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Background With the continued advancement of CFTR modulator therapies there is likely to be a burgeoning population of adult cystic fibrosis (CF) patients unable to expectorate sputum. Consequently, the detection and surveillance of pulmonary colonisation, previously reliant on sputum culture, needs re-examining. We hypothesised that cough swabs analysed with culture-independent analysis of the 16S gene could serve as a surrogate for colonisation of the lower airways. Methods Cough swabs and sputum samples were prospectively collected from consecutive adults and children with CF across two sites at regular outpatient appointments. Conventional culture analysis and next generation sequencing were used to compare paired same day samples. Results Twenty-two adults and 8 paediatric patients provided 75 paired cough swabs and sputum samples. Alpha diversity measures showed increased bacterial richness in sputum, while evenness and Simpson's diveristy index were higher in cough swabs. Within each sampling technique, microbial composition showed greater similarity when considering intra-patient variation. Poor concordance was observed between culture independent cough swabs and culture dependent/independent sputum analysis for specific pathogens, with cough swabs unable to accurately identify commonly associated CF pathogens (AUROCC range: 0.51 to 0.64). Conclusion Culture independent analysis of cough swabs provides an inaccurate diagnosis of lower respiratory tract colonisation and should not be used as a diagnostic test in patients with CF.

RationaleCystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).MethodsWe retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.ResultsFIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11–0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07–0.46; pConclusionThis study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Background It is unclear whether asthma and asthma medications increase or decrease the risk of severe COVID-19, and this is particularly true for patients with severe asthma receiving biologics. Objectives The aim of this study was to assess incidence and disease course of COVID-19 in patients with severe asthma on biologic therapy (omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab), as compared with COVID-19 data from the general Dutch population. Methods COVID-19 cases were identified through a prospective ongoing survey between March 17 and April 30, 2020 among all severe asthma specialists from 15 hospitals of the Dutch Severe Asthma Registry RAPSODI. From these cases, data was collected on patient characteristics, including co-morbidities, COVID-19 disease progression and asthma exacerbations. Findings were then compared with COVID-19 data from the general Dutch population. Results Of 634 severe asthma patients who received biologic therapy in RAPSODI, 9 (1.4%) were diagnosed with COVID-19. Seven patients (1.1%) required hospitalization for oxygen therapy, of which 5 were admitted to the intensive care for intubation and mechanical ventilation. One patient died (0.16%). All intubated patients had ≥1 co-morbidities. Odds (95%CI) for COVID-19 related hospitalization and intubations were 14 (6.6–29.5) and 41 (16.9–98.5) times higher, respectively, compared to the Dutch population. One patient presented with an asthma exacerbation. Conclusion Patients with severe asthma using biologic therapy showed to have a more severe course of COVID-19 compared to the general population. This may be due to co-morbidities, the severity of asthmatic airway inflammation, the use of biologics, or a combination of these.

BACKGROUND: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation.METHODS: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs.RESULTS: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome.CONCLUSIONS: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

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

Background: Beneficial effects of pulmonary rehabilitation at high-altitude (HAPR) in patients with severe refractory asthma have been reported earlier, but evidence for the effectiveness is limited. Aim: To investigate the effectiveness of high-altitude pulmonary rehabilitation to comparable treatment at sea-level (LAPR) on patient outcome parameters. Methods: Adults with severe refractory asthma living in The Netherlands were included. Treatment consisted of a 12-week personalized multidisciplinary rehabilitation program either at high-altitude (Davos Switzerland) (n = 93) or in a tertiary lung center at sea-level in The Netherlands (n = 45). At baseline, after treatment, and during 12 months follow-up asthma related quality of life (AQLQ), asthma control (ACQ), pulmonary function and OCS-dose were assessed. Patients could not be randomized resulting in different asthma populations. Groups were compared using linear regression analysis (ANCOVA) adjusted for baseline values, in addition to age, atopy, smoking history, BMI and gender. Results: After treatment, and at 12 months follow-up, improved AQLQ(0.92,p < 0.001 and 0.82,p = 0.001, respectively), ACQ(-0.87,p < 0.001 and −0.69,p = 0.008, respectively) and lower maintenance OCS dose (Unadjusted linear regression analysis-5.29 mg, p = 0.003 and Crude Odds Ratio-1.67, p = 0.003, respectively) were observed in the HAPR-group compared to the LAPR group. Patients receiving HAPR also had less asthma exacerbations (≥1 exacerbation: 20% vs 60%,p < 0.001) and showed improvement in lung function (%predFEV 1 3.4%,p = 0.014) compared to the LAPR group, but at 12 months no differences between groups were observed. Conclusion: HAPR resulted in a larger improvement in patient outcome parameters compared to LAPR, on the long run the improvement in patient reported symptoms and lower maintenance OCS-dose persists. Underlying factors that explain this observed effect need to be investigated.

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.

Background: Clinical trials investigating mepolizumab for eosinophilic severe asthma patients employed strict eligibility criteria. Nonetheless, patients not meeting these criteria are treated with mepolizumab in clinical practice. Aim: To investigate the extent and reasons for trial ineligibility of real-life, mepolizumab-treated severe asthma patients. To compare characteristics of these patients with trial populations. Methods: Trial criteria and patient characteristics of the SIRIUS, DREAM and MENSA trials were extracted. Baseline characteristics from mepolizumab-treated, oral glucocorticoid-dependent severe asthma patients were studied in RAPSODI (the Dutch severe asthma registry). Results: 7 of 70 mepolizumab-treated patients (10%) from RAPSODI fulfil the trial criteria, whereas 34 (48.6%) and 29 (41.4%) patients are ineligible on the basis of exclusion and inclusion criteria, respectively. Predominant deviations from criteria are summarised in table 1. Significant differences exist in age (56.5 vs 50.1 years), gender (41.4% vs 57.1% females) and FEV1 (2.49 vs 1.82 L) between the real-life and MENSA trial populations. Conclusion: Only a small part of mepolizumab-treated patients in clinical practice fulfils trial criteria and significant differences in patient characteristics exist between trial and real-life severe asthma populations, indicating limited representativeness. The RAPSODI registry was financially supported by GSK and Novartis.

Background: Bronchial Thermoplasty (BT) is a treatment for severe uncontrolled asthma patients. Although studies have shown clinical improvement after BT, not all patients respond equally well. Identifying optimal candidates for BT treatment is needed. Aim: To identify patient characteristic differences between BT responders and non-responders. Methods: Patients from the multicenter TASMA trial were included in this analysis. Before BT, a set of clinical, functional, inflammatory and airway biopsy data were collected (Table 1). A positive BT response was defined as a minimal clinically important change of >0.5 on asthma control questionnaire (ACQ) score, 6 months after BT. Results: 30 patients were analyzed. ACQ improved from 2.66 (±0.68) to 2.09 (±1.07) (p Conclusion: IgE and blood eosinophils before BT were higher in BT responders compared to non-responders and might therefore contribute in optimizing patient selection for BT.

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.

Background: Bronchial Thermoplasty (BT) is a bronchoscopic treatment for severe asthma which reduces airway smooth muscle (ASM). The optimal patient responder profile is still under debate. In asthma, mast cell density is increased within the ASM and relates to bronchial hyper responsiveness. Aim: To determine the effect of BT on mast cells in airway wall biopsies and ASM specific area and relate this to treatment response. Methods: 14 severe asthma patients included in the TASMA trial were evaluated. Airway wall biopsies were obtained before and after BT and stained with ASM specific desmin and mast cell specific tryptase antibodies. Mast cells were manually counted and automatic digital analysis was used to calculate ASM area (Fig 1A-B). Results: Before BT, mast cells within ASM had a median of 35.5/mm2 (range 10-83) and 26.5/mm2 (range 12-73) for the total biopsy area. After BT, ASM (%) reduced with 58% (median 12.0% to 4.98% after BT; p Conclusions: Mast cells within the total airway wall seem to increase following BT. Due to BT induced ASM reduction, mast cells might shift from the ASM to the (sub)mucosal area.

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.

Monitoring sputum eosinophils in asthma predicts exacerbations and improves management of asthma. Thus far, blood eosinophils and FE(NO) show contradictory results in predicting eosinophilic airway inflammation. More recently, serum periostin was proposed as a novel biomarker for eosinophilic inflammation. Quantifying the mutual relationships of blood eosinophils, FE(NO), and serum periostin with sputum eosinophils by external validation in two independent cohorts across various severities of asthma. The first cohort consisted of 110 patients with mild to moderate asthma (external validation cohort). The replication cohort consisted of 37 patients with moderate to severe asthma. Both cohorts were evaluated cross-sectionally. Sputum was induced for the assessment of eosinophils. In parallel, blood eosinophil counts, serum periostin concentrations and FENO were assessed. The diagnostic accuracy of these markers to identify eosinophilic asthma (sputum eosinophils ≥3%) was calculated using receiver operating characteristics area under the curve (ROC AUC). In the external validation cohort, ROC AUC for blood eosinophils was 89% (p

Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (≥3%) in different adult asthma phenotypes.Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex-)smoking and never-smoking asthma patients.Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78–0.87) for blood eosinophils, 0.82 (0.77–0.87) for FeNO and 0.69 (0.63–0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients.Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma.

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.

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.

The beneficial effects of high-altitude treatment in asthma have been attributed to allergen avoidance. Recent evidence shows that this treatment also improves airway inflammation in nonallergic patients. We hypothesised that high-altitude treatment is clinically equally effective in patients with severe refractory asthma, with or without allergic sensitisation. In a prospective observational cohort study, 137 adults with severe refractory asthma (92 with allergic sensitisation), referred for high-altitude (1,600 m) treatment in Davos, Switzerland, were consecutively included. We measured asthma control (Asthma Control Questionnaire (ACQ)), asthma-related quality of life (Asthma-Related Quality of Life Questionnaire (AQLQ)), sino-nasal symptoms (Sino-Nasal Outcome Test (SNOT-20)), medication requirement, postbronchodilator (post-BD) forced expiratory volume in 1 s (FEV(1)), 6-min walking distance (6MWD), total immunoglobulin (Ig)E, blood eosinophils and exhaled nitric oxide fraction (F(eNO)) at admission and after 12 weeks. Sensitised and nonsensitised patients showed similar improvements in ACQ (-1.4 and -1.5, respectively; p = 0.79), AQLQ (1.6 and 1.5, respectively; p = 0.94), SNOT-20 (-0.7 and -0.5, respectively; p = 0.18), post-BD FEV(1) (6.1% and 5.8% pred, respectively; p = 0.87), 6MWD (+125 m and +147 m, respectively; p = 0.43) and oral steroids (40% versus 44%, respectively; p = 0.51). Sensitised patients showed a larger decrease in total IgE, blood eosinophils and F(eNO). High-altitude treatment improves clinical and functional parameters, and decreases oral corticosteroid requirement in patients with severe refractory asthma, irrespective of allergic sensitisation.

To cite this article: van de Pol MA, Lutter R, Smids BS, Weersink EJM, van der Zee JS. Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics. Allergy 2011; 66: 39–47. Abstract Background: Previous studies suggest that pre/probiotics can be used in the prevention and treatment of early allergic disease in newborns and young children. Objective: To determine the effect of treatment with synbiotics (90% short-chain galacto-oligosaccharides, 10% long-chain fructo-oligosaccharides: Immunofortis® and Bifidobacterium breve M-16V) on allergic responses in adults with established allergic asthma. Primary outcome was allergen-induced bronchial inflammation as represented by eosinophil counts. Methods: Twenty-nine patients with asthma and house dust mite (HDM) allergy were randomized in a double-blind, parallel design to receive placebo or synbiotics for 4 weeks. At study entry and after treatment, a bronchial allergen challenge with HDM was performed, followed by lung function tests, collection of blood (in/ex vivo IL-5) and induced sputum (inflammatory parameters). During treatment, a diary was kept with peak expiratory flow (PEF) and asthma scores. Results: Treatment did not affect the allergen-induced increase in sputum eosinophils at 6 and 24 h after challenge. Likewise, other parameters for bronchial inflammation and early and late changes in lung function did not differ upon treatment. Both the morning and evening PEF, however, significantly increased during synbiotics treatment (morning P = 0.003, evening P = 0.011). Also, the increase in serum IL-5 after allergen challenge was significantly inhibited by synbiotics (P = 0.034), as was ex vivo allergen-induced Th2-cytokine (IL-5 and IL-4+ IL-13) production by PBMCs (P = 0.046). In vivo (24 h) and ex vivo IL-5 production were associated. Conclusion: Four-week treatment with synbiotics had no effect on bronchial inflammation and LAR, but did significantly reduce systemic production of Th2-cytokines after allergen challenge and improved PEF.

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

Historically, palliative care has been developed for cancer patients and is not yet generally available far patients suffering from chronic life-limiting illnesses, such as chronic obstructive pulmonary disease (COPD). To examine whether COPD patients experience similar or worse disease burden in comparison with non-small cell lung cancer (NSCLC) patients, we compared the health-related quality of life (HRQOL) scores of severe COPD patients with those of advanced NSCLC patients. We also formally updated previous evidence in this area provided by a landmark study published by Gore et al. in 2000. In updating this previous evidence, we addressed the methodological limitations of this study and a number of confounding variables. Eighty-two GOLD IV COPD patients and 19 Stage IIIb or IV NSCLC patients completed genetic and disease-specific HRQOL questionnaires. We used an individual patient data meta-analysis to integrate the new and existing evidence (total n = 201). Finally, to enhance between-group comparability, we performed a sensitivity analysis using a subgroup of patients with a similar degree of "terminality," namely those who had died within one year after study entry. Considerable differences in HRQOL were found for physical functioning, social functioning, mental health, general health perceptions, dyspnea, activities of daily living, and depression. All differences favored the NSCLC patients. The sensitivity analysis, using only terminal NSCLC and COPD patients, confirmed these findings. In conclusion, end-stage COPD patients experience poor HRQOL comparable to or worse than that of advanced NSCLC patients. We discuss these findings in the light of the notion that these COPD patients may have a similar need for palliative care. J Pain Symptom Manage 2009;37:973-981. (C) 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved

Rationale: Smoking influences airway inflammation, asthma severity and response to therapy in asthma patients. Consequently, risk factors for exacerbations may differ between (ex)smokers and never-smokers. Aim: To identify risk factors for frequent exacerbations in (ex)smoking and never-smoking asthmatics. Methods: Clinical, functional and inflammatory parameters from a cohort of 571 adult-onset asthma patients were used. Patients with uncontrolled asthma despite high dose asthma medication (GINA step 4-5) were selected (n=165). Logistic regression analysis was used to identify risk factors for frequent exacerbations (≥3 oral corticosteroid (OCS) bursts in the previous year) in (ex)smoking (n=92) and never-smoking (n=73) patients. Results: (Ex)smokers with frequent exacerbations (n=38) had a longer duration of asthma, used higher doses of inhaled corticosteroids (ICS), used more often OCS, had lower FEV 1 and higher blood neutrophils than patients with 1 , had increased airway hyperresponsiveness and had higher blood eosinophils than patients with Conclusion: Higher ICS dose and blood neutrophils are risk factors for frequent exacerbations in (ex)smokers, whereas higher blood eosinophils are risk factors in never-smokers. This suggests that exacerbations in smoking and never-smoking asthmatics have different aetiologies.

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.

Item does not contain fulltext BACKGROUND: Patients with severe asthma experience problems in different areas of their health status. Identification of these areas will provide insight in the patients needs and perhaps what determines the burden of disease. The Nijmegen Clinical Screening Instrument (NCSI) was recently developed for use in clinical practice in patients with COPD and provides a detailed picture of the patients' physiological functioning, symptoms, functional impairment, and Quality of Life. Main purpose of this study is to evaluate the use of the NCSI as compared to the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) in patients with severe asthma. METHODS: The NCSI, AQLQ, and ACQ were measured in 167 patients with severe asthma. Pearson correlations were calculated between NCSI sub-domains and the AQLQ domains and the ACQ. RESULTS: The NCSI measures more aspects of health status as compared to the ACQ and AQLQ in patients with severe asthma. Beside symptoms, subjective impairment, and emotions the NCSI also measures general Quality of Life, health related Quality of Life, satisfaction with relations, fatigue, and behavioural impairment. On all NCSI sub-domains proportions of patients with normal, mild, and severe problems were found. Heterogeneity was found on the number and on the combination of sub-domains on which patients reported severe problems. CONCLUSIONS: The NCSI provides a more detailed picture of the individual patient with severe asthma than the ACQ and AQLQ. The use of the NCSI might allow quick identification of the problem areas and possible factors that impair health status.

Rationale Adult-onset asthma differs from childhood-onset asthma in many respects. It is more heterogeneous, often severe and frequently associated with loss of lung function. To identify underlying mechanisms of adult-onset asthma and to capture predictors of disease progression, detailed characterization and phenotyping is necessary. Objectives To characterize adult-onset asthma and identify subphenotypes of adult-onset asthma. Methods A cohort of 200 patients with adult-onset (>18 year) asthma (age 54 (26–75) year) was recruited from one academic and three nonacademic pulmonary outpatient clinics in Amsterdam, the Netherlands. These patients were fully characterized with respect to clinical, functional and inflammatory markers. After data reduction, K-means nonhierarchical cluster analysis was performed to identify clusters of adult-onset asthma. Measurements and main results Patients with adult-onset asthma were predominately female (61%) and nonatopic (55%). Within this group of patients were identified three clusters of adult-onset asthma. Cluster 1 (n = 69) consisted of patients with severe eosinophilic inflammation-predominant asthma and persistent airflow limitation despite high-intensity anti-inflammatory treatment, with relatively low symptom scores. The second cluster was characterized by obese women with frequent symptoms, high healthcare utilization and low sputum eosinophils. The third cluster consisted of patients with mild-to-moderate, well-controlled asthma with normal lung function and low inflammatory markers. Repeatability accuracy was 98.2%. Conclusions Amongst patients with adult-onset asthma, three subphenotypes can be identified with distinct clinical and inflammatory characteristics. These subphenotypes help to understand the underlying pathobiology and provide clinicians with directions for personalized management.

SummaryBackground Patients with asthma have on average a more rapid decline in FEV 1 as compared with the general population. Recent cluster analysis has revealed different asthma phenotypes that can be distinguished by age of onset and reversibility of airflow limitation. Objective This study aimed at detecting risk factors associated with persistent airflow limitation in patients with the adult onset asthma phenotype. Methods We recruited 88 patients with adult onset (≥ 18 years) asthma from an academic pulmonary outpatient clinic in the Netherlands. The associations of age, age of asthma onset, asthma duration, gender, race, atopy, smoking packyears, BMI, use of oral corticosteroids with post-bronchodilator FEV 1/FVC were investigated. Results Multiple linear regression analysis showed an association of absence of atopy (r = −0.27, B = −0.26, P = 0.01) and male gender (r = 0.31, B = 0.30, P = 0.004) with post-bronchodilator FEV 1/FVC. Multiple logistic regression analysis showed that male patients were 10.8 (CI: 2.6–45.2) times the odds than women to have an FEV 1/FVC

Background In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown. Objective To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FENO) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worseningasthmacontrolorasthma-relatedqualityoflife. Methods In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n¼43) or guided by a novel internet-based monitoring system (internet strategy) (n¼52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV1), exacerbations, hospitalisations and patient’s satisfaction with the tapering strategy. Results Median cumulative sparing of prednisone was 205 (25e75th percentile � 221 to 777) mg in the internet strategy group compared with 0 (� 497 to 282) mg in the conventional treatment group (p¼0.02). Changes in prednisone dose (mixed effect regression model) from baseline were � 4.79 mg/day and +1.59 mg/day, respectively (p