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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.

evidence-based medicine 
Louis-Philippe Boulet, MD, FCCP; Remy R. Coeytaux, MD, PhD; Douglas C. McCrory, MD, MHS; Cynthia T. French, PhD, RN; Anne B. Chang, MBBS, PhD, MPH; Surinder S. Birring, MB ChB, MD; Jaclyn Smith, MB ChB, PhD; Rebecca L. Diekemper, MPH; Bruce Rubin, MEngr, MD, MBA; Richard S. Irwin, MD, Master FCCP; on behalf of the CHEST Expert Cough Panel

Background:  Since the publication of the 2006 ACCP Cough Guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present Committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to 1) assess the performance of tools designed to measure cough frequency, severity and/or impact in adults, adolescents, and children with chronic cough; and 2) make recommendations or suggestions related to these findings.

Methodology:  By following the CHEST methodological guidelines, the Expert Cough Panel based its recommendations/suggestions on a recently published comparative effectiveness review (CER) commissioned by the U.S. Agency for Healthcare Research and Quality (AHRQ), a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted upon during a meeting of the Expert Cough Panel.

Results:  We recommend or adults, adolescents (≥ 14 years of age) and children complaining of chronic cough that validated and reliable health-related quality of life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough on adult patients, such as the Leicester Cough Questionnaire (LCQ) and Cough-specific QoL Questionnaire (CQLQ); and for children, the Parent Cough-specific QoL questionnaire (PC-QOL). We recommend acoustic cough counting to assess cough frequency but not cough severity. There are limited data regarding the performance of visual analogue scales (VAS), numeric rating scales or tussigenic challenges.

Conclusions:  Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by VAS or numeric rating scales should be in a standardized fashion. Previously validated QoL questionnaires or other cough assessment tools should not be modified unless the new version has been shown to be reliable and valid. Finally, tussigenic challenges have a role in research settings to understand mechanisms of cough.

correspondence  FREE TO VIEW
Mario Castro, MD, MPH, FCCP; Gerard Cox, MB, FRCP(C); Michael E. Wechsler, MD, MMSc; Robert M. Niven, MD

The challenging of previously published work and reviews of studies with a new and different perspective is rational and academically appropriate when performed with scientific rigor and accuracy. However we were surprised by the recent commentary by Iyer and Lim regarding bronchial thermoplasty.

correspondence  FREE TO VIEW
Vivek N. Iyer; Kaiser G. Lim

“res ipsa loquitur” - the thing speaks for itself

We welcome the opportunity to engage in an open transparent discussion regarding the scientific merits of thermoplasty in asthma. Dr. Castro et al has submitted a rebuttal to our commentary. They imply that critical appraisal of a peer-reviewed published paper requires multicenter corroboration for accuracy. We stand by our commentary of the AIR-2 trial and would like to re-iterate several important facts.

correspondence  FREE TO VIEW
Richard S. Irwin, MD, Master FCCP

In their rebuttal to the Commentary on Bronchial Thermoplasty that appeared in the Journal, Castro, Cox, Wechsler, and Niven state that we published the Commentary without review for accuracy. This is not true. Given the importance of the subject matter, we made sure that the manuscript underwent careful and close scrutiny before publication. Our reasons for going ahead with publishing the Commentary are well reflected by the response of Iyer and Lim.

original research 
Gianluigi Li Bassi, MD, PhD; Nestor Luque, MD; Joan Daniel Marti, RPT, PhD; Eli Aguilera Xiol, Msc; Marta Di Pasquale, MD; Valeria Giunta, MD; Talitha Comaru, RPT, PhD; Montserrat Rigol, DVM, PhD; Silvia Terraneo, MD; Francesca De Rosa, MD; Mariano Rinaudo, MD; Ernesto Crisafulli, MD, PhD; Rogelio Cesar Peralta Lepe, MD; Carlos Agusti, MD, PhD; Carmen Lucena, MD; Miguel Ferrer, MD, PhD; Laia Fernandez, PhD; Antoni Torres, MD, PhD
Topics: , , ,

Background:  Improvements in the design of the endotracheal tube (ETT) have been achieved in recent years. We evaluated tracheal injury associated with ETTs with novel high-volume low-pressure (HVLP) cuffs and subglottic secretions aspiration (SSA) and the effects on mucociliary clearance (MCC).

Methods:  Twenty-nine pigs were intubated with ETTs comprising cylindrical or tapered cuffs and made of polyvinylchloride or polyurethane. In specific ETTs, every 2 h SSA was performed. Following 76 h of mechanical ventilation, pigs were weaned and extubated. Images of the tracheal wall were recorded before intubation, extubation and 24 and 96h thereafter, through a fluorescence bronchoscope. We computed the red-to-green intensity ratio (R/G) –an index of tracheal injury– and the green-plus-blue (G+B) intensity –an index of normalcy– of the most injured tracheal regions. MCC was assessed through fluoroscopic tracking of radio-opaque markers. After 96h from extubation, pigs were sacrificed, and a pathologist scored injury.

Results:  Cylindrical cuffs presented smaller increase in R/G vs. tapered cuffs (p=0.011). Additionally, cuffs made of polyurethane produced a minor increase in R/G (p=0.012) and less G+B intensity decline (p=0.022), vs. polyvinylchloride cuffs. Particularly, a cuff made of polyurethane and with smaller outer diameter outperformed all cuffs. SSA-related histological injury ranged from cilia loss to subepithelial inflammation. MCC was 0.9±1.8 and 0.4±0.9 mm/min for polyurethane and polyvinylchloride cuffs, respectively (p<0.001).

Conclusions:  HVLP cuffs and SSA produce tracheal injury, and the recovery is incomplete up to 96h following extubation. Small, cylindrical-shaped cuffs made of polyurethane cause less injury. MCC decline is reduced with polyurethane cuffs.

original research 
Igor Barjaktarevic, MD, MSc; Steven Springmeyer, MD; Xavier Gonzalez, MD; William Sirokman, BS; Harvey O. Coxson, PhD; Christopher B. Cooper, MD
Topics: , , , ,

BACKGROUND:  Quantitative analysis of high-resolution chest CT (QCT) is an established method for determining the severity and distribution of lung parenchymal destruction in patients with emphysema. Diffusing capacity for carbon monoxide (DLCO) is traditional physiological measure of emphysema severity and is probably influenced more by destruction of alveolar capillary bed (1/θ·Vc) than by membrane diffusion per se (1/Dm). We reasoned that DLCO should correlate with tissue volume from QCT.

METHODS:  460 patients with upper lobe predominant emphysema were enrolled in the study. The mean (SD) FEV1 was 30.6 (8.0)%, TLC 129.5 (18.1)%, DLCO 36.7 (13.1)% of predicted values. QCT was performed using custom software and relationship between DLCO and various metrics from QCT were evaluated using Pearson correlation coefficients.

RESULTS:  On average, whole body plethysmography (WBP) volumes were higher by 841 ml compared to QCT-calculated total lung volume. However, there was a strong correlation between these measurements (r=0.824, P<0.0001). DLCO correlated with total lung volume (r=0.314, P<0.0001), total tissue volume (r=0.498, P<0.0001), and percentage of lung with low density ( -950 Hounsfield Units) (r=-0.337, P<0.0001).

CONCLUSION:  In patients with severe emphysema, DLCO correlates best with total tissue volume supporting the hypothesis that pulmonary capillary blood volume is the main determinant of DLCO in the human lung. The relationships between DLCO and various anatomical metrics of lung parenchymal destruction from QCT inform our understanding of the relationship between structure and function of the human lung.

original research 
Yutao Guo, MD, PhD; Hao Wang, MD; Yingchun Tian, MD; Yutang Wang, MD, PhD; Gregory Y. H. Lip, MD
Topics: , , , , ,

Background  Much of the clinical epidemiology and treatment patterns for patients with atrial fibrillation (AF) are derived from Western populations. Limited data are available on antithrombotic therapy use over time and its impact on the stroke or bleeding events in newly diagnosed Chinese patients with AF.

Objective  The present study investigates time-trends in warfarin and aspirin use in China), in relation to stroke and bleeding events in a Chinese population.

Methods  We used a medical insurance database involving more than 10 million individuals for the years 2001 to 2012 in Yunnan, a southwestern province of China, and performed time-trend analysis on those with newly diagnosed AF. Cox proportional hazards time-varying exposures were used to determine the risk of stroke or bleeding events associated with antithrombotic therapy among AF patients.

Results  Among the randomly sampled 471,446 participants, there were 1,237 patients with AF, including 921 newly diagnosed AF, thus providing 4,859 person-years experience (62% males, mean attained age 70 years). The overall rate of antithrombotic therapy was 37.7% (347/921), with 4.1% (38/921) on warfarin and 32.3% (298/921) on aspirin. Antithrombotic therapy was not related to stroke/bleeding risk scores (CHADS2 score: P=0.522; CHA2 DS2 -VASc score: P=0.957; HAS-BLED: P=0.095). The use of antithrombotic drugs (mainly, aspirin) increased in both females and males over time, with the rate of aspirin from 4.0% in 2007 to 46.1% in 2012 in females, and from 7.7% in 2007 to 61.9% in 2012 in males (p value for trend, both < 0.005). In the overall cohort, the annual stroke rate approximated 6% and annual major bleeding rate was about 1%. Compared to non-antithrombotic therapy, the risk for ischaemic stroke (Hazard ratio, HR, [95% Confidence interval, CI]) was 0.68 (0.39-1.18) on aspirin, and 1.39 (0.54-3.59) on warfarin.

Conclusion  Aspirin use increased amongst newly diagnosed Chinese AF patients with no relationship to the patient’s stroke or bleeding risk. Warfarin use was very low. Given the healthcare burden of AF and its complications, our study has major implications for healthcare systems in non-Western countries, given the global burden of this common arrhythmia.

original research 
Carolyn S. Calfee, MD, MAS; David R. Janz, MD; Gordon R. Bernard, MD; Addison K. May, MD; Kirsten N. Kangelaris, MD, MAS; Michael A. Matthay, MD; Lorraine B. Ware, MD; the NIH NHLBI ARDS Network
Topics: ,

Background:  The Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (e.g. non-pulmonary sepsis); however, this hypothesis has not been well-studied in humans.

Methods:  We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single center study of 100 patients with ARDS and severe sepsis, and in a secondary analysis of 853 ARDS patients drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.

Results:  In both studies, direct ARDS patients had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein-D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2), compared with indirect ARDS patients. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, direct ARDS patients also had lower levels of von Willebrand factor antigen and interleukins 6 and 8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.

Conclusions:  Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct or indirect ARDS, respectively.

original research 
A.B. Chang; P.P. Van Asperen; N. Glasgow; C.F. Robertson; C.M. Mellis; I.B. Masters; L.I. Landau; L. Teoh; I. Tjhung; H.L. Petsky; P.S. Morris
Topics: , ,

Background:  Chronic cough is associated with poor quality of life and may signify a serious underlying disease. Differentiating non-specific cough (when ‘watchful waiting’ can be safely undertaken) from specific cough (treatment and/or further investigations are beneficial) would be clinically useful. In 326 children, we aimed to; (a) determine how well cough pointers (used in guidelines) differentiate specific from non-specific cough; and (b) describe the clinical profile of children whose cough resolved without medications (‘spontaneous-resolution’).

Methods:  A dataset from a multi-centre study involving children newly referred for chronic cough (median duration 3-4 months) was used to determine the sensitivity, specificity, predictive values and likelihood ratios (LR) of cough pointers (symptoms, signs and simple investigations [chest x-ray, spirometry]) recommended in guidelines.

Results:  The pre-test probability of specific cough was 88%. The absence of false positive results meant that most pointers had strongly positive LRs. The most sensitive pointer (wet cough) had a positive LR=26.2 (95%CI 3.8-181.5). While absence of other individual pointers did not change the pre-test probability much (negative LR≈1), the absence of all pointers had a strongly negative LR=0 (95%CI 0-0.03). Children in the ‘spontaneous-resolution’ group were significantly more likely to be older, non-Indigenous, have dry cough and normal chest x-ray.

Conclusion:  Children with chronic dry cough without any cough pointers can be safely managed using the ‘watchful waiting approach’. The high pre-test probability and high positive LRs of cough pointers support the use of individual cough pointers to identify high risk of specific cough in pediatric chronic cough guidelines.

  Children from this study included children enrolled in a RCT: Trial registration with http://www.anzctr.org.au number 12607000526471.

original research 
R.L. Hoiland, BHK.; G.E. Foster, PhD.; J. Donnelly, MB, ChB.; M. Stembridge, MSc.; C.K. Willie, PhD.; K.J. Smith, MSc.; N.C. Lewis, PhD.; S.J.E. Lucas, PhD.; J.D. Cotter, PhD.; D.J. Yeoman, BSc.; K.N. Thomas, BSc.; T.A. Day, PhD.; M.M. Tymko, BHSc.; K.R. Burgess, MD.; P.N. Ainslie, PhD.
Topics: , ,

Background:  The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting peripheral oxyhemoglobin saturation (SpO2) at HA would correlate better than HVR at SL to PASP at HA.

Methods:  In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min·-%SpO2-1) and resting PASP using echocardiography. Both resting SpO2 and PASP measures were repeated on day 2 (n=10), days 4-8 (n=12), and 2-3 weeks (n=8) after arrival at 5050m. These data were also collected at 5050m on life-long HA residents (Sherpa; n=21).

Results:  Compared to SL, SpO2 decreased from 98.6 to 80.5% (P<0.001), while PASP increased from 21.7 to 34.0mmHg (P<0.001) after 2-3 weeks at 5050m. Isocapnic HVR at SL was not related to SpO2 or PASP at any time point at 5050m (all P>0.05). Sherpa had lower PASP (P<0.01) than lowlanders on days 4-8 despite similar SpO2. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL, but lower than lowlanders at all HA time points. At 5050m, whilst SpO2 was not related to PASP in lowlanders at any point (all R2=<0.05; P>0.50), there was a weak relationship in the Sherpa (R2=0.16; P=0.07).

Conclusion:  We conclude that neither HVR at SL nor resting SpO2 at HA correlates with elevations in PASP at HA.

original research 
Anne Sophie Gamez, MD; Delphine Gras, PhD; Aurélie Petit, PhD; Lucie Knabe; Nicolas Molinari, PhD; Isabelle Vachier, PhD; Pascal Chanez, MD-PhD; Arnaud Bourdin, MD-PhD
Topics: , ,

Background:  Club cell secretory protein (CCSP) was found as a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking.

Objective:  We investigated the effect of CCSP as a therapeutic strategy restoring the balance between injury and repair in COPD simultaneously validating an ex vivo air liquid interface (ALI) culture of human bronchial epithelial cells.

Methods:  Endobronchial biopsies (EBB) have been obtained from 13 COPD patients, 8 smokers and 8 control subjects. Morphometric analysis of the initial EBB has been performed. ALI cultures derived from the same EBB were exposed to cigarette smoke extract (CSE) with or without exogenous rhCCSP supplementation. CCSP and CXCL8 concentrations were assessed at steady state and after CSE exposure.

Results:  Morphometric analysis of the initial EBB showed increased cell density but decreased immunostaining of CCSP+ cells in COPD (p=0.03 vs. controls). At steady state, lower CCSP (p=0.04) and higher CXCL8 levels (p<.0001) were found in COPD ALI epithelium. Exogenous rhCCSP supplementation dampened CSE-induced CXCL8-release in COPD patients which returned to similar levels as smokers and controls (p=.0001). A negative correlation was found between CXCL8-release in ALI and CCSP+ cells density in initial biopsies (p=.0073).

Conclusion:  In vitro, rhCCSP exogenous supplementation can reverse CSE-induced CXCL8-release in COPD indicating a potential use of this strategy in vivo.

original research 
Christopher N. Schmickl, MD, MPH; Michelle Biehl, MD; Gregory A. Wilson, RRT; Ognjen Gajic, MD, MSc
Topics: , , ,

Background:  Early differential diagnosis of acute lung injury (ALI) vs cardiogenic pulmonary edema (CPE) is important for selecting the most appropriate therapy but the prognostic implications of this distinction have not been studied. Accurate prognostic information is essential for providing appropriate informed consent prior to initiation of mechanical ventilation.

Methods:  This is a long term follow-up study of a previously established population-based cohort of critically-ill adult patients with acute pulmonary edema admitted at a tertiary-care center during 2006-2009, in which post-hoc expert review had established ALI vs CPE diagnosis. Using logistic and Cox regression, hospital mortality and long-term survival were compared in ALI vs CPE patients.

Results:  Of 328 patients (ALI=155, CPE=173) 240 patients (73%) died during a median follow-up of 160 days. After adjusting for confounders, ALI patients were significantly more likely to die in the hospital (Odds ratio=4.2; 95%-Confidence Interval [CI]= 2.3-7.8; n=325, P<0.001), but among hospital survivors the risk of death during follow-up was the same in both groups (Hazard ratio=1.13, 95%-CI= 0.79-1.62; n=229, P=0.50). Independent predictors of mortality included age and APACHE III score. Results were similar when restricting ALI patients to the subset with acute respiratory distress syndrome (ARDS, Berlin definition). In post-hoc analyses, the mortality rate in hospital survivors compared to the general US population was significantly higher during the first two years but essentially converged by year five.

Conclusions:  While hospital mortality is higher in ALI/ARDS compared to CPE patients, long-term survival is similar in hospital survivors from both groups.

original research 
Addison K. May, MD; Jacob S. Brady, BS; Joann Romano-Keeler, MD; Wonder P. Drake, MD; Patrick R. Norris, PhD; Judith M. Jenkins, MSN; Richard J. Isaacs, PhD; Erik M. Boczko, PhD
Topics: , , ,

Background:  Ventilator associated pneumonia (VAP) remains a common complication in critically ill surgical patients and its diagnosis remains problematic. Exhaled breath contains aerosolized droplets that reflect the lung microbiota. We hypothesized that exhaled breath condensate fluid (EBCF) in hygroscopic condenser humidifier/heat moisture exchange (HCH/HME) filters would contain bacterial DNA that qualitatively and quantitatively correlate with pathogens isolated from quantitative bronchoalveolar lavage (BAL) samples obtained for clinical suspicion of pneumonia.

Methods:  Forty-eight ventilated adult patients, undergoing 51 quantitative BAL for suspected pneumonia in the surgical intensive care unit were enrolled. Per protocol, patients fulfilling VAP clinical criteria undergo quantitative BAL bacterial culture. Immediately prior to BAL, time-matched HCH/HME filters were collected for study of EBCF by real-time polymerase chain reaction (RT-PCR). Additionally, convenience samples of serially collected filters in patients with BAL diagnosed VAP were analyzed.

Results:  Forty-nine of 51 time-matched EBCF/BALF samples were fully concordant (concordance > 95% by kappa statistic) relative to identified pathogens and strongly correlated with clinical cultures. Regression analysis of quantitative bacterial DNA in paired samples revealed a statistically significant positive correlation (r =0.85). In a convenience sample, qualitative and quantitative PCR analysis of serial HCH/HME samples for bacterial DNA demonstrates an increase in load that preceded the suspicion of pneumonia.

Conclusions:  Bacterial DNA within EBCF demonstrates a high correlation with BALF and clinical cultures. Bacterial DNA within EBCF increases prior to the suspicion of pneumonia. Further study of this novel approach may allow development of a non-invasive tool for the early diagnosis of VAP.

original research 
Edward T. H. Fysh, MBBS, BSc; Silvia Bielsa, MD; Charley A. Budgeon, BSc (Hons); Catherine A. Read, RGN, BSc (Hons); Jose M. Porcel, MD, FCCP, FACP; Nick A. Maskell, DM, FRCP; Y. C. Gary Lee, MBChB, PhD, FCCP
Topics: , ,

Background:  The clinical course of patients with malignant pleural effusions (MPE) varies. The decision to undertake ‘definitive therapy’ (pleurodesis and/or indwelling pleural catheter [IPC]) for MPEs is decided on a case-by-case basis. Identifying factors that predict definitive therapy may help guide early initiation of treatment.

Aim:  To identify clinical, laboratory and radiological predictors associated with clinicians’ prescription of definitive therapy for patients with MPE.

Methods:  A multicentre, observational study over 55 months involving tertiary centres in Perth, Australia and in Lleida, Spain. Demographic, clinical, radiological, biochemical and histological data and the treatments received were recorded. Logistic regression was performed to determine the variables useful for predicting definitive therapy.

Results:  Data of 540 patients (365 from Perth and 184 from Lleida) were analysed; 537 fulfilled the criteria of a MPE. Definitive therapy was used in 288 (53.6%) patients: 199 received a pleurodesis and 89 an IPC. Univariate analysis of the combined cohort revealed definitive therapy was more likely if the effusion: has low pH, either as a continuous variable (OR 30.30, p<0.01) or with a pH cut-off of <7.2 (OR 2.09, p=0.03); was large (>50% of hemithorax) (OR 2.75, p<0.01); or was associated with mesothelioma (OR 1.83, p<0.01). Following multivariate analysis low pleural pH (OR 37.04, p<0.01), large effusions (OR 3.31, p<0.01) and increasing age (OR 1.02, p=0.01) were associated with the use of definitive therapy.

Conclusion:  MPE patients with an effusion of low pleural fluid pH and large size on radiographs at first presentation are more likely to be treated with pleurodesis and/or IPC.

original research 
Tsuyoshi Tanabe, MD, Ph.D; Tadasuke Shimokawaji, MD, Ph.D; Soichiro Kanoh, MD, Ph.D; Bruce K. Rubin, MD, MEngr, MBA, FRCPC
Topics: , , , ,

Background:  Secretory phospholipases A2 (sPLA2) initiate the biosynthesis of eicosanoids, they are increased in the airway of persons with severe asthma, and they induce mucin hypersecretion. We used IL-13 transformed highly enriched goblet cells and differentiated (ciliary cell enriched) human bronchial epithelial (HBE) cell culture to evaluate the relative contribution of ciliated and goblet cells to airway sPLA2 generation and response. We wished to determine the primary source(s) of sPLA2 and leukotrienes in human airway epithelial cells.

Methods:  HBE cells from subjects without lung disease were differentiated to a ciliated-enriched or goblet-enriched cell phenotype. Synthesis of sPLA2, cysteinyl leukotrienes (cysLTs), and airway mucin mRNA and protein was measure by RT-PCR and ELISA and localization of mucin and sPLA2 to specific cells types was confirmed by confocal microscopy.

Results:  sPLA2 group IIa, V and X mRNA expression was increased in ciliated-enriched cells (p<0.001) but not in goblet-enriched cells. sPLA2 were secreted from the apical (air) side of ciliated-enriched cells but not goblet-enriched cells (p<0.001). Immunostaining of sPLA2 V was strongly positive in ciliated-enriched cells, but not goblet-enriched cells. sPLA2 released cysLTs from goblet-enriched cells but not ciliated-enriched cells and this was greatest with sPLA2 V (p<0.05). sPLA2 V increased goblet-enriched cell mucin secretion and this was inhibited by inhibitors of lipoxygenase or cyclooxygenase (p<0.02).

Conclusions:  sPLA2 are secreted from ciliated cells and appear to induce mucin and cysLT secretion from goblet cells strongly suggesting that airway goblet cells are proinflammatory effector cells.

original research 
Barbara Girerd, PhD; Florence Coulet, PharmD, PhD; Xavier Jaïs, MD; Mélanie Eyries, PhD; Cathelijne Van Der Bruggen; Frances De Man, PhD; Arjan Houweling, MD, PhD; Peter Dorfmuller, MD, PhD; Laurent Savale, MD, PhD; Olivier Sitbon, MD, PhD; Anton Vonk-Noordegraaf, MD, PhD; Florent Soubrier, MD, PhD; Gérald Simonneau, MD; Marc Humbert, MD, PhD; David Montani, MD, PhD
Topics: , , ,

Background:  Mutations in the BMPR2 gene encoding bone morphogenetic protein receptor type II (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling.

Methods:  A cohort-study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain.

Results:  We identified 171 PAH affected carriers with a mutatedBMPR2 gene. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared to other BMPR2mutation carriers (43.2±12.1 and 35.7±14.6 years; p=0.040), a lower pulmonary vascular resistance (13.3±3.5 and 17.4±6.7; p=0.023) and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, p=0.02). No statistically differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain.

Conclusion:  Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared to other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of theseBMPR2 mutations in BMPRII signaling pathways, and their possible role in pulmonary arterial remodeling.

original research 
Jens Ehrhardt, M.Sc.; Matthias Schwab, M.D.; Sigrid Finn, M.D.; Albrecht Guenther, M.D.; Torsten Schultze, M.Sc.; Otto W. Witte, M.D.; Sven Rupprecht, M.D.
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Background—  Carotid arteriosclerosis and sleep apnea are considered as independent risk factors for stroke. Whether sleep apnea mediates severity of carotid stenosis remains unclear. Sleep apnea comprises two pathophysiological conditions: obstructive (OSA) and central sleep apnea (CSA). Whilst OSA results from upper airway occlusion, CSA reflects enhanced ventilatory drive mainly due to carotid chemoreceptor dysfunction.

Methods—  Ninety-six patients with asymptomatic extracranial carotid stenosis of ≥50% underwent polysomnography to, I) determine prevalence and severity of sleep apnea for different degrees of carotid stenosis, and, II) analyze associations between OSA and CSA, carotid stenosis severity and other arteriosclerotic risk factors.

Results—  Sleep apnea was present in 68.8% of patients with carotid stenosis. Prevalence and severity of sleep apnea increased with degree of stenosis (P≤0.05) due to a rise in CSA (P≤0.01) but not in OSA. Sleep apnea (OR, 3.8, P≤0.03) and arterial hypertension (OR, 4.1, P≤0.05) were associated with stenosis severity whereas diabetes, smoking, dyslipidemia, BMI, age and sex were not. Stenosis severity was related to CSA (P≤0.06) but not to OSA. In addition, CSA but not OSA showed a strong association with arterial hypertension (OR, 12.5, P≤0.02) and diabetes (OR, 4.5, P≤0.04).

Conclusions—  Sleep apnea is highly prevalent in asymptomatic carotid stenosis. Further, it is associated with arteriosclerotic disease severity as well as presence of hypertension and diabetes. This vascular risk constellation seems to be stronger connected with CSA than with OSA, possibly attributable to carotid chemoreceptor dysfunction. Since sleep apnea is treatable, screening should be embedded in stroke prevention strategies.

original research 
Aurélie Hautefort, MSc; Barbara Girerd, PhD; David Montani, MD, PhD; Sylvia Cohen Kaminsky, PhD; Laura Price, MD, PhD; Bart N. Lambrecht, MD, PhD; Marc Humbert, MD, PhD; Frédéric Perros, PhD
Topics: , ,

Background:  Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic and T cells (DC and LT), key driver and effector cells respectively of the immune system, may allow the identification of immunopathological approaches to PAH management.

Methods:  We performed immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technique, we performed cytokine profiling of both populations following stimulation and/or coculture. We tested the immunomudulatory effects of the glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed, the immune polarization of PAH patients in blood DNA, by an epigenetic approach.

Results:  The profile of membrane costimulatory molecules of PAH-MoDCs was similar to controls. However, PAH-MoDCs retained higher levels of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH-MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared to controls.

Conclusions:  As previously demonstrated in other chronic inflammatory and autoimmune conditions, we have highlighted Th17 immune polarization in PAH patients for the first time.

original research 
Adam Andruska, MD; Scott T. Micek, PharmD; Yuichiro Shindo, MD; Nicholas Hampton, PharmD; Brian Colona, BS; Sandra McCormick, MSCIS; Marin H. Kollef, MD
Topics: , , ,

Background:  Hospital readmissions for pneumonia occur often and are difficult to predict. For fiscal year 2013 the Centers for Medicare & Medicaid Services readmission penalties have been applied to acute myocardial infarction, heart failure, and pneumonia. However, the overall impact of pneumonia pathogen characterization on hospital readmission is undefined.

Methods:  Retrospective six-year cohort study (August 2007 to September 2013).

Results:  We evaluated 9624 patients with a discharge diagnosis of pneumonia. Among these patients, 4432 (46.1%) were classified as having culture-negative pneumonia, 1940 (20.2%) as having pneumonia caused by antibiotic susceptible bacteria, 2991 (31.1%) as having pneumonia caused by potentially antibiotic resistant bacteria, and 261 (2.7%) as having viral pneumonia. The 90-day hospital readmission rate for survivors (n = 7637; 79.4%) was greatest for patients with pneumonia attributed to potentially antibiotic resistant bacteria (11.4%) followed by viral pneumonia (8.3%), pneumonia attributed to antibiotic susceptible bacteria (6.6%), and culture-negative pneumonia (5.8%) (P < 0.001). Multiple logistic regression analysis identified pneumonia attributed to potentially antibiotic resistant bacteria to be independently associated with 90-day readmission (OR, 1.75; 95% CI, 1.56 – 1.97; P < 0.001). Other independent predictors of 90-day readmission were Charlson comorbidity score > 4, cirrhosis, and chronic kidney disease. Culture-negative pneumonia was independently associated with lower risk for 90-day readmission.

Conclusions:  Readmission following hospitalization for pneumonia is relatively common and is related to pneumonia pathogen characterization. Pneumonia attributed to potentially antibiotic resistant bacteria is associated with an increased risk for 90-day readmission while culture-negative pneumonia is associated with lower risk for 90-day readmission.

original research 
Anna C. Bibby, MBChB; Amelia O. Clive, MBBS; Gerry C. Slade, RGN; Anna J. Morley, RGN; Janet Fallon, MBBS; Ioannis Psallidas, PhD; Justin C.T. Pepperell, BM, BCh; Mark G. Slade, MBBS; Andrew E. Stanton, MBChB; Najib M. Rahman, BM, BCh; Nick A. Maskell, BM, BS
Topics: , ,

Objectives  Malignant pleural effusion (MPE) incidence is increasing and prognosis remains poor. In-dwelling pleural catheters (IPCs) relieve symptoms, but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from 6 UK centers between 1/1/05 and 1/31/14.

Methods  Survival in patients with pleural infection was compared with 788 patients with MPE (LENT cohort) and with national statistics.

Results  Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20/25) had mesothelioma or lung cancer.Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 vs. 132 days, HR 0.67, p=0.07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs. <365 days), and double the median survival of patients with mesothelioma in the LENT cohort (339 days, 95% CI non-overlapping). Survival with lung and breast cancer did not differ significantly between the groups.61% of patients experienced early infection. There was no survival difference between patients with early and late infection (p=0.6).

Conclusion  This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.

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