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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 
Jeffrey H. Jennings, MD; Krishna Thavarajah, MD; Michael Mendez, MD; Michael Eichenhorn, MD; Paul Kvale, MD; Lenar Yessayan, MD
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Background:  Hospital readmissions for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) pose burdens to the healthcare system and patients. A current gap in knowledge is whether a pre-discharge screening and educational tool, administered to patients with COPD, reduces readmissions and emergency department (ED) visits.

Methods:  A single center, randomized trial of patients admitted with AECOPD was conducted at Henry Ford Hospital between February 2010 and April 2013. One hundred seventy-two patients were randomized either to the control (standard care) or bundle group in which patients received smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler teaching, and a 48-hour post-discharge phone call. The primary endpoint was the difference in the composite risk of hospitalizations or ED visits for AECOPD between the 2 groups in the 30 days following discharge. A secondary endpoint included 90-day readmission rate.

Results:  Of the 172 patients, 18 of 79 in the control group (22.78%) and 18 of 93 in the bundle group (19.35%) were readmitted within 30 days. The risk of ED visits or hospitalizations within 30 days was not different between the groups (risk difference = -3.43%, 95% confidence interval = -15.68%−8.82%; p= 0.58). Overall, the time to readmission in 30 days and 90 days was similar between groups (log-rank test p= 0.71 and p= 0.88, respectively).

Conclusion:  A pre-discharge bundle intervention in AECOPD is not sufficient to reduce the 30-day risk of hospitalizations or ED visits. Increased resources may be needed to generate a measurable effect on readmission rates.

original research 
Sanjiva M. Lutchmedial, MD; Whitney G. Creed, BA; Alastair J. Moore, MD; Ryan R. Walsh, MD; George E. Gentchos, MD; David A. Kaminsky, MD
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Background:  COPD has traditionally been defined by the presence of irreversible airflow limitation on spirometry using either the GOLD or ATS/ERS criteria (lower limit of normal, LLN). We have observed that some patients with clinical COPD and emphysema on chest computerized tomography (CT) have no obstruction on spirometry. The purpose of this study was to assess the prevalence of obstruction by GOLD and LLN criteria in patients with emphysema on CT and determine which radiographic criteria were associated with a clinical diagnosis of COPD.

Methods:  We retrospectively analyzed the clinical records and spirometry of all patients who had radiographically defined emphysema on chest CT scans completed at the University of Vermont in 2011. We compared spirometric criteria and CT factors with the presence of clinical COPD based on chart review.

Results:  We identified 274 patients with CT defined emphysema. GOLD detected obstruction in 228 (83%) and LLN in 206 (75%) of patients. However, GOLD failed to correctly identify 19 (6.9%) patients and LLN 38 (13.9%) patients (average 10.4%) who had radiographic emphysema and a clinical diagnosis of COPD. Obese patients had a lower prevalence of obstruction whether classified by LLN or by GOLD. Among patients with spirometric obstruction, there were greater degrees of emphysema, and more severely increased airway wall thickness. Factors that were independently associated with clinical COPD were lower FVC % predicted, lower FEV1/FVC ratio and increasing airway wall thickness.

Conclusions:  Spirometry missed 10.4% of patients with clinical COPD who have significant emphysema on chest CT.

original research 
Jonathan K. Alder; Susan E. Stanley; Christa L. Wagner; Makenzie Hamilton; Vidya Sagar Hanumanthu; Mary Armanios
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Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases. We identified a family with pulmonary fibrosis, idiopathic infertility and short telomeres. Exome sequencing of blood-derived DNA revealed two mutations in the telomere binding protein TINF2. The first was a 15 base pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele indicating the deletion seen in the blood was acquired and may have a protective advantage since it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to what has been described for Fanconi anemia. No mutations were identified in over forty uncharacterized pulmonary fibrosis probands suggesting mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of telomerase mutation carriers with TERT and TR mutations (5 of 45). Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis, and suggest infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.

original research 
María Luz Alonso-Álvarez, MD; Joaquin Terán-Santos, MD; Estrella Ordax Carbajo, MD, PhD; José Aurelio Cordero-Guevara, MD; Ana Isabel Navazo-Egüia, MD; Leila Kheirandish-Gozal, MD, MSc; David Gozal, MD, FCCP
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Objective:  To evaluate the diagnostic reliability of home respiratory polygraphy (HRP) in children with a clinical suspicion of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS)

Methods:  A prospective blind evaluation was performed. Children between 2 to 14 years-old, with clinical suspicion of OSAS, who were referred to the Sleep Unit were included. An initial HRP followed by a ulterior date, same night, in-laboratory overnight respiratory polygraphy and polysomnography (PSG) in the Sleep Laboratory were performed. The AHI-HRP were compared to AHI-PSG, and therapeutic decisions based on AHI-HRP and AHI-PSG were analyzed using intraclass correlation coefficients (ICC), Bland-Altman plots and receiver operator curves (ROC).

Results:  27 boys and 23 girls, with a mean age of 5.3 ± 2.55 years were studied, and 66% were diagnosed with OSAS based on a PSG-defined obstructive RDI ≥3/hrTST. Based on the availability of concurrent HRP-PSG recordings, the optimal AHI-HRP corresponding to the PSG-defined OSAS criterion was established as ≥5.6/hr. The latter exhibited a sensitivity of 90.9% (95% CI: 79.6% -100%) and a specificity of 94.1% (95% CI: 80%-100%).

Conclusions:  Home respiratory polygraphic recordings emerge as a potentially useful and reliable approach for the diagnosis of OSAS in children, However, more research is required for the diagnosis of mild OSAS using HRP in children.

original research 
Dan J. Raz, MD, MAS; Rebecca A. Nelson, PhD; Frederic W. Grannis, MD; Jae Y. Kim, MD
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BACKGROUND:  The natural history of typical pulmonary carcinoid tumors has not been described. This has important implications in counseling patients for surgical resection who are elderly or who are at high operative risk.

METHODS:  Data from the Surveillance Epidemiology and End Results (SEER) were used to identify 4111 patients with biopsy proven lymph node-negative typical carcinoid of the lung between 1988 and 2010. 306 had no resection, 929 underwent sub-lobar resection, and 2876 underwent lobectomy. Overall and disease-specific survival were analyzed using Kaplan-Meier plots. Multivariate analysis was used to determine predictors of survival.

RESULTS:  Five year overall survival (OS) for patients who underwent lobectomy, sub-lobar resection, and no surgery was 93%, 92%, and 69% (p<0.0001). Five year disease-specific survival (DSS) was 97%, 98%, and 88% (p<0.0001). Among patients with T1 tumors, DSS was 98% for patients who underwent lobectomy and sub-lobar resection, and 92% for no surgery; among T2 tumors, DSS was 97%, 100%, and 87%; among T3 and T4 tumors DSS was 96%, 100%, and 75%, respectively. On multivariate analysis, non-operative management was associated with increased risk of disease-specific mortality compared with lobectomy (HR 2.14, 95% CI 1.35-3.40, p=0.0013).

CONCLUSIONS:  In this population-based cohort, surgical resection of lymph node negative carcinoid tumors is associated with a survival advantage over non-operative treatment. Yet the disease-specific survival at 5 years is still high without any treatment. This suggests that observation of asymptomatic peripheral typical carcinoids or endoscopic management of symptomatic central carcinoids may be considered in patients at high risk for surgical resection.

original research 
Scott Apperley, MD; Hye Yun Park, MD; Daniel T. Holmes, MD; S.F. Paul Man, MD; Donald Tashkin, MD; Robert A. Wise, MD; John E. Connett, PhD; Don D. Sin, MD
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Background:  Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder associated with oxidative stress. Serum bilirubin has potent anti-oxidant actions and higher concentrations have been shown to protect against oxidative stress. The relation between serum bilirubin and COPD progression is unknown.

Methods:  Serum bilirubin was measured in 4,680 smokers aged 35-60 years old with mild to moderate airflow limitation. The relationship of serum bilirubin to post bronchodilator FEV1 and rate of FEV1 decline over three to nine years was determined using regression modeling. Total and disease-specific mortality was also ascertained.

Results:  Serum bilirubin was positively related to FEV1 (p<0.001). Serum bilirubin was also negatively related to the annual decline in FEV1 when adjusted for baseline demographics, pack years smoked and baseline measures of lung function (p=0.01). Additionally, serum bilirubin was negatively associated with risk of death from coronary heart disease (p=0.03); however, the relationships between bilirubin and other mortality endpoints were not statistically significant (p>0.05).

Conclusion:  Bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin was associated with a higher FEV1 and less annual decline in FEV1. Bilirubin was also associated with less coronary heart disease mortality. These data support the hypothesis that bilirubin has a protective effect on COPD disease progression, possibly through its anti-oxidant actions. Bilirubin may prove useful as an easily accessible and readily available blood based COPD biomarker.

original research 
Tina Shah, MD; Matthew M. Churpek, MD, PhD; Marcelo Coca Perraillon, MA; R. Tamara Konetzka, PhD
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Background:  The Hospital Readmissions Reduction Program (HRRP) penalizes hospitals for 30-day readmissions and was extended to chronic obstructive lung disease (COPD) in October 2014. There is limited evidence available on readmission risk factors and reasons for readmission to guide hospitals to initiate programs to reduce COPD readmissions.

Methods:  Medicare claims data from seven states were analyzed from 2006 to 2010, with an index admission for COPD defined by discharge ICD-9 codes as stipulated in the HRRP guidelines. Rates of index COPD admission, readmission, patient demographics, readmission diagnoses and utilization of post-acute care (PAC) were investigated.

Results:  Over the study period, there were 26,798,404 inpatient admissions, of which 3.5% were index COPD admissions. At 30 days, 20.2% were readmitted to the hospital. Respiratory-related diseases accounted for only half of the reasons for readmission and COPD was the most common diagnosis, explaining 27.6% of all readmissions. Patients discharged home without home healthcare were more likely to be readmitted for COPD than patients discharged to PAC (31.1% v. 18.8%, p<0.001). Readmitted beneficiaries were more likely to be dually enrolled in Medicare and Medicaid (30.6% v. 25.4%, p<0.001), have a longer median length of stay (5 v. 4 days, p<0.0001), and have more comorbidities (p<0.001).

Conclusion:  Medicare patients with COPD exacerbations are usually not readmitted for COPD, and these reasons differ depending on PAC utilization. Readmitted patients are more likely duals, suggesting that the addition of COPD to the readmissions penalty may further exacerbate the disproportionately high penalties seen in safety-net hospitals.

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
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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
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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
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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
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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
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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.
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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
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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.

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