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Background: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively. Methods: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture. Results: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p

BACKGROUND: Patients with severe asthma not meeting the strict trial eligibility criteria for mepolizumab are now routinely treated with this biological in clinical practice, but it remains unclear whether these ineligible patients respond differently to mepolizumab treatment.OBJECTIVE: This study investigated the extent and reasons for trial ineligibility of real-life, mepolizumab-treated patients with severe asthma and compared the characteristics of these patients with trial populations. Subsequently, therapeutic response in ineligible patients was assessed on the basis of oral corticosteroid (OCS) reduction.METHODS: Trial eligibility, population differences, and therapeutic response were assessed using the baseline characteristics of mepolizumab-receiving patients with severe asthma treated in the Amsterdam University Medical Centres and OCS dose at 6 months for OCS-dependent patients extracted from patients' electronic health records. Eligibility criteria and population characteristics from trials investigating mepolizumab were extracted from their original publications.RESULTS: A total of 82.4% of 119 mepolizumab-receiving, reallife patients with severe asthma were ineligible for trial inclusion, wherein 42.9% and 39.5% were excluded on the basis of inclusion and exclusion criteria, respectively. The clinical care population was older, more often male and demonstrating a better lung function under lower OCS maintenance dosages in comparison with trial populations. A total of 50% of 66 ineligible, OCS-dependent mepolizumab-treated patients were able to reduce their maintenance OCS dosage to

Molecular profiling of exhaled breath by electronic nose (eNose) might be suitable as a noninvasive tool that can help in monitoring of clinically unstable COPD patients. However, supporting data are still lacking. Therefore, as a first step, this study aimed to determine the accuracy of exhaled breath analysis by eNose to identify COPD patients who recently exacerbated, defined as an exacerbation in the previous 3 months. Data for this exploratory, cross-sectional study were extracted from the multicentre BreathCloud cohort. Patients with a physician-reported diagnosis of COPD (n=364) on maintenance treatment were included in the analysis. Exacerbations were defined as a worsening of respiratory symptoms requiring treatment with oral corticosteroids, antibiotics or both. Data analysis involved eNose signal processing, ambient air correction and statistics based on principal component (PC) analysis followed by linear discriminant analysis (LDA). Before analysis, patients were randomly divided into a training (n=254) and validation (n=110) set. In the training set, LDA based on PCs 1–4 discriminated between patients with a recent exacerbation or no exacerbation with high accuracy (receiver operating characteristic (ROC)–area under the curve (AUC)=0.98, 95% CI 0.97–1.00). This high accuracy was confirmed in the validation set (AUC=0.98, 95% CI 0.94–1.00). Smoking, health status score, use of inhaled corticosteroids or vital capacity did not influence these results. Exhaled breath analysis by eNose can discriminate with high accuracy between COPD patients who experienced an exacerbation within 3 months prior to measurement and those who did not. This suggests that COPD patients who recently exacerbated have their own exhaled molecular fingerprint that could be valuable for monitoring purposes., Exhaled breath analysis by eNose can identify COPD patients who recently exacerbated with high accuracy. This suggests that these patients have their own exhaled molecular fingerprint that could be valuable for monitoring purposes. https://bit.ly/34vTyrH

Introduction: The complexity and heterogeneous nature of asthma and chronic obstructive pulmonary disease (COPD) results in difficulties in diagnosing and treating patients. Biomarkers that can identify underlying mechanisms, identify patient phenotypes and to predict treatment response could be of great value for adequate treatment. Areas covered: Biomarkers play an important role for the development of novel targeted therapies in airways disease. Blood biomarkers are relatively non-invasive, easy to obtain and easy to apply in routine care. Several blood biomarkers are being used to diagnose and monitor chronic airways diseases, as well as to predict response to treatment and long-term prognosis. Blood eosinophils are the best studied biomarker, the most applied in clinical practice, and until now the most promising of all blood biomarkers. Other blood biomarkers, including serum periostin, IgE and ECP and plasma fibrinogen are less studied and less relevant in clinical practice. Recent developments include the use of antibody assays of many different cytokines at the same time, and ‘omics’ techniques and systems medicine. Expert commentary: With the exception of blood eosinophils, the use of blood biomarkers in asthma and COPD has been rather disappointing. Future research using new technologies like big-data analysis of blood samples from real-life patient cohorts will probably gain better insight into underlying mechanisms of different disease phenotypes. Identification of specific molecular pathways and associated biomarkers will then allow the development of new targets for precision medicine.

Bronchial Thermoplasty (BT) is an endoscopic treatment for moderate-to-severe asthma patients who are uncontrolled despite optimal medical therapy. Effectiveness of BT has been demonstrated in several randomized clinical trials. However, the asthma phenotype that benefits most of this treatment is unclear, partly because the mechanism of action is incompletely understood. BT was designed to reduce the amount of airway smooth muscle (ASM), but additional direct and indirect effects on airway pathophysiology are expected. This review will provide an overview of the different components of airway pathophysiology including remodeling, with the ASM as the key player. Current concepts in the understanding of BT clinical effectiveness with a focus on its impact on airway remodeling will be reviewed.

Currently, there is no noninvasive test that can reliably diagnose early invasive pulmonary aspergillosis (IA). An electronic nose (eNose) can discriminate various lung diseases through an analysis of exhaled volatile organic compounds. We recently published a proof-of-principle study showing that patients with prolonged chemotherapy-induced neutropenia and IA have a distinct exhaled breath profile (or breathprint) that can be discriminated with an eNose. An eNose is cheap and noninvasive, and it yields results within minutes. We determined whether Aspergillus fumigatus colonization may also be detected with an eNose in cystic fibrosis (CF) patients. Exhaled breath samples of 27 CF patients were analyzed with a Cyranose 320. Culture of sputum samples defined the A. fumigatus colonization status. eNose data were classified using canonical discriminant analysis after principal component reduction. Our primary outcome was cross-validated accuracy, defined as the percentage of correctly classified subjects using the leave-one-out method. The P value was calculated by the generation of 100,000 random alternative classifications. Nine of the 27 subjects were colonized by A. fumigatus . In total, 3 subjects were misclassified, resulting in a cross-validated accuracy of the Cyranose detecting IA of 89% ( P = 0.004; sensitivity, 78%; specificity, 94%). Receiver operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.89. The results indicate that A. fumigatus colonization leads to a distinctive breathprint in CF patients. The present proof-of-concept data merit external validation and monitoring studies.

Pseudomonas aeruginosa (PA) is one of the most pathogenic bacteria infecting the airways of patients with cystic fibrosis (CF). Sputum culture is the gold standard for detecting PA. However, this method is time-consuming. In this study we hypothesized that volatile organic compounds (VOCs) in exhaled breath can discriminate between PA infected and non-infected CF patients. Design: Cross-sectional baseline analysis of longitudinal cohort study. We collected exhaled air of both pediatric and adult CF patients with and without PA airways infection, in which VOCs were identified using Gas Chromatography – Mass Spectrometry (GC-MS). Infection was defined as culturing PA on the day of breath sampling, or chronic colonization with PA (in >50% of cultures (minimum of 4 samples) over the previous 12 months, or chronic maintenance treatment for PA). To identify VOCs relevant for distinction between the groups, univariate analysis (Mann Withney U test) was applied for each GC-MS compound. Features with a p-value below 0.05 retained for linear discriminant analysis. Diagnostic performed was evaluated by calculation of the area under the receiver operating characteristic - curve including 95% confidence Interval (CI). Complete data was available of 18 pediatric and 22 adult CF patients; 20 with and 20 without PA infection. Exploratory analysis of unselected patients showed that 3 out of 138 VOCs were consistently different in PA infected and non-infected patients, resulting in an AUC of 0.75 (CI 0.59 – 0.92). We discriminated PA infected and non-infected CF patients based on 3 VOCs with moderate accuracy. However, these preliminary results need to be validated in an independent patient cohort.

Background: The mechanism of action of Bronchial Thermoplasty (BT) and its related responder profile is unclear. Objective: Investigate if BT-induced airway smooth muscle mass (ASM) change correlates with FEV1. Methods: 16 severe asthma patients were analyzed. Before and after BT, pre- and post-bronchodilator FEV1 was measured and bronchial biopsies were taken and stained with ASM-specific desmin and ASM/myofibroblast/myoepithelial α-smooth muscle actin (α-SMA). Results: BT treatment reduced ASM mass significantly as assessed by both desmin (55%) and α-SMA analysis (40%)(Fig1A). Baseline pre-and post-bronchodilator FEV1 correlated negatively with desmin-determined baseline ASM mass (resp. R=-0.61;p=0.01 and R=-0.62;p=0.01). Furthermore desmin-determined ASM mass decrease correlated negatively with baseline pre- and post-bronchodilator FEV1 (resp. R=-0.61;p=0.01 and R=-0.54;p=0.03 Fig1B). Patients with FEV1 80%(n=10): 2.4%(0.4;6.3 IQR (p=0.01)Fig1C). This correlation was not found with α-SMA staining. Conclusions: The correlation between ASM and FEV1 seems to depend on the fully differentiated contractile ASM only. Patients with a FEV1< 80% show the most reduction of ASM mass after BT treatment. Whether this “obstructive” asthma phenotype qualifies as a responder criteria needs to be determined.

Background: Bronchial Thermoplasty (BT) is a novel bronchoscopic treatment for severe asthma. The response rate of BT and the specific phenotype benefitting from BT treatment is under discussion. AIMS Determine the clinical response rate following BT treatment and to identify responder characteristics. Methods: Before and 6 months after BT treatment the following outcome variables where obtained in 11 severe asthma patients (TASMA No. NCT02225392): asthma control (ACQ), quality of life (AQLQ), asthma exacerbation rate, blood eosinophils, IgE, spirometry, bronchial hyper responsiveness and airway smooth muscle (ASM) mass % in airway biopsies. Clinical responders rates were based on a minimal clinical important difference of >0.5 points in ACQ and AQLQ. Results: From 11 included patients, 55% (n=6) where classified as clinical responders with a median (range) change of the ACQ and AQLQ of -1.13 (-0.83 to -2.84) and 1.54 (0.72 to 2.57) respectively. Clinical responders (n=6) demonstrated a higher change in ASM% (median, range) than non-responders (n=5): - 60 (-28 to - 94)% vs -46 (-43 to 88)% respectively (p=0.86). Reduction of the exacerbation was observed in 82% (n=9/11) of patients showing a change of exacerbation rate of (median, range) -3 (-1 to -23). A specific responder profile cannot be assessed as yet with the current sample size. Conclusions: BT treatment shows an improvement in quality of life and reduction of exacerbation rate in the majority of severe asthma patients. A large reduction in ASM mass % is seen both in responders and non-responders.

Background Omalizumab is licensed as add-on therapy for patients with severe allergic asthma. Response is in most studies scored by the physician’s global evaluation of treatment effectiveness (GETE). A good clinical and validated parameter for treatment response is currently missing. Also, there are no established criteria for identifying patients who will respond to omalizumab based on pre-treatment characteristics. The Dutch National Omalizumab in Asthma Registry was developed in 2011 to better evaluate inclusion criteria and measure treatment response after 4 months. Methods This is a “real world” prospectively designed, observational data registry in which the outcomes of patients who received omalizumab between 2012 and 2015 were evaluated. Data were collected from all centers in the Netherlands comprising demographic features, criteria for starting treatment, GETE, FEV1, oral corticosteroid use and ACQ. Results 65.5% of the 403 patients had a good or excellent response to omalizumab after 16 weeks according to the treating physician GETE. 64.5% fulfilled all the criteria for prescribing omalizumab at baseline. The mean ACQ improved from 2.96 at baseline to 1.83 at 16 weeks (p

Background Persistent eosinophilic airway inflammation is an important driver for asthma exacerbations in non-smokers with asthma. Whether eosinophilic inflammation is also a predictor of asthma exacerbations in (ex)smokers is not known. Objective The aim was to investigate factors associated with frequent exacerbations in never smokers and (ex)smokers with asthma. Methods (Ex)smoking (n = 83) and never smoking (n = 70) patients with uncontrolled asthma despite high dose asthma medication (GINA treatment step 4–5) were selected from a cohort of 571 adult-onset asthma patients. Clinical, functional and inflammatory parameters were used in multivariate logistic regression analyses to identify factors associated with frequent exacerbations (≥3 oral corticosteroid (OCS) bursts in the previous year). Results Frequent exacerbations in (ex)smokers were independently associated with ICS dose (OR 1.2, 95%CI: 1.1–1.3) and blood neutrophil count (OR 1.5, 95%CI: 1.2–2.1). In never smokers frequent exacerbations were independently associated with blood eosinophil count (OR 18.9, 95%CI: 1.8–202.1). Conclusion and clinical relevance This study shows that never smoking and (ex)smoking patients with severe asthma have different predictors of frequent exacerbations: higher blood neutrophils in (ex)smokers versus higher blood eosinophils in never smokers. This suggests that different types of systemic background inflammation play a role in the aetiology of exacerbations in these patients. Clinical trial registration Netherlands Trial Register: NTR2217, NTR1846 and NTR1838.

Background: Adult-onset asthma is an important but relatively understudied asthma phenotype and little is known about its natural course and prognosis. The remission rate is believed to be low, and it is still obscure which factors predict remission or persistence of the disease. Objective: This study sought to determine the remission rate and identify predictors of persistence and remission of adult-onset asthma. Methods: Two hundred adult patients with recently diagnosed ( = 1 year and no asthma medication use for >= 1 year. Descriptive statistics and logistic regression analysis were performed. Results: Five-year follow-up data of 170 patients (85%) was available. Of these, 27 patients (15.9%) experienced asthma remission. Patients with asthma persistence were older, had worse asthma control, required higher doses of inhaled corticosteroids, had more severe airway hyperresponsiveness, more often nasal polyps, and higher levels of blood neutrophils as compared to patients who experienced clinical remission. In a multivariable logistic regression analysis, only moderate to severe bronchial hyperresponsiveness and nasal polyps were independent predictors of asthma persistence. Patients with these 2 characteristics had

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD).In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events.There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (−2.6 (−9.0–1.5)) and isotonic saline (−0.3 (−8.1–6.1)) in 22 patients (age range 22–73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild.12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials.