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Background Sarcoidosis is a multisystem granulomatous inflammatory disorder, that predominantly involves the lungs. Patients with Lofgren's syndrome (LS) are characterized by acute onset and usually have the HLA-DRB1*03 (DR3positive) allele and a good prognosis. Non-LS patients are usually DR3negative and are more likely to develop chronic disease. The study aimed to identify bronchoalveolar lavage fluid (BALF) cells that could associate with disease severity (reduced pulmonary function tests (PFTs), advanced chest radiographs, need for treatment) and/or chronicity (duration >2 years) in newly diagnosed LS and non-LS patients, respectively. Methods We retrospectively included data from 955 non-LS patients, 477 LS patients, and 295 healthy controls (HC) in this study. Intra-group comparison of patients with resolving versus chronic disease was performed in LS and non-LS, respectively. Non-LS patients were divided into two subgroups according to the binary BALF cell concentrations for intra-group comparison (i.e. higher or lower than the 95th percentile of the BALF cells references in healthy individuals). Results LS patients with a non-resolving disease course had higher BALF lymphocytes, neutrophils, and eosinophils than LS with a favourable outcome. In non-LS subjects increased BALF of the same cells and in addition also of basophils and mast cells were more likely associated with more severe disease course. Conclusion Increased BALF cells display prognostic significance in sarcoidosis. Certain BALF profiles should promote the clinician to monitor these patients more closely as they may associate non-resolving disease, in turn, resulting in future irreversible functional impairment.

International audience; Background: Growing consideration is emerging regarding the burden of persisting sequelae after SARS-CoV-2 infection. Out-patients exhibiting long Covid may benefit from ambulatory rehabilitation which is, to date, poorly documented. Methods: A longitudinal follow-up over a one-year period was conducted in two ambulatory rehabilitation structures in order to describe the characteristics of real-life patients referred with Covid-19 sequelae and their evolution over the course of rehabilitation. Results: 39 consecutive patients were included from April 1st, 2020 to April 1st, 2021. Patients were middle-aged (48 ± 15yr), without comorbidities, and mostly mild to moderate SARS-CoV-2 infection (25(64%) not requiring hospitalisation). Rehabilitation referral was considered with a median delay of 73[34–178] days after disease onset. Most prevalent symptoms were dyspnoea (n = 35(90%)) and fatigue (n = 30(77%)). Hyperventilation syndrome was highly frequent (n = 12(34%)). 29(74%) patients presented with prolonged functional sequelae, which was associated with younger age (43 ± 14 vs. 50 ± 10yr; p = 0.002), greater prevalence of hyperventilation syndrome (n = 12(41%) vs. 0(0%); p = 0.255) and poorer quality of life (VQ-11; 31 ± 10 vs. 23 ± 9; p = 0.030). Over the course of rehabilitation, exertional dyspnoea, 6-min walking distance, 3-min sit-to-stand test, hyperventilation syndrome prevalence and quality of life significantly improved. Conclusion: Hyperventilation is frequent in long Covid and may explain persistent dyspnoea as well as altered quality of life. Our data support screening of hyperventilation syndrome and functional impairment in mild Covid-19 out-patients as both of these components may improve with ambulatory rehabilitation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted through respiratory droplets, aerosols and close contact. Cross infections occur because viruses spread rapidly among humans. Nineteen percent (19%) of the infected patients developed severe pneumonia and acute respiratory distress syndrome (ARDS). Hypoxemia usually occurs and patients may require oxygen therapy or mechanical ventilation (MV) support. In this article, recently published clinical experience and observational studies were reviewed. Corresponding respiratory therapy regarding different stages of infection is proposed. Infection control principles and respiratory strategies including oxygen therapy, non-invasive respiratory support (NIRS), intubation evaluation, equipment preparation, ventilator settings, special maneuvers comprise of the prone position (PP), recruitment maneuver (RM), extracorporeal membrane oxygenation (ECMO), weaning and extubation are summarized. Respiratory equipment and device disinfection recommendations are worked up. We expect this review article could be used as a reference by health care workers in patient care while minimizing the risk of environmental contamination.

Introduction Dental caries and respiratory tract infections are among the most common infectious diseases worldwide and they both are appearing in the respiratory system. However, their relations are still unclear. This study investigated the association of dental caries on the risk of lower respiratory tract infections (LRTI) in young adulthood. Methods The study population consisted of 1,592 Finnish young adults participating in the 20-year follow-up of The Espoo Cohort Study. The information on the occurrence of LRTIs (pneumonia or acute bronchitis) during the preceding 12 months was based on the follow-up questionnaire and the National Hospital Discharge Register. Lifelong caries on permanent teeth was defined as a self-reported number of filled teeth (FT). The risk ratios (RR) of LRTIs with 95% confidence intervals (CI) were estimated using Poisson regression models. Results High FT number was associated with an increased occurrence of LRTIs with an adjusted RR of 1.24 per interquartile range (IQR) of FT (95% CI 1.06–1.44). The risk of LRTIs increased according to the increasing number of FTs, being highest among those subjects with 10 or more filled teeth (adjusted RR 2.30; 1.27–4.17). Family's socioeconomic status or smoking did not modify the effect. Conclusions Our results suggest that dental caries increases the risk of LRTIs. We did not find any significant effect modification by shared determinants of caries and LRTIs. However, it is possible, that common risk factors might explain at least partly the observed relation between FT and LRTIs or that the causality is bidirectional.

Exertional dyspnea increases when the mechanical output of the respiratory muscles becomes uncoupled from increases in neural respiratory drive. Combining measurements of inspiratory constraints and ventilatory inefficiency may better uncover the role of mechanical-ventilatory abnormalities on exertional dyspnea than the currently-recommended approach, i.e., a low breathing reserve.We determined the presence of a low breathing reserve (1-(peak ventilation (V̇E)/estimated maximal voluntary ventilation) x 100 15%), critical inspiratory constraints (tidal volume (VT)/exercise inspiratory capacity (ICThe agreement between breathing reserve and assessment of inspiratory constraints was only "fair" (kappa [confidence interval (CI)] = 0.264 [0.169-0.358]). Attainment of critical inspiratory constraints and an upward inflection in dyspnea ratings systematically preceded a low breathing reserve. Of note, ~55% (93/167) of subjects with normal breathing reserve showed critical inspiratory constraints despite largely preserved lung function. Regardless of the breathing reserve, subjects showing critical inspiratory constraints and/or poor ventilatory efficiency reported higher dyspnea and more impaired exercise tolerance compared to their counterparts (p 0.05). Poor ventilatory efficiency strongly predicted a high dyspnea/work rate in subjects without critical inspiratory constraints regardless of the breathing reserve (odds ratio [95% CI] = 4.21 [2.01-6.42; p 0.001).An integrated analysis of inspiratory constraints and ventilatory inefficiency is key to uncover physiological abnormalities germane to dyspnea in clinical populations in whom the origins of this distressing symptom are uncertain.

Background _The mitogen response in interferon-γ(IFN-γ) release assays(IGRAs) measures IFN-γ after binding to CD2, a surface adhesion marker found on T-cells and NK cells. A lower mitogen response implies either peripheral blood mononuclear cells have fewer adhesion molecules either in absolute numbers or per T-cells, or the pathway from adhesion molecules to IFN-γ production is not functioning well. To date, it remains poorly understood whether the mitogen response is associated with outcomes in tuberculosis patients. Methods _From 2012 to 2017, patients with culture-confirmed tuberculosis were tested for QuantiFERON-TB Gold In-Tube(QFT-GIT). The associations between patient outcomes and QFT-GIT as well as IFN-γ responses to the mitogen were investigated. Outcomes of interest included 1-year mortality after tuberculosis diagnosis and 2-month culture conversion. Results _In total, 466 culture-confirmed tuberculosis patients were enrolled and QFT-GIT was positive in 309(66%). Within 1 year of diagnosis, 20(4%) died and notably, 15(11%) out of 137 patients with a lower mitogen response did so. The multivariate Cox model showed that a lower mitogen response (hazard ratio, 8.789; 95% confidence interval, 3.074–25.129) was independently associated with 1-year mortality. Moreover, among 160 patients with smear-positive culture-confirmed pulmonary tuberculosis, multivariate logistic analysis indicated that a lower mitogen response (odds ratio, 3.966; 95% confidence interval, 1.182–13.303) was significantly associated with 2-month culture persistence. Conclusions _This study found that a lower mitogen response was associated with worse 1-year survival in tuberculosis patients and correlated with 2-month culture persistence in patients with sputum smear-positive culture-confirmed tuberculosis. These findings suggest another application of QFT-GIT for prognostication of tuberculosis patients.

Smart inhalers, connected to smartphones, can provide real-life objective information about the patterns of a patient's adherence and their inhaler technique during routine use. The e-modules contain the battery and measuring sensors. Many of these are add-on modules attached externally whilst others are integrated inside the inhaler. Smart inhalers that identify a dose has either been actuated or prepared do not confirm the dose was inhaled but they can send missed dose reminders and clinical studies have highlighted their potential to improve adherence and outcomes. The e-modules that measure an inhalation profile confirm a dose has been inhaled together with providing useful information about the inhaler technique. Studies confirm that the sensors are accurate and confirm their usefulness to provide information about real-life inhaler use. Add-on e-modules are generic whereas integrated smart inhalers can be approved containing active agents and, therefore, prescribed and instructed under healthcare guidance. Real-life studies need to be carried out to demonstrate their potential to improve disease control and prevent exacerbations to justifying their increased cost.

To evaluate whether elevated levels of cardiac troponin increases the risk of mortality in patients with acute PE.We conducted a systematic review and meta-analysis with rigorous statistical evaluation using publications (2000-2018) from Cochrane Library, MEDLINE, PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and Google Scholar databases. We searched for retrospective, prospective, and randomized controlled trials (RCT) or quasi-RCT studies that assessed the effect of elevated troponin versus normal levels on the outcomes of PE. The main outcome of interest was all-cause mortality. Extracted data included authors, the origin of studies, source population, study settings and duration, inclusion/exclusion criteria, data sources and measurement, sample size, and mortality. Data heterogeneity was assessed using the Cochrane Q homogeneity test with a significance set at p 0.10. If the studies were statistically homogeneous, a fixed effect model was selected.Out of 1825 references, 46 analytical studies were included with a total of 10842 patients with PE. The effect of elevated troponin on mortality had a pooled odd ratio (OR) of 4.33 for all studies, 3.7for HsTnT, 14.81 for HsTnI, 7.85 for cTnT, 2.81 for cTnI, 9.02 for low-risk PE and 4.80 for 90-day mortality. The pooled negative likelihood ratios for all-cause mortality using HsTnI, cTnI and cTnT assay were 0.21, 0.33 and 0.65, respectively.Regardless of the troponin assay, pooled analysis indicates that elevated troponin is significantly associated with higher mortality in patients with PE.

Background Few population-based studies on the effects of environmental exposure variation exist. Aim Assessing respiratory symptom/disease incidence related to risk factor exposure changes. Methods A longitudinal general population sample from two surveys (PISA2:1991–1993; PISA3:2009–2011; no. = 970), aged ≥20 years at baseline, completed a questionnaire on respiratory symptoms/diseases, risk factor exposure and performed spirometry. 18-year follow-up cumulative incidence of respiratory symptoms/diseases and longitudinal changes (persistence, incidence, remittance) in risk factor exposure were computed. Results Cumulative incidence values were: 3.2% (corresponding to a 1.8‰/year incidence rate), asthma; 6.6% (3.8‰/year), asthma attacks; 4.5% (2.6‰/year), wheeze; 31.7% (21.0‰/year), allergic rhinitis-AR; 7.6% (4.4‰/year), chronic obstructive pulmonary disease-COPD; 16.1% (9.7‰/year), usual cough; 18.5% (11.3‰/year), usual phlegm; 30.7% (20.1‰/year), dyspnoea 1+; 13.9% (8.3‰/year), airway obstruction. The following associations emerged among respiratory symptom/disease cumulative incidence and risk factor exposure changes: a two-to-five fold higher risk for COPD, phlegm, cough, dyspnoea, asthma attacks, airway obstruction in persistent smokers; a two-to-three fold higher risk for COPD in remittent smokers; a two-fold higher risk for AR, phlegm and a four-fold higher risk for asthma in subjects with persistent occupational exposure; a two-fold higher risk for cough, phlegm, dyspnoea, AR in subjects with incident occupational exposure; a two-fold higher risk for AR, asthma attacks, COPD in subjects with incident traffic exposure. Conclusions Our study showed noteworthy respiratory symptom/disease incidence values and indicated that life-style and environmental exposure changes can differently influence onset. This information could be useful for primary prevention strategies in order to reduce the chronic disease burden in the general population.

Introduction There are insufficient data on the treatment of latent tuberculosis infection (LTBI) in elderly patients. We investigated the completion rate of treatment in elderly LTBI patients. Methods A retrospective multicentre study was conducted at five university hospitals in South Korea. We reviewed the electronic medical records of patients aged 65 years and older who were diagnosed with LTBI via positive interferon-gamma release assay results between January 2016 and December 2018. Treatment completion was defined as ingestion of more than 80% of all prescribed medications without loss to follow-up. Results During the study period, 127 LTBI patients aged 65 years and older visited outpatient department. Among them, 77 patients aged 65–78 years (median age, 69 years [interquartile range, 66–71 years]) who received LTBI treatment were analysed. Common reasons for IGRA testing in elderly patients were health-care worker (n = 33, 42.9%) and household contact with infectious TB patients (n = 18, 23.4%). The overall completion rate of LTBI treatment was 83.1% (n = 64), and the completion rate of 3-month isoniazid plus rifampin regimen was 88.4%. Adverse effects were reported in 23 patients (29.9%), and an increase in aminotransferase level was the most common adverse effect (n = 11, 14.3%). Three patients (3.9%) with the adverse effect discontinued treatment and 10 (13.0%) patients were lost to follow-up. Conclusions LTBI treatment in patients aged 65–78 years was relatively well tolerated. In LTBI treatment in elderly patients, the majority of discontinuation of treatment was due to loss to follow-up rather than adverse effects of anti-TB medications.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with a course that is not uniform for all COPD patients. Although smoking is considered as the major cause of the disease, persistent or recurrent infections seem to play a particular role in the disease establishment and progression. COPD is characterized by dysregulated immunity that has been associated with the bacterial colonization and infections. The establishment of culture-independent techniques has shed new light on the relationships between bacterial ecology and health status and expanded our knowledge on the lung microbiome. Interactions between the host and lung microbiome result in inflammation and activation of resident cells. The lung microbiome contains populations of symbionts and pathobionts in balance which lose their equilibrium and disturb the balance of T-helper and regulatory T-cells (Treg) upon infection, or lung disease. In COPD factors such as disease severity, exacerbations, degree of inflammation, and type of treatment used (e.g inhaled or systemic steroids and antibiotics) affect the composition of lung microbiota. Recent data indicate that the presence of specific bacterial taxa in the airways has the potential to influence the host immune response and possibly to interfere with disease phenotype. Although, there is a growing body of evidence for the role of microbiome in COPD several unanswered questions still exist for its clinical relevance.

Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O20 patients (residual volume = 201.6 ± 63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 μg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation.Tiotropium/olodaterol was associated with marked lung deflation (p 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p 0.05).The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O

Lymphangioleiomyomatosis (LAM) is a rare diffuse lung cystic disease (DLCD) that occurs sporadically or in association with Tuberous Sclerosis Complex (TSC). The diagnostic pathway is tracked on the identification of the disease hallmarks on chest High-Resolution Computed Tomography (HRCT). Aim of this review is to discuss the thoracic HRCT pathognomonic features, essential to rule out other DLCD. It also examines the new evidences emerging from Computed Tomography (CT) quantitative studies that, by demonstrating a specific cysts distribution and a pathological aspect of the parenchyma near the cysts, could improve our understanding of this rare disorder and supply pulmonologists with a new tool for a more appropriate long-term management. Finally, the contribution of other image techniques as low dose chest CT, Magnetic Resonance Imaging (MRI) and Ultrasound (US) is discussed.

The COPD Assessment Test (CAT) is a self-administered questionnaire that measures symptomatic burden. CAT is used as part of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines refined ABCD tool and is usually performed during office visit assessment. Electronic medication monitors (EMMs) capture utilization of short-acting beta-agonists (SABA) that may indicate disease worsening in real-time. The primary objective was to assess the relationship of CAT with SABA utilization.From 8/2017-1/2019, COPD patients ≥40 years of age were enrolled in a digital health platform consisting of EMMs and a mobile application to track time and date of SABA use. Patients with a completed CAT and ≥81 days of continuous EMM data were included in analyses. Using one-way ANOVA, SABA use and maintenance medication adherence were compared by CAT score categories:10 (low burden), 10-20 (medium), 21-30 (high), and 31-40 (very high). Associations were additionally estimated in patients who used ≥1 puff/week of their rescue and maintenance medication.The population included 2196 COPD patients (mean age: 60 years). CAT scores from low to high burden were associated with greater SABA use, from 0.8 to 1.9 puffs/day (+1.1 [95% CI: 0.6, 1.6 puffs/day], P 0.001), and lower adherence, from 69% to 59%, (-10% [95% CI: -1, -19%], P = 0.04). Sensitivity analyses yielded similar results.This study found a significant association between greater SABA use and lower adherence with higher burden CAT scores. This finding may suggest that passive collection of inhaled medications could serve as a surrogate for CAT.

Background Evidence to support the implementation of telehealth (TH) interventions in the management of chronic obstructive pulmonary disease (COPD) varies throughout Europe. Despite more than ten years of TH research in COPD management, it is still not possible to define which TH interventions are beneficial to which patient group. Therefore, informing policymakers on TH implementation is complicated. We aimed to examine the provision and efficacy of TH for COPD management to guide future decision-making. Methods A mapping study of twelve systematic reviews of TH interventions for COPD management was conducted. This was followed by an in-depth review of fourteen clinical trials performed in Europe extracted from the systematic reviews. Efficacy outcomes for COPD management were synthesized. Results The mapping study revealed that systematic reviews with a meta-analysis often report positive clinical outcomes. Despite this, we identified a lack of pragmatic trial design affecting the synthesis of reported outcomes. The in-depth review visualized outcomes for three TH categories, which revealed a plethora of heterogeneous outcomes. Suggestions for reporting within these three outcomes are synthesized as targets for future empirical research reporting. Conclusion The present study indicates the need for more standardized and updated systematic reviews. Policymakers should advocate for improved TH trial designs, focusing on the entire intervention's adoption process evaluation. One of the policymakers' priorities should be the harmonization of the outcome sets, which would be considered suitable for deciding about subsequent reimbursement. We propose possible outcome sets in three TH categories which could be used for discussion with stakeholders.

Traditional medicine may not control bronchial asthma. Many patients have uncontrolled symptoms and the underlying ongoing inflammation is persistent. Objective to assess efficacy of laser acupuncture in improving asthma symptoms and underlying oxidative stress through monitoring exhaled 8-isoprostane. Method 48 asthmatic (case group) received successive low level laser acupuncture sessions to stimulate acupoints for chronic asthma and 24 asthmatics received deactivated laser acupuncture sessions (control group). Asthma symptoms, asthma control questionnaire, concentration of 8-Isoprostane in exhaled breath condensate and airway resistance were assessed before and after laser acupuncture therapy. Results After the completion of the course of laser acupuncture therapy, we observed significant improvement of asthma symptoms. Asthma control questionnaire improved from 9.7 ± 3.3 to 21.8 ± 3.6 (p 0.001). EBC 8-Isoprostane dropped from 14.7 ± 5.4 to 8.1 ± 5.0 (p 0.001). The airway resistance at R5 and R20 significantly decreased from 116.6 ± 25.8 & 124.5 ± 31.2 to 101.5 ± 25.6 &110.9 ± 29.9 respectively (p 0.001). Control patients who received sham acupuncture therapy did not show such improvement. Conclusion Laser acupuncture is an effective modality in treating bronchial asthma as evidenced by improved symptoms, airway resistance, and oxidative biomarkers.

Background Supplemental oxygen is a recommended therapy option in stable hypoxemic COPD patients. Often, supplemental oxygen is provided by continuous flow (CF). However, demand oxygen delivery systems (DODS) that provide an oxygen bolus only during inspiration have gained increasing use as they prolong oxygen cylinder life (beside battery life). However, there is a lack of evidence if different DODS and CF devices are equivalent. Methods Seventy hypoxemic COPD patients (FEV1 32 ± 9% predicted, PaO2 56±7 mmHg) on long-term oxygen therapy were included in this prospective single-blinded, randomized cross-over trial. Following an initial incremental shuttle walk test, patients performed 3 endurance shuttle walk tests (ESWT) at 85% of their maximum walking speed in random order with: (A) CF (ESWT-CF), (B) a DODS based on liquid oxygen (ESWT-DL) and (C) an DODS oxygen concentrator (ESWT-DC). The primary outcome was oxygen saturation (SpO2) at ESWT isotime. Secondary outcomes were total ESWT duration, heart rate (HR) and breathing frequency (BF) at isotime and dyspnea at end-exercise. Results SpO2 at ESWT isotime was not clinically different between devices: 90 ± 4% (CF), 89 ± 5% (DL) and 90 ± 5% (DC). However, 20% of the patients showed a ≥4% lower oxygen desaturation while using a DODS device. Secondary outcomes were similar under the three conditions. Conclusion Oxygen supplementation via DODS (based on liquid oxygen or as a concentrator) yielded comparable physiological effects during standardized walking in stable hypoxemic COPD patients like CF. However, 20% of patients showed a clinically relevant lower oxygen saturation while using a DODS device. Therefore, we suggest individual testing of oxygen saturation of DODS suitability.

The endothelial cells play a crucial role in the progression of angiogenesis, which causes cell re-modulation, proliferation, adhesion, migration, invasion and survival. Angiogenic factors like cytokines, cell adhesion molecules, growth factors, vasoactive peptides, proteolytic enzymes (metalloproteinases) and plasminogen activators bind to their receptors on endothelial cells and activate the signal transduction pathways like epidermal growth factor receptor (EGFR phosphatidylinositol 3-kinase and (PI3K)/AKT/mammalian target of rapamycin (mTOR) which initiate the process of angiogenesis. Cytokines that stimulate angiogenesis include direct and indirect proangiogenic markers. The direct proangiogenic group of markers consists of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) and hepatocyte growth factor (HGF) whereas the indirect proangiogenic markers include transforming growth factor-beta (TGF-β), interleukin 6 (IL-6), interleukin 8 (IL-8) and platelet-derived growth factor (PDGF). VEGF and FGF-2 are the strongest activators of angiogenesis which stimulate migration and proliferation of endothelial cells in existing vessels to generate and stabilize new blood vessels. VEGF is released in hypoxic conditions as an effect of the hypoxia-inducible factor (HIF-1α) and causes re-modulation and inflammation of bronchi cell. Cell re-modulation and inflammation leads to the development of various lung disorders like pulmonary hypertension, chronic obstructive pulmonary disease, asthma, fibrosis and lung cancer. This indicates that there is a firm link between overexpression of VEGF and FGF-2 with lung disorders. Various natural and synthetic drugs are available for reducing the overexpression of VEGF and FGF-2 which can be helpful in treating lung disorders. Researchers are still searching for new angiogenic inhibitors which can be helpful in the treatment of lung disorders. The present review emphasizes on molecular mechanisms and new drug discovery focused on VEGF and FGF-2 inhibitors and their role as anti-angiogenetic agents in lung disorders.

Introduction Primary ciliary dyskinesia (PCD) is a rare genetically heterogeneous disorder of motile cilia, which leads to recurrent and chronic airway infections. Detailed information about infection causing pathogens is scarce. With this study, we aimed to determine the prevalence and susceptibility of the most common respiratory pathogens in PCD patients retrospectively in a cross-sectional and the dynamics of the microbiological diversity in a longitudinal study. Methods Microbiological and clinical data of 106 patients between 2010 and 2016 were analysed cross-sectionally and of 28 patients longitudinally. Dynamics in microbiological diversity were assessed by calculating the mean rate of alteration (MRA). Results Haemophilus influenzae was the most common pathogen (n = 41; 38.7%) followed by Staphylococcus aureus (n = 36; 34%), Moraxella catarrhalis (n = 18; 17%) and Pseudomonas aeruginosa (n = 16; 15.1%). Nontuberculous mycobacteria were cultured from two patients (1.9%). H. influenzae was the most prevalent pathogen in children (n = 31; 45.6%), S. aureus in adults (n = 15; 39%). Two patients were infected by methicillin-resistant S. aureus. P. aeruginosa was mostly susceptible to standard antibiotics with highest rates of resistance against fosfomycin (63.6%; 7/11). The culture of P. aeruginosa correlated negatively with age adjusted FEV1% predicted (p = 0.04), while the MRA was positively associated with age (rho 0.411, p = 0.032). Discussion In PCD patients, the prevalence of pathogens differed in children and adults with H. influenzae and S. aureus being the most common pathogens in children, S. aureus and P. aeruginosa in adults, respectively. Unexpectedly, the MRA increased by age.

We explored the impact of FVC decline on subsequent FVC decline and mortality in the INPULSIS trials of nintedanib in patients with IPF and their open-label extension, INPULSIS-ON.Changes in FVC and mortality between weeks 24 and 52 of the INPULSIS trials were assessed in patients with an increase/no decline in FVC % predicted and with declines in FVC10% and ≥10% predicted from baseline to week 24. Changes in FVC and mortality in the first year of INPULSIS-ON were assessed in patients treated with nintedanib in the preceding INPULSIS trial who did and did not have a decline in FVC ≥10% predicted at week 52.The proportion of placebo-treated patients with decline in FVC ≥10% predicted between weeks 24 and 52 of INPULSIS was similar in patients with increase/no decline in FVC and with decline in FVC ≥10% predicted between baseline and week 24 (20.5% and 18.9%, respectively). Mortality between weeks 24 and 52 of INPULSIS was higher in patients with FVC decline ≥10% predicted than10% predicted between baseline and week 24 (13.2% vs 3.8%). Among nintedanib-treated patients in INPULSIS who had decline in FVC ≥10% versus10% predicted at week 52, 34.0% versus 21.4%, respectively, had decline in FVC ≥10% predicted in the first year of INPULSIS-ON. Mortality in the first year of INPULSIS-ON was 21.3% vs 5.7% in these groups, respectively.Decline in FVC did not predict FVC decline but was associated with mortality in patients with IPF.

Background Criteria of asthma severity and control lack standardization. Objective to compare classifications of asthma severity and control, applied to patients from a severe asthma clinic. Methods Cross-sectional study of 473 patients followed up for ≥6 months, reclassified using three criteria: 1) the World Health Organization (WHO) 2010, 2) the American Thoracic Society (ATS) 2000, and 3) the European Respiratory Society (ERS)/ATS 2014. In order to evaluate disease control, the 2012 and 2014 Global Initiative for Asthma (GINA) classifications were compared. Results According to the definition of WHO 2010, 429 had Difficult-to-treat severe asthma and only 12 presented Treatment-resistant severe asthma. 114 patients had Refractory asthma by ATS 2000 and 88 had Severe asthma by ERS/ATS 2014. Considering the definitions of WHO 2010, only 9 out of 12 with Treatment-resistant and 64 out of 429 with Difficult-to-treat severe asthma met the criteria of ATS 2000 and ERS/ATS 2014. As for GINA classification of control, 208 (44%) of the 473 subjects were classified as having asthma controlled by the 2014 criteria, whereas only 45 (10%) patients had controlled asthma by the GINA 2012 criteria. The Kappa statistic indicates the highest agreement of the severity classification occurred between the criteria of ATS 2000 and ERS/ATS 2014 (0.64). Conclusion Good agreement was found between Refractory asthma ATS 2000 and Severe asthma ERS/ATS 2014 classifications. However, poor agreement was observed between the severity rating proposed by the WHO and other classifications. The GINA control classifications of 2012 and 2014 also agreed poorly.

Background Inhaled corticosteroids (ICS) decrease airway inflammation and airway hyperresponsiveness (AHR). Previous studies have generally investigated the effect of ICS on methacholine-induced AHR following weeks or months of medium to high dose treatment. Purpose The short-term effects of once-daily fluticasone furoate (FF) 100 mcg on methacholine-induced AHR and airway inflammation were examined over the course of one week. Methods Eleven mild asthmatics completed this randomized, double-blind crossover study. Once-daily FF (100 mcg) and identical appearing placebo Ellipta® inhalers were given for 7 days with a 2-week washout. Methacholine challenges were performed before and 24 h after the first, third and seventh doses. Fractional exhaled nitric oxide (FeNO) was measured initially and at 7 days. Results FF significantly (p = 0.0009–0.0078) increased methacholine PD20 (provocative dose causing 20% fall in forced expiratory volume in 1 s) at all times. Doubling dose shifts (95% CI) were 1.23 (0.60–1.86), 1.17 (0.68–1.67) and 1.44 (0.93–1.94) after the first, third and seventh dose respectively. FeNO (geometric mean, 95% CI) decreased significantly (p = 0.0049) following FF treatment from 37.9 ppb (23.7–60.5) initially to 22.9 ppb (14.8–35.5) at 7 days. Placebo did not affect methacholine PD20 or FeNO. Conclusion Single-dose FF 100 mcg decreased methacholine AHR at 24 h without significant further improvement with continued daily use over 7 days. The inhibition in AHR after one week of daily dosing coincided with a significant decrease in FeNO at 7 days. Contrary to past assumptions, the ICS FF appears to rapidly reduce AHR to methacholine.

Rationale There are no reliable methods to predict lung function following lung transplantation. We sought to devise a prediction model of peak pulmonary function testing (PFT) post-transplant based on donor and recipient demographic characteristics. Methods Single center retrospective analysis of bilateral lung transplant recipients between 2011 and 2015 without evidence of allograft dysfunction in the first year was performed. Peak PFT post-transplant was determined by serially measured FEV1 and FVC. Using the NHANES III equation, donor demographic characteristics were used to calculate predicted lung function. Multivariable linear regression helped determine which donor and recipient characteristics affected peak lung function and identify the discrepancy between donor predicted and recipient observed PFT post-transplant. Results 146 donor/recipient patients were analyzed. 80 had obstructive lung disease, 66 had restrictive disease. Peak post-transplant FEV1 and FVC was reached in 64.30 ± 48.96 and 78.14 ± 50.68 weeks, respectively. Spirometry values peaked earlier in restrictive lung disease recipients. Higher peak FEV1 was significantly associated with younger donor age, non-African American donor race, male recipient sex, greater recipient height, underlying obstructive lung disease. Greater absolute differences between donor predicted and observed FEV1 were significantly associated with male donor sex, greater donor height, non-African-American donor race, female recipient sex, greater recipient height. Conclusions Donor and recipient characteristics can help predict lung function post-transplant. Patients without complications in the first year post-transplant may take greater than one year to achieve peak lung function. Such predictions can help guide clinical decision making in the right setting.

Background Multiple criteria have been proposed to define community-acquired pneumonia (CAP) severity and predict ICU admission. Validity studies have found differing results. We tested four models to assess severe CAP built upon the criteria included in the 2007 IDSA/ATS guidelines, hypothesizing that a model providing different weights for each individual criterion may be of better predictability. Methods Retrospective analysis of a prospective cohort study of adult hospitalizations for CAP at nine hospitals in Louisville, KY from June 2014 to May 2016. Four models were tested. Model 1: original 2007 IDSA/ATS criteria. Model 2: modified IDSA/ATS criteria by removing multilobar infiltrates and changing BUN threshold to ≥30 mg/dL; adding lactate level >2 mmol/L and requirement of non-invasive mechanical ventilation (NIMV). CAP was severe with 1 major criterion or 3 minor criteria. Model 3: same criteria as model 2, CAP was severe with 1 major criterion or 4 minor criteria. Model 4: multiple regression analysis including the modified criteria as described in models 2 and 3 with a score assigned to each variable according to the magnitude of association between variable and need for ICU. Results 8284 CAP hospitalizations were included. 1458 (18%) required ICU. Model 4 showed highest prediction of need for ICU with an area under the curve of 0.91, highest accuracy, specificity, positive predictive value, and agreement among models. Conclusion Assigning differential weights to clinical predictive variables generated a score with accuracy that outperformed the original 2007 IDSA/ATS criteria for severe CAP and ICU admission.

Magnetic resonance imaging (MRI) has been emerging as an imaging modality to assess interstitial lung diseases (ILD). An optimal chest MRI protocol for ILDs should include non-contrast breath-holding sequences, steady-state free-precession sequences, and contrast-enhanced sequences. One of the main MRI applications in ILDs is the differentiation between areas of active inflammation (i.e. reversible stage) and fibrosis. Alveolitis presents high signal intensity on T2-weighted sequences (WS) and early-enhancement on contrast-enhanced MR sequences, while fibrotic-predominant lesions present low signal and late-enhancement in these sequences, respectively. MRI can be useful in connective tissue diseases, idiopathic pulmonary fibrosis, and sarcoidosis. The aim of this state-of-the-art review was to perform a state-of-the-art review on the use of MRI in ILDs, and propose the optimal MRI protocols for imaging ILDs.

Introduction Bleomycin pulmonary toxicity (BPT) is a potentially life-threatening consequence of bleomycin usage in patients. An overproduction of epithelium-derived cytokines, habitually linked to allergic inflammation, has been recently revealed in experimental models of BPT. Methods We assessed retrospectively our cohort of patients with Hodgkin Lymphoma treated with bleomycin between 2014 and 2016 for their demographic, clinical features, including BPT development, atopy status and risk factors for BPT. Then they were invited for allergy testing and blood sample collection. The samples were stimulated with different stimuli (Bleomycin, IL-33, TSLP) for 24 h on cell culture. The culture supernatants were analysed for TGF-β, Galectin3, Arginin, Amphiregulin, Eotaxin, IFNγ, TNFα, IL1β, 4, 5, 6, 10, 13, 17, MIP-1α, and bleomycin hydrolase (BLH) levels. Results The cohort consisted of 51 patients showed that atopy was the only significant risk factor for BPT occurrence (OR: 7.2, p = 0.007). Fourteen subjects were included for blood analysis. The analysis of supernatants at the unstimulated condition revealed that BLH and Amphiregulin were significantly lower in patients who had BPT than controls. The BLH cut-off that best identified a history of BPT was 175.31 (Sensitivity: 62.5%, specificity: 100%). Following the stimulation, BLH reduced compared to the unstimulated condition and the difference between groups remained significant (p Conclusion Our study is the first to report that low levels of bleomycin hydrolase in allergic individuals may be predisposing to a possible pathway of fibrosis.

Background Asthmatics are at increased cardiovascular disease risk, which has been linked to beta2(β2)-agonist use. Inhalation of β2-agonists increases sympathetic nerve activity (SNA) in healthy individuals, however the systemic impact of salbutamol in asthmatics using β2-agonists regularly is unknown. Objectives This study compared the systemic vascular responses to a clinical dose of salbutamol (Phase I) and following an acute increase in SNA (Phase II) in asthmatics and controls. Methods Fourteen controls and 14 asthmatics were recruited for Phase I. On separate days, flow-mediated dilation (FMD) and peripheral arterial stiffness (pPWV) were evaluated at baseline and following either 400 μg inhaled salbutamol or a placebo inhaler. For Phase II, heart rate, blood pressure, vascular conductance, pPWV, and central (c)PWV were evaluated in response to a large increase in SNA brought on by cold-water hand immersion (i.e. cold-pressor test) or body-temperature water hand immersion (i.e. control) in 10 controls and 10 asthmatics. Results Following salbutamol, asthmatics demonstrated reduced FMD (−3.0%, p Conclusion Inhaled Salbutamol leads to increased arterial stiffness and reduced FMD in asthmatics. As asthmatics and controls had similar vascular responses to an increase in SNA, these findings suggest asthmatics have heightened sympathetic responses to β2-agonists which may contribute to the increased cardiovascular risk in asthma.

Developmental lung anomalies represent a heterogeneous group of diverse, yet related abnormalities that involve the lung parenchyma, pulmonary vasculature or a combination of both-which usually present prenatally and in early childhood. However, a substantial number of cases go unnoticed during childhood and present either incidentally or with recurrent respiratory infections progressing into adulthood. Defective development of the tracheobronchial tree and the pulmonary vasculature are proposed to cause these developmental anomalies. Encountering these lung anomalies in adults is a diagnostic challenge given their rarity and they are often mistaken as other serious pathological conditions, resulting in unnecessary diagnostic tests and procedures. The developmental lung anomalies in adults can be broadly divided into three categories: bronchopulmonary anomalies encompassing congenital bronchial atresia, bronchogenic cysts, congenital lobar emphysema and congenital pulmonary airway malformations. Vascular anomalies include pulmonary agenesis-aplasia- hypoplasia complex, unilateral absence of the pulmonary artery, pulmonary artery sling, partial anomalous pulmonary venous return, pulmonary venous varix and pulmonary arteriovenous malformations. Finally combined lung parenchymal-vascular anomalies of the lung involve hypogenetic lung (scimitar) syndrome and bronchopulmonary sequestration. This article discusses the spectrum of these developmental anomalies of the lung, their etiopathogenesis, clinical and radiographic presentations in adults and management in brief.

Introduction In CF, people with higher FEV1 are less aggressively treated with intravenous (IV) antibiotics, with resultant negative impact on their health outcomes. This could be entirely clinician-driven, but patient choice may also influence IV use. In this prospective observational study, we explored IV recommendations by clinicians and IV acceptance by adults with CF to understand how clinical presentations consistent with exacerbations resulted in IV use. Methods Clinical presentations consistent with exacerbations, IV recommendation by clinicians and IV acceptance by patients were prospectively identified for every adult with CF in Sheffield throughout 2016, excluding those who had lung transplantation (n = 7) or on ivacaftor (n = 13). Relevant demographic data, e.g. %FEV1, were extracted from medical records. Multi-level mixed-effects logistic regression models were used to compare IV recommendations vs non-recommendations for all clinical encounters, and IV acceptance vs non-acceptance for all IV recommendations. Results Among 186 adults (median age 27 years, median FEV1 78.5%), there were 434 exacerbation events and 318 IV use episodes following 1010 clinical encounters. Only 254 (58.5%) of exacerbations were IV treated. A diagnosis of exacerbation, higher number of symptoms and lower %FEV1 were independent predictors for IV recommendation by clinicians. Higher number of symptoms and lower %FEV1 were also independent predictors for IV acceptance by adults with CF. Conclusions Lower IV use among adults with higher %FEV1 was influenced by both clinicians' and patients’ decisions. Using IV antibiotics as an exacerbation surrogate could under-estimate exacerbation rates and conceal differential treatment decisions according to varying clinical characteristics.

Background: Management of chronic cough relies on the recognition of cough background disorders. It is not known whether certain cough triggers are associated with specific background disorders. Methods: This was an e-mail study to public service employees of two towns in Finland. The questionnaire included twelve triggers. Current asthma was defined as doctor's diagnosis of asthma and current wheezing. Chronic rhinosinusitis was defined as either nasal blockage or nasal discharge and either facial pain/pressure or reduction/loss of smell for more than three months. Gastroesophageal reflux disease was defined as heartburn and/or regurgitation on at least one day a week during the last three months. Idiopathic cough was defined as absence of any of them. Results: There were 421 subjects with current cough that had lasted at least eight weeks. Subfreezing air as a cough trigger was associated with an adjusted odds ratio (aOR) of 7.27 (4.09-12.9), (p

Study objectives Aim of the study was to investigate the association between obstructive sleep apnoea (OSA) and cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors. Methods In this prospective study, 378 patients of the DIAST-CHF cohort were screened for OSA by home polygraphy. Inclusion criteria were risk factors for diastolic heart failure, such as hypertension, diabetes mellitus, atherosclerotic disease, or history of chronic heart failure. Patients were followed up after 1, 2, 5, 9 and 10 years for the occurrence of major adverse cardiac and cerebrovascular events (MACE and MACCE). Results 344 patients were included in the analysis, of which 60% were diagnosed with OSA (apnoea-hypopnoea index ≥5/h). Overall mortality was higher in the OSA group (14.9% vs. 5.9%; p = 0.007), but significance disappeared after adjustment for age and sex (hazard ratio (HR) 1.89, 95% confidence interval (CI) 0.86–4.16, p = 0.12). There was no significant difference in the occurrence of MACE or MACCE in patients with OSA compared to those without OSA (MACE: 31% vs. 30%; p = 0.61; MACCE: 32% vs. 30%; p = 0.53). Conclusion We did not find evidence of an adverse effect of OSA on cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors.

The aim of the present study was to determine the effect of obstructive sleep apnea (OSA) with hypertension on telomerase activity, visfatin and adipsine concentration in the blood and vascular endothelial function assessed by ultrasound measured flow-mediated dilatation of the brachial artery (FMD).The study involved a group of 106 people (average age: 54.79 years). The determination of telomerase activity and blood visfatin and adipsine concentrations, brachial artery ultrasound examination with endothelium-dependent dilatation evaluation (FMD) and polysomnography were carried out.Patients with hypertension without OSA were characterized by significantly greater FMD in comparison to patients with arterial hypertension and OSA (8.13 ± 5.12 %vs. 6.82 ± 5.36%; p 0.05). Negative linear relationship between apnea-hypopnea index (AHI) and FMD (r = -0.22, p 0.05) has been demonstrated. Negative linear relationship between adipsine concentration in the blood and length of REM (Rapid Eye Movement) sleep (r = -0.21, p 0.05) was found. Positive linear relationship between the concentration of visfatin in the blood and the length of REM sleep (r = 0.22, p 0.05) was also observed. Higher body mass index, higher total cholesterol, triglyceride and glucose levels have been shown to be independent predictors of higher AHI values, while greater telomerase activity, greater FMD and use of angiotensin converting enzyme inhibitors are independent predicators for lower AHI values.Higher values of AHI index in polysomnography in hypertensive patients can be related to lower telomerase activity in the blood and impaired function of vascular endothelial function assessed using ultrasound.

Objective To assess the incidence and determinants of the triple inhaled therapy in chronic obstructive pulmonary disease (COPD) primary care patients. Methods Data derived from the Health Search Database (HSD) gathering information on 700 Italian general practitioners. A cohort of COPD patients, prescribed for the first time with inhaled treatments, was followed-up between January 2002 and December 2014. The outcome was the first incident prescription of a triple inhaled therapy, namely the combination of inhaled corticosteroids (ICS), long-acting beta agonists (LABA), and long-acting muscarinic antagonists (LAMA). Cox regressions were used to test the association (hazard ratios, HR) between candidate determinants and the outcome. Results Out of 17589 patients (mean age 71.1 ± 11.3 years; 37.4% females), 3693 (21%) were prescribed with a triple inhaled therapy during follow-up. Older age (HR = 1.79 to 2.61), current and former smoking habit (HR = 1.72 and 1.66), higher GOLD stage (HR = 1.45 to 2.79), the number of moderate and severe COPD exacerbations (HR = 1.10 to 2.63), and heart failure (HR = 1.17) resulted statistically significantly associated with an increased incident prescription of the triple inhaled therapy. Female sex (HR = 0.80) and some comorbidities (HR = 0.21 to 0.87) resulted negatively associated with the outcome. Furthermore, patients initially treated with LAMA (HR = 1.5) and LABA/ICS (HR = 1.23) were more likely to escalate to the triple therapy, than those on LABA. Conversely, patients initially treated with ICS presented a negative hazard (HR = 0.72). Conclusions The knowledge of demographic and clinical determinants of the escalation to the triple inhaled therapy in real-world COPD patients may help clinicians to better personalize respiratory pharmacological treatments of their patients, and inform international societies that issue clinical guidelines.

While there is a good knowledge of the natural course of lung function in interstitial lung diseases (ILD) like idiopathic lung fibrosis (IPF), many ambiguities remain in patients with asbestosis. Therefore, we evaluated the change in lung function in asbestos exposed subjects with pleural plaques and asbestosis and analysed corresponding morphology of computer tomography of the thorax. Methods 93 asbestos exposed subjects with pleural plaques and asbestosis were analysed retrospectively at the Klinikum Bergmannsheil of the Ruhr-University of Bochum. Parameters of lung function were obtained at least twice and annual changes of FVC, TLC and DLCOsb were calculated. In addition, we assessed the predominant pattern in high-resolution computer tomography of the thorax (HRCT) and differentiated three phenotypes: p (pleural) –type, f (fibrosis) -type and m (mixed) –type. Results FU data are available in 56/93 (60.2%) patients. The annual deterioration (Mean ± SEM) of FVC is −31.46 ± 17.34 ml, of TLC -55.55 ± 25.67 ml, of DLCOsb −0.38 ± 0.07 mmol/min/kPa and of DLCOva −0.05 ± 0.01 mmol/min/kPa/L. A categorical change of FVC > −100 ml was found in 12/56 (21.4%) and 18/56 (32.1%) patients showed an annual loss of TLC > −100 ml. The greatest annual decline of FVC was observed in patients with the fibrotic phenotype on HRCT (−76.76 ± 66.43 ml) and the mixed phenotype (−81.52 ± 24.79 ml), while the pleural phenotype was less affected (−10.52 ± 25.07 ml). Conclusion More than 20% of our cohort have a progressive disease with an annual loss of FVC > −100 ml. Patients with the fibrotic-phenotype or mixed-phenotype on HRCT are particularly at risk.

Introduction and aim Pseudomonas aeruginosa could acquire a mucoid phenotype due to mutations in mucA (mucoid Pseudomonas aeruginosa - mPA) that is a hallmark of poor prognosis in patients with bronchiectasis. Despite the higher prevalence of Pseudomonas aeruginosa in bronchiectasis, how mPA and non-mucoid Pseudomonas aeruginosa (non-mPA) phenotypes could affect viscoelastic properties of sputum is unknown. Our aim was to determine the relationship between Pseudomonas aeruginosa phenotypes isolation, the viscoelastic properties of sputum and the clinical outcomes in patients with bronchiectasis. Methods A cross-sectional study was conducted of sputum samples obtained by spontaneous expectoration and sent for microbiology and rheology analysis. Elasticity and viscosity were measured at two oscillatory frequencies (1 and 100 rad/s). Socio-demographic and clinical data were recorded. Results We analyzed 17 patients with mPA, 14 with non-mPA and 17 with no organism reported (NOR). Compared with the NOR group, the mPA group showed higher elasticity (median 10.30 vs. 5.70, p = 0.023), viscosity (2.40 vs. 1.50, p = 0.039), and stiffness (10.70 vs. 6.00, p = 0.024). Values in the mPA group tended to be higher compared with non-mPA. Clinically, the mPA group showed greater hospitalizations during the previous year and greater affected lobes than the non-mPA and NOR groups. Conclusions The mPA phenotype is associated with increased elasticity, viscosity and stiffness of bronchiectatic sputum. Viscoelastic properties could be used as a marker of poor mucociliary clearance in mPA, with potentially important clinical implications.

As many as 25% of all patients undergoing invasive pulmonary procedures are receiving at least one antiplatelet or anticoagulant agent. For those undergoing elective procedures, the decision-making process is uncomplicated and the procedure may be postponed until the antiplatelet or anticoagulant agent may be safely held. However, many invasive pulmonary procedures are semi-elective or emergent in nature in which case a risk-benefit calculation and discussion occur between the provider and patient or surrogate decision-maker. Therefore, it is critical for providers to have an awareness of the risk of bleeding complications with different pulmonary procedures on various antiplatelet and anticoagulant agents. This systematic review summarizes the bleeding complications associated with different pulmonary procedures in patients on various antiplatelet or anticoagulant agents in the literature and reveals a paucity of high-quality evidence across a wide spectrum of pulmonary procedures and antiplatelet or anticoagulant agents. The results of this review can help inform providers of the bleeding risk in these patients to aid in the shared decision-making process and risk vs benefit discussion.

Background Dyspnea is a cardinal but often underestimated symptom in amyotrophic lateral sclerosis (ALS). The newly developed Dyspnea-ALS-Scale (DALS-15) is highly relevant for therapeutic decisions because dyspnea is a separate criterion to consider noninvasive ventilation (NIV) in ALS. In comparison to the limited effects of neuroprotective compounds, NIV has the greatest impact on survival and improves quality of life. Objective To investigate whether dyspnea corresponds to parameters of respiratory status mainly used in clinical neurological practice. We also investigated if the DALS-15 could help identify patients for consideration of NIV in whom neither spirometry nor blood gas parameters indicate the need for NIV (forced vital capacity (FVC) 2 ≥45 mmHg). Methods Seventy ALS patients with dyspnea according to the DALS-15 obtained blood gas analysis and spirometry (FVC in sitting and supine positions). The supine decline in FVC was calculated. Results There was no linear relationship between dyspnea and spirometry as well as blood gases. 83% of our patients had an upright FVC still greater than 50% and no daytime hypercapnia. Conclusions Our study clearly shows that dyspnea can occur independently of objective indicators of respiratory impairment like spirometry or blood gases. Hence, the DALS-15 covers another aspect of respiratory impairment than these tests and refers to the subjective component of respiratory impairment. It detects dyspnea in a considerable proportion of patients in whom NIV should thus be considered although their spirometric and blood gas results do not point towards NIV. The DALS-15 therefore may help to improve the stratification of patients with respiratory impairment for more efficient symptom management and timely coordination of care.

Introduction: Our aim was to describe how the prevalence of subjects exposed to environmental tobacco smoke (ETS) has changed from 1992 to 2012 in Finland. We also investigated the association between ETS and chronic bronchitis and cause-specific and all-cause mortality. Methods: The study population is composed of 38 494 subjects aged 25-74 years who participated in the National FINRISK Study between 1992 and 2012. Each survey included a standardized questionnaire on exposure to ETS, symptoms of chronic bronchitis, smoking habits and other risk factors, and clinical measurements at the study site. Data on mortality was obtained from the National Causes of Death Register. Results: In 2012, 5% of the participants were exposed to ETS compared to 25% in 1992. The adjusted odds ratio (OR) for ETS exposure in 2012 compared with that in 1992 was 0.27, p

Objective Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies. Data sources A search was performed in PubMed using search terms ‘tiotropium’ and ‘asthma.’ Relevant references cited in those articles were reviewed. Study selections English language articles published from December 2008–December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included. Results Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting. Conclusions An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.

Medication adherence is an important factor in the management of chronic obstructive pulmonary disease (COPD). However, the rate of non-adherence to medications is high in COPD and is associated with worsened clinical outcomes and health-related quality of life for patients.Our study aimed to evaluate the impact of a pharmaceutical care program led by pharmacists in the improvement of medication adherence and quality of life for COPD patients in Vietnam.A pre- and post-intervention study was conducted over 12 months. Pharmacists provided brief counselling which focused on the role of COPD medications and the importance of adherence. Morisky Medication Adherence Scale was used to evaluate patients' adherence. Quality of life was assessed using the EQ-5D-5L questionnaire and clinical outcomes were evaluated by symptom scores. These outcomes were reassessed at baseline (T0), after 3 months (T1), 6 months (T2) and 12 months (T3).Study participants consisted of 211 COPD patients (mean age: 66.6 ± 8.2 years). The percentage of patients with good adherence significantly increased from 37.4% to 53.2% (p 0.001) after the program. Mean medication adherence scores improved from 6.7 (T0) to 7.4 (T2) and 7.4 (T3) (p 0.001). EQ-5D-5L index values also increased from 0.47 (T0) to 0.59 (T3) (p 0.001). There was no significant change in symptom scores across the duration of the study.Medication adherence and quality of life of COPD patients improved considerably after implementation of a pharmaceutical care program, thus supporting a vital role for pharmacists alongside physicians in the management of COPD.

The impact of hospitalization on patient outcomes is increasingly recognized and considered in the prognostication of many pulmonary disorders. We sought to evaluate the impact of hospitalization on survival in connective tissue disease-interstitial lung disease (CTD-ILD) patients.A chart review of patients with CTD-ILD followed at a tertiary care center was performed. Patients were stratified into two groups based on hospitalization status. Outcomes of the groups were compared using Kaplan-Meier survival analyses as well as multivariate competing risk analysis.There were 137 patients identified with confirmed CTD-ILD. Patients who underwent hospitalization for any reason had a significant decrease in transplant-free survival compared to the never hospitalized cohort (3-year survival 60% vs. 94%; p = 0.0001). Hospitalization for ≥7 days was associated with worse outcomes than those hospitalized for7 days (median survival 1.59 years vs. 7.17 years, p = 0.0012). Based on multivariate competing risk analysis, factors associated with death, with lung transplantation as a competing risk, were age (HR = 1.05 [95% 1.01-1.09]; P = 0.0443), male gender (HR = 4.94 [95% CI: 1.58-15.41]; P = 0.006), and all cause hospitalization (HR = 11.97 [95% CI: 1.36-105.49]; P = 0.0253).This study highlights the impact of hospitalization on subsequent outcomes in the CTD-ILD population with a significantly reduced transplant-free survival demonstrated, especially after cardiopulmonary hospitalization events.

Background Quality of life (QoL) is an important outcome in the management of children with asthma. Mobile Health (m-Health) and Therapeutic Education Programs (TEPs) are increasingly recognized as essential components of pediatric asthma management to improve disease outcomes. Objective To evaluate the effect of an education program (MyTherapeutic Education Program, MyTEP) that couples multidisciplinary TEP intervention with an m-Health Program (mHP) in improving QoL in asthmatic children. Methods This single-center study employed a nonblinded randomized clinical trial design. Italian-speaking children (6–11 years) with mild-moderate asthma were eligible for participation. Participants were randomly paired 1:1 with a control group that received mHP (smartphone app) or an intervention group that received MyTEP (TEP plus a smartphone app). Patients were followed up for 3 months. Descriptive statistics, Least Square (LS) mean change and Generalized Linear Mixed model were used for analysis. Results Fifty patients were enrolled. The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) score improved in both MyTEP (p = 0.014) and mHP (p = 0.046) with the minimally clinically significant difference of ⩾0.5 points reached in 23% of MyTEP and in 16% of mHP. Changes in PAQLQ scores were significantly greater in MyTEP than in mHP (LS mean difference: 0.269 p = 0.05). PAQLQ score was: positively associated with MyTEP (p = 0.023) and study time (p = 0.002); and inversely associated with current passive smoke exposure (p = 0.003). Conclusion Despite the small sample size and short observation period, this study demonstrated that implementing a multidisciplinary TEP with an m-Health program results in gains in QoL of children with asthma.

Background Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment. Methods In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium. Results Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg. Conclusions Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.

Background Beneficial effects from non-invasive ventilation (NIV) in acute COPD are well-established, but the impact of nebulization during NIV has not been well described. Aim To compare pulmonary deposition and distribution across regions of interest with administration of radiolabeled aerosols generated by vibrating mesh nebulizers (VMN) and jet nebulizer (JN) during NIV. Methods A crossover single dose study involving 9 stable subjects with moderate to severe COPD randomly allocated to receive aerosol administration by the VMN Aerogen and the MistyNeb jet nebulizer operating with oxygen at 8 lpm during NIV. Radiolabeled bronchodilators (fill volume of 3 mL: 0.5 mL salbutamol 2.5 mg + 0.125 mL ipratropium 0.25 mg and physiologic saline up to 3 mL) were delivered until sputtering during NIV (pressures of 12 cmH2O and 5 cmH2O - inspiratory and expiratory, respectively) using an oro-nasal facemask. Radioactivity counts were performed using a gamma camera and regions of interest (ROIs) were delimited. Aerosol mass balance based on counts from the lungs, upper airways, stomach, nebulizer, circuit, inspiratory and expiratory filters, and mask were determined and expressed as a percentage of the total. Results Both inhaled and lung doses were greater with VMN (22.78 ± 3.38% and 12.05 ± 2.96%, respectively) than JN (12.51 ± 6.31% and 3.14 ± 1.71%; p = 0.008). Residual drug volume was lower in VMN than in JN (3.08 ± 1.3% versus 46.44 ± 5.83%, p = 0.001). Peripheral deposition of radioaerosol was significantly lower with JN than VMN. Conclusions VMN deposited > 3 fold more radioaerosol into the lungs of moderate to severe COPD patients than JN during NIV.

Introduction A proportion of patients with idiopathic pulmonary fibrosis (IPF) have autoantibodies directed against intracellular targets. This study aimed to determine the relationship between serologic status, lung function decline and survival. Methods IPF patients assessed for antinuclear antibody (ANA) and related antigen-specific serology detected by addressable laser bead immunoassay (ALBIA) were included. Demographics, serial pulmonary function tests and survival were compared between patients with and without autoantibodies. Linear mixed models were used to estimate changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Cox-proportional hazards models were used to compare survival, adjusted for a composite score including age, sex and baseline lung function. Results Of 61 included patients, the mean baseline age was 70 years (SD = 9), 77% were male, and 87% were Caucasian. Either ANA or antigen-specific serology by ALBIA was positive in 25 (41%) during follow-up. ANA was detected in 23 (38%), and specific autoantibodies by ALBIA in 6 (10%). There was no difference in age, sex, race, smoking status, anti-fibrotic use or baseline FVC or DLCO in patients with and without autoantibodies. There was no association between autoantibody status and survival (HR = 1.18, 95% CI 0.61, 2.29), rate of decline in FVC or DLCO (difference in FVC = 4.2 mL/year, p = 0.82; difference in DLCO = 4.6*10−4 mL/min/mmHg/year, p = 0.20). Conclusion These data suggest that autoantibodies are common in IPF and that patients with a subset of autoantibodies, but without features of autoimmunity, demonstrate similar disease behaviour to those without autoantibodies.

Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology that affects the lungs in 90% of patients, but has a wide range of disease manifestations and outcomes including chronic and progressive courses. Noninvasive biomarkers are needed to assess these outcomes and guide decisions for long term monitoring and treatment. Interferon-gamma (IFN-γ)-inducible chemotactic cytokines (chemokines), CXCL9, CXCL10 and CXCL11, show promise in this regard because they have been implicated in the pathogenesis of and reflect the burden of granulomatous inflammation. CXCL11 has been reported to have unique functional properties in modulating adaptive immunity in model systems so our goal was to examine serum levels of CXCL11 in relation to clinical outcomes in a heterogeneous cohort of sarcoidosis subjects. METHODS: CXCL19, CXCL10, and CXCL11 serum levels were measured in sarcoidosis and healthy subjects using ELISA assay. We determined relationships between CXCL11 and standard clinical inflammatory markers, expression of IFN-γ-related genes in whole blood, organ involvement, dyspnea scores, and measures of pulmonary function. RESULTS: In a cross-sectional analysis of 104 sarcoidosis subjects, serum CXCL11 was significantly elevated compared to 49 healthy controls (p < 0.001). CXCL11 was positively correlated with CXCL9 and CXCL10 (p < 0.001), sedimentation rate (p < 0.01), and mean expression of three IFN-γ-related genes in whole blood (GBP1, STAT1, and STAT2) (p < 0.001). CXCL11 was inversely correlated with FVC %predicted (%pred) and FEV1 %pred and higher levels were associated with higher patient-reported dyspnea scores. We found positive correlations between CXCL11 and number of organs involved. Using survival analyses, we found that CXCL11 levels were predictive of future pulmonary function test (PFT) decline (log rank

Mild asthma is present in 50–75% of patients with asthma and is defined by the Global Initiative for Asthma as asthma that can be well controlled with low-intensity treatments (Steps 1 and 2). Despite this definition, ‘mild’ asthma is often not well controlled in reality, and can have a significant impact on an individual's symptom burden and quality of life. We performed a PubMed literature search to investigate the burden of ‘mild’ asthma in the lives of patients, including future risk and asthma control, and the current management strategies. While clinical guidelines recommend long-term, daily, low-dose inhaled corticosteroids (ICS)for ‘mild’ asthma, published data suggest that ICS are often under-prescribed or used intermittently as symptoms arise. Furthermore, patients and physicians tend to overestimate disease control, impacting the accuracy of diagnosing ‘mild asthma’ and subsequent management. This disconnect may be amplified by miscommunication between patients and physicians, limited objective assessment of control, and differences in guidelines. As with moderate and severe asthma, current evidence supports early initiation of regular ICS in ‘mild’ asthma to address the underlying inflammation, achieve symptom control and reduce risk of exacerbations. Adherence to ICS treatment is key and can be improved by educating both patients and healthcare professionals. The results of this literature search challenge the term ‘mild’ asthma and suggest strategies to improve the proactive management of the disease to enable patients to live symptom-free.

Background Sarcoidosis is a systemic disease that primarily affects the younger population. Longitudinal studies of the economic burden of sarcoidosis are scarce. This study evaluates overall the economic burden of sarcoidosis in Denmark before and after initial diagnosis. Methods We identified patients with sarcoidosis in the Danish National Patient Registry (1998–2010). All controls were randomly selected and matched concerning age, gender and residence. Data on direct and indirect costs, including frequency of primary and secondary sector contacts and procedures, medication, unemployment benefits and social transfer payments were extracted from national databases for patients and controls. Results We identified 9119 patients with sarcoidosis and 36,432 matching controls. Patients with sarcoidosis had significantly higher rates of health-related contacts, higher usage of medication and more received unemployment and social payments compared with controls. The total health expenses were significantly higher in the sarcoidosis group 11 years before and 11 years after diagnosis than among controls. Income from public transfer payments was significantly higher in the sarcoidosis group five years prior of diagnosis until nine years post diagnosis. Especially women between 40 and 59 years have a lower income than their controls. Conclusion Sarcoidosis has a socioeconomic impact on adults especially during their prime working and providing years and this is evident several years prior to and post diagnosis. The authors advocate that further research should focus on identifying the proportion of patients with sarcoidosis that imposes the largest economic burden. Increased focus on early diagnosis and disease management may reduce the socioeconomic burden of sarcoidosis.

Background Central obesity and polycyclic aromatic hydrocarbons (PAHs) exposure were reported as independent risk factors for lung function decline. However, the interaction between central obesity and PAHs exposure on lung function is still unclear. Objectives To evaluate the impact of central obesity, urinary polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and their combined effects on lung function in general population. Methods Lung function and urinary OH-PAHs were measured for 3,749 participants from the Wuhan-Zhuhai cohort. Central obesity was evaluated by waist-to-hip ratio. Generalized linear regression was used to estimate combined effect of central obesity and OH-PAHs on lung function. Results Compared with participants without central obesity and with low urinary total OH-PAHs (∑OH-PAHs) level, those with central obesity and high urinary ∑OH-PAHs level had 59.4 mL and 61.0 mL reductions for forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1), respectively (P Conclusion Polycyclic aromatic hydrocarbons exposure has combined effect with central obesity on lung function parameters.