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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 
Zegabriel Tedla; Minh-Ly Nguyen; Thabisa Sibanda; Samba Nyirenda; Tefera B. Agizew; Sonali Girde; Charles E. Rose; Taraz Samandari
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Background:  The World Health Organization recommends 36 months of isoniazid preventive therapy (36IPT) for HIV-infected adults living in tuberculosis endemic countries. We determined the rates and risk factors for isoniazid-associated hepatitis with the use of 36IPT.

Methods:  1006 HIV-infected adults received 36IPT during a pragmatic randomized trial set in Botswana public health clinics providing HIV care. Enrollment exclusion criteria included jaundice or elevations of serum transaminases (EST) >2.5-fold the upper limit of normal (ULN). Participants with any CD4+ lymphocyte count were eligible and received antiretroviral therapy (ART) when CD4+ <200 cells/mm3. 36IPT was stopped for severe hepatitis (>5-fold ULN EST) but not for moderate hepatitis (2.5 to 5-fold ULN EST).

Results:  Pharmacy refill records showed 2237 person-years of isoniazid receipt; 48% of participants initiated ART by 36 months. 1.9% (19/1006) of participants were diagnosed with severe hepatitis; three were jaundiced and two of these developed hepatic encephalopathy. Another 3.1% (31/1006) of participants experienced moderate hepatitis. 38% (19/50) of participants with moderate-to-severe hepatitis concomitantly received ART. Forty percent (20/50) of moderate-to-severe cases occurred within the first two months of IPT and – during this period – were not associated with receipt of ART at baseline, hazard ratio 1.49 (95% confidence interval 0.20-11.1, P=0.70).

Conclusions:  HIV-infected adults receiving 36IPT did not have an increased incidence of moderate-to-severe hepatitis or hepatic encephalopathy compared with published reports among HIV-infected or -uninfected persons in trials or public health programs. Compared with participants not receiving ART, the risk of moderate-to-severe hepatitis was not increased by ART.

original research 
Robert M. Kaplan, Ph.D.; Qiankun Sun, PhD; Andrew L. Ries, M.D, M.P.H.
Topics: , ,

Background:  Surgical and medical treatments for emphysema may affect both quality and quantity of life. The purpose of this paper is to report outcomes from the National Emphysema Treatment Trial (NETT) using an index that combines quality and quantity of life.

Design:  Prospective Randomized Clinical Trial. Following pulmonary rehabilitation, 1218 patients with severe emphysema were randomly assigned to maximal medical therapy or to lung volume reduction surgery (LVRS). A generic quality of life (QoL) measure, known as the Quality of Well-bing (QWB) Scale, was administered at baseline and again at 6, 12, 24, 36, 48, 60 and 72 months following treatment assignment.

Result:  At baseline, QWB scores were comparable for the Medical and LVRS groups. For both groups, scores significantly improved following the rehabilitation program. The QWB scores before death for patients in the LVRS group improved up to the Year 2 visit, while scores for the Medical group dropped significantly following the baseline visit. Imputing zeros (0) for death, QWB scores decreased significantly for both groups. With or without scoring death as 0, the LVRS group achieved better outcomes and the significant differences were maintained until the sixth year. Over six years of follow-up LVRS produced an average of 0.30 QALYs, or the equivalent of about 3.6 months of well life.

Conclusions:  In comparison to maximal medical therapy alone, patients undergoing maximal medical therapy plus LVRS experienced improved health related quality of life and gained more quality-adjusted life years.

ClinicalTrials.gov Identifier:  NCT00000606

original research 
Amédée Ego, MS; Jean-Charles Preiser, MD, PhD; Jean-Louis Vincent, MD, PhD, FCCP
Topics: ,

Background:  Ventilator-associated pneumonia (VAP) is a frequent complication of prolonged invasive ventilation. Because VAP is largely preventable, its incidence has been used as an index of quality-of-care in the intensive care unit (ICU). However, the incidence of VAP varies according to which criteria are used to identify it. We compared the incidence of VAP obtained with different sets of criteria.

Methods:  We collected data from all adult patients admitted to our 35-bed Dept of Intensive Care over a 7-month period who had no pulmonary infection on admission or within the first 48 hours and who required mechanical ventilation for >48 hours. To diagnose VAP, we applied six published sets of criteria and 89 combinations of criteria for hypoxemia, inflammatory response, purulence of tracheal secretions, chest radiography findings and microbiological findings of varying levels of severity. The variables used in each diagnostic algorithm were assessed daily.

Results:  Of 1,824 patients admitted to the ICU during the study period, 91 were eligible for inclusion. The incidence of VAP ranged from 4% to 42% when using the 6 published sets of criteria, and from 0-44% when using the 89 combinations. The delay before diagnosis of VAP increased from 4 to 8 days with increasingly stringent criteria and mortality from 50 to 80%.

Conclusions:  Applying different diagnostic criteria to the same patient population can result in wide variation in the incidence of VAP. The use of different criteria can also influence the time of diagnosis and the associated mortality rate.

original research 
Sadasivam Suresh, FRACP; Michael O’Callaghan, FRACP; Peter D. Sly, DSc; Abdullah A. Mamun, PhD
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Background:  Poor fetal growth rate is associated with lower respiratory function; however there is limited understanding of the impact of growth trends and body mass index(BMI) during childhood on adult respiratory function.

Methods:  The present study data are from the Mater-University of Queensland Study of Pregnancy birth cohort. Prospective data were available from 1740 young adults who performed standard spirometry at 21 years and birth weight, and weight, height and BMI was available at 5, 14 and 21 years of age. Catch-up growth was defined as increase of 0.67 Z-score in weight between measurements. The impact of catch-up growth on adult lung function and the relationship between childhood BMI trends and adult lung function was assessed using regression analyses.

Results:  Lung function was higher at 21 years in those demonstrating catch-up growth from birth to 5years;FVC [(males:5.33L v 5.54L), (females:3.78L v 4.03L)] and FEV1 [(males:4.52l/s v 4.64l/s), (females:3.31l/s v 3.45l/s)]. Subjects in the lowest quintile of birth [IUGR] also showed improved lung function if they had catch-up growth in the first five years of life.There was a positive correlation with increasing BMI and lung function at 5 years of age. However in the later measurements when BMI increases into the obese category a drop in lung function was observed.

Conclusion:  These data show evidence for a positive contribution of catch-up growth in early life to adult lung function. However, if weight gain or onset of obesity occurs after 5 years of age adverse impact on adult lung function is noted.

original research 
Bradley D. Freeman, MD; Kevin Butler, MS; Dragana Bolcic-Jankovic, MS; Brian R. Clarridge, PhD; Carie R. Kennedy, RN; Jessica LeBlanc, BA; Sara Chandros Hull, PhD
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Background:  Collection of genetic biospecimens as part of critical illness investigations is increasingly commonplace. Oversight bodies vary in restrictions imposed on genetic research, introducing inconsistencies in study design, potential for sampling bias, and the possibility of being overly prohibitive of this type of research altogether. We undertook this study to better understand whether restrictions on genetic data collection beyond those governing research on cognitively intact subjects reflect the concerns of surrogates for critically ill patients.

Methods:  We analyzed survey data collected from 1,176 patients in non-urgent settings and 437 surrogates representing critically ill adults. Attitudes pertaining to genetic data (familiarity, perceptions, interest in participation, concerns) and demographic information were examined using univariate and multivariate techniques.

Results:  We explored differences among respondents who were receptive (1,333) and non-receptive (280) to genetic sample collection. Whereas factors positively associated with receptivity to research participation were ‘complete trust’ in health care providers (OR 95%CI 2.091 (1.544-2.833)), upper income strata (2.319 (1.308-4.114)), viewing genetic research ‘very positively’ (3.524 (2.122-5.852)) and expressing ‘no worry at all’ regarding disclosure of results (2.505 (1.436-4.369)), African American race was negatively associated with research participation (0.410 (0.288-0.585)). We could detect no difference in receptivity to genetic sample collection comparing ambulatory patients and surrogates (0.738 (0.511-1.066)).

Conclusions:  Expressing trust in health care providers and viewing genetic research favorably were associated with increased willingness for study enrollment while concern regarding breach of confidentiality and African American race had the opposite effect. Study setting had no bearing on willingness to participate.

original research 
Brian H. Rowe, MD, MSc; Cristina Villa-Roel, MD, MSc; Sumit R. Majumdar, MD, MPH; Riyad B. Abu-Laban, MD, MHSc; Shawn D. Aaron, MD, MSc; Ian G. Stiell, MD, MSc; Jeffrey Johnson, PhD; Ambikaipakan Senthilselvan, PhD; for the AIR Investigators
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Background:  Acute asthma is a common emergency department (ED) presentation. In a prospective multicenter cohort study we determined the frequency and factors associated with asthma relapse following discharge from the ED.

Methods:  Adults aged 18-55 years who were treated for acute asthma and discharged from 20 Canadian EDs underwent a structured ED interview and follow-up telephone interview four weeks later. Standardized anti-inflammatory treatment was offered at discharge. Multivariable analyses were performed.

Results:  Of 807 enrolled patients, 58% were female and the median age was 30 years. Relapse occurred in 144 patients (18%) within four weeks of ED discharge. Factors independently associated with relapse occurrence were: female sex (22% vs 12% males, adjusted odds ratio [aOR] = 1.9, 95% confidence interval [CI]: 1.2, 3.0), symptom duration of > 24 hours prior to ED visit (19% vs 13% short duration, aOR = 1.7, 95% CI: 1.3, 2.3), ever using oral corticosteroids (21% vs 12% for never use, aOR = 1.5, 95% CI: 1.1, 2.0), current use of an inhaled corticosteroids[ICS]/long-acting β-agonist combination product (25% vs 15% for ICS monotherapy, aOR = 1.9, 95% CI: 1.1, 3.2), and owning a spacer device (24% vs 15% not owning one aOR = 1.6, 95% CI: 1.3, 1.9).

Conclusions:  Despite receiving guideline-concordant anti-inflammatory treatments at ED discharge, almost one-in-five patients relapsed within four weeks. Female sex, prolonged symptoms, treatment-related factors and markers of prior asthma severity were significantly associated with relapse. These results may help clinicians target more aggressive interventions for patients at high risk of relapse.

original research 
Ali Akbar Velayati; Parissa Farnia; Mohadese Mozafari; Donya Malekshahian; Amir Masoud Farahbod; Shima Seif; Snaz Rahideh; Mehdi Mirsaeidi
Topics: , , , , , ,

Background  The potential role of environmental M. tuberculosis in the epidemiology of tuberculosis (TB) remains unknown. We investigated the transmission of M. tuberculosis from humans to the environment and the possible transmission of M. tuberculosis from the environment to humans.

Methods  A total of 1,500 samples were collected from three counties of the Tehran metropolitan area, Iran from February 2012 to January 2014. A total of 700 (47%) water and 800 (53%) soil samples were collected. Spoligotypes and MIRU-VNTR typing method performed on DNA extracted from single colonies. Genotypes of M. tuberculosis strains isolated from the environment were compared with the genotypes obtained from 55 confirmed pulmonary TB patients diagnosed during the study period in the same three counties.

Results  M. tuberculosis was isolated from (11/800, 1%) of soil and (71/700, 10%) of water samples. T family (56/82; 68%) followed by Delhi/CAS (11/82; 13.4%) were the most frequent M. tuberculosis superfamilies in both water and soil samples. Overall, 27.7% of isolates in clusters were related. No related typing patterns were detected between soil, water and clinical isolates. The most frequent superfamily of M. tuberculosis in clinical isolates was Delhi/CAS (142; 30.3%) followed by NEW-1(127;27%). The bacilli in contaminated soil (36%) and damp water (8.4%) remained reculturable in some samples up to 9 months.

Conclusion  Although the dominant M. tuberculosis superfamilies in soil and water did not correspond to the dominant M. tuberculosis family in patients, the presence of circulating genotypes of MTB in soil and water highlight the risk of transmission.

original research 
Rachael A. Evans, MBChB, PhD; Eric Kaplovitch, BSc (H), MD; Marla K. Beauchamp, PhD; Thomas E. Dolmage, MSc; Roger S. Goldstein, MBChB; Clare L. Gillies, PhD; Dina Brooks, PhD; Sunita Mathur, PhD
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Background  Although the aerobic profile of the quadriceps muscle is reduced in COPD, there is conflicting evidence whether this leads to reduced quadriceps muscle endurance. We therefore performed a systematic review of studies comparing quadriceps endurance in individuals with COPD to healthy controls.

Methods  Relevant studies were identified by searching six electronic databases (1946-2011). Full text articles were obtained after two researchers independently reviewed the abstracts. The results were combined in a random effects meta-analysis and meta-regression models were fitted to assess the influence of type of measurement.

Results  Data were extracted from 21 studies involving 728 individuals with COPD and 440 healthy controls. Quadriceps endurance was reduced in COPD compared to healthy controls SMD 1.16 (95% CI: 1.02 to 1.30, p<0.001) with a 44.5 (4.5 to 84.5) second (p=0.029) reduction in COPD (large effect size) when measured using a non-volitional technique. The relationship between quadriceps endurance in COPD and controls did not differ when comparing non-volitional and volitional techniques (p = 0.22) or when high or low intensity tasks (p = 0.44) were used.

Conclusion  Quadriceps endurance is reduced in individuals with COPD compared to healthy controls independent of the type of task performed.

original research 
Jing Liu, MD, PhD; Shui-Wen Chen, MD; Fang Liu, MD; Qiu-Ping Li, MD, PhD; Xiang-Yong Kong, MD, PhD; Zhi-Chun Feng, MD, PhD
Topics: ,

BACKGROUND AND OBJECTIVES:  Generally,the diagnosis of neonatal pulmonary atelectasis (NPA) is based on history, clinical and chest x-ray (CXR) findings while ultrasound could not be used in lung disease diagnostics. Recently, ultrasound has been used for the diagnosis of many kinds lung conditions, but few studies have investigated ultrasound for the diagnosis of NPA. In this study, we evaluated the usefulness of lung ultrasound for the diagnosis of NPA.

METHODS:  From May 2012 to December 2013, 80 neonates with NPA and 50 neonates without lung disease were enrolled in this study. In a quiet state, infants were placed in the supine, lateral or prone position for the examination. Each lung of every infant was divided into the anterior, lateral and posterior regions by the anterior axillary and posterior axillary lines. Each region of both lungs was scanned carefully with the probe perpendicular or parallel to the ribs. The ultrasound findings were confirmed by CXR or computed tomography findings.

RESULTS:  Sixty of the 80 patients with signs of NPA on lung ultrasound also had signs of NPA on CXR (termed focal type of atelectasis), and the other 20 patients had signs of NPA on chest computed tomography (termed occult lung atelectasis). In NPA patients,the main ultrasound findings were large areas of lung consolidation with clearly demarcated borders, air bronchograms, pleural line abnormalities, and absence of A-lines, as well as presence of lung pulse and absence of lung sliding on real-time ultrasound. The sensitivity of lung ultrasound for the diagnosis of NPA was 100%, whereas the sensitivity of CXR was 75%. Large areas of lung consolidation with clearly demarcated borders were only observed in patients with NPA (specificity of 100% for NPA).

CONCLUSIONS:  Lung ultrasound is an accurate and reliable method for diagnosing NPA, most importantly, it can find those occult lung atelectasis that could not be detected on CXR. Routine lung ultrasound is a useful method of diagnosing or excluding NPA in neonates.

original research 
John H. Newman, MD; Evan L. Brittain, MD; Ivan M. Robbins, MD; Anna R. Hemnes, MD
Topics: , ,

Background:  Pulmonary vascular capacitance (PVC) is reduced in pulmonary arterial hypertension (PAH). In normal lung PVC is largely a function of vascular compliance. In PAH, increased resistance (PVR) arises from the arterioles. PVR and PVC share pressure and volume variables. The dependency between the two qualities of the vascular bed is unclear in a state of intense vasoconstriction.

Methods:  We compared PVC and PVR before and during nitric oxide (NO) inhalation during right heart catheterization in 8 NO responsive PAH patients. NO only directly affects tone in parenchymal vessels.

Results:  During NO inhalation, Pa systolic decreased, 80± 20 STD to 48 ± 20 mmHg and stroke volume increased , 62 ± 19 to 86 ± 24 ml. (p<0.01). PVR dropped from 10 ± 4.4 to 4.7 ± 2.2 Wood units (p<0.012), and PVC increased from 1.4 ± 1.1 to 3.2 ± 1.8 ml/mmHg (p <0.018). The magnitude of PVR drop was 57± 6% and the decrease in 1/PVC was 54 ± 14%, p=ns.

Conclusions:  In vasoresponsive PAH, PVC is a function of the pressure response of the vasoconstricted arterioles to stroke volume. Immediately upon vasodilation, the capacitance increases markedly. The compliance vessels are thus the same as the resistance vessels. The immediate reduction in Pa pressure during NO suggests that large vessel remodeling is not a major contributor to systolic pressure in these patients.

original research 
Martina Bonifazi, MD; Francesca Bravi, PhD; Stefano Gasparini, MD; Carlo La Vecchia, MD; Armando Gabrielli, MD; Athol U. Wells, MD; Elisabetta A. Renzoni, MD
Topics: , ,

Background.  An increased cancer risk in sarcoidosis patients has been suggested, although results are conflicting in a number of case-control and cohort studies. We conducted a systematic review of all available data and performed a meta-analysis to better define and quantify the association between sarcoidosis and cancer.

Methods.  We searched Medline and Embase for all original articles on cancer and sarcoidosis published up to January 2013. Two independent authors reviewed all titles/abstracts to identify studies according to predefined selection criteria. We derived summary estimates using random effects model and reported as relative risk (RR). Publication bias was evaluated by using funnel plot and was quantified by Egger's test.

Results.  Sixteen original studies, involving more than 25,000 patients, were included in the present review. The summary RR to develop all invasive cancers was 1.19 (95% CI, 1.07-1.32). The results for selected cancer sites indicated a significant increased risk of skin (RR 2.00; 95% CI, 1.69-2.36), haematopoietic (RR 1.92; 95% CI, 1.41-2.62), upper digestive tract (RR 1.73; 95% CI, 1.07-2.79), kidney (RR 1.55; 95% CI, 1.21-1.99), liver (RR 1.79; 95% CI, 1.03-3.11) and colorectal cancers (1.33; 95% CI, 1.07-1.67). There was no evidence of publication bias for all cancers (p=0.8), nor for any specific cancer site.

Conclusions.  The present meta-analysis suggests a significant, though moderate, association between sarcoidosis and malignancy.

original research 
Alda Marques, PhD; Cristina Jácome, MSc; Joana Cruz, MSc; Raquel Gabriel, MSc; Dina Brooks, PhD; Daniela Figueiredo, PhD
Topics: , , ,

Background:  Involving family as part of the patient’s rehabilitation plan of care might enhance the management of Chronic Obstructive Pulmonary Disease (COPD). The primary aim of this study was to investigate the impact of a family-based pulmonary rehabilitation (PR) program on patients and family members’ coping strategies to manage COPD.

Methods:  Family dyads (patient and family member) were randomly assigned to family-based (experimental) or conventional PR (control). Patients from both groups underwent exercise training three times a week and psychosocial support and education once a week, during 12 weeks. Family members of the family-based PR attended the psychosocial support and education sessions together with patients. In the conventional PR, family members did not participate. Family coping and psychosocial adjustment to illness were assessed in patients and family members of both groups. Patients’ exercise tolerance, functional balance, muscle strength and health-related quality of life were also measured. All measures were collected pre/post-program.

Results:  Forty-two dyads participated (patients: FEV1 70.4±22.1% predicted). Patients (p=0.048) and family members (p=0.004) in the family-based PR had significantly greater improvements in family coping than the control group. Family members of the family-based PR had significantly greater changes in sexual relationships (p=0.026) and in psychological distress (p=0.033) compared to the control group. Patients from both groups experienced significant improvements in exercise tolerance, functional balance, knee extensors strength and health-related quality of life after intervention (p<0.001).

Conclusions:  This research supports family-based PR programs to enhance coping and psychosocial adjustment to illness of the family system.

Clinical Trials registration number:  NCT02048306

original research 
S.L. Harrison; T. Janaudis-Ferreira; D. Brooks; L. Desveaux; R.S. Goldstein
Topics: , ,

Background:  Self-management (SM) reduces hospital admissions in patients with stable Chronic Obstructive Pulmonary Disease (COPD). However, its role immediately post-acute exacerbation (AE) is unclear. The objectives of this review were to; describe SM interventions delivered immediately following an AECOPD and to conduct a systematic review with meta-analysis of its impact on healthcare utilisation and health outcomes.

Method:  Randomised controlled trials reporting on SM interventions delivered during hospitalisation for an AECOPD or within one month of hospital discharge were included. Seven papers were identified. Data were extracted and assessed for quality by two researchers.

Results:  By definition all interventions included action plans, education and at least two SM skills. Nurses were responsible for providing all SM interventions. The delivery and follow up periods varied widely. At 12 months there were no significant differences between those who completed the SM intervention and control subjects in the number of patients readmitted to hospital (p=0.38), or in health-related quality of life (HRQOL) (p=0.27). No effects were found on; rate of mortality, depressive symptoms, primary care usage or exercise capacity. Minimal effects were found on; self-efficacy, anxiety symptoms, and health promoting behavior. SM was associated with positive effects on knowledge and management of an AECOPD.

Conclusions:  SM interventions delivered immediately post-AE vary widely and outcome measures are inconsistent, making it difficult to draw strong recommendations regarding its effectiveness. The evaluation of SM interventions, delivered by trained health care professionals to selected patients and which offer structured follow up, appears necessary.

evidence-based medicine  FREE TO VIEW
Gerard J. Criner, MD, FCCP; Jean Bourbeau, MD, FCCP, FRCPC; Rebecca L. Diekemper, MPH; Daniel R. Ouellette, MD, FCCP; Donna Goodridge, RN, PhD; Paul Hernandez, MDCM, FRCPC; Kristen Curren, MA; Meyer S. Balter, MD, FCCP, FRCPC; Mohit Bhutani, MD, FCCP, FRCPC; Pat G. Camp, PT, PhD; Bartolome R. Celli, MD, FCCP; Gail Dechman, PT, BScPT, PhD; Mark T. Dransfield, MD; Stanley B. Fiel, MD, FCCP; Marilyn G. Foreman, MD, FCCP; Nicola A. Hanania, MBBS, FCCP; Belinda K. Ireland, MD, MSc; Nathaniel Marchetti, DO, FCCP; Darcy D. Marciniuk, MD, FCCP; Richard A. Mularski, MD, FCCP; Joseph Ornelas, MS, PhD(c); Jeremy D. Road, MD, FRCPC; Michael K. Stickland, PhD
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Chronic obstructive pulmonary disease (COPD) is a common disease with substantial associated morbidity and mortality. Patients with COPD usually have a progression of airflow obstruction that is not fully reversible and can lead to a history of progressive worsening breathlessness that can impact daily activities and health-related quality of life. COPD is the fourth leading cause of death in Canadian men and women and the third in the U.S., it claimed 133,965 U.S. lives in 2009. In 2011, 12.7 million U.S. adults were estimated to have COPD. However, approximately 24 million U.S. adults have evidence of impaired lung function, indicating an under diagnosis of COPD. While 4% of Canadians aged 35 to 79 self-reported being diagnosed with COPD, direct measurements of lung function from the Canadian Health Measures Survey (CHMS) indicate that 13% of Canadians had a lung function score indicative of COPD.

evidence-based medicine  FREE TO VIEW
Gerard J. Criner, MD, FCCP; Jean Bourbeau, MD, FCCP, FRCPC; Rebecca L. Diekemper, MPH; Daniel R. Ouellette, MD, FCCP; Donna Goodridge, RN, PhD; Paul Hernandez, MDCM, FRCPC; Kristen Curren, MA; Meyer S. Balter, MD, FCCP, FRCPC; Mohit Bhutani, MD, FCCP, FRCPC; Pat G. Camp, PT, PhD; Bartolome R. Celli, MD, FCCP; Gail Dechman, PT, BScPT, PhD; Mark T. Dransfield, MD; Stanley B. Fiel, MD, FCCP; Marilyn G. Foreman, MD, FCCP; Nicola A. Hanania, MD, MS, FCCP, FRCPC; Belinda K. Ireland, MD, MSc; Nathaniel Marchetti, DO, FCCP; Darcy D. Marciniuk, MD, FCCP; Richard A. Mularski, MD, MSHS, MCR, FCCP; Joseph Ornelas, MS, PhD(c); Jeremy D. Road, MD, FRCPC; Michael K. Stickland, PhD
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Background:  Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the United States as well as the rest of the world. An exacerbation of COPD, periodic escalations of symptoms of cough, dyspnea and sputum production, is a major contributor to the worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and costs of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has recently accumulated about the prevention of acute exacerbations.

Methods:  In recognition of the importance of the prevention of exacerbations in the life of a COPD patient, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. The 3 key clinical questions were developed using the PICO (population, intervention, comparator, and outcome of interest) format, that addressed the prevention of acute exacerbations of COPD were non-pharmacologic therapies, inhaled therapies, and oral therapies. We utilized recognized document evaluation tools to allow us to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendation in each PICO category in a balanced and unbiased fashion.

Results:  The AECOPD Guideline is unique not only for the topic of the guideline, prevention of acute COPD exacerbations, but also for the first-in-kind partnership between two of the largest thoracic societies of North America. The Guidelines Oversight Committee (GOC) of the American College of Chest Physicians in partnership with the COPD Clinical Assembly of the Canadian Thoracic Society launched this project with the objective that a systematic review and critical evaluation of the published literature that was conducted by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the COPD patient.

Conclusion:  This guideline is unique because it provides an up-to-date, rigorous evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.

original research 
Meeta Prasad Kerlin, MD, MSCE; Michael O. Harhay, MPH; Jeremy M. Kahn, MD, MSc; Scott D. Halpern, MD, PhD
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Background:  Evidence regarding nighttime physician staffing of intensive care units (ICUs) is suboptimal. We aimed to determine how nighttime physician staffing models influence patient outcomes.

Methods:  We performed a multicenter retrospective cohort study in a multicenter registry of US ICUs. The exposure variable was the ICU’s nighttime physician staffing model. The primary outcome was hospital mortality. Secondary outcomes included new limitations on life support, ICU length-of-stay, hospital length-of-stay, and duration of mechanical ventilation. Daytime physician staffing was studied as a potential effect modifier.

Results:  The study included 270,742 patients in 143 ICUs. Compared to nighttime staffing with an attending intensivist, nighttime staffing without an attending intensivist was not associated with hospital mortality (OR 1.03; 95% CI 0.92, 1.15; p=0.65). This relationship was not modified by daytime physician staffing (interaction p=0.19). When nighttime staffing was subcategorized, neither attending non-intensivist nor physician trainee staffing was associated with hospital mortality, compared to attending intensivist staffing. However, nighttime staffing without any physician was associated with reduced odds of hospital mortality (OR 0.79; 95% CI 0.68, 0.91; p=0.002) and new limitations on life support (OR 0.83; 95% CI 0.75, 0.93; p=0.001). Nighttime staffing was not associated with ICU or hospital length-of-stay. Nighttime staffing with an attending non-intensivist was associated with a slightly longer duration of mechanical ventilation (HR 1.05; 95% CI 1.02, 1.09; p<0.001).

Conclusions:  We found little evidence that nighttime physician staffing models impact patient outcomes. ICUs without physicians at night may exhibit reduced hospital mortality, possibly attributable to differences in end-of-life care practices.

original research 
John D. Brannan, PhD; Johan Bood, PhD; Ahmad Alkhabaz, MD; David Balgoma, PhD; Joceline Otis, BSc; Ingrid Delin, BSc; Barbro Dahlén, MD, PhD; Craig E. Wheelock, PhD; Parameswaran Nair, MD, PhD; Sven-Erik Dahlén, MD, PhD; Paul M. O’Byrne, MB
Topics: , , , , ,

Background:  Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchospasm (EIB). It has not been determined if omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in persons with mild-moderate asthma.

Methods:  In a double-blind, crossover trial, asthmatic subjects who had BHR to inhaled mannitol (n=23, 14 males, mean age 28, half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0g/day eicosapentaenoic acid and 2.0g/day docosahexaenoic acid) or matching placebo for 3-weeks, separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) required to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil counts, spirometry, asthma control questionnaire (ACQ), serum triacylglycerides and lipid mediator profile in urine and serum.

Results:  PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119) was not different to placebo (88mg, 56-139)(p=0.5). There were no changes in sputum eosinophils (mean±SD) in a sub-group of subjects (omega-3s;8.4±8.2%: placebo;7.8±11.8%,p=0.9)(n=11). At the end of each treatment period there were no differences in FEV1 (% predicted)(omega-3s;85±13%: placebo;84±11%,p=0.9) or ACQ (omega-3s;1.1±0.5%: placebo;1.1±0.5%,p=0.9)(n=23). Omega-3s caused significant lowering of blood triglycerides and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators.

Conclusion:  Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophils or inhibit urinary excretion of mast cell mediators in persons with mild-moderate asthma indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma.

Clinical Trial Registration:  URL: http://www.clinicaltrials.gov (Identifier Number NCT00526357).

original research 
Gustavo J. Rodrigo, MD; José A. Castro-Rodríguez, MD, PhD
Topics: , ,

Background.  The role of tiotropium for the treatment of asthma has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium in asthma patients.

Methods.  Randomized, placebo-controlled trials were included. Primary outcomes were peak and trough forced expiratory volume in the first second (FEV1), and morning and evening peak expiratory flow (PEF).

Results.  Thirteen studies (4,966 patients) were included. Three different therapeutic protocols were identified. Tiotropium as add-on to inhaled corticosteroids (ICS) showed statistically and clinically significant increases in PEF (22-24 L/min) and FEV1 (140-150 mL). Also, tiotropium decreased the rate of exacerbations (Number need to treat for benefit [NNTB] = 36) and improved asthma control. The use of tiotropium in patients poorly controlled despite the use of medium to high doses of ICS was not inferior to salmeterol. Finally, the use of tiotropium as add-on ICS/salmeterol combination increased pulmonary function in a clinically significant magnitude, reduced asthma exacerbations (Relative risk = 0.70; 95% CI: 0.53 to 0.94, p<0.02, I2=0%, NNTB = 17), and improved asthma control compared with ICS/salmeterol. Tiotropium was well tolerated and no potential safety signals were observed.

Conclusions.  Tiotropium resulted non-inferior to salmeterol and superior to placebo in patients with moderate-severe asthma who were not adequately controlled by ICS or ICS/salmeterol. Major benefits were concentrated in the increase in lung function, and in the case of severe asthmatics, in the reduction of exacerbations.

editorials 
Derek C. Angus, M.D., M.P.H; Clifford S. Deutschman, M.S., M.D; Jesse B. Hall, M.D; Kevin C. Wilson, M.D; Cindy L. Munro, APRN-BC, Ph.D; Nicholas S. Hill, M.D
Topics: , ,

Overuse of medical tests and treatments wastes health care resources and leads to unnecessary complications, while underuse results in delayed or missed diagnoses and treatment opportunities. Such problems are well recognized and there have been multiple attempts to correct inappropriate diagnostic testing and treatment over the past several decades. However, sustainable solutions have proven to be elusive.

original research 
Amelia Shoemark; Mellisa Dixon; Philip Beales; Claire Hogg
Topics: ,

  Cilia line the surface of the respiratory tract and beat in a coordinated wave to protect the lungs against infection. Bardet Biedl Syndrome (BBS) is rare condition attributed to cilia dysfunction. Murine models of BBS suggest a respiratory phenotype, however, no reports have studied the translation of these findings in patients.

  We assessed clinical symptoms of motile cilia dysfunction and histology of ciliated respiratory epithelium in patients with BBS.

  We report an increased prevalence of neonatal respiratory distress at birth (12%), GP diagnosed asthma (21%), otitis media (33%) and rhinitis (36%) in patients with BBS. These symptoms, however, occurred at a significantly reduced incidence compared to patients with known motile cilia dysfunction (Primary Ciliary Dyskinesia, PCD). Respiratory epithelial assessment revealed cellular damage, significant ciliary depletion (on 60% ciliated cells) and goblet cell hyperplasia in patients with BBS (50% goblet cells). These findings were quantifiably similar to that of patients with asthma (p>0.05). Surprisingly motile cilia function and ultrastructure was grossly normal with the exception of occasional unique inclusions within the ciliary membrane.

  In conclusion motile ciliary structure and function is essentially normal in patients with BBS.

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