels of heparan sulfate, chondroitin sulfate, dermatan sulfate and matrix metalloproteinases (MMPs) in BAL were measured by ELISA.

Results:  Heparan sulfate and chondroitin sulfate were significantly increased in BAL of patients at exacerbation. Levels of heparan sulfate were higher in the BAL of patients with microbial infections. Chondroitin sulfate was negatively correlated with FEV1% predicted but not with DLCO% predicted, indicating that chondroitin sulfate is associated with airway remodeling leading to obstruction rather than to emphysema. Furthermore, heparan sulfate and chondroitin sulfate were significantly correlated with MMP-9, MMP-2 and MMP-12 in BAL, indicating that they were cleaved from their respective proteoglycans by MMPs and subsequently washed out in BAL.

Conclusions:  During AE-COPD there is increased expression of heparan sulfate and chondroitin sulfate in BAL. These molecules are significantly correlated with MMPs in BAL, indicating that they may be associated with airway remodeling and may lead to lung function decline during exacerbations of COPD.

original research 
Eleni Papakonstantinou, MD, PhD; Michael Roth, PhD; Ioannis Klagas, PhD; George Karakiulakis, MD, PhD; Michael Tamm, MD; Daiana Stolz, MD
Topics: , ,

Background:  Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and remodeling, with serious modifications of the extracellular matrix (ECM). Hyaluronic acid (HA) is an abundant ECM molecule in the lung with various biological functions that are depended on its molecular weight (MW). High-MW HA exhibits anti-inflammatory and immune-suppressive effects, while low-MW HA is pro-inflammatory. In this study, we investigated whether acute exacerbations of COPD (AECOPD), which affect quality of life and survival of COPD patients, are associated with altered HA turnover in bronchoalveolar lavage (BAL).

Methods:  We used bronchoalveolar lavage (BAL) from COPD patients, with stable disease (n=53) or at AECOPD (n=44), matched for their demographics and clinical characteristics, and BAL from controls (n=15). HA, HA-synthase-1 (HAS-1) and hyaluronidase (HYAL) were determined by ELISA and HYAL activity by HA zymography. The MW of HA was analyzed by agarose electrophoresis.

Results:  HA, HAS-1 and HYAL were significantly increased in BAL of COPD patients at a stable state and at exacerbation, as compared to controls. HYAL activity was significantly increased in BAL of AECOPD patients, resulting in an increase of low-MW HA during exacerbations. In AECOPD patients, we also observed a significant negative correlation of HA and HYAL levels with FEV1% predicted, but not with DLCO% predicted, indicating that increased HA degradation may be associated with airway obstruction than with emphysema.

Conclusions:  AECOPD are associated with increased HYAL activity in BAL and subsequent degradation of HA which may contribute to airway inflammation and subsequent lung function decline during exacerbations.

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