Bronchiectasis is a potentially serious condition characterized by permanent and abnormal widening of the airways, the prevalence of which is not well described. We sought to describe the trends, associated conditions and risk factors for bronchiectasis among adults ≥ 65 years.

A 5% sample of the Medicare outpatient claims database was analyzed for bronchiectasis trends among beneficiaries aged ≥ 65 years from 2000-2007. Bronchiectasis was identified using the ICD-9-CM claim diagnosis codes for acquired bronchiectasis. Period prevalence was used to describe sex and race/ethnicity specific rates and annual prevalence was used to describe trends and age specific rates. We estimated trends using Poisson regression and odds of bronchiectasis using multivariate logistic regression.

From 2000-2007, 22,296 persons had at least one claim for bronchiectasis. The eight year period prevalence of bronchiectasis was 1106 cases/100,000 persons. Bronchiectasis increased by 8.7% per year. We identified an interaction between number of thoracic CT scans and race/ethnicity; period prevalence varied by a greater degree by number of thoracic CT scans among Asian as compared to whites or blacks. Among persons with one CT scan, Asians had a 2.5 and 3.9 fold higher period prevalence as compared to whites and blacks.

Bronchiectasis prevalence increased significantly from 2000-2007 in the Medicare outpatient setting and varied by age, sex and race/ethnicity. This increase could be due to a true increase in the condition or increased recognition of previously undiagnosed cases.

The tumor microenvironment, of which cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are the major cellular components, plays an important role in tumor progression. This study evaluated the significance of podoplanin-positive CAFs and CD204-positive TAMs, which may reflect tumor-promoting CAFs and TAMs, as risk factors for recurrence in patients with stage I lung adenocarcinoma.

The expression of podoplanin in CAFs and CD204 in TAMs was analyzed by immunohistochemistry in 304 stage I lung adenocarcinoma patients who underwent surgical resection between September 1992 and July 2004. The recurrence-free proportion (RFP) was estimated using the Kaplan-Meier method.

The presence of podoplanin-positive CAFs and the higher number of CD204-positive TAMs were associated with a lower 5-year RFP (p < 0.001 and p = 0.001, respectively). Podoplanin-positive CAFs was shown to be an independently statistically significant risk factor for recurrence with the highest hazard ratio (HR 3.474, p = 0.029, by multivariate Cox proportional hazards model). According to subgroup analyses combining podoplanin-positive CAFs and other independent risk factors (visceral pleural invasion and intratumoral vascular invasion), the 5-year RFPs were 95.6%, 92.3%, 80.5%, and 30.3% (p = 0.294, p = 0.067, and p < 0.001) for patients with zero, one, two, or three risk factors, respectively.

Podoplanin-positive CAFs was the most powerful independent risk factor for recurrence in patients with stage I lung adenocarcinoma. Podoplanin-positive CAFs may be useful for identifying patients with a high risk of recurrence who might benefit from adjuvant chemotherapy.

Cheyne-Stokes respiration (CSR) is often occurred in patients with congestive heart failure (CHF) and may be a predictor for poor outcome. Phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF. We report the clinical use of transvenous PNS in CHF patients with CSR.

Nineteen CHF patients with CSR were enrolled. A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left pericardiophrenic vein. PNS stimulation was performed using the Eupnea System software (RespiCardia Inc., Minnetonka, MN, USA). Respiratory properties were assessed prior to and post-PNS. PNS was assessed at a maximum of 10 mA.

Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in 3 patients due to dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. When PNS was applied following a series of central sleep apneic events, a trend towards stabilization of breathing and heart rate, as well as improvement in oxygen saturation, were seen. Compared with pre-PNS, during PNS there was a significant decrease in indices of apnea/hypopnea (33.8±9.3 vs 8.1±2.3, P = 0.00), increase in mean and minimal pulse oxygen saturation (89.7±1.6 % vs 94.3±0.9% and 80.3±3.7% vs 88.5±3.3%, all P = 0.00), and end-tidal carbon dioxide (ETCO₂) (38.0±4.3mmHg vs 40.3±3.1mmHg, P =0.02), but no significant difference in sleep efficiency (74.6±4.1% vs 73.7±5.4%, P =0.36).

The preliminary results showed that in a small group of patients with HF and CSR, one night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

Feasibility Study to Determine the Effects of Phrenic Nerve Stimulation in Patients with Periodic Breathing.

Number: NCT00909259

Up to 50% of the participants in computer tomography (CT) lung cancer screening trials have at least one pulmonary nodule. The role of a conventional bronchoscopy in the work-up of suspicious screen-detected pulmonary nodules to date is unknown. If a bronchoscopic evaluation could be eliminated, the cost-effectiveness of a screening program could be enhanced and the potential harms of bronchoscopy avoided.

All consecutive participants showing a positive test result between April 2004 and December 2008 were enrolled. The diagnostic sensitivity and negative predictive value (NPV) were calculated at the level of the suspicious nodules. In 95% of the nodules the gold standard for the outcome of the bronchoscopy was based on surgical resection specimens.

A total of 318 suspicious lesions were evaluated by bronchoscopy in 308 subjects. The diameter of the nodules averaged 14.6 mm (SD: 8.7) while only 2.8% of nodules were> 30 mm in diameter. The sensitivity of bronchoscopy was 13.5% (95% confidence interval (CI): 9.0%-19.6%), the specificity 100%, the PPV 100% and the NPV 47.6% (95% CI: 41.8%-53.5%) Of all cancers detected, 1% was detected by bronchoscopy only and retrospectively invisible on both low-dose CT and CT with intravenous contrast.

Conventional white-light bronchoscopy should not be routinely recommended for test-positive participants in a lung cancer screening program.

Chronic mountain sickness is characterized by a combination of excessive erythrocytosis, severe hypoxemia and pulmonary hypertension, all of which affect exercise capacity.

Thirteen chronic mountain sickness patients and 15 healthy highlander and 15 newcomer lowlander controls were investigated at an altitude of 4350m (Cerro de Pasco). All of them underwent measurements of lung diffusing capacity for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test.

The chronic mountain sickness patients, the healthy highlanders and the newcomer lowlanders reached a similar maximal oxygen uptake, at 32±1, 32±2 and 33±2 ml.min^-1.kg^-1 respectively, mean ± SE, p=0.8, with ventilatory equivalents for CO₂ versus end-tidal PCO₂, measured at the anaerobic threshold, of 0.9±0.1, 1.2±0.1 and 1.4±0.1 mmHg^-1, p<0.001, arterial O₂ content of 26±1, 21±2 and 16±1 ml.dl^-1, p<0.001, diffusing capacity for carbon monoxide corrected for alveolar volume of 155±4, 150±5 and 120±3% predicted, p<0.001, with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7±0.1 at sea-level decreased to 3.6±0.1, 3.7±0.1 and 3.9±0.1, p<0.05 and a maximal exercise mean pulmonary arterial pressure at 56±4, 42±3, and 31±2 mmHg, p<0.001.

The aerobic exercise capacity of chronic mountain sickness patients is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

Esophageal pressure monitoring during polysomnography in children offers a gold-standard, "preferred" assessment for work of breathing, but is not commonly used in part because prospective data on incremental clinical utility are scarce. We compared a standard pediatric apnea/hypopnea index to quantitative esophageal pressures as predictors of apnea-related neurobehavioral morbidity and treatment response.

Eighty-one children aged 7.8±2.8 [s.d.] years, including 44 boys, had traditional laboratory-based pediatric polysomnography, esophageal pressure monitoring, multiple sleep latency tests, psychiatric evaluations, parental behavior rating scales, and cognitive testing, all just before clinically indicated adenotonsillectomy, and again 7.2±0.8 months later. Esophageal pressures were used, along with nasal pressure monitoring and oro-nasal thermocouples, to identify respiratory events but also more quantitatively to determine the most negative esophageal pressure recorded, and percent of sleep time spent with pressures lower than -10 cm of water.

Both sleep-disordered breathing and neurobehavioral measures improved after surgery. At baseline one or both quantitative esophageal pressure measures predicted a disruptive behavior disorder (DSM-IV-defined Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, or Oppositional Defiant Disorder) and more sleepiness, and their future improvement after adenotonsillectomy (each p<.05). The pediatric apnea/hypopnea index did not predict these morbidities or treatment outcomes (each p>.10). Addition of respiratory effort-related arousals to the apnea/hypopnea index did not improve its predictive value. Neither the pre-operative apnea/hypopnea index nor esophageal pressures predicted baseline hyperactive behavior, cognitive performance, or their improvement after surgery.

Quantitative esophageal pressure monitoring may add predictive value for some, if not all neurobehavioral outcomes of sleep-disordered breathing.

Study registered with www.clinicaltrials.gov (NCT00233194).

27-Hydroxycholesterol (27-OHC) is produced from cholesterol by sterol 27-hydroxylase as an intermediate in the biosynthesis pathway of bile acid. Recently, 27-OHC was reported to cause inflammation and apoptosis in various types of cells. The aim of this study is to assess the production of 27-OHC in the airways of chronic obstructive pulmonary disease (COPD) and to elucidate the possible role of 27-OHC in the tissue fibrosis of COPD.

Lung tissues were obtained from 6 control subjects and 6 COPD patients and sputum samples were obtained from 11 healthy subjects and 15 COPD patients. The expression of sterol 27-hydroxylase in the lung was investigated by immunohistochemistry. The amounts of 27-OHC in the sputum were quantified by liquid chromatography-tandem mass spectrometry method. Because peribronchial fibrosis in peripheral airways is involved in the airflow limitation of COPD, we investigated the pro-fibrotic effects of 27-OHC in vitro.

The expression of sterol 27-hydroxylase was significantly enhanced in the lung tissues from COPD patients compared to control subjects. The amounts of 27-OHC in the sputum were significantly increased in COPD patients (p < 0.01) and the degree of 27-OHC production was negatively correlated with the lung function (p < 0.01). 27-OHC augmented the differentiation of lung fibroblasts into myofibroblasts and the production of extracellular matrix protein through activation of nuclear factor-kappa B and subsequent transforming growth factor-β₁ up-regulation.

27-OHC production was enhanced in the airways of COPD patients and might be involved in the pathogenesis of COPD.

The coexistence of Obstructive (OSA) and Central Sleep Apnea (CSA) and Cheyne-Stokes Respiration (CSR) is common in patients with Heart Failure (HF). While Continuous Positive Airway Pressure (CPAP) improves CSA/CSR by about 50%, maximal suppression is crucial in improving clinical outcomes. Auto Servo-Ventilation (ASV) effectively suppresses CSA/CSR in HF, but few trials have been performed in patients with co-existing OSA and CSA/CSR.

Randomized, controlled trial to compare the efficacy of ASV and CPAP in reducing breathing disturbances and improving cardiac parameters in patients with HF and co-existing sleep-disordered breathing.

Both modes were delivered using the BiPAP autoSV®, Respironics, USA over a twelve month period. 70 patients (63 male, 66.3±9.1 y., BMI 31.3±6.0 kg/m²) had co-existing OSA and CSA/CSR, arterial hypertension, coronary heart disease or cardiomyopathy and clinical signs of heart failure NYHA II-III. Polysomnography, brain natriuretic peptide, spiroergometry and echocardiography were performed at baseline, after 3 and 12 months of treatment.

Both modes of therapy significantly improved respiratory disturbances, oxygen desaturations and arousals over the study period. ASV reduced the central AHI (Baseline CPAP 21.8±11.7, ASV 23.1±13.2, 12 months CPAP 10.7±8.7, ASV 6.1±7.8, p<0.05) and BNP levels (Baseline CPAP 686.7±978.7ng/ml, ASV 537.3±891.8, 12 months CPAP 847.3±1848.1, ASV 230.4±297.4, p<0.05) significantly more effectively as compared to CPAP. There were no relevant differences in exercise performance and echocardiographic parameters between the groups.

ASV improved CSA/CSR and brain natriuretic peptide over a 12 month period more effectively than CPAP.

There is no consensus at the present time about the effect of welding on lung function decline. This study compared lung function decline between blue-collar workers exposed and not exposed to welding fumes in a French longitudinal cohort of 21,238 subjects aged 37 to 52 at inclusion.

Medical data, occupation, sector of activity and spirometry were recorded twice by occupational physicians in 1990 and 1995. A Job-Exposure Matrix was used to identify 503 male blue-collar workers exposed to welding fumes and 709 controls and to define the weekly duration of exposure to welding fumes.

Baseline lung function parameters were higher in workers exposed to welding fumes than in controls. After a 5 year follow-up, welding-fume exposure was associated with non-significant decline of FVC (p=0.06) and FEV₁ (p=0.07) after adjustment for age, pack-years, body mass index and baseline value of the parameter. A significant accelerated decline of FEV₁ (p=0.046) was also observed in never smokers exposed to welding fumes. An "exposure-response" relationship was observed between FEV₁ decline and weekly duration of exposure to welding fumes in non-smokers but not in smokers.

Blue-collar workers exposed to welding fumes show accelerated decline in lung function which was related to weekly duration of exposure in non-smokers.

The aim of this study was to evaluate the lung-protective effect of combined remote ischemic pre- and post-conditioning (RIPC_pre plus RIPC_post) in patients undergoing complex valvular heart surgery.

This was a randomized, placebo-controlled, and double-blind trial. Fifty-four patients were randomly allocated into the RIPC_pre plus RIPC_post group or Control group (1:1). Patients in the RIPC_pre plus RIPC_post group received three 10-min cycles of right lower limb ischemia of 250 mmHg at both 10 min after anesthetic induction and weaning from cardiopulmonary bypass. Primary endpoint was to compare postoperative PaO₂/FiO₂. Secondary endpoints were to compare pulmonary variables, incidence of acute lung injury and inflammatory cytokines.

In both groups, PaO₂/FiO₂ at 24 h after operation was significantly decreased compared to each corresponding baseline value. However, intergroup comparisons of pulmonary variables including PaO₂/FiO₂ and incidence of acute lung injury revealed no significant differences. Serum levels of interleukin-6, 8 and 10, and tumor necrosis factor-α were all significantly increased in both groups compared to each corresponding baseline value without any significant intergroup differences. There were also no significant differences in transpulmonary gradient of interleukin 6 and 10, and tumor necrosis factor-α between the groups.

RIPC as tested in this RCT did not provide significant pulmonary benefit following complex valvular cardiac surgery.

Subjective measurement of physical activity using questionnaires has prognostic value in COPD. However, their lack of accuracy and large individual variability limit their use for evaluation on an individual basis. We evaluate the capacity of the objective measurement of daily physical activity in COPD patients using accelerometers to estimate their prognostic value.

In 173 consecutive subjects with moderate-very severe COPD, daily physical activity was measured using a triaxial accelerometer providing a mean of 1-minute movement epochs as vector magnitude units (VMU). Patients were evaluated by lung function testing and six-minute walk, incremental exercise and constant-work rate tests. Patients were followed during 5-8 years and the end points were all-cause mortality, hospitalization for COPD exacerbation and annual declining FEV₁.

After adjusting for relevant confounders, a high VMU decreases the mortality risk (adjusted hazard ratio [HR]: 0.986 [95%CI 0.981-0.992]) and in a multivariate model, comorbidity, endurance time and VMU were retained as independent predictors of mortality. The time until first admission due to COPD exacerbation was shorter for the patients with lower levels of VMU (adjusted HR: 0.989 [95%CI 0.983-0.995]). Moreover, patients with higher VMU had a lower hospitalization risk than those with a low VMU (adjusted incidence rate ratio: 0.099 [95%CI 0.033-0.293). In contrast, VMU was not identified as an independent predictor of the annual FEV₁ decline.

The objective measurement of the daily physical activity in COPD patients using an accelerometer constitutes an independent prognostic factor for mortality and hospitalization due to severe exacerbation.

The Registry to EValuate Early And Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the US. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation.

Newly or previously diagnosed patients (aged ≥3 months at diagnosis) with PAH enrolled from March 2006–December 2009 at 55 US centers were included in the current analysis.

A total of 2635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91 ± 2%, 74 ± 2%, 65 ± 3%, and 59 ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation.

Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past two decades since establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts.ClinicalTrials.gov Registration Number: NCT00370214

The chronic obstructive pulmonary disease (COPD) Assessment Test™ (CAT) is an eight-item questionnaire suitable for routine clinical use that shows reliability and validity in stable and exacerbating COPD.

Study 1 assessed CAT responsiveness to changes in health status in 67 patients during an exacerbation, (Days 1-14). Study 2 assessed CAT responsiveness in 64 patients undergoing pulmonary rehabilitation, (Days 1-42). Correlations between CAT and other outcome measures were examined.

In Study 1, mean 14-day improvement in CAT score was –1.4 units ± 5.3 (p = 0.03). In patients judged to be responders (clinician-defined) change in score was –2.6 ± 4.4; in non-responders it was –0.2 ± 5.9. In Study 2, the mean improvement in CAT score was –2.2 ± 5.3 (p = 0.002); the effect size for the change was –0.33. Effect size for changes in the Chronic Respiratory Questionnaire – Self Administered Standardized form (CRQ-SAS) domain scores ranged from –0.02 to 0.34. Change in 6-minute walk distance was 41 ± 55 m. CAT and CRQ-SAS domain scores correlated at baseline (r = –0.54 to –0.69, p < 0.0001) and in terms of change following pulmonary rehabilitation (r = –0.39 to –0.63, p < 0.01). Correlations were less strong between change in the CAT and SGRQ in Study 1 (r<0.24), and for 6-minute walk distance (r<0.11) in Study 2.

These studies indicate that the CAT is sensitive to changes in health status following exacerbations and is as responsive to pulmonary rehabilitation as more complex COPD health status measures.

Most measures of dyspnea assess a single aspect (intensity or distress) of the symptom. We developed the Multidimensional Dyspnea Profile (MDP) to measure qualities and intensities of the sensory dimension and components of the affective dimension. The MDP is not indexed to a particular activity and can be applied at rest, during exertion, or clinical care. We report on the development and testing of the MDP in patients with a variety of acute and chronic cardiopulmonary conditions.

151 adults admitted to the emergency department (ED) with breathing complaints completed the MDP three times in the ED, twice at least 1 hour apart (T1, T2), and near discharge from the ED (T3). Measures were repeated in 68 patients twice in a follow-up session 4 to 6 weeks later (T4-T5). The ED sample was 56 % male with a mean age of 53 (±15 sd) years; the follow-up sample was similar.

Factor analysis resulted in a two-factor solution with a total explained variance of 63%, 74% and 72% at T1, T2 and T3 respectively. One domain related to primary sensory qualities and immediate unpleasantness, the second encompassed emotional response. For the two domains Cronbach's α ranged from 0.82-0.95 and Intraclass Correlation Coefficient ranged from 0.91-0.98. Repeated measures analysis was significant for change (T1,T3,T4) showing responsiveness to change in MDP domains with treatment (F=19.67 [2,66] p>0.001).

These analyses support the reliability, validity, and responsiveness to clinical change of the MDP with two domains in an acute care and follow-up setting.

Clinical data with use of serial interferon release assay (IGRA) testing in US health care workers (HCWs) is limited.

This is a single center, retrospective chart review of health care workers (HCWs) from 2007-2010, who underwent pre-employment testing with QuantiFERON-TB Gold In-Tube™ (QFT-GIT). Demographic data, BCG history, prior TST result if done, baseline and serial IGRA values of the HCWs were obtained. The number of IGRA converters and reverters and their subsequent management by Infectious Disease (ID) physicians were reviewed. Quantitative IGRA negative values were not available.

7374 IGRAs were performed on newly hired HCWs. Of these, 486 (6.6%) were positive at baseline, 305 (4.1%) were indeterminate, and 6583 (89.3%) were negative. During 2007-2010, 52 (2.8%) of 1857 HCWs with serial IGRA tests were identified as converters, with a serial IGRA median value of 0.63 IU/ml. Seventy-one percent of HCWs with IGRA conversion had values ≤1 IU/mL. None of the converters had active TB or were part of an outbreak investigation.

Clinical significance of most QFT-GIT conversions in serial testing remains a challenging task for clinicians. The use of single cut-off point criteria for IGRA may lead to over diagnosis of new TB infections. Clinical assessment and evaluation may help prevent unnecessary therapy in these cases. The criteria for defining conversions and reversions by establishing new cut-offs needs to be further evaluated, especially in HCWs.

Previous studies of patients with bronchiectasis have found that the cause is idiopathic in the majority of cases, but these studies were done in homogeneous populations. We hypothesized that the etiology of bronchiectasis can be determined in a higher percentage of patients in a diverse U.S. population, and will differ significantly based on ethnicity.

One hundred twelve patients with bronchiectasis confirmed by chest CT scan entered the study. Data from 106 patients were available for full evaluation. Clinical questionnaire, pulmonary function tests, sputum microbiology, laboratory data and immune function testing were done. Results were analyzed by ethnicity and etiology.

Patients were 61.6% European American (EA), 26.8% African American (AA), 8.9% Hispanic American (HA), and 2.7% Asian American. A cause of bronchiectasis was determined in 93.3% of patients. In 63.2% of patients, bronchiectasis was caused by immune dysregulation, either deficiency (18 patients, 17%), autoimmune disease (33 patients, 31.1%), hematologic malignancy (15 patients, 14.2%), or allergic bronchopulmonary aspergillosis (1 patient, 0.9%). Rheumatoid arthritis was the cause of bronchiectasis in 28.6% of AA patients versus 6.2% of EA patients (P < 0.05). Hematologic malignancy was the etiology in 20.0% of the EA patients versus none in the AA patients (P = 0.02). A significantly higher percentage of HA patients had Pseudomonas aeruginosa in their sputum compared to AA and EA patients (P = 0.01).

The etiology of bronchiectasis can be determined in the majority of patients in a heterogeneous U.S. population and is most often due to immune dysregulation. Rheumatoid arthritis is more likely in AA patients compared to EA patients. HA patients are more likely to have P. aeruginosa in their sputum.

Pulmonary metastasectomy with lung sparing local excisions is a widely accepted method to treat stage IV malignancies in selected cases. The ability to predict postoperative lung function is an unresolved issue, especially when multiple wedge resections are planned. To help develop a method to predict postoperative lung function after wedge resections, we present this prospective observational study.

A total of 77 patients who underwent one or more wedge resections to remove lung metastases completed the study protocol. Spirometry results, diffusion capacity for carbon monoxide (DLCO) and blood gases and potential confounding factors were measured prior to, immediately following and three months after the procedure and were analyzed.

Seventy-seven patients with a median age of 61.3 years underwent one up to 22 wedge resections. The mean lung function losses were FVC (-7.5 %), TLC (-7.9 %), FEV1 (-9.2 %) and DLCO (-8.8 %) and all were statistically significant (p < 0.001). The lung function losses differed also significantly between those having a single and those with more than eight wedge resections. Using regression analysis we found that for every additional wedge resection, there was a reduction in FVC of 30 ml (0.7%), in TLC of 44 ml (0.65%) and in FEV1 of 23 ml (0.58%).

Metastasectomy by wedge resection significantly reduces lung function parameters. As a benchmark, we can predict a 0.6% decrease in spirometry values and DLCO for every additional wedge resection and a decrease of approximately 5 % that may be attributed to the thoracotomy.

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β₂ agonist with inherent 24-h activity under development as once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose-response, efficacy and safety of VI at doses of 3–50μg in patients with moderate-severe COPD.

602 patients (intent-to-treat) were randomized (double blind) to VI 3, 6.25, 12.5, 25, or 50μg, or placebo once daily for 28 days. The primary endpoint was change from baseline in trough FEV₁ at the end of the 28-day treatment period. Secondary endpoints included 0–24-h weighted mean FEV₁ on Days 1 and 28 and time to increases of ≥100 mL or ≥12% from baseline FEV₁ on Day 1. Safety assessments included adverse events, vital signs, electrocardiogram assessment, and clinical laboratory tests.

VI once daily for 28 days significantly improved trough FEV₁ in a dose-dependent manner versus placebo. Clinically relevant treatment differences of ≥130 mL in trough and 0–24-h weighted mean FEV₁ were observed with VI 25 and 50μg doses, versus placebo. All doses of VI were associated with a low incidence of treatment-related AEs/SAEs, with no suggestion of effects on blood pressure, pulse rate or QTcF interval, or blood glucose and potassium levels.

VI 25 and 50μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.

Visceral pleural invasion (VPI) has been defined as invasion beyond the elastic layer (PL1) including invasion to the visceral pleural surface (PL2). The aim of this study is to evaluate the prognostic factors and patterns of recurrence in resected node-negative non-small cell lung cancer (NSCLC) with VPI.

We retrospectively reviewed the clinicopathologic characteristics of 355 patients of resected node-negative NSCLC with VPI at Taipei Veterans General Hospital between 1990 and 2006. The prognostic value and patterns of recurrence were analyzed, and were compared between PL1 and PL2 groups.

The median follow-up time was 54.2 months. The 5-year overall survival rate and probability of freedom from recurrence were 61.9% and 66.2%, respectively. The extent of VPI was PL1 in 300 (84.5%) and PL2 in 55 (15.5%) patients. During follow-up, 107 (30.1%) patients developed recurrence. The patterns of recurrence included local recurrence only in 20 (18.7%), distant metastasis only in 59 (55.1%), and both local and distant in 28 (26.2%) patients. Thirteen (12.1%) of the 107 patients with recurrence developed malignant pleural effusion. The percentage of malignant pleural effusion in PL2 group was significantly higher than that in PL1 group (P = 0.006). Patients with PL2 had significantly worse overall survival (P = 0.046) and lower probability of freedom from recurrence (P = 0.028) in multivariate analysis.

PL2 was a significant prognostic factor for recurrence and worse overall survival in node-negative NSCLC with VPI. This information is important for further design of clinical trials for aggressive adjuvant therapy.

The prevalence of obstructive sleep apnea syndrome (OSAS) is higher in children with sickle cell disease (SCD) as compared to the general pediatric population. It has been speculated that overgrowth of the adenoid and tonsils, is an important contributor.

The current study used magnetic resonance imaging (MRI) to evaluate such an association. We studied 36 SCD subjects (age 6.9±4.3yrs) and 36 controls (age 6.6±3.4yrs).

Compared to controls, SCD children had a significantly smaller upper airway (2.8±1.2cm³ vs. 3.7±1.6cm³, p<0.01), and significantly larger: adenoid (8.4±4.1cm³ vs. 6.0±2.2cm³, p<0.01), tonsils (7.0±4.3cm³ vs. 5.1±1.9cm³, p<0.01), retropharyngeal nodes (3.0±1.9cm³ vs. 2.2±0.9cm³, p<0.05), and deep cervical nodes (15.7±5.7cm³ vs. 12.7±4.0cm³, p<0.05). Polysomnography showed that 19.4% (7/36) of SCD children had OSAS compared to 0% (0/20) of controls (p< 0.05), and that in SCD children the apnea-hypopnea index correlated positively with upper airway lymphoid tissues size (r=0.57, p<001). In addition, SCD children had lower SpO₂ nadir (84.3±12.3 vs. 91.2±4.2%, p<0.05), increased peak end-tidal CO₂ (53.4±8.5 vs. 42.3±5.3 mmHg, p<0.001), and increased arousals (13.7±4.7 vs. 10.8±3.8 events/hr, p<0.05).

Children with SCD have reduced upper airway size due to overgrowth of the surrounding lymphoid tissues, which may explain their predisposition to OSAS.

Despite strong preferences for discussions about end-of-life care, patients with COPD do not often have these discussions with their providers. Our objective was to determine whether patients who reported having had end-of-life discussions also reported higher perceived markers of quality of care and health status.

A cross-sectional study of data collected at baseline for a trial to improve the occurrence and quality of end-of-life communication in patients with COPD. The primary exposure was self-reported acknowledgement of previously having had discussions about end-of-life planning with their clinicians. The primary outcome measures were patient-reported quality of care and satisfaction with care that were dichotomized as best imaginable quality of care vs. other ratings of quality and highest satisfaction vs. other ratings of satisfaction. We adjusted for confounding factors including patient and provider characteristics using logistic regression clustered by provider.

376 patients were enrolled, of which 55 (14.6%) reported having had end-of-life discussions. Individuals who reported previously having had end-of-life discussions with their clinicians were significantly more likely to rate their quality of care as the best imaginable (odds ratio 2.07, 95% CI 1.05-4.09) and to be very satisfied with their medical care (odds ratio 1.98, 95% CI 1.10-3.55). Discussions were more likely to have occurred among patients with worse health status as measured by St. George's Respiratory Questionnaire total and impact scores.

Patients who reported having end-of-life care discussions with their clinicians have higher perceived quality of care and satisfaction with their clinicians. Discussing end-of-life care with patients who have COPD may improve their perceived overall quality of and satisfaction with care.

Periodic leg movements (PLMs) may appear during nasal CPAP titration, persisting despite elimination of hypopneas.

Systematic recordings of expiratory abdominal muscles on the right and left sides with surface EMG electrodes lateral to navel, and close from the lateral side of abdomen were added during nasal continuous positive-airway –pressure (CPAP) titration for treatment of obstructive sleep apnea. PAP was titrated during nocturnal polysomnography (PSG), based on analysis of the flow curve derived from the CPAP equipment and EEG analysis including persistence of phase A2 and A3 of the cyclic-alternating-pattern. Requirement was to eliminate AASM hypopnea but also flow limitation and abnormal EEG patterns. When CPAP pressure reached valid results, it was lowered at time of an awakening by 2 or 3 cm H₂Oand titration was performed again.

Data collected during a 7 month period on adult with a prior diagnosis of obstructive sleep apnea and having received treatment with nasal CPAP regardless of age and gender, were rendered anonymous and retrospectively rescored by a blinded investigator.

Eighty-one successively seen patients with periodic-leg-movements- PLMs- during CPAP titration were investigated. Elimination of AASM hypopnea was not sufficient to eliminate the PLMs observed during the titration; higher CPAP-pressure eliminated flow limitation and cyclic-alternating-pattern phases A2 and A3 and persisting PLMs. PLMs were associated with simultaneous EMG bursts in expiratory abdominal muscles.

Presence of PLMs during CPAP titration indicates persistence of sleep-disordered-breathing. And PLMs during CPAP titration are related to presence of abdominal expiratory muscle activity.

Cystic fibrosis (CF) is one of the leading indications for lung transplantation. The incidence and pre lung transplant risk factors for post transplant renal dysfunction in the CF population remains undefined.

We conducted a cohort study using adults (≥18 years old) in the CF Foundation Patient Registry from 2000-2008 to determine the incidence of post lung transplant renal dysfunction, defined by an estimated glomerular filtration rate of < 60 ml/min/1.73m². Multivariable Cox proportional hazards modeling was used to identify independent pre-transplant risk factors for post lung transplant renal dysfunction.

The study cohort included 993 CF adult lung transplant recipients, with a median follow-up of 2 years. During the study period, 311 individuals developed renal dysfunction, with a 2-year risk of 35% (95% CI 32%-39%). Risk of post transplant renal dysfunction increased substantially with increasing age (25 to <35 years versus 18 to <25 years: HR 1.60, 95% CI 1.15-2.23; vs. ≥35 years: HR 2.45, 95% CI 1.73-3.47) and female gender (HR 1.56, 95% CI 1.22-1.99). CF-related diabetes requiring insulin therapy (HR 1.30, 95% CI 1.02-1.67) and pre-transplant renal function impairment (eGFR 60-90 ml/min/m² vs. >90 ml/min/m²: HR 1.58, 95% CI 1.19-2.12) also increased the risk of post transplant renal dysfunction.

Renal dysfunction is common following lung transplant in the adult CF population. Increased age, female gender, CF-related diabetes requiring insulin, and pre transplant renal impairment are significant risk factors.

Sleep apnea is an important co-morbidity in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Although the increased prevalence of sleep apnea in patients with ESRD is well established, few studies have investigated the prevalence of sleep apnea in patients with non-dialysis dependent kidney disease and no single study has examined the full spectrum of kidney function. We sought to determine the prevalence of sleep apnea and associated nocturnal hypoxia in patients with CKD and ESRD. We hypothesized that the prevalence of sleep apnea would increase progressively as kidney function declines.

254 patients were recruited from out-patient nephrology clinics and hemodialysis units. All patients completed an overnight cardio-pulmonary monitoring test to determine the prevalence of sleep apnea (respiratory disturbance index ≥15) and nocturnal hypoxia (oxygen saturation <90% for ≥12% of monitoring). Patients were stratified into 3 groups based on estimated glomerular filtration rate (eGFR, mL/min/1.73m²): eGFR≥60 (n=55); CKD (eGFR<60 not on dialysis, n=124); and ESRD (on hemodialysis, n=75).

The prevalence of sleep apnea increased as eGFR declined (eGFR≥60 (27%), CKD (41%), ESRD (57%); p=0.002). The prevalence of nocturnal hypoxia was higher in patients with CKD and ESRD (eGFR≥60 (16%), CKD (47%), ESRD (48%); p<0.001).

Sleep apnea is common in patients with CKD, and increases as kidney function declines. Almost 50% of patients with CKD and ESRD experience nocturnal hypoxia, which may contribute to loss of kidney function and increased cardiovascular risk.

Little is known about the association between left ventricular (LV) diastolic dysfunction and outcomes in patients with idiopathic or heritable PAH. Our rationale was to investigate the prevalence of LV diastolic dysfunction, and its association with disease severity and outcomes, in idiopathic or heritable pulmonary arterial hypertension (PAH) patients.

Using the Cleveland Clinic Pulmonary Hypertension Registry we identified subjects with heritable or idiopathic PAH who had Doppler echocardiography and RHC. Echocardiographic diastolic parameters were assessed in each patient.

A total of 61 patients met the inclusion criteria (idiopathic 85 %, heritable 15 %) The age at the time of echocardiography was 48.3 ± 18 years, 84 % of the subjects were women and 48 % were on PAH-targeted therapies. Normal LV diastolic function, impaired relaxation and pseudonormalization were seen in 10 %, 88 % and 2 % of the patients, respectively. Peak E velocity was directly associated with LV end-diastolic volume and cardiac index, and inversely associated with the degree of RV dilation, RA pressure and pulmonary vascular resistance. Peak E velocity was associated with mortality adjusted for age and gender (HR: 1.5 (95% CI: 1.1-2) per 10-cm/s decrease, p=0.015) and age, gender, 6MWD and CO (HR: 1.8 (95% CI: 1.2-2.9) per 10-cm/s decrease, p=0.01).

LV diastolic dysfunction of the impaired relaxation type is observed in the majority of patients with advanced idiopathic or heritable PAH. A decrease in transmitral flow peak E velocity is associated with worse hemodynamics and outcome.

There are limited data describing contemporary trends in the management and outcomes of patients with COPD who develop acute myocardial infarction (AMI).

The study population consisted of patients hospitalized with AMI at all greater Worcester (MA) medical centers between 1997 and 2007.

Of the 6,290 patients hospitalized with AMI, 17% had a history of COPD. Patients with COPD were less likely to be treated with beta-blockers, lipid lowering therapy, and have undergone interventional procedures during their index hospitalization that patients without COPD. Patients with COPD were at higher risk for dying during hospitalization (13.5% vs. 10.1%), and at 30 days after discharge (18.7% vs. 13.2%) and their outcomes did not improve during the decade long period under study. After multivariable adjustment, the adverse effects of COPD remained on both in-hospital (OR: 1.25, 95% CI: 0.99-1.50) and 30-day all-cause mortality (OR: 1.31, 95% CI: 1.10-1.58). The use of evidence-based therapies for all patients with AMI increased between 1997 and 2007, with a particularly marked increase for patients with COPD.

Our results suggest that the gap in medical care between patients with and without COPD hospitalized with AMI narrowed substantially between 1997 and 2007. Patients with COPD, however, remain less aggressively treated and are at increased risk for hospital adverse outcomes than patients without COPD in the setting of AMI. Careful consideration is necessary to ensure that these high risk complex patients are not denied the benefits of effective cardiac therapies.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with high risk of cardiovascular morbidity and mortality. Adiponectin is a hormone that has anti-inflammatory, anti-diabetic, and anti-atherogenic activities. We investigated the relationship of serum adiponectin to health outcomes in COPD.

We measured adiponectin levels in serum samples from participants of the Lung Health Study (LHS), who were smokers with mild to moderate airflow limitation. We determined the relationship of serum adiponectin to hospitalization and mortality using Cox proportional hazards model and to baseline lung function measurements and to bronchial reactivity using multiple regression methods.

Serum adiponectin concentrations were inversely related to hospitalizations and mortality from coronary heart disease (hazard ratio, HR, 0.73; 95% CI, 0.62 to 0.86) and to cardiovascular disease (HR, 0.83; 95% CI, 0.73 to 0.94) and positively related to deaths from respiratory causes (HR, 2.09; 95% CI, 1.41 to 3.11). However, serum adiponectin concentrations were not significantly related to total mortality (HR, 1.10; 95% CI, 0.93 to 1.29) or cancer-related mortality (HR, 1.11; 95% 0.92 to 1.34). Serum adiponectin concentrations were significantly related to increased bronchial reactivity and an accelerated decline in lung function (both p<.0001). Smoking status had no material influence on serum adiponectin concentrations.

Adiponectin is a complex serum biomarker in COPD, which is associated with decreased risk of cardiovascular events but increased risk of respiratory mortality. Because serum adiponectin is not significantly influenced by smoking status, it is a very promising biomarker of cardiovascular outcomes in COPD.

To determine the current staffing models of practice and the frequency of 24/7 coverage in academic medical centers in the United States, and to assess the perceptions of critical care trainees and program directors towards these models.

A cross-sectional national survey was conducted using an Internet-based survey platform. The survey was distributed to fellows and Program Directors of 374 Critical Care training programs in U.S. academic medical centers.

We received 518 responses: 138 from Program Directors (PDs) (37% of 374 programs) and 380 fellow responses. 24/7 coverage by a board-certified or board- eligible intensivist physician was reported by 33% of PD respondents, and was more common among Pediatric and Surgical Critical Care programs. Mandatory in-house call for critical care trainees was reported by 48% of the PDs. Mandatory call was also more common among Pediatric-Critical Care programs compared to the rest (p<0.001). Advanced nurse practitioners with critical care training were reported available by 27% of the PDs. The majority of respondents felt that 24/7 coverage would be associated with better patient care in the ICU and improved education for the fellows, although 65% of them believed this model would have a negative impact on trainees’ autonomy.

24/7 intensivist coverage was not commonly used in U.S. academic centers responding to our survey. Significant differences in coverage models among critical care medicine specialties appear to exist. Program director and trainee respondents felt that 24/7 coverage was associated with better outcomes and education, but also expressed concerns about the impact of this model on fellows’ autonomy.

Acute lung injury (ALI) mortality is increased among African Americans compared with Americans of European descent, and genetic factors may be involved. A functional T-46C polymorphism (rs2814778) in the promoter region of Duffy antigen/receptor for Chemokines (Darc) gene, present almost exclusively in people of African descent, results in isolated erthyrocyte DARC deficiency and has been implicated in ALI pathogenesis in preclinical and murine models, possibly due to an increase in circulating Duffy-binding, pro-inflammatory chemokines like interleukin (IL)-8. We sought to determine the effect of the functional rs2814778 polymorphism, C/C genotype (Duffy null state), on clinical outcomes in African Americans with acute lung injury.

Clinical data and biological specimens from African Americans with ALI enrolled in three randomized controlled trials were analyzed. Multivariate analysis accounted for proportion of African ancestry, sex, cirrhosis, and severity of illness on presentation.

Among 132 subjects, 88 (67%) were Duffy null (C/C genotype). The Duffy null state was associated with a 17% absolute risk increase (95% CI 1.4% to 33%) in mortality at 60 days, a median of 8 fewer ventilator-free days (95% CI 1 to 18.5) and 4.5 fewer organ failure-free days (95% CI 0 to 18) compared to individuals with the C/T or T/T genotypes (all P values < 0.05). Estimates were similar on multivariate analysis. In African Americans without the null variant, clinical outcomes were similar to those in patients of European descent. A subgroup analysis suggested that plasma IL-8 levels are increased in Duffy null individuals.

Our results provide evidence that the functional rs2814778 polymorphism in the gene encoding Duffy antigen/receptor for chemokines is associated with worse clinical outcomes among African Americans with ALI, possibly, via an increase in circulating IL-8.

Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases.

To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathological, radiological, and epidemiologic data for all reported cases and workplaces was undertaken.

Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease (ILD) 4–13 years after first exposure (n=7) or PAP 1–2 years after first exposure (n=3). Common pulmonary histopathological features in these patients included intraalveolar exudate typical of alveolar proteinosis (n=9), cholesterol clefts and granulomas (n=10), and fibrosis (n=9). Two patients with ILD had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographical data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among co-workers.

Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.

With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiological imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17 year period from radiological procedures, and changing trends of imaging modalities over this period.

Estimated cumulative effective dose (CED) from all thoracic and extra-thoracic imaging modalities and interventional radiology procedures for both adult and pediatric CF patients, exclusively attending a nationally designated CF center between 1992-2009 for >1year, was determined. The study period was divided into 3 equal tertiles and estimated CED attributable to all radiological procedures was estimated for each tertile.

230 patients met inclusion criteria (2,240 person-years of follow-up; 5596 radiological procedures). CED was >75mSv for 1 patient (0.43%), 36 patients (15.6%) had a CED between 20-75mSv, 56 patients (24.3%) had a CED between 5-20mSv and in 138 patients (60%) the CED was estimated to be between 0-5mSv over the study period. The mean annual CED/patient increased consecutively from 0.39mSv/yr to 0.47mSv/yr to 1.67mSv/yr, over the tertiles 1-3 of the study period respectively (p<0.001). Thoracic imaging accounted for 46.9% of the total CED and abdomino-pelvic imaging accounted for 42.9% of the CED respectively. There was an associated 5.9 fold increase in the use of all CT scanning per patient (p<0.001).

This study highlights the increasing exposure to ionizing radiation to CF patients as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed.

Cystic Fibrosis [C08.381.187], Radiation Dosage [N06.850.810.250], Diagnostic Imaging [E01.370.350]

Pneumonia is the leading infectious cause of death. Early deterioration and death commonly result from progressive sepsis, shock, respiratory failure, and cardiac complications. Recent data suggest that cardiac arrest may also be common, yet few previous studies have addressed this. Accordingly, we sought to characterize early cardiac arrest in hospitalized patients with co-existing pneumonia.

We performed a retrospective analysis of a multicenter cardiac arrest database, with data from more than 500 North American Hospitals. We included in-hospital cardiac arrest events that occurred in community-dwelling adults with pneumonia within the first 72 hours after hospital admission. We compared patient and event characteristics for patients with and without pneumonia. For patients with pneumonia we also compared events according to event location.

We identified 4,453 episodes of early cardiac arrest in patients hospitalized with pneumonia. Among patients with preexisting pneumonia, only 36.5% were receiving mechanical ventilation, and only 33.3% were receiving infusions of vasoactive drugs prior to cardiac arrest. Only 52.3% patients on the ward were receiving electrocardiographic monitoring prior to cardiac arrest. Shockable rhythms were uncommon in all pneumonia patients (ventricular tachycardia or fibrillation, 14.8%). Ward patients were significantly older than patients in the ICU.

In patients with pre-existing pneumonia, cardiac arrest may occur in the absence of preceding shock or respiratory failure. Clinicians should be alert to the possibility of abrupt cardiopulmonary collapse, and future studies should address this possibility. The mechanism may involve myocardial ischemia, a maladaptive response to hypoxia, sepsis-related cardiomyopathy, or other phenomena.

β-lactams are routinely employed as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism, required for effective treatment. Changes in renal function in this setting can significantly impact on the probability of achieving such targets.

Analysis of trough plasma drug concentrations obtained via therapeutic drug monitoring (TDM), compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high performance liquid chromatography, and corrected for protein binding. Therapeutic levels were defined as ≥ MIC, and ≥ 4 x MIC (maximum bacterial eradication) respectively. Renal function was assessed by means of an 8-hour creatinine clearance (CL_CR).

Fifty-two concurrent trough concentrations and CL_CR measures were employed in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), while empirical cover and Staphylococcus spp. were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n=30) was the trough drug concentration ≥ MIC, falling to 31% (n=16) when using 4 x MIC as the target. CL_CR values ≥ 130ml/min/1.73m² were associated with trough concentrations < MIC in 82% (p<0.001), and < 4 x MIC in 72% (p<0.001). CL_CR remained a significant predictor of sub-therapeutic concentrations in multivariate analysis.

Elevated CL_CR appears to be an important predictor of sub-therapeutic β-lactam concentrations, and suggests an important role in identifying such patients in the intensive care unit.

In response to the Agency for Healthcare Research and Quality statement questioning the usefulness of "screening spirometry", the National Heart Lung and Blood Institute and the COPD Foundation held a consensus conference in June 2008 to establish a procedure to detect cases of chronic obstructive pulmonary disease in the general population. Conference participants developed a three-stage approach, using a brief questionnaire, peak flow measurement with a pocket spirometer, and diagnostic quality spirometry. The overall objective of this study was to examine the utility of a simple questionnaire and peak flow measurement in screening for COPD in a self-selected population. We hypothesized that this combination would efficiently screen for clinically relevant COPD.

We queried individuals attending public events regarding presence of wheeze, asthma, mucus production, dyspnea, exposure to irritants, and tobacco use. Peak expiratory flow (PEF) was then measured with a pocket spirometer. If PEF was <70% of predicted, spirometry was performed. In order to estimate the false negative rate, a random sample of every 10th participant was also selected for spirometry.

Between June 2008 and December 2009, 5,761 adults completed the risk assessment questionnaire. Mean age was 54 years, 58% were female, 88% were Caucasian. Of these, 5,638 participants completed pocket spirometry, and 315 (5.6%) had PEF<70% predicted. Of 5,323 with normal PEF, 651 underwent spirometry. The performance of the PEF was assessed via positive and negative predictive values relative to a diagnosis of clinically significant airflow obstruction, defined as FEV₁/FEV₆<LLN and FEV₁<60% predicted. Of 4,238 subjects with ≥2 risk factors, 267 (6.3%) had PEF<70%, compared to 48 (3.4%) of the 1,400 subjects with <2 risk factors (p<0.001). Based on 729 participants with acceptable spirometry, 63.1% (113/179) of those with abnormal PEF tested positive for clinically significant airflow obstruction, compared to 5.5% (30/550) with normal PEF (p<0.001). Estimated prevalence of significant COPD among the 5,638 screened was 8.7%, and sensitivity and specificity were 40.7% and 97.7%, respectively.

A staged approach to COPD screening in adults is useful for detecting clinically significant airflow obstruction in our study population.

Inflammatory response in community-acquired pneumonia (CAP) depends on the host and on the challenge of the causal microorganism. Here we analyze the patterns of inflammatory cytokines, procalcitonin (PCT) and C-reactive protein (CRP) in order to determine their diagnostic value.

Prospective study of 658 patients admitted with CAP. PCT and PCR were analyzed by immunoluminometric and immunoturbidimetric assays. Cytokines (TNFα , IL-1β, IL-6, IL-8 and IL-10) were measured using enzyme immunoassay.

The lowest medians of CRP, PCT, TNFα and IL-6 were found in CAP of unknown etiology and the highest in patients with positive blood cultures. Different cytokine profiles and biomarkers were found depending on etiology: atypical bacteria (lower PCT and IL-6), viruses (lower PCT and higher IL-10), Enterobacteriaceae (higher IL-8), S. pneumoniae (high PCT) and L. pneumophila (higher CRP and TNFα). PCT ≥0.36 mg/dL to predict positive blood cultures showed sensitivity (S) of 85%, specificity (E) 42% and negative predictive value (NPV) of 98%, whereas a cutoff of ≤0.5 mg/dL to predict viruses/atypical versus bacteria showed S 89/81%, E 68/68%, positive predictive value (PPV) 12/22% and NPV 99/97%. In a multivariate Euclidean distance model, the lowest inflammatory expression was found in unknown etiology and the highest in L. pneumophila, S. pneumoniae and Enterobacteriaceae. Atypical bacteria exhibit an inflammatory pattern closer to that of viruses.

Different inflammatory patterns elicited by microorganisms may provide a useful tool for diagnosis. Recognizing these patterns provides additional information that may facilitate a broader understanding of host inflammatory response to microorganisms.

The pulmonary hypertension connection (PHC) equation predicts contemporary survival in idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension (PAH).

To validate the PHC equation in a prospective PAH population cohort and compare its predictability with the French equation.

We compared the rates of actual survival in patients prospectively followed for up to 3.5 years in four double-blind, randomized trials, and their open label extension studies with predicted survival calculated using the PHC equation [(P(t) = e^(-A(x,y,z)t), A(x,y,z) = e^{(-1.270-0.0148x+0.0402y-0.361z)}, where P(t) is probability of survival, t the time interval in years, x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index] and the French equation in idiopathic, heritable, and anorexigenassociated PAH patients (n=449).

Mean age was 44±15 years, 77% were female, and 80% had WHO functional class III-IV symptoms. The mean six-minute walk distance was 354±95 meters. The baseline hemodynamics were: mean right atrial pressure 10±6 mm Hg, mean pulmonary artery pressure 59±15 mm Hg, and cardiac output 4.1±1.5 L/min. The 1-, 2-, and 3-year Kaplan Meier survival rates were 89%, 80%, and 70%, respectively; the non-adjusted survival rates were 91%, 87%, and 84%, respectively. The expected survival predicted by both the PHC and the French equations were similar to the actual observed Kaplan-Meier survival and were within its 95% confidence limits. The PHC equation also performed well when used in patients with WHO functional class III/IV, or cardiac output < 4 liters/minute, or six-minute walk distance < 380 meters.

Risk prediction equations (PHC and French) accurately predicted survival and may be useful for risk estimation in patients with idiopathic, heritable, and anorexigen-associated PAH in large cohort studies. Their use for survival prediction for individual patients needs further study.

A recent estimate for the normal range of forced expiratory tracheal collapse differs substantially from that in an earlier study performed with comparable measurement methods. Given differences in subject characteristics between the two samples, we hypothesized that these discrepant findings may reflect a heretofore unrecognized association between forced expiratory tracheal collapse and age or gender.

We enrolled 40 female and 41 male healthy volunteers between 25 and 75 years who were without respiratory symptoms or known risk factors for tracheomalacia. Subjects underwent low-dose CT at total lung capacity (TLC) and during forced exhalation (Expdyn) with spirometric monitoring and coaching. Percentage forced expiratory collapse was regressed on age for the total sample and separately within gender.

Mean tracheal cross-sectional area (CSA) was 2.54 cm² ± 0.57 cm² at TLC and 1.15 cm² ± 0.53 cm² at Expdyn. Mean percentage forced expiratory collapse (%collapse) was 54 ± 20%. Males age 24 to 31 (n=12) had mean %collapse of 36 ± 19%, comparable to results previously reported for similarly aged males (35 ± 18%). Males, but not females, showed a significant positive correlation (R²=0.40, P < 0.001) between %collapse and age. Older males had both greater CSA at TLC (P = 0.02) and smaller CSA at Expdyn (P = 0.001) than younger males.

Males exhibit positive age dependence of forced expiratory tracheal collapse. The influence of age and gender on forced expiratory tracheal collapse should be considered in the diagnostic evaluation of expiratory dynamic airway collapse and/or tracheomalacia.

Debate exists as to the scientific evidence for their claims that e-cigarettes have no health related ramifications. Our aim was to assess whether using an e-cigarette for five minutes has an impact on pulmonary function tests and exhaled nitric oxide (FeNO) among healthy adult smokers.

30 healthy non smokers (ages 19-56, 14 male) participated in this laboratory based experimental vs. control group study. Ab lib use of an e-cigarette for 5 minutes with the cartridge included (experimental group n=30) or removed from the device (control group n=10) was assessed.

Using an e-cigarette for 5 minutes was found to lead to an immediate decrease in exhaled FeNO within the experimental group by 2.14_ppb, (p=0.005) while not in the control group (p=0.859). Total impedance (Z5Hz) in the experimental group was found to also increase by 0.033_kPa/(L/s) (p<0.001) while flow resistance at R5Hz, R10Hz and R20Hz also statistically increased.). Regression analyses controlling for baseline measurements indicated statistically significant decrease in FeNO and an increase in impedance by 0.04_kPa/(L/s), (p=0.003), resistance at R5Hz by 0.04_kPa/(L/s), (p=0.003),at R10Hz by 0.034_kPa/(L/s), (p=0.008), at R20Hz by 0.043_kPa/(L/s), (p=0.007), and overall peripheral airway resistance (beta: 0.042 _kPa/(L/s), (p=0.024), after using an e-cigarette.

E-cigarettes assessed in the context of this study were found to have immediate adverse physiologic effects after short term use that are similar to some of the effects seen with tobacco smoking, however the long term health effects of e-cigarette use are unknown but potentially adverse and worthy of further investigation.

Comparisons of lung manifestations in primary pulmonary versus disseminated nontuberculous mycobacterial disease have not been well described.

The clinical, histopathologic, and radiologic disease manifestations of primary pulmonary or disseminated nontuberculous mycobacterial disease were compared in an autopsy series.

Medical and microbiologic records, autopsy reports, histopathologic slides of the lungs, and chest computed tomography scans were reviewed on patients at the NIH with nontuberculous mycobacterial disease who died between 1996-2010.

The 11 primary pulmonary nontuberculous mycobacterial disease patients were predominantly female (n=9) with symptom onset at median 50 (range 35, 71) years and time from onset until death of 12 (3, 34) years. Bronchiectasis with cavity formation and necrotizing bronchocentric granulomatous inflammation predominated but extrapulmonary infection was absent. The five patients with disseminated disease and systemic immune defects were all males with age at onset of 2 (0.33, 33) years and time from onset of disease until death of 9 (1, 31) years. Miliary nodules and/or consolidation with poorly formed granulomatous inflammation were noted in the three disseminated patients with mycobacterial lung involvement. Significant extrapulmonary infection was noted in all five with a relative paucity of lung findings.

Nontuberculous mycobacteria can cause progressive, fatal disease. Primary pulmonary disease is bronchocentric and lacks extrathoracic infection consistent with impaired airway surface defenses. In contrast, fatal disseminated infections involving the lung have hematogenous spread, extensive extrathoracic disease and a distinct pulmonary histopathology consistent with systemic immune dysfunction.

The most serious complications of airway stenting are long term, including infection and granulation tissue formation. However, no studies have quantified the incidence rate of long term complications for different stents.

To compare the incidence of complications of different airway stents, we conducted a retrospective cohort study of all patients at our institution that had airway stenting for malignant airway obstruction from January 2005 to August 2010. Patients were excluded if more than one type of stent was in place at the same time. Complications recorded were lower respiratory tract infections, stent migration, granulation tissue, mucus plugging requiring intervention, tumor overgrowth, and stent fracture.

One hundred seventy-two patients with 195 stent procedures were included. Aero® stents were associated with an increased risk of infection (HR=1.98; 95% CI, 1.03–3.81; P=0.041). Dumon™ silicone tube stents had an increased risk of migration (HR=3.52; 95% CI, 1.41–8.82; P=0.007). Silicone stents (HR=3.32; 95% CI, 1.59–6.93; P=0.001) and lower respiratory tract infections (HR=5.69; 95% CI, 2.60–12.42; P<0.001) increased the risk of granulation tissue. Lower respiratory tract infections were associated with decreased survival (HR=1.57; 95% CI, 1.11–2.21; P=0.011).

Significant differences exist among airway stents in terms of infection, migration, and granulation tissue formation. These complications, in turn, are associated with significant morbidity and mortality. Granulation tissue formation develops because of repetitive motion trauma and infection.

In senior subjects, diffusing capacity of the lung for carbon monoxide (DLCO) is interpreted using prediction equations derived from primarily younger adult populations. Our objectives were to provide reference equations for single-breath DLCO for a cohort of healthy never-smoking Caucasian European adults between 65 and 85 years of age and to compare the predicted values of this sample with those from other studies involving middle-aged adults.

Reference equations were derived from a randomly selected sample from the general population of 431 healthy never-smoker subjects aged 65–85 yrs (262 females and 169 males). Spirometry, lung volume determinations by plethysmography and single-breath DLCO (corrected for hemoglobin) were performed following the American Thoracic Society/European Respiratory Society guidelines. Reference values and lower and upper limits of normal were derived using a piecewise polynomial model.

In addition to age, our reference equations confirm the height and body size dependence of DLCO and diffusing capacity for alveolar volume (DLCO/VA) in older subjects. Practically all the reference values obtained by extrapolating reference equations of middle-aged adults underestimate the true diffusing capacity of our healthy elderly volunteers. Middle-aged reference equations underestimate DLCO by 2.1-22.3% in females and 2.8-37.8% in males. In addition, DLCO/VA was overestimated up to 18% and 39.8% in females and males, respectively; whereas, other equations underestimate DLCO/VA up to 22.2% and 11.9% in females and males, respectively.

These results underscore the importance of using prediction equations appropriate to the origin and age characteristics of the subjects being studied.

Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen–regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD despite of hypoxia. Here we show that COPD patients fail to induce HIF-1α and VEGF under hypoxic condition due to a reduction in histone deacetylase (HDAC) 7.

Peripheral blood mononuclear cells (PBMCs) were obtained from moderate to severe COPD patients (n=21), smokers (n=12) and non-smokers (n=15). PBMCs were exposed to hypoxia (1% O₂, 5% CO₂, and 94% N₂) for 24 hrs, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by SDS-PAGE/Western blotting. HIF-1α was significantly induced by hypoxia in each group when compared with normoxic condition (12-fold induction in non-smokers, 24-fold induction in smokers, 4-fold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in COPD than that in both non-smokers and smokers (p<0.05 and p<0.01, respectively). VEGF mRNA detected by qRT-PCR was correlated with HIF-1α protein in nuclei (r=0.79, p<0.05), and HDAC 7 protein expression was correlated with HIF-1α protein in nuclei (r=0.46, p<0.05). HDAC7 knock-down inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to VEGF promoter in A549 cells.

HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.

Excess sudden death (SD) due to ventricular tachyarrhythmias remains a major mode of mortality in patients with systolic heart failure. The aim of this study was to determine the association of nocturnal ventricular arrhythmias in patients with low ejection fraction heart failure. We incorporated a large number of known pathophysiological triggers to identify potential targets for therapy to reduce the persistently high incidence of SD in this population in spite of contemporary treatment.

86 ambulatory male patients with stable low (≤ 45%) EF heart failure underwent full-night attendant polysomnography and simultaneous Holter recordings. Patients were divided into groups according to presence or absence of couplets (paired premature ventricular excitations, PVEs), and ventricular tachycardia (VT) (≥ three consecutive, PVEs) during sleep. In multiple regression analysis four variables, current smoking status, increased number of arousals, plasma alkalinity and old age were associated with VT and two variables, AHI and low right ventricular EF were associated with couplets during sleep.

We speculate that cessation of smoking; effective treatment of sleep apnea and plasma alkalosis could collectively decrease the incidence of nocturnal ventricular tachyarrhythmias and the consequent risk of SD which remains high in spite of use of beta blockades.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is performed with a dedicated 22- or 21-gauge needle while suction is applied. Fine-needle sampling without suction (capillary sampling) has been studied for endoscopic ultrasound and for biopsies at various body sites and has resulted in similar diagnostic yield and fewer traumatic samples. However, the role of EBUS-guided transbronchial needle capillary sampling (EBUS-TBNCS) remains to be determined.

Adults with suspicious hilar or mediastinal lymph nodes (LNs) were included in a single-blinded prospective randomized trial comparing EBUS-TBNA and EBUS-TBNCS. The primary endpoint was concordance rate between the two techniques in terms of adequacy and diagnosis of cytologic samples. Secondary endpoint was concordance rate between the two techniques in terms of quality of samples.

A total of 115 patients and 192 LNs were studied. Concordance between EBUS-TBNA and EBUS-TBNCS was high, with no significant difference in adequacy (88% vs. 88%, respectively [P=0.858]; concordance rate, 83.9% [95% confidence interval (CI), 77.9-88.8]); diagnosis (36% vs. 34%, respectively [P=0.289]; concordance rate, 95.8% [95% CI, 92-92.8]); diagnosis of malignancy (28% vs. 26%, respectively [P=0.125]; concordance rate, 97.9% [95% CI, 94.8-99.4]); or sample quality (concordance rate, 83.3% [95% CI, 73.3-88.3]). Concordance between EBUS-TBNA and EBUS-TBNCS was high irrespective of LN size (<1 cm vs >1 cm).

Regardless of LN size, no differences in adequacy, diagnosis, and quality were found between samples obtained using EBUS-TBNA and those obtained using EBUS-TBNCS. There is no evidence of benefit of the practice of applying suction to EBUS-guided biopsies.

ClinicalTrials.gov registry; No.: NCT00886847; URL: www.clinicaltrials.gov

Cough is a significant symptom in patients with scleroderma interstitial lung disease (SSc-ILD), affecting 73 % of the 158 patients enrolled in the Scleroderma Lung Study (SLS), a multicenter randomized trial of oral cyclophosphamide (CYC) vs. placebo (PLA) in patients with active ILD.

We examined the correlation of cough frequency, severity and phlegm production at baseline in 156 SLS participants with other baseline variables representing SSc-ILD disease activity and the cough response to one year of treatment with CYC vs. placebo (PLA).

Patients with cough at baseline had significantly lower DLCO, dyspnea, the quality of life physical component summary, and the maximal fibrosis (MAXFIB) score on HRCT compared with non-coughers at baseline. Cough severity and frequency correlated with % FVC predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with PLA, and was significantly different from PLA at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or DLCO observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC.

Cough is a common symptom in SSc-ILD and correlates with the extent of fibrosis. Cough frequency decreases significantly in response to treatment with CYC but returns to baseline 1 year after withdrawal of treatment. Cough may be a symptom of ongoing fibrosis and an independent variable in assessing therapeutic response to CYC.

Early and accurate risk stratification in community-acquired pneumonia is an unmet clinical need.

We enrolled 341 unselected patients presenting to the Emergency Department (ED) with CAP in whom blinded measurements of NT-proBNP, MR-proANP and BNP, were performed. The potential of these natriuretic peptides to predict short- (30-day) and long-term mortality was compared with the pneumonia severity index (PSI) and CURB-65. The median follow-up was 942 days.

NT-proBNP, MR-proANP and BNP levels at presentation were higher in short- (median 4882 vs. 1133 pg/ml; 426 vs. 178 pmol/l; 436 vs. 155 pg/ml, all P<0.001) and long-term non-survivors (3515 vs. 548 pg/ml; 283 vs. 136 pmol/l; 103 vs. 318 pg/ml, all P<0.001) as compared to survivors. Receiver-operating characteristics analysis to quantify the prognostic accuracy showed comparable areas under the curve (AUC) for the three natriuretic peptides to PSI for short-term (PSI 0.76, 95%CI 0.71-0.81; NT-proBNP 0.73, 95%CI 0.67-0.77; MR-proANP 0.72, 95%CI 0.67-0.77; BNP 0.68, 95%CI 0.63-0.73) and long-term (PSI 0.72, 95%CI 0.66-0.77; NT-proBNP 0.75, 95%CI 0.70-0.80; MR-proANP 0.73, 95%CI 0.67-0.77, BNP 0.70, 95%CI 0.65-0.75) mortality. In multivariable Cox regression analysis NT-proBNP remained an independent mortality predictor (HR 1.004, 95%CI 1.00-1.01, P=0.02 for short-term; HR 1.004, 95%CI 1.00-1.01, P=0.001 for long-term, increase of 300 pg/ml). A categorical approach combining PSI point values and NT-pro-BNP levels adequately identified patients at low, medium and high short and long-term mortality risk.

Natriuretic peptides are simple and powerful predictors of short- and long-term mortality in CAP. Their prognostic accuracy is comparable to PSI.

The clinical manifestations of r bronchial remodelling in asthma and the potential impact of this process on lung function remain unclear..

We aimed to determine whether the presence of pathological features of airway remodelling in asthma patients was associated with steroid responsiveness in the short term..

Sixty-three consecutive severe asthma patients with chronic airflow impairment (post bronchodilator FEV1s < 80% predicted values) were recruited, clinically characterised, and had an initial bronchoscopy where endobronchial biopsy and bronchoalveolar lavage were i performed. BAL cellular content was reported and Reticular Basement Membrane (RBM) thickness was measured by validated repeated measures. Patients were then treated with directly administered intravenous one mg/kg/day of methyl prednisone for 10 days. A threshold of 15% FEV1s improvement was used to discriminate responsive (group 1) and refractory patients (group 2).

Thirty-eight patients had a steroid responsiveness greater than 15% (group 1) and a thinner RBM at the biopsy level (5.78 ± 2.0 vs. 7.60 ± 2.2 μm, p .001) compared to non-steroid responsive group 2 patients as defined. No long-term treatment with oral steroids and increased RBM thickness were the best predictors for being unresponsive. The associated ROC curve indicated that RBM thickness could predict steroid responsiveness below 15% with an AUC of 0.747 (p 0.0002) at a threshold of 7 μm.

Features of airway remodelling are associated with limited short-term steroid responsiveness in severe asthma.

Up to 80 % of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux (GER) and aspiration of (duodeno)-gastric contents into the lungs.

To assess aspiration in CF patients, by measuring duodenogastric components in induced sputum, and to investigate whether the presence of bile acids (BA) in sputum was correlated with disease severity and markers of inflammation.

In 41 CF patients, 15 healthy volunteers, 29 asthma patients and 28 patients with chronic cough, sputum was obtained after inhalation of hypertonic saline. Sputum supernatant was tested for BA and neutrophil elastase (NSE). Spirometry and BMI were assessed on the day of sputum collection.

2/15 healthy (13%), 8/29 (28%) asthma patients, 4/28 (14%) patients with chronic cough and 23/41 CF patients (56%) showed BA in sputum. BA concentrations were similar in BA positive patients with genotype F508del homozygote, F508del heterozygote and other CF mutations and were not related with BMI and age. CF patients with BA in sputum had a higher concentration of NSE compared to patients without BA in sputum [31.25 (20.33-54.78) vs. 14.45 (7.11-27.88) μg/ml, p<0.05]. There was a significant correlation between BA concentrations and dynamic lung volumes [FEV₁% predicted (r=-0.53, p<0.01), FVC% (r=-0.59, p<0.01)] as well as with number of days of antibiotic IV treatment (r=0.58, p<0.01).

BA are present in sputum of more than half of CF patients, suggesting aspiration of duodenogastric contents. Aspiration of BA was associated with increased airway inflammation. In patients with BA aspiration, the levels of BA were clearly associated with the degree of lung function impairment as well as the need for IV antibiotic treatment.

The purpose of this systematic literature review was to examine current empirical research on general and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia (BPD).

We searched 7 databases up to end November 2010 (Medline, PubMed, Embase, PsycINFO, Maternity & Infant Care, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Web of Knowledge). We independently screened and included only those studies concerning the assessment of outcome measures in adult survivors of BPD. Data on methodological design and findings were extracted from each included study; in addition the methodological quality of each study was assessed using the Critical Appraisal Skills Programme (CASP) checklist.

Fourteen cohort studies met the review criteria. Of those, a total of 8 studies were considered to be of high quality (score 9-12), 5 of moderate quality (score 5-8) and only 1 was of low quality (score 0-4). In all studies of adult survivors of BPD, differences were found between index and control groups, suggesting that many BPD adults born preterm or with very low birth weight had more respiratory symptoms and pulmonary function abnormalities compared with their peers. Five studies concerning radiological findings reported structural changes persisting into adulthood. Findings from three studies suggested impairment in exercise capacity although firm conclusions were limited by the small sample size in the studies reviewed.

Compared to adults born at term, bronchopulmonary dysplasia survivors have more impairment in general and respiratory health which does not seem to diminish over time.

Acquired somatic mutations induced by oxidative stress may contribute to the molecular pathogenesis of chronic inflammatory airway diseases.

To assess the intensity of oxidative DNA damage and the presence of Microsatellite DNA Instability (MSI), a marker of acquired somatic mutations, in patients with chronic obstructive pulmonary disease (COPD), in patients with non-cystic fibrosis bronchiectasis, and in controls.

Induced sputum and peripheral blood from 97 subjects were analyzed; 36 COPD patients, 36 bronchiectasis patients, 15 non-COPD smokers and 10 healthy controls. DNA was extracted and analyzed for MSI. 8-OHdG, a specific marker of oxidant-induced DNA damage was measured in serum and sputum supernatants.

Neither of the bronchiectasis patients nor controls (non-COPD smokers, healthy subjects) exhibited any genetic alteration. In contrast, MSI was found in 38% of COPD specimens. Sputum 8-OHdG was statistically significant increased in COPD when compared with bronchiectasis (p=0.0002), with non-COPD smokers (p=0.0056) and healthy subjects (p=0.0003). Sputum 8-OHdG in MSI-positive COPD patients differed significantly from MSI-negative COPD patients (p=0.04) and non-COPD smokers (p=0.008), but not statistically different (p=0.07) among MSI-negative COPD patients and non-COPD smokers. Serum 8-OHdG was significantly increased in MSI-positive compared with MSI-negative COPD patients, (p=0.001) but not statistically significant in non-COPD smokers (p=0.09). Serum 8-OHdG was increased in non-COPD smokers versus MSI-negative COPD patients (p=0.009).

There is a clear disparity in COPD regarding oxidant-induced DNA damage and somatic mutations. This may reflect a difference in the oxidative stress per se or a deficient antioxidant and/or repair capacity in the lungs of COPD patients.

Animal models suggest that immunomodulatory properties of macrolide antibiotics have therapeutic value during acute lung injury. We investigated the association between receipt of macrolide antibiotics and clinical outcomes in patients with acute lung injury.

Secondary analysis of multicenter, randomized, controlled trial data from the Acute Respiratory Distress Syndrome Network (ARDSNet) Lisofylline and Respiratory Management of Acute Lung Injury Trial, which collected detailed data regarding antibiotic use among participants with acute lung injury.

47 (20%) of 235 participants received a macrolide antibiotic within 24 hours of trial enrollment. Among patients who received a macrolide, erythromycin was most common (57%), followed by azithromycin (40%). The median duration of macrolide use after study enrollment was 4 days (interquartile range 2-8). 11/47 (23%) who received macrolides died as compared with 67/188 (36%) who did not receive a macrolide, p=0.11. Participants administered macrolides were more likely to have pneumonia as an acute lung injury risk factor, were less likely to have non-pulmonary sepsis or to be randomized to low tidal volume ventilation, and had shorter length-of-stay prior to trial enrollment. After adjusting for potentially confounding covariates, use of macrolide was associated with lower 180 day mortality [hazard ratio (HR) 0.46, 95% confidence interval 0.23-0.92, p=0.028] and shorter time to successful discontinuation of mechanical ventilation (HR 1.93, 95% CI 1.18-3.17, p=0.009). In contrast, fluoroquinolone (n=90) and cephalosporin antibiotics (n=93) were not associated with improved outcomes.

Macrolide antibiotics were associated with improved outcomes in acute lung injury.

Although balance deficits are increasingly recognized in chronic obstructive pulmonary disease (COPD), little is known regarding the disordered subcomponents underlying control of balance. We aimed to determine the specific components of balance that are impaired in COPD and to investigate the association between balance and peripheral muscle strength and physical activity.

Balance, physical activity and lower extremity muscle strength were assessed in 37 patients with COPD and 20 age-matched healthy controls using the Balance Evaluation Systems Test (BESTest), the Physical Activity Scale for the Elderly (PASE), and an isokinetic dynamometer, respectively. A subset of subjects (20 COPD and 20 controls) underwent a second testing session in which postural perturbations were delivered using a lean-and-release system.

Subjects with COPD (age 71 ± 7 yrs; FEV₁ 39 ± 16 percent predicted) exhibited significantly lower scores than controls (age 67 ± 9 yrs) on all of the BESTest subscales (all p < 0.001). In response to anterior perturbations, subjects with COPD showed a longer time to foot-off (p = 0.027), foot-contact (p = 0.018), and a longer duration anticipatory phase (p = 0.008) compared to controls. Muscle strength (p = 0.008) and self-reported physical activity (p = 0.033) explained 35% of the variance in balance in subjects with COPD.

Individuals with COPD exhibit impairments in all balance subcomponents and demonstrate slower reaction times in response to perturbations. Deficits in balance are associated with reduced physical activity levels and skeletal muscle weakness.

Generally, the use of a rollator improves mobility in patients with COPD. Nevertheless, not all patients benefit from its use and many patients feel embarrassed about its use. Therefore, other walking aids are worthwhile to consider. We compared the direct effects of a ‘new’ ambulation aid (a modern draisine) to a rollator on six-minute walk distance (6MWD) in COPD.

21 patients with COPD performed two 6-minute walk tests (6MWTs) during pre-rehabilitation assessment (best 6MWD: 369±88 m). Additionally, two extra 6MWTs were performed on two consecutive days in random order: 1x with rollator and 1x with modern draisine. Walking pattern (n=21) was determined using an accelerometer and metabolic requirements (n=10) were assessed using a mobile oxycon.

Walking with the modern draisine resulted in a higher 6MWD compared to the rollator (466±189 vs. 383±85 m). Moreover, patients had fewer strides (245±61 vs. 300±49) and a greater stride length (1.89±0.73 vs. 1.27±0.14 m) using the modern draisine compared to the rollator (all: p≤0.001). Oxygen uptake, ventilation, heart rate, oxygen saturation and Borg symptom scores were comparable between both walking aids. Ten percent of the patients felt embarrassed using the modern draisine compared to 19% for rollator; while a significantly smaller proportion of patients would use the modern draisine in daily life.

The mean difference in 6MWD between modern draisine and rollator seems clinically relevant, with the same metabolic requirements and symptom Borg scores. Therefore, this ‘new’ ambulation aid could be a good alternative for the rollator to improve functional exercise performance in patients with COPD.

The Lung Volume Reduction Coil (LVR-coil) is a new experimental device to achieve lung volume reduction by bronchoscopy in patients with severe emphysema, working in a manner unaffected by collateral airflow. We investigated the safety and efficacy of LVR-coil treatment in patients with heterogeneous emphysema.

In this prospective cohort pilot study patients were treated bronchoscopically with Nitinol LVR-coils under fluoroscopic guidance in either one, or two sequential procedures. Follow-up tests included SGRQ, pulmonary function testing and 6MWT.

Twenty-eight LVR-coil procedures were performed in 16 patients (baseline FEV₁ 28% (±7.6%) predicted). Four patients were treated in one, and 12 patients were treated in both lungs. Median 10 (5-12) coils in 36.5 (20-60) minutes were placed per lung. Adverse events rated as possibly related to either the device or the procedure <30 days after treatment were pneumothorax (n=1), pneumonia (n=2), COPD exacerbation (n=6), chest pain (n=4), or mild (<5mL) hemoptysis (n=21). From 30 days to 6 months these were: pneumonia (n=3), and COPD exacerbation (n=14). All events resolved with standard care. Six months after LVR-coil treatment there were significant improvements in SGRQ: -14.9 points (±12.1 points, with 11 patients improving >4 points), in FEV1 (+14.9% ±17.0%), FVC (+13.4% ±12.9%), RV (-11.4% ±9.0%), and 6MWT (+84.4m ±73.4m), all p<0.005.

LVR-coil treatment is a promising technique for the treatment of patients with severe heterogeneous emphysema. The treatment is technically feasible and results in significant improvements in pulmonary function, exercise capacity and quality of life with an acceptable safety profile.

The mechanisms by which neuromuscular electrical stimulation training (NMES) may improve limb muscle function and exercise tolerance in COPD are poorly understood. We investigated the functional and muscular effects of NMES in advanced COPD.

Twenty of 22 patients with COPD were randomly assigned to NMES (n = 12) or sham (n = 8) training in a double-blind controlled study. NMES was performed on quadriceps and calf muscles, at home, 5 days/week for 6 weeks. Quadriceps and calf muscle cross sectional area (CSA), quadriceps force and endurance and the shuttle-walking distance with cardio-respiratory measurements were assessed before and after training. Quadriceps biopsies were obtained to explore the IGF/AKT signaling pathway (p70S6K, Atrogin-1).

NMES training improved muscle CSA (p < 0.05), force and endurance (p < 0.03) when compared to sham training. Phospho-p70S6K levels (anabolism) were increased after NMES as compared with sham (p = 0.03), while atrogin-1 levels (catabolism) were reduced (p = 0.01). Changes in quadriceps strength and ventilation during walking independently contributed to variations in walking distance after training (r = 0.77, p < 0.001). Gains in walking distance were related to the ability to tolerate increasing current intensities during training (r = 0.95, p < 0.001).

In patients with severe COPD, NMES improved muscle CSA. This was associated with a more favorable muscle anabolic to catabolic balance. Improvement in walking distance after NMES training was associated with gains in muscle strength, reduced ventilation during walking and with the ability to tolerate higher stimulation intensity.

The study is registered with ClinicalTrials.gov, number NCT00874965

Airway inflammatory responses to specific inhalation challenge (SIC) with low- (LMW) and high-molecular weight (HMW) agents have not been thoroughly studied. We assessed the changes in airway inflammatory cells following SIC in sensitized workers, and looked at the influence of various factors on the pattern of inflammatory responses to SIC.

Induced sputum analysis was performed in workers sensitized to LMW (n=41) or HMW agents (n=41) after a control day and after a positive SIC. Cell counts were compared with lung function and various clinical parameters.

In the LMW group, eosinophils were increased following late asthmatic responses (median [interquartile range]: (0.02 [0.04] vs 0.30 [0.80]X10⁶ cells/g and 1.0 [3.5] vs 8.9 [8.0]% respectively, p<0.05), as were neutrophil numbers (0.8 [1.3] vs 2.3 [5.4]X10⁶ cells/g, p=0.04). In the HMW group, eosinophil percentages increased both after early (1.0 [2.2] vs 5.5 [14.5]%, p=0.003) and dual asthmatic responses (4.5 [3.7] vs 15.0 [13.7]%, p=0.02). In the LMW group, the increases in neutrophils were higher in current smokers compared to ex-smokers or non-smokers. The length of exposure to the agent, tobacco use, and baseline percentage of eosinophils were independent predictors of the change in eosinophils, while age and baseline neutrophil percentage were predictors of the change in neutrophils.

This study confirms that eosinophils and neutrophils are increased after SIC whatever the causal agent. The type of agent is not predictive of the inflammatory response to SIC. Smoking is associated with a more neutrophilic response after SIC with a LMW agent.

Although up to 90% of patients with type 2 diabetes mellitus (T2DM) have obstructive sleep apnea (OSA), the rate by which primary care providers diagnose OSA in diabetic patients has not been assessed.

To determine the proportion of patients with T2DM managed in primary care clinics that were diagnosed with OSA and to identify factors associated with an OSA diagnosis, a retrospective population-based multi-clinic study was performed. Electronic health records of adult patients with a diagnosis of T2DM were reviewed for a co-existing diagnosis of OSA, and diagnostic prevalence of OSA was compared with the expected prevalence.

A total of 16,066 diabetic patients with one or more primary care office visits in 27 primary care ambulatory practices during an 18-month period from 2009 to 2010 were identified. Analysis revealed that 18% of the study population carried an OSA diagnosis, which is less than the 54-94% prevalence previously reported. The 23% prevalence of OSA among obese study patients was lower than the expected 87% prevalence. In a logistic model, male gender, body mass index (BMI), several chronic conditions, and lower low density lipoprotein levels and HgbA1c identified patients more likely to carry an OSA diagnosis (likelihood ratio 2=1,713 with p<0.0001).

Primary care providers underdiagnose OSA in patients with T2DM. Obese males with co-morbid chronic health conditions are more likely to receive a diagnosis of OSA. Efforts to improve awareness of the association of OSA with T2DM and implement OSA screening tools should target primary care physicians.

Data are scarce with regard to risk factors for acute community-acquired alveolar pneumonia (CAAP) in children, but it is known that children with sleep disordered breathing (SDB) experience more respiratory infections. We aimed to assess whether SDB is a risk factor for CAAP in early childhood.

A prospective, nested, case-control study assessing children <5 years with CAAP, diagnosed based on the World Health Organization radiographical criteria. Demographic and clinical data was collected. SDB symptoms were documented using a structured questionnaire. CAAP study and retrospective sleep laboratory databases were compared. SDB presence and severity were determined by questionnaire and polysomnography (PSG).

14,913 children underwent chest radiography during the study period. 1,546 children with radiographically proven CAAP (58% boys) and 441 controls (54% boys) were prospectively enrolled. Frequent snoring was reported in 18.6% vs. 2.9% CAAP and controls respectively (P<0.001). The respective figures for restless sleep, nocturnal breathing problems, abnormal behavior, and chronic rhinorrhea were 21.6% vs. 5.3%; 5% vs. 1.4%; 6.4% vs. 0.2%; and 12.9% vs. 1.8%, (P<0.001 for each). Fifty (3.3%) children with CAAP vs. 3 (0.7%) controls underwent adenoidectomy (P<0.001). Polysomnographic diagnosis of obstructive sleep apnea (OSA) had been previously established in 79 (5%) CAAP patients vs. 6 (1.3%) of the controls (OR: 3.7 [1.6-10.0]; P<0.001), with higher severity in CAAP patients than controls.

Sleep disordered breathing is common in children with CAAP and is possibly a predisposing risk for CAAP in children <5 years old. We recommend considering SDB in young children diagnosed with CAAP.

pulmonary restriction associates with increased mortality in adult and elderly. Previous studies, however, have used the forced vital capacity (FVC) as a surrogate for the TLC. We evaluated the association between a reduced TLC, mortality and health care resources use, and compared this association with a reduced FVC.

752 over 60 years/old patients undergoing spirometry were recruited. The main analyses were performed in patients without bronchial obstruction (N = 405). Mortality and admission to acute care hospitals were derived. Pulmonary restriction was alternatively defined as a TLC or a FVC below the LLN. Unadjusted relative risk of mortality associated with pulmonary restriction and adjusted incidence rate ratio were determined. Survival analysis was repeated using time to first hospital admission as dependent variable.

overall mortality was significantly higher in the group with reduced TLC compared with lower FVC (10.2 vs 4.27/100 persons, respectively) with mortality rate ratios of 6.87 (95% CI: 2.54 – 18.24) and 2.73 (95% CI: 1.04 – 7.66) respectively. After adjustment, the hazard ratio for mortality associated with pulmonary restriction diagnosed using the FVC was reduced to 2.05 (95% CI: 0.70 – 6.02). Reduced TLC remained strongly associated with mortality (HR: 4.52, 95% CI: 1.32 – 15.51). No association was found between restriction (diagnosed using either parameter) and risk for hospitalization.

reduced TLC is strongly associated with mortality in elderly. Reduction of the FVC is a weaker risk factor for mortality.

Current rapid response team (RRT) activation criteria were not statistically derived using ward vital signs, and the best vital sign predictors of cardiac arrest (CA) have not been determined. In addition, it is unknown when vital signs begin to accurately detect this event prior to CA.

We conducted a nested case-control study of 88 patients suffering CA on the wards of a university hospital between November 2008 and January 2011 matched 1:4 to 352 controls residing on the same ward at the same time as the case CA. Vital signs and Modified Early Warning Scores (MEWS) were compared on admission and during the 48 hours preceding CA.

Cases were older (64±16 vs. 58±18; P=0.002) and more likely to have had a prior ICU admission than controls (41% vs. 24%; P=0.001), but had similar admission MEWS (2.2±1.3 vs. 2.0±1.3; P=0.28). In the 48 hours preceding CA, maximum MEWS was the best predictor (AUC 0.77; 95%CI 0.71-0.82), followed by maximum respiratory rate (AUC 0.72; 95%CI, 0.65-0.78), maximum heart rate (AUC 0.68; 95%CI, 0.61-0.74), maximum pulse pressure index (AUC 0.61; 95%CI, 0.54-0.68), and minimum diastolic blood pressure (AUC 0.60; 95%CI 0.53-0.67). By 48 hours prior to CA, the MEWS was higher in cases (P=0.005), with increasing disparity leading up to the event.

The MEWS was significantly different between CA and control patients by 48 hours prior to the event, but includes poor predictors of CA such as temperature and omits significant predictors such as diastolic blood pressure and pulse pressure index.

Mast cell localization to airway smooth muscle (ASM) bundle in asthma is important in the development of disordered airway physiology. Thymic stromal lymphopoietin (TSLP) is expressed by airway structural cells. Whether it has a role in the crosstalk between these cells is uncertain.

We sought to define TSLP expression in bronchial tissue across the spectrum of asthma severity, and to investigate the TSLP and TSLPR expression and function by primary ASM and mast cells alone and in co-culture.

TSLP expression was assessed in bronchial tissue from 18 subjects with mild to moderate asthma, 12 with severe disease and 9 healthy controls. TSLP and TSLPR expression in primary mast cells and ASM was assessed by immunofluorescence, flow cytometry and ELISA and its function by calcium imaging. The role of TSLP in mast cell and ASM proliferation, survival, differentiation, synthetic function and contraction was examined.

TSLP expression was increased in the ASM bundle in mild-moderate disease. TSLP and TSLPR were expressed by mast cells and ASM and were functional. Mast cell activation by TSLP increased the production of a broad range of chemokines and cytokines, but did not affect mast cell or ASM proliferation, survival or contraction.

TSLP expression by the bronchial epithelium and ASM was up-regulated in asthma. TSLP promoted mast cell synthetic function, but did not contribute to other functional consequences of mast cell-ASM cross talk.

Asthma is a common chronic respiratory condition whose diagnosis depends on symptoms and objective evidence of variable airflow obstruction or airway hyper-responsiveness. The proportion of people who have had objective pulmonary function testing around the time of diagnosis and factors associated with receiving testing are not well understood.

A retrospective cohort study using the health administrative data of all individuals age 7 and older with newly physician diagnosed asthma living in Ontario, Canada between 1996 and 2007 was conducted. Receipt of pulmonary function testing in the peridiagnostic period was determined and examined across patient socio-demographic and clinical factors.

Only 42.7% (95% CI: 42.6 to 42.9%) of the 465,866 Ontarians newly diagnosed with asthma received pulmonary function testing between 1 year prior and 2.5 years following the time of diagnosis. In adjusted analyses, individuals 7 to 9 years old and those 70 years or older were less likely to receive testing than younger adults, individuals in the lowest neighborhood income quintile were less likely to receive testing than those in the highest, and individuals seeing a medical specialist were more likely to receive testing than those seeing only a general practitioner.

Less than half of patients with new physician diagnosed asthma in Ontario, Canada received objective pulmonary function testing around the time of diagnosis. Further study is needed to determine why more pulmonary function testing is not being used to diagnose asthma and how barriers to its appropriate use can be overcome.

The responses of oxygen uptake efficiency (i.e. oxygen uptake/ventilation =$$\stackrel{.}{\mathrm{V}}$$O₂/$$\stackrel{.}{\mathrm{V}}$$E) and its highest plateau (OUEP) during incremental cardiopulmonary exercise testing (CPET) in patients with chronic left heart failure (HF) have not been previously reported. We planned to test the hypothesis that OUEP during CPET is the best single predictor of early death in HF.

We evaluated OUEP, slope of $$\stackrel{.}{\mathrm{V}}$$O₂/log($$\stackrel{.}{\mathrm{V}}$$E) (OUES), oscillatory breathing, and all usual CPET measurements in 508 low ejection fraction(<35%) HF patients. Each had further evaluations at other sites, including cardiac catheterization. Outcomes were 6-month all-reason mortality and morbidity (death or >24 hours cardiac hospitalization). Statistical analyses included area under curve (AUC) of receiver operating characteristics, odds ratios, univariate and multivariate Cox regression, and Kaplan-Meier plots.

OUEP, which requires only moderate exercise, was often reduced in HF patients. A low %predicted OUEP was the single best predictor of mortality (p<0.0001), with an odds ratios of 13.0 (p<0.001). When combined with oscillatory breathing the odds ratio increased to 56.3, superior to all other resting or exercise parameters or combinations of parameters. Other statistical analyses and morbidity analysis confirmed those findings.

OUEP is often reduced in HF patients. Low %predicted OUEP (<65%pred), is the single best predictor of early death, better than any other CPET or other cardiovascular measurement. Paired with oscillatory breathing, it is even more powerful.

Endothelial dysfunction (ED) can develop in the context of both obesity and obstructive sleep apnea (OSA) in children. However, the potential interactions between OSA and obesity have not been defined.

Pre-pubertal non-hypertensive children were recruited. Endothelial function was assessed in a morning fasted state, using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries, and blood was drawn for assessment of MRP8/14 levels using a commercial ELISA. Overnight polysomnography defined the presence (OSA) or absence (NOSA) of sleep-disordered breathing. Anthropometric measurements were performed to assign subjects to the obese (OB) and non-obese (NOB) categories.

54 obese and non-obese children with OSA (mean age 7.90±0.26 years, mean BMI z-score: 1.70±0.3, OAHI: 7.36±1.09) were compared to 54 obese and non-obese children without OSA (mean age 8.26±0.24years, mean BMI z-score 1.41±0.18, OAHI 0.86±0.07). 62.5% of OB- OSA, 38.7 % of OB-NOSA; and 20.0% of NOB-OSA had evidence of ED compared to 0.0% of NOB-NOSA (p<0.01). The degree of ED in all groups was associated with circulating MRP8/14 levels (r=0.343, p<0.001).

Both obesity and OSA can independently increase the risk for ED, and the concurrent presence of both markedly increases such risk. Although the mechanisms underlying ED remain unclear, a potential role for MRP8/14 as an inflammatory biomarker of ED is suggested.

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) may be one of the most prevalent forms of pulmonary arterial hypertension (PAH) worldwide. However the clinical and hemodynamical response to specific PAH therapy in Sch-PAH is not known.

We retrospectively analyzed the charts of all Sch-PAH patients who initiated specific PAH treatment between June/2003 and June/2010 in a single PAH reference center in São Paulo, Brazil. Clinical and haemodynamical data were retrospectively collected and evaluated in two periods: baseline and post treatment.

The study population consisted of 12 Sch-PAH patients. They were treated with phosphodiseterase-5 inhibitors (7 patients); endothelin receptors antagonists (4 patients) or combination therapy (1 patient). Mean treatment period was 34.9 ± 15.5 months. Patients with Sch-PAH presented significant improvements in terms of functional class, 6MWT distance (439±85 to 492±79m, p=0.032), cardiac index (2.66±0.59 to 3.08±0.68 L/min/m², p=0.028) and indexed pulmonary vascular resistance (20.7±11.6 to 15.9±9W/m², p=0.038) with the introduction of specific PAH-treatment.

We conclude that specific PAH therapy may be of benefit to Sch-PAH patients, considering clinical, functional and hemodynamic parameters.

The treatment of cough is a significant clinical unmet need, as there is little evidence that current therapies are effective. Based on evidence supporting a role for N-methyl D-aspartate receptors (NMDAR) in cough, we hypothesised that memantine, a low affinity, uncompetitive NMDAR channel blocker in routine use for the treatment of Alzheimer's disease, could be an effective, well-tolerated anti-tussive therapy. The aim of this study was to establish pre-clinical evidence that memantine has anti-tussive effects.

We studied the influence of memantine on experimentally induced coughing in response to citric acid and bradykinin inhalation in guinea pigs. We also compared the potency and efficacy of memantine as an anti-tussive to other NMDAR antagonists, dextromethorphan and ketamine, and to the GABA_B receptor agonist baclofen.

Compared with control, 10 mg/kg memantine significantly reduced the cumulative number of coughs evoked by both citric acid [median 24.0 coughs (IQR 13.0-25.5) versus 1.5 (IQR 0.3-10.3), p=0.012] and bradykinin aerosols, [median 16.0 coughs (IQR 9.5-18.5) versus 0.0 (IQR 0-0.75), p=0.002]. Memantine 10mg/kg produced a similar reduction in the cumulative number of coughs to baclofen 3mg/kg, and demonstrated comparatively greater cough suppression than 30mg/kg dextromethorphan or 30 mg/ kg ketamine. This dose of memantine produced no sedative or respiratory depressive effects.

This study illustrates that memantine has marked anti-tussive effects in guinea pigs, most likely mediated via NMDAR channel blockade. Memantine therefore has the potential to be a safe, effective and well-tolerated anti-tussive agent.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare pulmonary disease caused by functional deficiency of granulocyte macrophage-colony stimulating factor (GM-CSF). Administration of GM-CSF represents a potential therapeutic strategy in management of aPAP. Herein, we systematically review the efficacy of GM-CSF therapy in aPAP.

We searched the PubMed and EmBase databases for studies reporting the use of GM-CSF in aPAP. We calculated the proportion with 95% confidence intervals (CI) to assess the response and relapse rates of GM-CSF therapy in individual studies and pooled them using a random-effects model. Statistical heterogeneity was assessed using the I² and Cochran-Q tests. Publication bias was analyzed using funnel plot, and Egger and Begg-Mazumdar tests.

Our initial searches yielded 1585 studies. Of these, five observational studies (involving 94 patients) were included for analysis. Three studies used the subcutaneous route while two studies employed the inhalational route for GM-CSF administration. The response rate of GM-CSF varied from 43-92% with the pooled response rate being 58.6% (95% CI, 42.7-72.9). The relapse rate in GM-CSF responders was 29.7% (95% CI, 10.5-60.4). There was no evidence of statistical heterogeneity or publication bias for the outcome of response. GM-CSF therapy was associated with minor complications like fever and local complications at the site of administration.

GM-CSF represents a useful approach in the treatment of aPAP. The optimal indication, dose and duration of therapy, factors predicting response and relapse need to be defined by future studies.

The accuracy of combined clinical examination (CE) and chest radiography (CXR) (CE+CXR) versus thoracic ultrasonography in the acute assessment of pneumothorax, hemothorax and lung contusion in chest trauma patients is unknown.

We conducted a prospective, observational cohort study involving 119 adult patients admitted to the emergency room with thoracic trauma. Each patient, secured on to a vacuum mattress, underwent a subsequent thoracic CT scan after first receiving a CE, CXR, and thoracic ultrasound. The diagnostic performance of each method was also evaluated in a subgroup of 35 patients with hemodynamic and/or respiratory instability.

Of the 237 lung fields included in the study, we observed 53 pneumothoraces, 35 hemothoraces and 147 lung contusions, according to either thoracic CT or thoracic decompression if placed before the CT scan. The diagnostic performance of ultrasonography was higher than that of CE+CXR, as shown by their respective areas under the receiver operating characteristic curves (AUC-ROC): 0.75 (0.67-0.83) (mean, 95% confidence interval) versus 0.62 (0.54-0.70) in pneumothorax cases, and 0.73 (0.67-0.80) versus 0.66 (0.61-0.72) for lung contusions, respectively (all p<0.05). In addition, the diagnostic performance of ultrasonography to detect pneumothorax was enhanced in the most severely injured patients: 0.86 (0.73-0.98) versus 0.70 (0.61-0.80) with CE+CXR. No difference between modalities was found for hemothorax.

Thoracic ultrasound as a bedside diagnostic modality is a better diagnostic test than CE and CXR in comparison to CT scanning when evaluating supine chest trauma patients in the emergency setting, particularly for diagnosing pneumothoraces and lung contusions.

B cells play an important role in allergic asthma. However, the mechanisms by which these cells are activated in the airways remain poorly understood.

we have used a mouse model of OVA-induced allergic inflammation to study CXCL13 and investigate concentration of this chemokine in the bronchoalveolar lavage (BAL) fluid derived from asthmatic- and normal control subjects.

here we have shown that OVA-challenged mice upregulate the CXCL13/CXCR5 axis which is associated with several changes in their airways including recruitment of B- and CD4⁺cells, development of bronchial associated lymphoid tissue (BALT) and airway inflammation. Treating sensitized mice with an anti-CXCL13 antibody reduced cell recruitment, BALT formation and airways inflammation. Interestingly, measurements of CXCL13 using ELISA showed that levels of this cytokine were significantly elevated in BALF from asthmatics compared with normals (median, 162 pg/ml; range; 120 – 296 pg/ml versus median, 31 pg/ml; range120 – 156 pg/ml p=0.005). These findings all together suggest that CXCL13 is involved in the allergic airway inflammatory process and targeting this chemokine may constitute a novel approach in asthma.

For clinicians discussing advance care planning with patients with life-limiting illness, it is important to understand the stability of patients’ preferences for life-sustaining treatments and the factors that predict a change in preferences. Our objectives were to investigate one-year stability of preferences regarding cardiopulmonary resuscitation (CPR) and mechanical ventilation (MV) for outpatients with advanced chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF) or chronic renal failure (CRF) and to identify predictors of changes in preferences.

265 clinically stable outpatients with advanced COPD, CHF or CRF were visited at baseline and then every four months for one year, to assess preferences regarding CPR and MV in their current health status. Generalized estimating equations were used to examine the association between change in life-sustaining treatment preferences and several potential predictors, including changes in co-morbidities, hospital admissions, generic health status, care dependency, mobility and symptoms of anxiety or depression.

One-year follow-up was completed by 77.7% of patients. Preferences regarding CPR or MV changed in 38.3% of the patients during follow-up. Changes over time in generic health status, mobility, symptoms of anxiety and depression, and marital status were associated with changes in life-sustaining treatment preferences.

More than a third of the outpatients with advanced COPD, CHF or CRF change their preferences regarding CPR and/or MV at least once during one year. Regular re-evaluation of advance care planning is necessary, in particular when patients experience a change in health status, mobility, symptoms of anxiety or depression, or marital status.

The purpose of this study was to evaluate the high-resolution computed tomography (HRCT) findings of patients with the reversed halo sign (RHS) and to identify distinguishing features among the various etiologies. Two chest radiologists reviewed the high-resolution CT scans of 79 patients with RHS and determined CT findings by consensus. We studied the morphological characteristics, number of lesions, and presence of features associated with RHS. Forty patients presented with infectious diseases (paracoccidioidomycosis, tuberculosis, zygomycosis, invasive pulmonary aspergillosis, Pneumocystis jiroveci pneumonia, histoplasmosis, cryptococcosis) and 39 presented with noninfectious diseases [cryptogenic organizing pneumonia, pulmonary embolism, sarcoidosis, edema, lepidic predominant adenocarcinoma (formerly bronchioloalveolar carcinoma), Wegener granulomatosis]. RHS walls were smooth in 58 cases (73.4%) and nodular in 21 cases (26.6%). Lesions were multiple in 44 cases (55.7%) and single in 35 cases (44.3%). The presence of nodular walls or nodules inside the halo of RHS is highly suggestive of granulomatous diseases.

The present study investigated alterations in both the sensory (intensity) and affective component (unpleasantness) of dyspnea in patients with medically unexplained dyspnea (MUD) during repeated hypercapnic challenges.

The sensory and affective components were assessed every 20 sec during the baseline, rebreathing and recovery phases of three subsequent trials in patients (N=17) and matched healthy controls (N=15). Fractional end-tidal carbon dioxide (FetCO₂) was monitored simultaneously and continuously. Peak intensity and unpleasantness were compared and intra-individual linear regression slopes between the dyspnea components and FetCO₂ were calculated.

Both intensity and unpleasantness of dyspnea perception were higher in patients than in healthy controls. Also the regression slopes were steeper, but this was more prominent for the affective than for the sensory component in patients. Moreover, also across-trial increases in unpleasantness of peak dyspnea and of slopes of both components were observed in patients.

MUD patients are particularly hypersensitive to the unpleasantness of dyspnea. The elevated breathlessness further increases across repeated challenges, documenting sensitization and suggesting that basic learning mechanisms contribute to exaggerated responding to respiratory challenges.

Atrial fibrillation (AF) is common in acute coronary syndromes (ACS). We aimed to describe the value of the CHADS₂ score as a risk assessment tool for mortality and stroke in ACS, irrespective of the presence or absence of AF.

Consecutive patients with ACS admitted to the coronary care unit were prospectively included in a risk stratification study. We calculated CHADS₂ score from the data collected at admission, and all patients were followed until January 1, 2007 or death.

Of 2335 patients with ACS, 442 (71±8 years, 142 women) had AF. Their mean CHADS₂ score was 1.6±1.4, versus 1.0±1.1 in patients without AF (p<0.0001). The all-cause mortality at 10 years was strongly associated with CHADS₂ score in patients with AF (hazard ratio [HR] and 95% confidence interval per unit increase in the 6-grade CHADS₂ score 1.21 [1.07-1.36], p=0.002), but also in patients without AF (HR 1.38 [1.28-1.48], p<0.0001), after adjustment for potential confounders. The more complicated GRACE risk score provided a better prediction for short- and long-term mortality than the simpler CHADS₂ score (p<0.0001). Hospitalization for stroke was significantly associated with the CHADS₂ score in patients without (but not in those with) AF after adjustment (HR 1.46 [1.27-1.68], p<0.0001).

In ACS, AF is associated with poor prognosis. The CHADS₂ score developed for AF has even greater prognostic value in non-AF patients, and may help to identify patients with high risk for subsequent stroke or death and a need for optimization of risk reducing treatment.

Acute eosinophilic pneumonia (AEP) is an idiopathic disease characterized by pulmonary eosinophilia. Since the fraction of exhaled nitric oxide (FeNO) is a surrogate of eosinophilic inflammation, we evaluated the levels, changed treatments and the diagnostic role of FeNO in patients with AEP.

We prospectively enrolled patients at the Armed Forces Capital Hospital who had diffuse pulmonary infiltrates and a febrile illness and who were clinically suspected to have AEP between June 2010 and March 2011. We measured FeNO twice at the initial visit (pre-treatment) and two weeks after the initial measurement (post-treatment).

A total of 60 subjects were enrolled and 31 were diagnosed with AEP. The pre-treatment FeNO levels of the patients with AEP were significantly higher than the non-AEP patients (median 48 [range 5-41] ppb vs. median 14 [range 10-138] ppb, P < 0.001). The cut-off value(23.5 ppb) showed that the maximum area under the ROC curve predicted AEP with a sensitivity of 0.87 and a specificity of 0.83. The post-treatment FeNO levels decreased significantly in the AEP patients, and the levels were similar to the non-AEP patients (median 19 [range 7-44] ppb vs. median 14 [range 1-58] ppb, P = 0.21)

The FeNO level was significantly higher in AEP than non-AEP patients. FeNO measurement can be used as a diagnostic tool to differentiate AEP from non-AEP patients.

To assess the usefulness of emphysema scores in predicting death from chronic obstructive pulmonary disease (COPD) and lung cancer.

Emphysema was assessed on low-dose CT scans performed on 9,047 men and women on whom age and smoking history were documented. Each scan was scored as to the presence of emphysema: none, mild, moderate, or marked. Follow-up time was calculated from time of CT scan to time of death, or December 31, 2007, whichever came first. Cox regression analysis was used to calculate the hazard ratio of emphysema as a predictor of death.

Median age was 65 years, 4,433 (49%) were men; 4,133 (46%) were currently smoking or had quit within 5 years. Emphysema was identified in 2,637 (29%). It was a significant predictor of death from COPD (hazard ratio = 9.3, 95% CI: 4.3-20.2, P < 0.0001) and from lung cancer (hazard ratio = 1.7, 95% CI: 1.1 – 2.5, P = 0.013), even when adjusted for age and smoking history.

Visual assessment of emphysema on CT is a significant predictor of death from COPD and lung cancer.

A lower (more caudal) position of the larynx may result in a longer collapsible segment of the upper airway. One could thus hypothesize that the lower the larynx the greater the risk for obstructive sleep apnea (OSA). In order to test this hypothesis, we measured the upper airway length to the level of the vocal cord, and horizontal and vertical segment of the supralaryngeal vocal cord tract (SVT) using multislice CT in Japanese OSA patients.

We recruited 249 consecutive patients who had polysomnography for suspected OSA (age 47.8 ± 14.8 years, BMI 24.8 ± 4.3 kg/m²). Using CT images, we measured airway length (AL), airway length to vocal cord (ALVC), ALVC-AL, horizontal segment of SVT (SVTH), and vertical segment of SVT (SVTV). The ratio SVTR (SVTH / SVTV) was calculated. The correlation between these measurements and age, BMI, and AHI were evaluated.

Males had a longer ALVC than females. AL, ALVC, SVTR was significantly correlated with age, and AHI in all patients. Logistic regression analysis showed that ALVC >0.24 (OR 4.2, CI; 2.3-7.6) and BMI >25 (OR 4.8, CI; 2.7-8.5) were significant variables predicting AHI>30. Even after controlling for BMI, the effect of ALVC was still significant.

The laryngeal position is lower in males than females. Aging is associated with a lower laryngeal position, and a longer ALVC is independently associated with OSA severity in Japanese patients. We conclude that both laryngeal descent and BMI may be risk factors for OSA.

We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyper-responsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use and lung function in primary care.

164 persistent asthmatics were randomised in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either mannitol PD₁₀ (AHR strategy) or a control group (reference strategy) over a 1 year period.

119 participants (n=61 AHR, n=58 control) completed. Time to first mild exacerbation was not significantly different: HR 1.29 (95%CI 0.716 - 2.31), p=0.40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs. control (n= 84 vs. n=115, p=0.03), there was no difference in severe exacerbations (n=12 vs. n=13). No other significant differences were seen between groups with the exception of mannitol PD10 and ICS dose. There was a 1.52 (95%CI 0.61-2.42), p=0.001, doubling dose difference in mannitol PD₁₀ between AHR vs. control. The final mean daily ciclesonide dose was higher (p<0.0001) in AHR vs. control (514 ug vs. 208 ug), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for methacholine PC20 (p<0.05), salivary eosinophilic cationic protein (p<0.05), exhaled nitric oxide (p<0.05), symptoms (p<0.005) and reliever use (p<0.001).

Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in more severe patients may now be warranted to further define its role.

The World Trade Center (WTC) collapse produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-9/11.

In a cohort of 801 never smokers with normal pre-9/11 FEV₁, we correlated inflammatory biomarkers and complete blood counts at monitoring entry within 6 months of 9/11/2001 with a median FEV₁ at SPE (34 months, IQR 25-57). Cases of airflow obstruction had FEV₁ < LLN (100/801; 70/100 had serum) while controls had FEV₁ ≥ LLN (153/801; 124/153 had serum).

From monitoring entry to SPE, years later, FEV₁ declined 12% in cases and increased 3% in controls. Cases had elevated serum MDC, GM-CSF, G-CSF and IP-10. Elevated GM-CSF and MDC increased the risk for subsequent FEV₁ < LLN by 2.5 fold (95% CI; 1.2-5.3) and 3.0 fold (1.4-6.1) in a logistic model adjusted for exposure, BMI, age on 9/11, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI 27-51), specificity of 88% (80-93).

Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure.

Many patients with advanced cystic fibrosis (CF) lung disease receive intensive treatments such as noninvasive and invasive mechanical ventilation for respiratory failure after little or no communication with physicians.

Using surveys and follow-up interviews, physicians at two major CF care centers reported their practices for discussing intensive treatment preferences with CF patients and about barriers and facilitators to communication.

Surveys were completed by 30 (88%) and 26 (76%) of 34 eligible CF physicians who provide care for children (60%), adults (23%) or both (17%). Respondents described variable timing and content of discussions. They identified patient/family factors such as denial of disease severity, optimistic expectations of treatment outcomes, inability of ill patients to participate in discussions, and family disagreements about treatments as primary barriers to discussions. They also acknowledged physician factors, including concern for taking away hope and uncertainty about when to address treatment preferences. Patient/family factors were also the most common facilitators identified, particularly disease severity and inquiry about intensive treatments. They recommended: (1) developing standards for communication, (2) offering training in communication for physicians, (3) creating decision support tools for patients and families, and (4) utilizing the multidisciplinary CF care team to facilitate communication.

CF physicians describe numerous patient/family factors barriers to communicating about intensive treatments for respiratory failure. They recommend changing physician and organizational factors to improve practice and promote effective communication. Innovation in clinical training, team roles, and decision support may prompt changes in practice standards.

Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children. We hypothesize that pediatric obesity-associated asthma will be characterized by T helper 1(Th1), rather than the Th2 polarization associated with atopic asthma. Moreover, we speculate that Th1 biomarkers and anthropometric measures will correlate with pulmonary function tests (PFTs) in obese asthmatics.

We recruited 120 children with 30 in each of the 4 study groups: obese asthmatics, non-obese asthmatics, obese non-asthmatics and non-obese non-asthmatics. All underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae, were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-gamma (IFN) (Th1) or IL-4 (Th2) within the CD4 population.

Obese asthmatics had significantly higher Th1 responses to PMA (p<0.01) and tetanus toxoid (p<0.05) and lower Th2 responses to PMA (p<0.05) and D. farinae (p<0.01) compared to non-obese asthmatics. Th cell patterns did not differ between obese asthmatics and obese non-asthmatics. Obese asthmatics had lower FEV₁/FVC (p<0.01) and RV/TLC ratios (p<0.005) compared to the other study groups, which negatively correlated with serum interferon inducible protein-10 (IP-10) and IFN levels, respectively. PFTs, however, did not correlate with BMI z-score or waist hip ratio.

We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatics.

Interferon-gamma release assays (IGRAs) have been recently incorporated into several national guidelines for LTBI diagnosis. However, their optimal application is still controversial and evolving. The aim of this study is to evaluate the performance of confirmatory IGRA in addition to TST-positive contacts in tuberculosis (TB) outbreaks in a high BCG-vaccinated population.

We conducted a retrospective observational study of contacts in five school TB outbreaks in South Korea. The progression rates of TB within two years were compared among the groups classified based on the results of tuberculin skin tests (TSTs) and QuantiFERON®-TB Gold assay (QFT-G).

Among 1826 contacts, 21 (1.2%) develop to active TB. Of untreated groups, the rate of progression to TB was higher in the group with TST+ (6.1%, 6/99) than in that with TST– (0.6%, 10/1556) (p < 0.001). Among TST+ contacts, the rate of progression to TB was higher in the group with QFT-G+ (18.75%, 6/32) than QFT-G- (0%, 0/67) (p = 0.001). None of the 67 contacts with TST+/QFT-G- progressed to active TB.

A confirmatory IGRA in addition to TST-positive contacts could effectively focus targeting of LTBI treatment to fewer contacts in an intermediate-incidence setting in a high BCG-vaccinated population.

The detection of pulmonary nodules (PN) is likely to increase, especially with the release of the National Lung Screen Trials. When tissue diagnosis is desired, transthoracic needle aspiration (TTNA) is recommended. Several guided-bronchoscopy technologies have developed to improve the yield of transbronchial biopsy (TBBx) for PN diagnosis: electromagnetic navigation (ENB), virtual bronchoscopy (VB), radial endobronchial ultrasound (R-EBUS), ultrathin bronchoscope, and guide sheath. We undertook this meta-analysis to determine the overall diagnostic yield of guided bronchoscopy using one or combination of the above modalities.

We performed a Medline search using "bronchoscopy" and "solitary pulmonary nodule." Studies evaluating the diagnostic yield of ENB, VB, R-EBUS, ultrathin bronchoscope, and/or guide sheath for peripheral nodules were included. The overall diagnostic yield and yield based on size were extracted. Adverse events, if reported, were recorded. Meta-analysis techniques incorporating inverse variance weighting and random-effects meta-analysis approach was used.

A total of 3,052 lesions from 39 studies were included. The pooled diagnostic yield was 70% which is higher than the yield for traditional TBBx. The yield increased as the lesion size increased. The pneumothorax rate was 1.6% which is significantly smaller than that reported for TTNA.

This meta-analysis shows that the diagnostic yield of guided bronchoscopic techniques is better than traditional TBBx. Although the yield remains lower than TTNA, the procedural risk is lower. Guided bronchoscopy may be an alternative or be complementary to TTNA for tissue sampling of PN, but further study is needed to determine its role in the evaluation of peripheral pulmonary lesions.

The airway contains airway smooth muscle and airway vascular smooth muscle. While the acute effects of inhaled long-acting β2-adrenergic agonists (LABAs) alone or in combination with an inhaled glucocorticoid (ICS) on airway smooth muscle tone in asthma are known, their effect on airway vascular smooth muscle tone have not previously been investigated.

To investigate the immediate effect of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma.

Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 μg), fluticasone (250 μg), salmeterol/fluticasone (50/250 μg) or placebo; Qaw was measured before and serially for 240 min post drug administration.

Mean Qaw increased after salmeterol and salmeterol/fluticasone with a peak at 60 min of 34% and 40 %, respectively; mean Qaw returned toward baseline by 240 min post inhalation. Fluticasone alone caused a transient decrease in mean Qaw. The maximum changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone, and -19 % for fluticasone (p< 0.05 vs. placebo for all).

The LABA salmeterol has an acute vasodilator action in the airway of subjects with stable asthma. The addition of fluticasone, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway. Registered at Clinicaltrials.gov - NCT01231230 URL: clinicaltrials.gov

Small vessel disease is a major determinant of a poor outcome after performing a pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH). Out-of-proportion pulmonary vascular resistance (PVR) may indicate the presence of small vessel disease, but it Is a very subjective evaluation. We investigated poor subpleural perfusion as a marker for small vessel disease, and assessed its association with the disease severity and surgical outcome of CTEPH.

We assessed the subpleural perfused area in the capillary phase of pulmonary angiography in 104 consecutive patients including 45 who underwent surgery, and then divided the patients into either the well-perfused group (n=75: the subpleural space in at least one segment was well perfused) or the poorly-perfused group (n=29: subpleural spaces were either unperfused or minimally perfused in all segments). We compared the pulmonary haemodynamics, degree of distal thrombi, and surgical outcome between these two groups.

The poorly-perfused group had significantly higher PVR (937±350 [SD] vs. 754±373 dyn.s.cm-5, p=0.02) and more distal thrombi, resulting in fewer surgically-treated patients (27.6% vs. 49.3%, p=0.04), compared to the well-perfused group. This group showed a higher surgical mortality (62.5% vs. 2.7%) and higher postoperative PVR (656±668 vs. 319±223 dyn.s.cm^-5, p=0.04). Even in a multivariate analysis, poor subpleural perfusion was associated with surgical mortality.

Poor subpleural perfusion in the capillary phase of pulmonary angiography might therefore be related to small vessel disease and a poor surgical outcome of CTEPH.

Inadequate localized drug concentrations and systemic adverse effects are among the concerns when regional infections are treated with systemic antibiotics. We designed and fabricated a poly(D,L)-lactide-co-glycolide (PLGA)-based biodegradable drug delivery system and evaluated the release of antibiotics both in vitro and in vivo.

PLGA copolymer and penicillin G sodium were mixed, compressed, and sintered to fabricate biodegradable antibiotic beads. The beads were placed in a phosphate buffered saline (PBS) to test the characteristics of in vitro drug release. The beads were then introduced into the pleural cavities of six New Zealand white rabbits via chest tubes. Daily pleural effusion was collected to measure the antibiotic concentration and bacterial inhibitory characteristics.

Forty percent of the penicillin was released in the first day in the in vitro study. The rest of the antibiotic was then gradually released in the following 30 days. All of the six animals survived the experiment. The initial surge of drug release was less significant in the pleural cavity than in PBS. The drug concentrations were well above the minimum inhibitory concentration (MIC) breakpoint for penicillin susceptibility throughout the study period in both in vitro (30 days) and in vivo studies (14 days).

These preliminary findings demonstrated that the biodegradable PLGA antibiotic beads could achieve a fairly steady antibiotic release in the pleural cavity for at least two weeks. This drug delivery system may have the potential to serve as an adjuvant treatment for pleural cavity infection.

Exercise tolerance in COPD is only moderately well predicted by airflow obstruction assessed by forced expiratory volume in 1 second (FEV₁). We determined whether other phenotypic characteristics, including computerized tomography (CT) measures, are independent predictors of 6 minute walk distance (6MWD) in the COPDGene^® cohort.

COPDGene^® recruits non-Hispanic Caucasian and African-American current and ex-smokers. Phenotyping measures include post-bronchodilator FEV₁%predicted, inspiratory and expiratory CT lung scans. We defined %emphysema as percent lung voxels below -950 Hounsfield Units (HU) on the inspiratory scan and %gas trapping as percent lung voxels below -856 HU on the expiratory scan.

Data of the first 2,500 participants of the COPDGene^® cohort were analyzed. Participant age was 61±9 y; 51% were men; 76% were non-Hispanic Caucasians and 24% were African-Americans. Fifty-six percent had spirometrically-defined COPD with 9.3%, 23.4%, 15.0% and 8.3%, in GOLD stages I–IV respectively. Higher %emphysema and %gas trapping predicted lower 6MWD (p<0.001). However, in a given spirometric group, after adjustment for age, gender, race, and BMI, neither %emphysema nor %gas trapping, nor their interactions with FEV₁%predicted, remained a significant 6MWD predictor. In a given spirometric group, only 16-27% of variance in 6MWD could be explained by age, male gender, Caucasian race and lower BMI as significant predictors of higher 6MWD.

In this large cohort of smokers, in a given spirometric stage phenotypic characteristics were only modestly predictive of 6MWD. CT measures of emphysema and gas trapping were not predictive of 6MWD after adjustment for other phenotypic characteristics.

Previous studies suggested that fetal smoke exposure is associated with increased risks of wheezing during childhood. The underlying pathways are unknown. We examined the associations of parental smoking during pregnancy with wheezing in preschool children and whether these associations are explained by postnatal smoke exposure or small for gestational age at birth (SGA).

This study was embedded in a population-based prospective cohort study. Parental smoking was prospectively assessed by questionnaires. Wheezing was reported at 1 to 4 years. SGA was available from registries. The analyses were based on 4,574 subjects.

Maternal smoking during the first trimester only was not associated with wheezing. Continued maternal smoking in pregnancy was associated with the risk of wheezing at 1 to 4 years (p-trends <0.05). The strongest effect estimates were observed for frequent wheezing (≥ 4 episodes of wheezing per year) until 3 years (odds ratio (95% confidence interval): age 1: 1.64 (1.12, 2.40); age 2: 1.64 (1.01, 2.64); age 3: 2.19 (1.24, 3.86)). Among children of non-smoking mothers, fetal exposure to paternal smoking was not consistently associated with the risks of wheezing. The associations of continued maternal smoking during pregnancy with wheezing symptoms were independent of postnatal smoke exposure or SGA.

Fetal exposure to continued maternal smoking is associated with increased risks of wheezing in preschool children. Further research is needed to explore the effects of paternal smoking. Diminishing maternal smoking before conception or in early pregnancy is likely to have the greatest impact on reducing childhood wheezing.

Until now, many investigators have focused on describing right ventricular (RV) dysfunction in groups of patients with Pulmonary Arterial Hypertension (PAH) but very few have addressed the deterioration of RV function over time. The aim of this study was to investigate time courses of RV geometric changes during the progression of RV failure.

42 PAH patients were selected who underwent right heart catheterization and CMR at baseline and after 1-year follow-up. Based on the survival after this one-year run-in period, patients were classified into two groups: survivors (26 patients): subsequent survival of more than 4 years, and non-survivors (16 patients): subsequent survival of less than 4 years. Four-chamber cine imaging was used to quantify RV longitudinal shortening (apex-base distance change), RV transverse shortening (septum-free wall distance change), and RV fractional area change (RVFAC) between end-diastole and end-systole.

Longitudinal shortening, transverse shortening, and RVFAC measured at the beginning of the run-in period and 1 year later, were significantly higher in subsequent survivors than in non-survivors (P<0.05). Longitudinal shortening did not change during the run-in period in either patient group. Transverse shortening and RVFAC did not change during the run-in period in subsequent survivors, but decreased in subsequent non-survivors (P<0.05). This decrease was caused by increased leftward septal bowing.

Progressive RV failure in PAH is associated with a parallel decline in longitudinal and transverse shortening until a floor effect is reached for longitudinal shortening. A further reduction of RV function is due to progressive leftward septal displacement. Because transverse shortening incorporates both free wall and septum movements, this parameter can be used to monitor the decline in RV function in end-stage PAH.

Patients with COPD consistently express a desire to discuss end-of-life care with clinicians, but these discussions rarely occur.

We assessed whether an intervention using patient-specific feedback about preferences for discussing end-of-life care would improve the occurrence and quality of communication between patients with COPD and their clinicians.

A cluster-randomized trial randomizing clinicians and examining patients clustered under their clinicians from outpatient clinics at the VA Puget Sound Health Care System.

Using self-report questionnaires, we assessed patients’ preferences for communication, life-sustaining therapy, and experiences at the end of life. The intervention clinicians and patients received a 1-page patient-specific feedback form, based on questionnaire responses, to stimulate conversations. The control group completed questionnaires but did not receive feedback. Patient-reported occurrence and quality of end-of-life communication (QOC) was assessed within 2 weeks of a targeted visit. Intention-to-treat regression analyses were performed with generalized estimating equations to account for clustering of patients within clinician.

Ninety-two clinicians contributed 376 patients. Patients in the intervention arm reported nearly a 3-fold higher rate of discussions about end-of-life care (unadjusted: 30% vs. 11%, p<0.001). Baseline end-of-life communication was poor (intervention group QOC score 23.3 (95%CI: 19.9 to 26.8), control QOC score 19.2 (95%CI:15.9 to 22.4)). Patients in the intervention arm reported higher quality end-of-life communication that was statistically significant although the overall improvement was small (Cohen effect size: 0.21)

A 1-page patient-specific feedback form about preferences for end-of-life care and communication improved the occurrence and quality of communication from patients’ perspectives.

Pulmonary arterial hypertension (PAH) is a progressive angioproliferative disease with high morbidity and mortality. Although the histopathology is well described, its pathogenesis is largely unknown. We previously identified the increased presence of mast cells and their markers in a rat model of flow-associated PAH. The aim of this study was to test the effect of mast cell stabilization on pulmonary vascular remodelling in experimental PAH.

Rats with flow-associated PAH, created by monocrotaline and an aorto-caval shunt were treated with the mast cell stabilizer cromolyn and compared with untreated rats and control rats. Further, we treated a group of rats with PAH with an inhibitor (TY-51469) of chymase, one of the mast cell proteases. The effects on pulmonary vascular remodeling and hemodynamics were assessed.

Rats with PAH had increased mast cells, chymase activity and inflammatory markers. Treatment with mast cell stabilizer attenuated pulmonary vascular remodeling but not hemodynamics. A lower pulmonary chymase activity correlated with more favorable pulmonary vascular remodeling as well as hemodynamics and inflammatory markers.

We showed in rats with PAH that mast cell stabilization attenuated pulmonary vascular remodeling and that a lower chymase activity correlated with more favorable hemodynamics and pulmonary vascular remodeling. The results of this experimental study support the concept of the use of anti-inflammatory therapy by mast cell stabilizers, a group of drugs already licensed for clinical use, to attenuate disease progression in PAH.

Myeloid derived suppressor cells (MDSC) are increased in inflammatory and (auto)-immune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in PH lungs of humans and animals, and we hypothesized that they would be increased in the blood of PH patients versus controls.

26 children with PH and 10 undergoing cardiac catheterization for arrhythmia ablation were studied. 5 milliliters of fresh blood was analyzed by flow cytometry. Results were confirmed by magnetic bead sorting and immunofluorescence, while qPCR and intracellular urea concentration were used as measures of MDSC arginase-1 activation.

Flow cytometry demonstrated enrichment of circulating MDSC among patients with PH (n =26, 0.271 X 10⁶ cells/mL ± 0.17, 1.86% of CD45+ population ± 1.51) vs. controls (n =10, mean 0.176 X 10⁶ cells/mL ± 0.05, 0.57% of CD45+ population ± 0.29, p < 0.05). Higher numbers of circulating MDSC correlated to increasing mean pulmonary artery pressure (r = 0.510, p < 0.05). Among PH patients, females had a 2-fold increase in MDSC compared to males. Immunofluorescence analysis confirmed the results of flow cytometry. Quantitative RTPCR for arginase-1 and measurement of intracellular urea revealed increased activity of MDSC from patients with PH versus controls.

Circulating activated MDSC are significantly increased in children with PH compared to controls. Further investigation of these cells is warranted, and we speculate that they might play significant immunomodulatory roles in the disease pathogenesis of PH.

Comorbid ischemic heart disease (IHD) is a common and important cause of morbidity and mortality in COPD patients. The impact of IHD on COPD in terms of health status, exercise capacity and symptoms is not well understood.

We analyzed stable state data of 386 patients from the London COPD Cohort between 1995 and 2009 and prospectively collected exacerbation data in those who had completed symptom diaries for ≥one year.

Patients with IHD (n=64,16.6%) had significantly worse health status as measured by SGRQ (56.9±18.5 vs 49.1±19.0, p=0.003) and a larger proportion of this group reported more severe breathlessness in the stable state with an MRC dyspnea score of ≥four (50.9% vs 35.1%, p=0.029). In subsets of the sample, stable COPD patients with IHD had a higher median (IQR) serum NT-proBNP concentration than those without IHD (38 (15,107) vs 12 (6,21) pg/ml, p=0.004), and a lower exercise capacity (6MWD 225±89m vs 317±85m, p=0.002). COPD exacerbations were not more frequent in those with IHD (1.95 (1.20,3.12) vs 1.86 per year (0.75,3.96), p=0.294), but the median symptom recovery time was five days longer (17.0 (9.8,24.2) vs 12.0 (8.0,18.0), p=0.009), resulting in significantly more days per year reporting exacerbation symptoms (35.4 (13.4,60.7) vs 22.2 (5.7,42.6), p=0.028). These findings were replicated in multivariate analyses allowing for age, gender and FEV_1, and exacerbation frequency where applicable.

Comorbid IHD is associated with worse health status, lower exercise capacity and more dyspnea in stable COPD patients and longer exacerbations, but not an increased exacerbation frequency.

The quantification and interpretation of cardiorespiratory fitness in obesity is important for adequately assessing cardiovascular conditioning, underlying comorbidities, and properly evaluating disease risk. We retrospectively compared $$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ (i.e., cardiorespiratory fitness) in absolute terms, and relative terms (%predicted) using three currently suggested prediction equations (Equations R, W, and G).

19 nonobese and 66 obese participated. Subjects underwent hydrostatic weighing and incremental cycling to exhaustion. Subjects characteristics were analyzed by independent t-test, and %predicted $$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ by a two-way ANOVA (group and equation) with repeated measures on one factor (equation).

$$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ (L•min^–1) was not different between nonobese and obese adults [2.35±0.80(SD) vs. 2.39±0.68L•min^–1]. $$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ was higher (p<0.02) relative to body mass and lean body mass in the nonobese (34±8 vs. 22±5mL•min^–1•kg^–1, 42±9 vs. 37±6mL•min^–1•LBM^–1). Cardiorespiratory fitness assessed as percent predicted was not different in the nonobese and obese [91±17 vs. 95±15%predicted] using Equation R, while using Equation W and G, cardiorespiratory fitness was lower (p<0.05) but within normal limits in the obese [94±15 vs. 87±11; 101±17 vs. 90±12%predicted, respectively], depending somewhat on gender.

Traditional methods of reporting $$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ do not allow adequate assessment and quantification of cardiorespiratory fitness in obese adults. Predicted $$\stackrel{\cdot }{\hbox{ V }}{{\mathrm{O}}_{2}}_{\hbox{ peak }}$$ does allow a normalized evaluation of cardiorespiratory fitness in obese, although care must be taken in selecting the most appropriate prediction equation, especially in women. In general, otherwise healthy obese are not grossly deconditioned as is commonly believed, although cardiorespiratory fitness may be slightly higher in nonobese subjects depending on the uniqueness of the prediction equation.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a 3-year median survival. Lung volume and diffusion capacity at rest are usually used to monitor the clinical course. Due to its high mortality, identification of patients at high-risk is crucial for treatment strategies such as lung transplantation (LTX). This study was designed to determine if tumor markers could accurately characterize disease severity and survival in patients with IPF.

The study population consisted of 61 patients with progressive IPF, referred for LTX. Pulmonary function tests, cardiopulmonary exercise test, 6-minute walk distance test, and Doppler echocardiogram were assessed at baseline and compared to tumor marker levels. Participants were prospectively followed for at least 25 months to determine the relationship between test parameters and survival. Tumor marker levels were reassessed in LTX patients. Forty-one age and sex matched patients (21 LTX recipients) with chronic obstructive pulmonary disease (COPD) served as controls.

In the IPF group, 9 patients (14.7%) died during follow-up and 20 (32.8%) underwent LTX. Univariate analysis showed correlations between CA 125 and FEV1 % (P=0.0001). CA 19-9 yielded the best correlations with exercise parameters and PAP. Significant correlation with survival was noted with CA 15-3 (P=0.04) only. All tumor marker levels decreased significantly following LTX, except CA 125. CA15-3 had the largest decrease (P=0.001). Among the COPD group, tumor marker levels before LTX were significantly lower compared to the IPF and did not decrease following LTX. No patient in either group developed malignancy.

CA 15-3 levels may predict disease severity in IPF. Levels decreased in patients with IPF but not with COPD following LTX and were not associated with malignancy. This novel and preliminary observation suggests that mucin has a role in the pathogenesis of IPF and possibly is a marker for disease activity

Glucose-regulated protein 78 (GRP78) involves in not only the progression of non-small-cell lung cancer (NSCLC) but chemotherapy effects. We hypothesized that an intronic polymorphism (rs430397 G > A) in GRP78 may affect survival among patients with NSCLC treated with platinum-based chemothrapy.

Blood samples of advanced NSCLC (IIIB/IV) patients were maintained in our specimen bank between 2001 and 2006. Genomic DNA was genotyped for rs430397. Associations between rs430397 and platinum-based treatment response, overall survival (OS), NSCLC-related survival, progression-free survival (PFS) and relapses were evaluated. GRP78 RNA and protein in NSCLC tissues were tested by real-time PCR and immunohistochemistry.

The AA genotype is significantly associated with platinum-based chemoresistance (P = 0.019) and the NSCLC-related death (P = 0.022). OS, NSCLC-related survival and PFS of the AA genotype group are decreased compared with the GG and AG genotype groups (Log-rank P < 0.05, respectively). The AA group shows a higher prevalence of early NSCLC relapses than the AG and GG group (P = 0.030). In addition, the AA genotype shows a significantly increased risk for OS (HR 1.95) and PFS (HR 1.80) compared with the GG group. Functional analysis shows NSCLC tissues with genotype AA have higher GRP78 RNA and protein expression compared with those carrying GG at rs430397.

The rs430397 AA genotype of GRP78 is associated with reduced survival and higher prevalence of early relapses in advanced NSCLC patients treated with platinum-based chemotherapy.

Since many different reference equations are available for pulmonary function testing (PFT) and different interpretive strategies could affect the interpretation of results, we assessed variation in practice among 17 PFT laboratories.

PFT laboratory directors/supervisors in 17 hospitals (near Cleveland, Ohio) were surveyed between 9/15/10 and 1/5/11. The survey assessed features of the laboratory, including equipment used, types of tests offered, volume of testing, reference equations used, and the interpretive strategies employed (e.g., how normal was determined, how tests were actually read, etc.)

Responses were received from all 17 laboratories and verified using submitted sample PFT reports. The daily median number of tests performed and patients evaluated were 16 and 6, respectively. Great variation was observed not only in the choice of reference equations for spirometry, but also in criteria used to define airflow obstruction. Great variation was also observed in the reference equations used for lung volumes and diffusing capacity, as well as the criteria used to define physiologic derangements, like restriction, hyperinflation, air trapping, and impaired diffusing capacity. Only three of the 17 laboratories reported and used the "lower limit of normal" (LLN) to define PFT abnormality.

This survey demonstrated substantial variation in PFT laboratory practices, including the choice of reference equations, the criteria used to define abnormality, and the strategies for interpreting tests. The degree of variation raises concern about the consistency of the interpretation of results among laboratories and emphasizes the value of compliance with official guidelines to drive standardization.

An increase in airway caliber (airway distensibility) with lung inflation is attenuated in COPD. Furthermore, some subjects have a decrease in airway caliber with lung inflation. We aimed to test the hypothesis that airway caliber increases are lower in subjects with emphysema-predominant (EP) compared to airway-predominant (AP) CT subtypes. Additionally, we compared clinical and CT features of subjects with (airway constrictors) and without a decrease in airway caliber.

Based on GOLD stages and CT subtypes, we created a control group (N=46) and matched COPD groups (N=23 each): GOLD-2-AP, GOLD-2-EP, GOLD-4-AP, and GOLD-4-EP. In the CT scans of all 138 subjects we measured emphysema, lung volumes, and caliber changes in the 3^rd and 4^th airway generations of two bronchi. We expressed airway distensibility (ratio of airway lumen diameter change to lung volume change from end tidal breathing to full inspiration) as a global or lobar measure based on normalization by whole-lung or lobar volume changes.

Global distensibility in the 3^rd and 4^th airway generations was significantly lower in EP groups in GOLD-2 and GOLD-4 stages than controls. In GOLD-2 subjects, lobar distensibility of the right upper lobe 4^th airway generation was significantly lower in those with EP than AP. In multivariate analysis, emphysema was an independent determinant of global and lobar airway distensibility. Compared to non-constrictors, airway constrictors experienced more dyspnea, were more hyperinflated, and had higher percentage emphysema.

Distensibility of large-to-medium sized airways is reduced in subjects with an emphysema-predominant CT subtype. Emphysema seems to alter airway-parenchyma interdependence. (ClinicalTrials.gov Number NCT00608764)

Morphological and sonographic features of endobronchial ultrasound convex probe (EBUS-CP) images have been shown to be helpful in predicting metastatic lymph nodes. Greyscale texture analysis is a well established methodology that has been applied to US images in other fields of medicine. The aim of this study was to determine if this methodology could differentiate between benign and malignant lymphadenopathy of EBUS images.

Lymph nodes from digital images of EBUS procedures were manually mapped to obtain a region of interest (ROI) and analysed in a prediction set. The ROIs were analysed for the following greyscale texture features in MATLAB (v7.8.0.347 (R2009a)); mean pixel value, difference between maximum and minimum pixel value, standard deviation of the mean pixel value, entropy, correlation, energy and homogeneity. Significant greyscale texture features were used to assess a validation set compared to FDG-PET-CT findings where available.

Fifty two malignant nodes and 48 benign nodes were in the prediction set. Malignant nodes had a higher difference in the maximum and minimum pixel values, standard deviation of the mean pixel value, entropy, and correlation and a lower energy (p<0.0001 for all values). Fifty one lymph nodes were in the validation set; 44/51(86.3%) were correctly classified. Eighteen of these lymph nodes also had FDG-PET-CT assessment which correctly classified 14/18(77.8%) nodes, compared to greyscale texture analysis which correctly classified 16/18(88.9%) nodes.

Greyscale texture analysis of EBUS-CP images could be used to differentiate malignant and benign lymphadenopathy. Preliminary results are comparable to FDG-PET-CT.

An important consequence of sleep-disordered breathing (SDB) is excessive daytime sleepiness (EDS). EDS often predicts a favorable response to treatment of SDB, though in the setting of cardiovascular disease, particularly heart failure, SDB and EDS do not reliablycorrelate. Atrial fibrillation (AF) is another highly prevalent condition strongly associated with SDB. We sought to assess the relationship between EDS and SDB in patients with AF.

We conducted a prospective study of 151 patients referred for direct current cardioversion for AF who also underwent sleep evaluation and nocturnal polysomnography (PSG). The Epworth Sleepiness Scale (ESS) was administered prior to the PSG and considered positive if ≥11. The apnea-hypopnea index (AHI) was tested for correlation with the ESS, with a cutoff of ≥5 events/hour to diagnose SDB.

Mean age among study participants was 69.1±11.7 years, mean body mass index was 34.1±8.4 kg/m², and 76% were men. The prevalence of SDB in this population was 81.4% and 35% had EDS. The association between ESS score and AHI was low (R²=0.014; P=0.64). The sensitivity and specificity of the ESS for the detection of SDB in patients with AF were 32.2% and 54.5%.

Despite a high prevalence of SDB in this population with AF, most patients do not report EDS. Furthermore, EDS does not appear to correlate with severity of SDB or to accurately predict the presence of SDB. Further research is needed to determine whether EDS impacts the natural history of AF or modifies the response to SDB treatment.

The efficacy and safety of twice-daily aclidinium bromide, a novel, long-acting, muscarinic antagonist was assessed in patients with moderate-to-severe COPD.

In this Phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate-to-severe COPD received aclidinium 400 μg BID, tiotropium 18 μg QD and placebo for 15 days, with a 9-15 day washout between treatment periods. Treatments were administered via the Genuair^®* or HandiHaler^® dry powder inhalers. The primary endpoint was mean change from baseline in FEV₁ AUC_0-12/12h on Day 15. Secondary endpoints were changes from baseline in AUC_12-24/12h, AUC_0-24/24h, morning pre-dose, and peak FEV₁, and COPD symptom scores.

Thirty COPD patients were randomized, and 27 completed the study. Mean change from baseline in FEV₁ AUC_0-12/12h at Day 15 was significantly greater for aclidinium and tiotropium over placebo (P<.0001). FEV₁ AUC_12-24/12h, FEV₁ AUC_0-24/24h, morning pre-dose FEV₁ and peak FEV₁ were significantly greater for aclidinium and tiotropium over placebo (P<.0001 for all except P<.001 for FEV₁ AUC_12-24/12h tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on Day 1 for all of the normalized AUC values of FEV₁, as well as on Day 15 for FEV₁ AUC_12-24/12h (P<.05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P<.05), but not with tiotropium.

In COPD patients, aclidinium 400 μg BID compared with placebo provided clinically meaningful improvements in 24-hour bronchodilation that were generally comparable to tiotropium 18 μg QD, but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg BID on bronchodilation and COPD symptoms. This trial was registered on ClinicalTrials.gov (NCT00868231) as "Efficacy of Aclidinium Bromide Administered in Chronic Obstructive Pulmonary Disease (COPD) Patients".

Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world. In its more advanced stages exercise intolerance is often found, but the underlying mechanism is not known. Recent evidence indicates that exercise-induced pulmonary hypertension is markedly exaggerated in CMS. We speculated that this problem may cause pulmonary fluid accumulation and aggravate hypoxemia during exercise.

We assessed extra-vascular lung water (chest ultrasound), pulmonary artery pressure and left ventricular function in 15 patients with CMS and 20 control subjects at rest and during exercise at 3600 m.

Exercise at high altitude rapidly induced pulmonary interstitial fluid accumulation in all but one (14/15) patients with CMS and further aggravated the pre-existing hypoxemia. In contrast, in healthy high-altitude dwellers exercise did not induce fluid accumulation in the vast majority (16/20) of subjects (P=0.002 vs. CMS) and did not alter arterial oxygenation. Exercise-induced pulmonary interstitial fluid accumulation and hypoxemia in CMS patients was accompanied by a more than 2-times larger increase of pulmonary artery pressure than in controls (P<0.001), but no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension (P<0.01) and interstitial fluid accumulation (P<0.05) in patients with CMS, but had no detectable effects in controls.

These findings provide the first direct evidence that exercise induces rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS that appear to be related to exaggerated pulmonary hypertension. We suggest that this problem contributes to exercise intolerance in patients with CMS.

Clinical Trials Gov Registration # NCT01182792

The primary cause of COPD and lung cancer is smoking. Thus, COPD patients frequently have lung cancer and are often inoperable. Stereotactic body radiation therapy (SBRT) is anticipated to be the standard of care for inoperable early-stage non-small cell lung cancer. The most critical toxicity following SBRT is radiation pneumonitis (RP). We analyzed predictive factors for RP following SBRT and to investigate the degree and occurrence of RP in patients with severe COPD.

We retrospectively evaluated 265 lung tumors treated with SBRT between 2005 and 2010 with a minimum follow-up of 6 months. Predictive factors for RP, including GOLD stage and pack-years, were evaluated by univariate and multivariate analyses. RP was graded according to the CTCAE v3.0 scale.

Median follow-up was 19.2 months (range: 6.0–72.0 months). RP grades of 0/1/2/3/4/5 occurred in 101/102/49/12/0/1 patients, respectively. Multivariate analysis revealed that high V20, fewer pack-years, and high total dose were significant predictive factors for RP ≥ grade 1, and high V20, fewer pack-years, and history of lung resection were predictive for RP ≥ grade 2. RP in patients with more severe COPD was relatively milder than in patients with normal lung function and with mild COPD. Pack-year scales were significantly correlated with GOLD stage.

RP following SBRT in patients with severe COPD was relatively mild. Heavy smoking was the strongest negative predictor for severe RP and was correlated with severe COPD. Further follow-up and quantitative analysis of lung function might be needed to ascertain longer tolerability to SBRT.

The burden of disease in children with non-cystic fibrosis (CF) bronchiectasis is unknown. Our study aimed to identify the determinants of quality of life (QOL) and parental mental health in this group of patients and their parents; and to evaluate the effect of exacerbations on these parameters.

Parents of 69 children (median age 7 years) with non-CF bronchiectasis prospectively completed two questionnaires [parent-proxy cough-specific QOL (PC-QOL) and Depression, Anxiety and Stress scale (DASS)] at stable and exacerbation states. Data on clinical, investigational and lung function parameters were also collected.

During stable-state, the median [Inter-quartile range (IQR)] PC-QOL was 6.5 (5.3-6.9) and DASS-21 was 6 (0-20). Young age of children correlated with worse QOL (r_s=0.242, p=0.04) but radiological extent, lung function, underlying etiology, environmental tobacco smoke exposure and chronic upper-airway disease did not influence these scores. Exacerbations caused significant worsening in PC-QOL [median (IQR) 4.6 (3.8-5.4); p=<0.001] and DASS scores [22 (9-42); p<0.001; 38% with elevated anxiety 54% abnormal depression/stress scores during exacerbation]. Presence of viral infection, hypoxia and hospitalization did not influence exacerbation PC-QOL and DASS scores.

There is a significant burden of disease, especially during exacerbation, on parents of children with bronchiectasis. Prevention, early detection and appropriate management of exacerbations are likely to reduce psychological morbidity in this group.

Open studies suggest that treatment of obesity hypoventilation syndrome (OHS) by non-invasive ventilation (NIV) restores sleep quality, daytime vigilance and reduces cardio-vascular morbidity. However, no randomized controlled trial (RCT) comparing NIV to conservative measures is available in the field.

To assess in OHS patients, during a RCT, effects of one-month NIV compared to life counseling on blood gases, sleep quality, vigilance, cardiovascular, metabolic and inflammatory parameters.

Thirty-five newly diagnosed OHS patients were randomized either to the NIV group or the control group represented by lifestyle counseling. Assessments included blood gases, subjective daytime sleepiness, metabolic parameters, inflammatory (hsCRP, Leptin, RANTES, MCP1, IL6, IL8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL1-RA) cytokines, sleep studies, endothelial function (RH-PAT), and arterial stiffness.

Despite randomization, NIV group patients (n=18) were older (58±11 versus 54±6 years) with a higher baseline PaCO₂ (47.9±4.2 versus 45.2±3 mmHg). In intention to treat analysis, compared to control group, NIV significantly reduced daytime PaCO₂ (difference between treatments: -3.5 mmHg; 95%CI:-6.2 to -0.8) and apnea-hypopnea-index (-40.3/h 95%CI:-62.4 to -18.2). Sleep architecture was restored although non-respiratory micro-arousals increased (+9.4/hour of sleep; 95%CI: 1.9 to 16.9) and daytime sleepiness was not completely normalized. Despite a dramatic improvement in sleep hypoxemia, glucidic and lipidic metabolism parameters as well as cytokines profiles did not vary significantly. Accordingly, neither RH-PAT (+0.02; 95%CI: -0.24 to 0.29) nor arterial stiffness (+0.22m.s^-1; 95%CI: -1.47 to 1.92) improved.

One month of NIV although improving dramatically sleep and blood gases did not change inflammatory, metabolic and cardiovascular markers.

Clinical trial registration number: NCT00603096.

Obesity and asthma both cause breathlessness and there is a risk of mis-diagnosis of asthma in obese patients. Impaired Health related quality of life (HRQoL) and increased body mass index (BMI) increase physician attendance rates increasing this risk. We explored the possibility of mis-diagnosis and the relationship between BMI, HRQoL and other traditional measures of asthma severity in obese subjects with a doctor diagnosis of asthma.

Data was obtained from overweight subjects with physician diagnosed asthma screened as part of another study including bronchial responsiveness to methacholine (PC20) or reversibility to bronchodilators, HRQoL measured using generic (Short Form-36 (SF-36)) and disease specific (St George Respiratory Questionnaire (SGRQ), Impact of Weight on Quality of Life-Lite (IWQOL-Lite)) questionnaires. Exhaled nitric oxide (FeNO), height, weight and atopic status were also recorded.

Of 91 subjects, (mean BMI 38Kg/m², mean FEV1% 85.8%, mean FEV1/FVC ratio 70.0%, mean FeNO 25.1 ppb taking a mean CFC-beclomethasone-equivalent dose of 1273.5 μg/d) 36.3% had no bronchial hyper-responsiveness (possible mis-classification of asthma diagnosis.)

BMI and HRQoL were significantly related: SGRQ total (r=0.33, p<0.001), SF36 Physical Health subtotal (r=-0.42, p<0.001), SF36 Mental Health subtotal (r=-0.39, p<0.001) and IWQOL-Lite total (r=0.51, p<0.001) with no relationship to airway inflammation and bronchial reactivity. There was no significant difference in quality of life scores in subjects with or without bronchial hyper-reactivity.

We found evidence of mis-diagnosis of asthma in obese people. BMI in obese asthmatics negatively correlates with HRQoL which may relate to the diagnostic uncertainty and requires further exploration.

A pneumothorax is a potentially life threatening condition. Although Computed Tomography (CT) is the reference standard for diagnosis, chest x-rays (CXR) are commonly used to rule out the diagnosis. We compared the test characteristics of ultrasonography and supine CXR in adult patients clinically suspected of having a pneumothorax, using CT-scan or release of air on chest tube placement as reference standard.

We searched for English literature in MEDLINE and EMBASE, and performed hand searches. Two independent investigators used standardized forms to review papers for inclusion, quality (QUADAS tool) and data extraction. We calculated kappa agreement for study selection and evaluated clinical and quality homogeneity before meta-analysis.

We reviewed 570 papers, and selected 21 for full review (kappa 0.89); 8 papers (total of 1,048 patients) met all inclusion criteria (Kappa 0.81). All studies but one used the ultrasonographic signs of lung sliding and comet tail to rule out pneumothorax. CXR data was available for 864/1048 patients evaluated with ultrasonography. Ultrasonography was 90.9% sensitive (95%CI 86.5-93.9), and 98.2% specific (95%CI 97.0-99.0) for the detection of pneumothorax. CXR was 50.2% sensitive (95%CI 43.5-57.0), and 99.4% specific (95%CI 98.3-99.8).

Performance of ultrasonography for the detection of pneumothorax is excellent and is superior to supine CXR. Considering the rapid access to bedside ultrasonography and the excellent performance of this simple test, this study supports the routine use of ultrasonography for the detection of pneumothorax.

We retrospectively analyzed preoperative factors that may predict pathologically invasive tumor characteristics, including lymph node involvement, and pleural and vessel invasion in patients with cT1aN0M0 peripheral non-small cell lung cancer (NSCLC), in an attempt to identify candidates for pulmonary resection less than lobectomy.

We reviewed the charts of 363 patients in whom cT1aN0M0 lung cancer in the lung periphery had been diagnosed or was suspected, based on high-resolution computed tomography (HRCT) of 1- or 2-mm slice intervals, within 1 month before surgical resection, and examined the relationships between preoperative clinical information and pathological invasive characteristics, corresponding to lymph node involvement and pleural and vessel invasion.

Multivariate analysis showed that a tumor disappearance ratio (TDR) < 0.5, the presence of spiculation and an absence of air bronchograms were statistically significant independent predictors of pathological invasiveness. Most TDR ≥ 0.5 tumors were non-invasive (98.7%), and there was only 1 patient with recurrence within 5 years after surgical resection. Of the tumors with a TDR ≥ 0.5 without spiculation, 98.3% were non-invasive, and all those patients remained recurrence-free for 5 years after surgery.

The combination of a TDR ≥ 0.5 and the absence of spiculation was highly predictive of non- or minimally invasive NSCLC. Future studies should evaluate whether limited resection of these tumors provides acceptable outcomes.

To assess the performance of 2 prognostic models (the European Society of Cardiology [ESC] model and the simplified Pulmonary Embolism Severity Index [sPESI]) in predicting short-term mortality in patients with pulmonary embolism (PE).

We compared the test characteristics of the ESC model and the sPESI for predicting 30-day outcomes in a cohort of 526 patients with objectively confirmed PE. The primary end point of the study was all-cause mortality. The secondary end point included all-cause mortality, nonfatal symptomatic recurrent VTE, or nonfatal major bleeding.

Overall, 40 out of 526 patients died (7.6%; 95% confidence interval [CI], 5.3% to 9.9%) during the first month of follow-up. The sPESI classified fewer patients as low risk (31% [165/526], 95% CI: 27% to 35%) compared to the ESC model (39% [207/526], 95% CI: 35% to 44%; P < 0.01). Importantly however, low-risk patients based on the sPESI had no 30-day mortality compared to 3.4% (95% CI, 0.9-5.8) in low-risk patients by the ESC model. The secondary end point occurred in 1.8% of patients in the sPESI low-risk and 5.8% in the ESC low-risk group (difference, 4.0 percentage points; 95% CI, 0.2 to 7.8). The prognostic ability of the ESC model remained significant in the subgroup of patients at high-risk according to the sPESI model (OR 1.95, 95% CI 1.41 to 2.71, P < 0.001).

Both the sPESI and the ESC model successfully predict 30-day mortality after acute symptomatic PE, but exclusion of an adverse early outcome does not appear to require routine imaging procedures or laboratory biomarker testing.

To better understand the inter-relationships between disease severity, inspiratory capacity, breathing pattern and dyspnea, we studied responses to symptom-limited cycle exercise in a large cohort with COPD.

Analysis was conducted on data from two previously published replicate clinical trials in 427 hyperinflated patients with COPD. Patients were divided into disease severity quartiles based on FEV₁ %predicted. Spirometry, plethysmographic lung volumes and physiological and perceptual responses to constant work rate (CWR) cycle exercise at 75% of the peak incremental work rate were compared.

Age, body size and COPD duration were similar across quartiles. As FEV₁ quartile worsened (means of 62, 49, 39 and 27 % predicted): FRC increased (144, 151, 164 and 185 %predicted), IC decreased (86, 81, 69 and 60 %predicted), peak incremental cycle work rate decreased (66, 55, 50, 44 %predicted) and CWR endurance time was 9.7, 9.3, 8.2 and 7.3 min, respectively. During CWR exercise as FEV₁ quartile worsened, peak ventilation (V_E) and tidal volume (V_T) decreased, while an inflection or plateau of the tidal volume response occurred at a progressively lower V_E (p<0.0005), similar percentage of peak V_E (82-86%) and similar V_T/IC ratio (73-77 %). Dyspnea intensity at this inflection point was also similar across quartiles (3.1-3.7 Borg units) but accelerated steeply to intolerable levels thereafter.

Progressive reduction of the resting IC with increasing disease severity was associated with the appearance of critical constraints on V_T expansion and a sharp increase in dyspnea to intolerable levels at a progressively lower ventilation during exercise.

Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular morbidity and mortality. Although previous echocardiographic studies have demonstrated short term improvement in cardiovascular remodeling in OSA patients on continuous positive airway pressure (CPAP), a long term study incorporating cardiac biomarkers, echocardiography and cardiac magnetic resonance imaging (CMR) has not been performed to date.

A prospective study of 47 OSA patients was performed between 2007 and 2010. Cardiac biomarkers including C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (nt-proBNP) and troponin T (TnT) were measured at baseline and serially over one year. All patients underwent baseline and serial transthoracic echocardiography (TTE) and CMR to assess for cardiac remodeling.

Following 12 months of CPAP therapy, levels of CRP, nt-proBNP, and TnT did not change significantly from normal baseline values. As early as 3 months after initiation of CPAP, TTE revealed an improvement in right ventricular end-diastolic diameter, left atrial volume index, right atrial volume index, and the degree of pulmonary hypertension, which continued to improve over one year of follow-up. Finally, LV mass, as determined by CMR, decreased from 159±12 g/m² to 141±8 g/m² as early as 6 months into CPAP therapy and continued to improve until completion of the study at one year.

Both systolic and diastolic abnormalities in OSA patients can be reversed as early as 3 months into CPAP therapy, with progressive improvement in cardiovascular remodeling over one year, as assessed by both TTE and CMR.

Pulmonary hypertension (PH) associated with Pulmonary Fibrosis (PF) is a severe condition with poor outcome. It is unknown whether PF patients with associated PH (APH) represent a distinct phenotype of the disease. We hypothesized that the lung tissue gene expression pattern of patients with APH has a characteristic profile when compared with PF patients without APH. We sought to determine if different gene expression signatures in PF could be determined based on pulmonary arterial pressures (PAP) and to provide new insights into the pathobiology of APH.

Microarray analysis (Affymetrix) was performed after RNA was extracted from explanted lungs in 116 PF consecutive patients (development set, n=84; validation set, n=32) and 7 subjects with idiopathic pulmonary arterial hypertension undergoing lung transplantation (LTx). PAP were recorded intraoperatively immediately before starting LTx. The development set was divided into three groups according to mean PAP (mPAP): Severe PH group (mPAP≥40 mmHg, n=17); Intermediate PH group (mPAP 21-39 mmHg, n=45); NoPH group (mPAP≤20 mmHg, n=22).

Distinct gene signatures were observed. Severe PH patients showed increased expression of genes, gene-sets and networks related to myofibroblast proliferation and vascular remodeling, whereas NoPH patients strongly expressed pro-inflammatory genes. Two-dimensional hierarchical clustering based on 222 differentially expressed genes (Severe PH vs. NoPH) dichotomized subjects into two phenotypes in the Intermediate PH group and in the validation set. Real-Time RT-PCR confirmed the differential expression of selected genes.

Gene expression profiles distinguish PF phenotypes with and without APH. This observation can have important implications for future trials.

The pathophysiology of refractory asthma is not well understood and thus treatment modalities are not targeted to specific phenotypes, but rather a broad based treatment approach is used. The objective of this study was to develop refractory asthma phenotypes based on bronchoscopic evaluation, and from this information, to develop specific, directed personalized therapy.

Fifty-eight difficult to treat (refractory) asthmatic patients were characterized by the use of fiberoptic bronchoscopy with visual scoring systems of the upper and lower airways as well as bronchoalveolar lavage, endobronchial biopsy and brush. Response to changes in therapy was evaluated by changes in the Asthma Control Test and pulmonary function.

Five mutually exclusive phenotypes were formulated based on bronchoscopic evaluation: gastroesophageal reflux, subacute bacterial infection, tissue eosinophilia, combination, and nonspecific. Specific directed therapy yielded a significant improvement in the Asthma Control Test and pulmonary function for the entire group as well as for each defined subgroup except for the nonspecific group. Of interest, visual scoring of the supraglottic abnormalities identified 34/35 patients with gastroesophageal reflux and may give a better insight into asthmatic problems associated with chronic proximal reflux than standard testing.

Bronchoscopic evaluation of the upper and lower airways can provide important information regarding characterizing refractory asthma so as to better individualize therapeutic options and improve asthma control and lung function in these difficult to treat patients.

We evaluated survival and hospitalization rates in patients with Group 1 portopulmonary hypertension (PoPH) in the Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL).

REVEAL is a multicenter, observational, US-based study evaluating demographics and management of patients with PAH. Outcomes were examined using Kaplan-Meier time-to-event estimates and compared to patients with idiopathic PAH (IPAH) or familial PAH (FPAH).

One hundred seventy-four patients with PoPH were enrolled in REVEAL (IPAH/FPAH; n=1478) from March 2006–December 2009. Mean age was 53±10 years, 52% were female, 32% newly diagnosed, and 6% New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH versus IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%; P<0.001), 5-year survival from time of diagnosis (40% vs 64%; P<0.001), and 2-year freedom from all-cause hospitalization (49% vs 59%; P=0.019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH versus IPAH/FPAH, respectively: mean pulmonary artery pressure (49 vs 53 mmHg; P<0.001), mean right atrial pressure (9 vs 10 mmHg; P=0.005), pulmonary vascular resistance (8 vs 12 Wood units; P<0.001), and cardiac output (5 vs 4 L/min; P<0.001). Compared with IPAH/FPAH patients, PoPH patients were less likely to be on a PAH-specific therapy at enrollment (P<0.001), suggesting potential delays in therapy for PoPH patients.

Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns.

Inpatient venous thromboembolism (VTE) prophylaxis is underutilised. This study evaluated the effectiveness of a low-cost, multifaceted National Inpatient Medication Chart (NIMC) intervention on improving the quality of VTE prophylaxis and reducing disease. The NIMC intervention incorporated: 1) a VTE risk stratification and appropriate prophylaxis guidance tool, 2) a prophylaxis contraindication screening instrument, and 3) a prophylaxis prescription prompt.

Retrospective analysis of 2371 consecutive medical and surgical admissions at a regional referral hospital over one year, both before and after the intervention. Outcomes measured included the frequency of prophylaxis utilisation, timing of prophylaxis initiation, adherence of prescribed prophylaxis regimen to guidelines, incidence of VTE disease and prophylaxis related complications.

Following NIMC intervention, prophylaxis utilisation increased from 52.7% to 66.5% in medical patients and from 77.5% to 89.1% in surgical patients (p<0.001). This increase was still evident twelve months post-intervention. After intervention, prophylaxis initiated on admission increased from 65.0% to 83.6% in medical patients and from 60.7% to 78.0% in surgical patients (p<0.01), adherence rates to recommended guidelines increased from 55.6% to 71.0% in medical patients and from 53.6% to 75.6% in surgical patients (p<0.01). More VTE risk factors independently triggered prophylaxis usage post-intervention. The improved quality of prophylaxis did not significantly reduce VTE incidence (RR=0.88; 95% CI=0.48 – 1.62). The rate of prophylaxis related complications remained similar before and after intervention.

A multifaceted NIMC intervention resulted in a sustained increase in appropriate and timely VTE prophylaxis in medical and surgical inpatients.

The aim of this study was to characterize the practice of routinely obtaining tracheal aspirate cultures in children with tracheostomy tubes and to analyze the appropriateness of using this information to guide antibiotic selection for treatment of subsequent lower respiratory infections.

Listservs of pediatric otolaryngologists and pulmonologists were surveyed regarding surveillance culture practices. Records of children with tracheostomy tubes from 1/1/03 through 12/31/07 were reviewed. Consecutive cultures were compared for similarity of bacteria and antibiotic sensitivity when a clinic culture preceded a culture when the child was ill and received antibiotics, and when a hospital culture preceded a hospital culture from a separate hospitalization.

79 of 146 Pulmonologists and 5 of 33 Otolaryngologists obtained routine surveillance tracheal aspirate cultures (p<0.001); 97% of Pulmonologists used these cultures to guide subsequent empiric therapy. There were 36 of 170 children with one or more eligible pairs of cultures. Nearly all children had a change in flora in their tracheal cultures. Limiting empiric antibiotic choices to those that would cover microbes isolated in the previous culture likely would not have been effective in covering one or more microbes isolated in the second culture in 56% of pairs with the first culture from hospitalization versus 30% with the first culture from an outpatient setting (p= 0.15).

This study demonstrated that there are significant changes in bacteria or antibiotic sensitivity between consecutive tracheal cultures in children with tracheostomy tubes. Use of prior tracheal cultures from these children was of limited value for choosing empiric antibiotic therapy in treating acute lower respiratory exacerbations. Surveillance cultures thus are an unnecessary burden and expense of care.

Lower respiratory tract infection (LRTI) is common in the community, and may result in hospitalization or death. This observational study aimed to investigate the role of antibiotics in the management of LRTI in UK primary care.

Patients receiving a first diagnosis of LRTI during 2004 and satisfying inclusion and data quality criteria were identified in the General Practice Research Database. Factors associated with respiratory infection-related admissions and death in the 3 months following initial diagnosis were identified using Cox proportional hazards regression.

Antibiotic prescribing on the day of diagnosis was associated with a decreased rate of respiratory infection-related admission (hazard ratio: 0.73; 95% confidence interval: 0.58–0.92), while antibiotic prescribing in the previous 7 days (1.92; 1.24–2.96) and prior referral or hospitalization (1.48; 1.20–1.83) were associated with an increased risk of admission. Female sex (0.73; 0.64–0.84), allergic rhinitis (0.48; 0.27–0.83), influenza vaccination (0.75; 0.65–0.87), prior inhaled corticosteroid use (0.63; 0.52–0.76) and antibiotic prescription on the day of diagnosis (0.31; 0.26–0.37) were associated with decreased respiratory infection-related mortality, while a Charlson comorbidity index of > 2 (2.24; 1.72–2.92), antibiotic prescription in the previous 7 days (1.56; 1.20–2.03) and frequent consultation (1.62; 1.09–2.40) were associated with increased mortality.

Antibiotic prescribing on the day of LRTI diagnosis was associated with reductions in admissions and mortality related to respiratory infection. Antibiotics may help to prevent adverse outcomes for some patients with LRTI.

Congenital central hypoventilation syndrome (CCHS) is characterized by compromised chemo-reflexes resulting in sleep hypoventilation. We report a Chinese family with PHOX2B mutation-confirmed CCHS, with a clinical spectrum from newborn to adulthood, to increase awareness on its various manifestations.

After identifying central hypoventilation in an adult male (index case), clinical evaluation was performed on the complete family, which consisted of the parents, five siblings, and five offsprings. Pulmonary function tests, overnight polysomnography, arterial blood gases, hypercapnia ventilatory response, and PHOX2B gene mutation screening were performed on living family members. Brain MRI, 24-h Holter, and echocardiography were done on members with clinically diagnosed central hypoventilation.

The index patient and four offsprings manifested with clinical features of central hypoventilation. The index patients had hypoxia and hypercapnia while awake, polycythemia, and hematocrit of 70%. The first and fourth children had frequent cyanotic spells and both died of respiratory failure. The second and third children remained asymptomatic until adulthood, when they experienced impaired hypercapnic ventilatory response. The third child had nocturnal hypoventilation with nadir SpO₂ of 59%. Adult-onset CCHS with PHOX2B gene mutation of the + 5 alanine expansions were confirmed in the index patient and the second and third children. The index patient and the third child received BiPAP treatment, which improved the hypoxemia, hypercapnia, and polycythemia without altering their chemo-sensitivity.

Transmission of late-onset CCHS is autosomal-dominant. Genetic screening of family members of CCHS probands allows for early diagnosis and treatment.

This randomised control trial compared the efficacy of utilising chronic disease management principles for tobacco dependence using a tailored intervention with standard care. As tobacco dependence is a chronic relapsing condition, the tailored intervention was chosen to account for possible interim setbacks.

Four hundred and forty-three eligible participants received five telephone-counselling calls and 4 weeks of nicotine replacement therapy. They were randomised to receive continuing counselling and nicotine replacement therapy for 1 year (longitudinal care, LC) or to receive one additional call at 8 weeks (evidence-based usual care, UC). The primary outcome was 6 months of prolonged abstinence, measured at 18 months following initial quit date. Secondary outcomes included abstinence rates before 6 months and smoking reduction.

At 18 months, 30.2% of LC participants reported 6 months of abstinence from smoking, compared with 23.5% in UC. Prior to 6 months, abstinence rates were slightly higher with UC than LC. At all time points, those who did not quit had greater smoking...