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 
Andrew S. Chang, B.S.; Jeffrey Munson, M.D.; Alex H. Gifford, M.D.; Donald A. Mahler, M.D., FCCP
Topics: , ,

Background:  Although patients may find it difficult to describe their breathing discomfort, most are able to select statements among a list to describe their experience. The primary objective of this study was to examine sensitivity and specificity of descriptors of breathing discomfort prospectively in patients with common respiratory conditions as well as those patients who had refractory dyspnea.

Methods:  Out-patients answered “Yes” or “No” for each of 15 statements describing breathing discomfort, next selected the best three that most closely applied, and then completed the hospital anxiety depression scale-anxiety subscale. Sensitivity, specificity, and predictive values were calculated for the descriptors by diagnosis.

Results:  “Work/effort” descriptors were selected as the best three by patients with chronic obstructive pulmonary disease (n = 68), respiratory muscle weakness (n = 11), and those with refractory dyspnea (n = 17). Along with “work/effort” descriptors, “My chest feels tight” was among the best three in asthma (n = 22) with 38% sensitivity and 88% specificity. Along with “work/effort” descriptors, “My breathing is shallow” was among the best three in interstitial lung disease (n = 8) with 33% sensitivity and 84% specificity. Affective descriptors “frightening” (61% vs. 31%; p = 0.002) and “awful” (66% vs. 37%; p = 0.004) were reported more frequently in those with high anxiety scores compared with low anxiety scores.

Conclusions:  Although no descriptor achieved satisfactory sensitivity and specificity for identifying a particular condition, chest “tightness” was unique for asthma, while ”shallow breathing” was unique for ILD. Affective descriptors were associated with high anxiety scores.

original research 
Kefang Lai, MD, PhD; Baojuan Liu, MD, PhD; Danyuan Xu, MD; Lina Han, MD; Ling Lin, MD; Yin Xi, MD; Faxia Wang, MD; Ruchong Chen, MD, PhD; Wei Luo, MD; Qiaoli Chen, MD; Nanshan Zhong, MD
Topics: ,

Objective:  The long-term prognosis of nonasthmatic eosinophilic bronchitis (NAEB) is still unclear. This study aims to observe the frequency of relapse among NAEB patients and the likelihood of developing into chronic airflow obstruction over time.

Methods:  The eligible patients with NAEB from 2003 to 2013 were followed up for at least 1 year. During the follow-up period, we collected the patients’ clinical symptoms, sputum eosinophil count, spirometry and bronchial hyperresponsiveness for evaluation. Linear mixed model was adopted to determine the relationship between time and lung function.

Results:  A total of 234 patients with NAEB were identified, of whom 141 were followed up for over one year with the median period of 4.1 years. Up to 59.6% patients had relapse after treatments. Both allergic rhinitis (OR 4.37, 95%CI 1.049~18.203, P=0.043) and sputum eosinophilia after 4-week treatment with inhaled corticosteroids (OR 9.493, 95%CI 2.381~37.850, P=0.001) were risk factors for relapse. Among the 141 patients, eight of them (5.7%) developed mild asthma. During the follow-up period, no progressive decline in FVC, FEV1, FEV1/FVC were observed (P>0.05). Although the proportion of small airway dysfunction (MMEF<65%)significantly increased at the last visit in all groups (all P<0.05), only relapse group showed MMEF decline at the end of follow-up (P<0.05) in linear mixed model.

Conclusion:  Over 50% patients with NAEB have repeated episodes associated with persistent sputum eosinophilia after treatment and allergic rhinitis. In our cohort, chronic airway obstruction does not develop despite small airway dysfunction increases over time.

original research 
Sebastian Zaremba, MD; Noomi Mueller; Anne Heisig; Christina H. Shin, BA; Stefanie Jung, MD; Lisa R. Leffert, MD; Brian T. Bateman, MD, MSc; Lori J. Pugsley, LJ, RN, BSN; Yasuko Nagasaka, MD, PhD; Ingrid Moreno Duarte, MD; Jeffrey L. Ecker, MD; Matthias Eikermann, MD, PhD
Topics: , ,

Background:  During pregnancy, upper airway resistance is increased, predisposing vulnerable women to pregnancy-related obstructive sleep apnea (OSA). Elevation of the upper body increases upper airway cross-sectional area (CSA) and improves severity of OSA in a subgroup of non-pregnant patients (positional dependent sleep apnea). We tested the hypothesis that elevated position of the upper body improves OSA early after delivery.

Methods:  Following IRB approval, we conducted a randomized, cross-over study on two postpartum units of Massachusetts General Hospital. Women during the first 48 h after delivery were included. Polysomnography was performed in non-elevated and 45 degrees elevated upper body position. Upper airway CSA was measured by acoustic pharyngometry in non-elevated, 45 degrees elevated and sitting body position. NCT01719224

Results:  55 patients were enrolled and measurements of airway CSA obtained. 30 patients completed polysomnography in both body positions. Elevation of the upper body significantly reduced apnea-hypopnea index (AHI) from 7.7±2.2/h in non-elevated to 4.5±1.4/h in 45 degrees elevated upper body position (p=0.031) during sleep. Moderate to severe OSA (AHI >15/h) was diagnosed in 20% of postpartum patients and successfully treated by elevated body position in half of them. Total sleep time and sleep architecture were not affected by upper body elevation. Change from non-elevated to sitting position increased inspiratory upper airway CSA from 1.35±0.1 cm2 to 1.54±0.1cm2 during wakefulness. Position-dependent increase in CSA and decrease in AHI were correlated (r=0.42, p=0.022).

Conclusion:  Among early postpartum women, 45 degrees upper body elevation increased upper airway cross-sectional area and mitigated sleep apnea. Elevated body position might improve respiratory safety in women early after delivery.

original research 
Helen Ward, MBChB; Brendan G. Cooper, PhD; Martin R. Miller, MD
Topics: , ,

Background.  Consensus on how best to express bronchodilator reversibility (BDR) is lacking. We tested different BDR criteria against the null hypotheses that BDR should show no sex or size bias. To determine the best criterion for defining BDR we hypothesized that clinically important BDR should be associated with better survival compared to respiratory patients without BDR.

Methods.  We used the first BDR test of 4231 patients who had known subsequent survival status (50.8% males; mean age 60.9 years; mean survival 5.2 years, range 0.1 to 16.5). BDR for forced expiratory volume in 1 second (FEV1) was expressed as absolute change, % baseline change and change as % of predicted FEV1.

Results.  Having BDR defined from absolute change was biased to men (M:F ratio 2.70) and to those with larger baseline FEV1. BDR defined by % change from baseline was biased towards those with lower baseline values. BDR defined by % predicted had no sex or size bias. Multivariate Cox regression found those with FEV1BDR >8% predicted (33% of our subjects) had an optimal survival advantage (hazard ratio = 0.56, 95% CI 0.45 to 0.69) compared to those with BDR <=8% predicted. Those with FEV1BDR >8% predicted had survival not significantly different from those with FEV1BDR >14% predicted and significantly better than those with FEV1BDR <0.

Conclusions.  We have shown that expressing FEV1BDR as % predicted avoids sex and size bias. FEV1BDR >8% predicted showed optimal survival advantage and may be the most appropriate criterion to define clinically important reversibility.

contemporary reviews in sleep medicine 
Gerard Torres; Manuel Sánchez-de-la-Torre; Ferran Barbé
Topics: ,

There is a bidirectional association between obstructive sleep apnea (OSA) and systemic hypertension. The strengths of this relationship appear to be modulated by factors such as age, sex and somnolence. The 24-hour blood pressure (BP) circadian pattern also appears to be influenced by OSA. Patients with this syndrome exhibit a high prevalence of non-dipping or riser circadian patterns, which are related to clinical and subclinical organ damage in the heart and brain. However, the influence of OSA on nocturnal hypertension development has not yet been clarified. A special area of interest is the recognized relationship between OSA and resistant hypertension. The majority of patients with resistant hypertension suffer OSA. Continuous positive airway pressure (CPAP) treatment significantly reduces BP in such patients and could have a clinical role in the management of BP in these patients. Several meta-analyses have demonstrated a concordant mild effect of CPAP on systemic hypertension. This effect is related with CPAP compliance, somnolence status and baseline BP. The effects of oral appliances on BP in patients with OSA must be evaluated in randomized controlled trials. In the absence of additional data reported by clinical studies on other antihypertensive drug treatments, diuretics, particularly anti-aldosteronic diuretic agents, should be considered the first line antihypertensive drug treatment in patients with OSA. By reducing para-pharyngeal edema and secondary upper airway obstruction, these drugs appear to improve OSA severity and also to reduce BP.

original research 
Douglas F. Willson, MD; Jonathon D. Truwit, MD, MBA; Mark R. Conaway, PhD; Christine S. Traul, MD; Edmund E. Egan, MD
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Background:  Surfactant has been shown to be dysfunctional in acute respiratory distress syndrome and exogenous surfactant has proven effective in many forms of neonatal and pediatric acute lung injury. In view of the positive results of our studies in children along with evidence that SP-B containing pharmaceutical surfactants might be more effective, we designed a multi-institutional, randomized, controlled, and masked trial of calfactant, a calf lung surfactant, in adults and children with ALI/ARDS due to direct lung injury.

Methods:  Adult subjects within 48 hours of initiation of mechanical ventilation for direct acute respiratory distress syndrome were randomized to receive up to three interventions with instilled calfactant versus air placebo. The primary outcome was 90-day all cause mortality.

Results:  317 subjects were enrolled, 308 which could be evaluated. There were no significant baseline differences between groups. Calfactant administration was not associated with improved survival, lengths of stay, or oxygenation. Calfactant instillation was frequently associated with transient hypoxia and hypotension. The study was stopped at the first interim analysis at the sponsor’s request.

Conclusions:  Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, and masked trial. At present exogenous surfactant cannot be recommended for routine clinical use in acute respiratory distress syndrome.

original research 
David J. Lederer, MD; Williamson Z. Bradford, MD, PhD; Elizabeth A. Fagan, MS, MD; Ian Glaspole, MB BS, PhD; Marilyn K. Glassberg, MD; Kenneth F. Glasscock, BS; David Kardatzke, PhD; Talmadge E. King, Jr., MD; Lisa H. Lancaster, MD; Steven D. Nathan, MD; Carlos A. Pereira, MD; Steven A. Sahn, MD; Jeffrey J. Swigris, DO, MS; Paul W. Noble, MD
Topics: , , , ,

Background:  Forced vital capacity (FVC) outcomes in clinical trials in idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary endpoint of FVC change in a Phase 3 trial evaluating pirfenidone in adults with IPF.

Methods:  Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the ASCEND study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary endpoint of change from baseline to week 52 in FVC.

Results:  The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis.

Conclusion:  Our results confirm the robustness of the statistical finding on the primary endpoint of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF.

Clinical Trial Registration Number:  NCT01366209 (www.clinicaltrials.gov)

original research 
William T. Kuo, MD; Arjun Banerjee, BS; Paul S. Kim, MD; Frank J. DeMarco, Jr, MD; Jason R. Levy, MD; Francis R. Facchini, MD; Kamil Unver, MBiomedE, MBA; Matthew J. Bertini, MD; Akhilesh K. Sista, MD; Michael J. Hall, MD; Jarrett K. Rosenberg, PhD; Miguel A. DeGregorio, MD, PhD
Topics: , , ,

BACKGROUND  Systemic thrombolysis for acute PE carries up to a 20% risk of major bleeding, including a 2-5% risk of hemorrhagic stroke. We evaluated the safety and effectiveness of catheter-directed therapy (CDT) as an alternative treatment for acute PE.

METHODS  One hundred one consecutive patients receiving CDT for acute PE were prospectively enrolled in a multicenter registry. Massive PE (n=28) and submassive PE (n=73) were treated with immediate catheter-directed mechanical or pharmacomechanical thrombectomy and/or catheter-directed thrombolysis via low-dose hourly drug infusion with tPA or urokinase. Clinical success was defined as meeting all criteria: stabilization of hemodynamics, improvement in pulmonary hypertension and/or right heart strain, and survival to hospital discharge. Primary safety outcomes were major procedure-related complications and major bleeding events.

RESULTS  There were 53 men and 48 women with average age of 60 years (range, 22-86 years) and mean BMI of 31.03±7.20 kg/m2. The average thrombolytic doses were 28.0±11 mg tPA (n=76) and 2,697,101±936,287 IU for urokinase (n=23). Clinical success was achieved in 24/28 (85.7%)(95% CI, 67.3%-96.0%) patients with massive PE and 71/73 (97.3%)(95% CI, 90.5%-99.7%) with submassive PE. The mean PA pressure improved from 51.17±14.06 mmHg to 37.23±15.81 mmHg (n=92)(P<0.0001). Among patients monitored with follow-up echocardiography, 57/64 (89.1%)(95% CI, 78.8%-95.5%)(p<0.0001) showed improvement in right heart strain. There were no major procedure-related complications, no major hemorrhages, and no hemorrhagic strokes.

CONCLUSIONS  Catheter-directed therapy improves clinical outcomes in acute PE patients while minimizing the risk of major bleeding. At experienced centers, CDT is a safe and effective treatment for both acute massive and submassive PE.

CLINICAL TRIAL REGISTRATION:  NCT01097928, available at http://clinicaltrials.gov/show/NCT01097928

ahead of the curve 
G.J. Geersing, MD, PhD; J.A. de Groot, PhD; J.B. Reitsma, MD, PhD; professor A.W. Hoes, MD, PhD; F.H. Rutten, MD, PhD
Topics: , ,

Mortality caused by acute cardiopulmonary disease is decreasing and in many countries the population is aging rapidly. Yet, the life-years gained are often spent with multiple chronic and slowly progressive conditions, and this particularly applies to cardiopulmonary patients. Affected individuals often have multiple diagnoses related to the cardio-pulmonary-metabolic axis with accelerated aging and gradually progressive failure of organs that provide the body with oxygen and nutrients. This more or less reflects an “engine running out of fuel”. This, for instance, is the case with the concurrent presence of COPD and heart failure in one patient that is often combined with other co-morbidity such as atrial fibrillation, renal failure, or diabetes. This asks for a paradigm shift: away from single-disease oriented patient management and towards patient-tailored multi-morbidity medicine. Daily clinical practice is already recognizing this on a daily basis, yet clinical research and guidelines are still lagging behind. Thus, novel research approaches are needed in order to better guide evidence-based clinical practice. These approaches include the construction of diagnostic models to predict the presence of multiple diseases simultaneously, individual patient data meta-analysis as a method to examine variation in the effects of treatments or diagnostic tests depending on co-morbidity, and the construction of therapeutic prediction models that predict the therapeutic effect of drugs based on the presence (or absence) of relevant co-morbidity. We argue that multi-morbidity should be regarded as a “friend” and not as a “foe” in clinical research addressing the current clinical problems in daily practice.

ahead of the curve 
Asger R. Bihlet, MSc.; Morten A. Karsdal, PhD.; Anne-Christine Bay-Jensen, PhD; Simon Read, MD, PhD.; Jacob Hull Kristensen, MSc.; Jannie Marie Bülow Sand, MSc.; Diana Julie Leeming, PhD.; Jeppe Ragnar Andersen, MSc.; Peter Lange, MD, DMSc.; Jørgen Vestbo, MD, DMSc.
Topics: , ,

Despite massive investments in development of novel treatments for heterogeneous diseases such as Chronic Obstructive Pulmonary Disease (COPD), the resources spent have only benefitted a fraction of the population treated. Personalized Health Care to guide selection of a suitable patient population already in the clinical development of new compounds could offer a solution. In this review, we discuss past successes and failures in drug development and biomarker research in COPD. We describe research in COPD phenotypes, and the required characteristics of a suitable biomarker for identifying patients at higher risk of progression. We review the role of extra-cellular matrix proteins found to be upregulated in COPD. Novel biomarkers of connective tissue remodeling which may provide added value for a personalized approach by detecting subgroups of patients with active disease suitable for pharmacological intervention are discussed.

contemporary reviews in sleep medicine 
Tracey L. Stierer, MD; Nancy A. Collop, MD
Topics: ,

The overwhelming majority of surgical procedures performed in the United States are done on an outpatient basis. Patients with complicated medical problems are routinely scheduled for ambulatory procedures that have become progressively more complex. Appropriate patient selection is paramount in ensuring optimal perioperative outcomes, and the patient with known or suspected obstructive sleep apnea presents unique challenges to the anesthesia care team with regard to airway management, pain control, and postoperative monitoring requirements. Currently, there is a relative paucity of high quality evidence on which to base guidelines or recommendations for the anesthetic care of these patients. It is generally agreed that early identification of those at risk for OSA allows for planning and implementation of strategies to help reduce the risk of adverse perioperative events. While various national societies have published consensus statements aimed at providing guidance on the perioperative management of the patient at risk for OSA, it is clear that more studies are needed to help define the optimal approach to the perioperative care of this population.

evidence-based medicine  FREE TO VIEW
Anne E. Vertigan, PhD, MBA; Mohammad H. Murad, MD, MPH; Tamara Pringsheim, MD; Anthony Feinstein, MPhil, PhD; Anne B. Chang, MBBS, PhD, MPH; Peter A. Newcombe, PhD; Bruce K. Rubin, MEngr, MD, MBA; Lorcan P. McGarvey, MD; Kelly Weir, MSpPath; Kenneth W. Altman, MD, PhD; Miles Weinberger, MD, FCCP; Richard S. Irwin, MD, Master FCCP on behalf of the CHEST Expert Cough Panel
Topics: ,

Background:  We conducted a systematic review on the management of psychogenic cough, habit cough, and tic cough to update the recommendations and suggestions of the 2006 guideline on this topic.

Methodology:  We followed the CHEST methodological guidelines and the GRADE framework. The Expert Cough Panel based their recommendations on data from the systematic review, patients’ values and preferences and the clinical context. Final grading was reached by consensus according to Delphi methodology.

Results:  The results of the systematic review revealed only low quality evidence to support how to define or diagnose psychogenic or habit cough with no validated diagnostic criteria. With respect to treatment, low quality evidence allowed the committee to only suggest therapy for children thought to have psychogenic cough. Such therapy might consist of non-pharmacological trials of hypnosis or suggestion therapy or combinations of reassurance, counselling, and referral to a psychologist, psychotherapy and appropriate psychotropic medications. Based on multiple resources and contemporary psychological, psychiatric and neurological criteria (DSM-5 and tic disorder guidelines), the committee suggests that the terms psychogenic and habit cough are out of date and inaccurate.

Conclusions:  Compared to the 2006 CHEST Cough Guidelines, the major change in suggestions is that the terms psychogenic and habit cough be abandoned in favour of Somatic Cough Syndrome and Habit Cough, respectively, even though the evidence to do so at this time is of low quality.

medical ethics 
Nancy S. Jecker, Ph.D.; Denise M. Dudzinski, Ph.D., M.T.S.; Douglas S. Diekema, M.D., M.P.H.; Mark Tonelli, M.D., M.A.
Topics: ,

Caring for Ebola Virus Disease (EVD)-affected patients while simultaneously preventing EVD transmission represents a central ethical challenge of the EVD epidemic. To address this challenge, we propose a model policy for “Resuscitation and Emergent Procedure Policy of EVD Patients” and set forth ethical principles that lend support to this policy. The policy and principles we propose bear relevance beyond the EVD epidemic, offering guidance for the care of patients with other highly contagious, virulent, and lethal diseases. The policy establishes (1) a Limited Code Status for confirmed or suspected EVD patients. Limited Code Status means that a Code Blue will not be called for patients with confirmed or suspected EVD at any stage of the disease; however properly protected providers (those already in full protective equipment) may initiate resuscitative efforts if, in their clinical assessment, these efforts are likely to benefit the patient. The policy also requires that (2) resuscitation not be attempted for patients with advanced EVD, as resuscitation would be medically futile; (3) providers caring for or having contact with confirmed or suspected EVD patients be properly protected and trained; (4) the treating team identify and treat in advance likely causes of cardiac and respiratory arrest to minimize the need for emergency response; (5) EVD patients and their proxies be involved in care discussions; and (6) care team and provider discretion guide the care of EVD patients. We discuss ethical issues involving medical futility and the duty to avoid harm, and propose a utilitarian-based principle of triage to address resource scarcity in the emergency setting.

original research  OPEN ACCESS
Jennifer Y. Lam, MD; Steven Lopushinsky, MD, MSc; Irene Ma, MD, MSc; Frank Dicke, MD, MBA; Mary Brindle, MD, MPH
Topics: ,

Background:  Patent ductus arteriosus (PDA) in the non-premature pediatric patient is currently treated by surgical ligation or catheter occlusion. There is no clear superiority of one technique over the other. This meta-analysis compares the clinical outcomes of the two treatment options for PDA.

Methods:  We performed a literature search of MEDLINE, Embase, PubMed, and Cochrane database of randomized controlled trials (RCTs) from 1950 until Feb 2014 and hand-searched references from included studies. We excluded studies of adult or premature patients and those without direct comparison between surgical and catheter-based treatments of PDAs. Outcomes of interest were re-intervention, total complications, length of stay and cost.

Results:  1333 manuscripts were screened. Eight studies fulfilled the inclusion criteria- one RCT and seven observational studies (total n = 1107). In pooled observational studies there was a significantly decreased odds (OR 0.12; 95% CI 0.03,0.42) for re-intervention in the surgical ligation group but an insignificantly higher odds for overall complications (OR 2.01; 95% CI 0.68,5.91). There were no complications reported in the RCT but surgical ligation was associated with decreased odds for re-intervention and a longer length of stay. Funnel plots revealed possible publication bias and quality review identified comparability bias.

Conclusion:  Both therapies have comparable outcomes. Re-intervention is more common with catheter-based treatment but overall complication rates were not higher and hospital stay is shorter. Our data span more than two decades and may not reflect current surgical and catheterization outcomes. Large, randomized prospective studies may help determine the optimal treatment strategy.

original research 
Kyuichi Kadota, MD, PhD; Yi-Chen Yeh, MD; Jonathan Villena-Vargas, MD; Leonid Cherkassky, MD; Esther N. Drill, MS; Camelia S. Sima, MD, MS; David R. Jones, MD, FACS; William D. Travis, MD; Prasad S. Adusumilli, MD, FACS, FCCP
Topics: , ,

Background:  Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma.

Methods:  Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and FoxP3+ lymphocytes, CD68+ macrophages, IL-7R, and IL-12Rβ2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using competing risks method.

Results:  In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs. 12%, P < 0.001), which was confirmed in the validation cohort (P = 0.005). Tumor budding stratified risk of recurrence for acinar-predominant (22% vs. 9%, P < 0.001), papillary-predominant (22% vs. 13%, P = 0.045), and solid-predominant (39% vs. 19%, P = 0.022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7R overexpression (P < 0.001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (HR, 1.61; P = 0.008).

Conclusions:  Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at invading edge as a biological driver of tumor aggressiveness.

original research 
Lisette I.Z. Kunz, MD; Dirkje S. Postma, MD, PhD; Karin Klooster; Thérese S. Lapperre, MD, PhD; Judith M. Vonk, PhD; Jacob K. Sont, PhD; Huib A.M. Kerstjens, MD, PhD; Jiska B. Snoeck-Stroband, MD, PhD; Pieter S. Hiemstra, PhD; Peter J. Sterk, MD, PhD; the GLUCOLD Study Group
Topics: ,

Background:  We previously observed that 30 months of inhaled corticosteroids (ICS) can attenuate FEV1-decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1-decline, airway hyperresponsiveness (AHR) and quality of life (QOL) deteriorate after ICS cessation even after prolonged use.

Methods:  114 moderate-to-severe COPD patients finished randomized treatment with 6-month (F6) or 30-month fluticasone (F30) (500µg, bid), 30-month fluticasone/salmeterol (FS30) (500/50µg, bid) or placebo (GLUCOLD-1 [GL1]). The subsequent five years, patients were prospectively followed annually, treated by their physician (GL2). Post-bronchodilator FEV1, AHR and QOL were initially recorded at baseline, 30 months (GL1) and annually during GL2. Analysis was performed by linear mixed-effects models.

Results:  Amongst 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICS during GL1, but only using ICS 0-50% of time during GL2 (n=56/79) had significantly accelerated annual FEV1-decline compared to GL1 (difference GL2-GL1 [95%CI]: FS30 -68ml/year [-112 to -25], p=0.002; F30 -73ml/year [-119 to -26], p=0.002), accompanied by deterioration in AHR and QOL.

Conclusions:  ICS discontinuation after 30-month in COPD can worsen lung function decline, AHR and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease modifying effect after treatment cessation.

Trial registry:  ClinicalTrials.gov registration number: NCT00158847.

contemporary reviews in critical care medicine 
Ian P. Sinha, PhD; Antonia K.S. McBride, MbChB; Rachel Smith, MbChB; Ricardo M. Fernandes, MD
Topics: , , ,

Some infants with bronchiolitis develop severe respiratory failure, because of a complex pathophysiological process that involves increased airways resistance, alveolar atelectasis, muscle fatigue, and hypoxaemia due to mismatch between ventilation and perfusion. Nasal continuous positive airway pressure (CPAP) and high flow nasal cannula oxygen (HFNC) may improve work of breathing and oxygenation. Although the mechanisms behind these non-invasive modalities of respiratory support are not well understood, they may help infants by way of distending pressure, and delivery of high concentrations of warmed and humidified oxygen.

  Observational studies, of varying quality, suggest that CPAP and HFNC may confer direct physiological benefits to infants with bronchiolitis, and that their use has reduced the need for intubation.

  No trials have compared CPAP with HFNC in bronchiolitis. Two randomized trials have compared CPAP with oxygen delivered by low flow nasal cannula oxygen or facemask, and found some improvements in blood gas results and some physiological parameters, but were unable to demonstrate reduction in the need for intubation. Two trials have evaluated HFNC in bronchiolitis (one comparing it with headbox oxygen and the other with nebulized hypertonic saline), and the results do not seem to suggest important clinical or physiological benefits. In this paper we review the pathophysiology of respiratory failure in bronchiolitis, discuss these trials in detail, and consider how future research studies may be designed to best evaluate CPAP and HFNC in bronchiolitis.

point and counterpoint 
Mark V. Avdalovic; Susan Murin

The use of e-cigarettes continues to dramatically increase, and the debate over their safety and appropriate use has heated up, in parallel. We as pulmonary clinicians are called upon to advise our patients and others about e-cigarettes, which presents challenges given the current limitations of the data upon which our advice should be based. What do we say?

point and counterpoint 
Mark V. Avdalovic; Susan Murin
Topics: , , , , , , , , , , , , , , , , , ,

We agree with many of the points raised by Dr. Middlekauff. In comparison to traditional cigarettes it appears that e-cigarettes are less carcinogenic and their use in lieu of cigarettes would likely lead to less chronic cardiovascular and respiratory disease. In an ideal world, millions of traditional cigarette smokers would switch to the e-cigarette and the global burden of lung cancer, coronary disease and COPD would dramatically decrease over time. Unfortunately, we do not live in an ideal world, and the dream that e-cigarettes will lead to a decrease in total tobacco consumption may be replaced with the nightmare that e-cigarettes may instead increase the total number of tobacco smokers. At the heart of the argument are the changing demographics of e-cigarette users. Although most states (though no federal laws) prohibit the sale of e-cigarettes to minors, e-cigarettes and nicotine solutions (many with enticing added flavors) are easily purchased online, and the age of the first time e-cigarette user is decreasing. A recent report form the California Department of Public Health stated that 8th and 10th graders now use e-cigarettes two times more that they do traditional cigarettes, that 17% of 12th graders use e-cigarettes, and e-cigarette use among younger adults has tripled in the last year. The theoretical concern over e-cigarettes being a “gateway” to tobacco consumption is no longer theoretical, it’s a reality. In fact, a recent study reported that 43% of e-cigarette-using teens had a positive intention to use traditional cigarettes in the future. Perhaps the best proof of e-cigarettes being a gateway for traditional cigarettes is the fact that “big tobacco” has gotten into the e-cigarette business in a big way.

point and counterpoint 
Holly R. Middlekauff, MD

Although the medical community is unanimous in its wish to limit, or even eliminate tobacco smoking, the role of electronic(e)-cigarettes in this process has been controversial. Will e-cigarettes be part of the solution by harm reduction – and are e-cigarettes really less harmful? Or will e-cigarettes contribute to the problem by serving as a gateway to tobacco cigarettes? As we are debating, regulations are being issued - and challenged. Unfortunately, due to a paucity of data, the calls for regulations in some cases sound alarmist. Certainly contributing to the strong opposition roused by the e-cigarette is our well-founded distrust of anything associated with the $85 billion U.S. combusted-cigarette industry. Tobacco cigarette smoke is responsible for ∼480,000 deaths/year in the U.S. Approximately 18% of adult Americans smoke, a number which has not significantly decreased for a decade, despite anti-smoking campaigns, high cigarette taxes, and smoke-free policies. The position argued here is that an emotion-based, rather than evidenced-based, response to e-cigarettes may lead to a premature and scientifically unjustified rejection of a potentially beneficial means to reduce the enormous adverse health effects of tobacco cigarettes.

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