Long COVID exhibits clinically distinct phenotypes at 3-6 months post-SARS-CoV-2 infection: results from the P4O2 consortium.

BACKGROUND: Four months after SARS-CoV-2 infection, 22%-50% of COVID-19 patients still experience complaints. Long COVID is a heterogeneous disease and finding subtypes could aid in optimising and developing treatment for the individual patient. METHODS: Data were collected from 95 patients in the P4O2 COVID-19 cohort at 3-6 months after infection. Unsupervised hierarchical clustering was performed on patient characteristics, characteristics from acute SARS-CoV-2 infection, long COVID symptom data, lung function and questionnaires describing the impact and severity of long COVID. To assess robustness, partitioning around medoids was used as alternative clustering. RESULTS: Three distinct clusters of patients with long COVID were revealed. Cluster 1 (44%) represented predominantly female patients (93%) with pre-existing asthma and suffered from a median of four symptom categories, including fatigue and respiratory and neurological symptoms. They showed a milder SARS-CoV-2 infection. Cluster 2 (38%) consisted of predominantly male patients (83%) with cardiovascular disease (CVD) and suffered from a median of three symptom categories, most commonly respiratory and neurological symptoms. This cluster also showed a significantly lower forced expiratory volume within 1 s and diffusion capacity of the lung for carbon monoxide. Cluster 3 (18%) was predominantly male (88%) with pre-existing CVD and diabetes. This cluster showed the mildest long COVID, and suffered from symptoms in a median of one symptom category. CONCLUSIONS: Long COVID patients can be clustered into three distinct phenotypes based on their clinical presentation and easily obtainable information. These clusters show distinction in patient characteristics, lung function, long COVID severity and acute SARS-CoV-2 infection severity. This clustering can help in selecting the most beneficial monitoring and/or treatment strategies for patients suffering from long COVID. Follow-up research is needed to reveal the underlying molecular mechanisms implicated in the different phenotypes and determine the efficacy of treatment.

Exhaled breath analyses for bronchial thermoplasty in severe asthma patients.

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Although multiple trials have demonstrated clinical improvement after BT, optimal patient selection remains a challenge and the mechanism of action is incompletely understood. The aim of this study was to examine whether exhaled breath analysis can contribute to discriminate between BT-responders and non-responders at baseline and to explore pathophysiological insights of BT. METHODS: Exhaled breath was collected from patients at baseline and six months post-BT. Patients were defined as responders or non-responders based on a half point increase in asthma quality of life questionnaire scores. Gas chromatography-mass spectrometry was used for volatile organic compounds (VOCs) detection and analyses. Analytical workflow consisted of: 1) detection of VOCs that differentiate between responders and non-responders and those that differ between baseline and six months post-BT, 2) identification of VOCs of interest and 3) explore correlations between clinical biomarkers and VOCs. RESULTS: Data was available from 14 patients. Nonanal, 2-ethylhexanol and 3-thujol showed a significant difference in intensity between responders and non-responders at baseline (p = 0.04, p = 0.01 and p = 0.03, respectively). After BT, no difference was found in the compound intensity of these VOCs. A negative correlation was observed between nonanal and IgE and BALF eosinophils (r = -0.68, p < 0.01 and r = -0.61, p = 0.02 respectively) and 3-thujol with BALF neutrophils (r = -0.54, p = 0.04). CONCLUSIONS: This explorative study identified discriminative VOCs in exhaled breath between BT responders and non-responders at baseline. Additionally, correlations were found between VOC's and inflammatory BALF cells. Once validated, these findings encourage research in breath analysis as a non-invasive easy to apply technique for identifying airway inflammatory profiles and eligibility for BT or immunotherapies in severe asthma.

Airway smooth muscle and long-term clinical efficacy following bronchial thermoplasty in severe asthma.

The mechanism of action of bronchial thermoplasty (BT) treatment for patients with severe asthma is incompletely understood. This study investigated the 2.5-year impact of BT on airway smooth muscle (ASM) mass and clinical parameters by paired data analysis in 22 patients. Our findings demonstrate the persistence of ASM mass reduction of >50% after 2.5 years. Furthermore, sustained improvement in asthma control, quality of life and exacerbation rates was found, which is in line with previous reports. An association was found between the remaining ASM and both the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for alpha smooth muscle actin (SMA)) and post-bronchodilator forced expiratory volume in 1 s predicted percentage (r=-0.69, p=0.03 for desmin, r=-0.58, p=0.08 for alpha SMA). This study provides new insight into the long-term impact of BT.

Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma.

BACKGROUND: Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling. OBJECTIVE: We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes. METHODS: This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored. RESULTS: Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 µm to 5.74 µm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV1 reversibility. CONCLUSIONS: Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV1 reversibility.

Stepwise Introduction of Elexacaftor-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and Liver Cirrhosis Child-Pugh A or B Using Clinical and Therapeutic Drug Monitoring: A Case Series.

PURPOSE: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring. METHODS: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC. FINDINGS: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously. IMPLICATIONS: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.

Long-Term Weight Changes After Starting Anti-IL-5/5Ra Biologics in Severe Asthma: The Role of Oral Corticosteroids.

BACKGROUND: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics significantly reduce OCS use, but their long-term effects on weight are unknown. OBJECTIVES: To examine (1) weight change up to 2 years after anti-IL-5/5Ra initiation in subgroups on the basis of maintenance OCS use at start of treatment and (2) whether cumulative OCS exposure before or changes in OCS exposure during treatment are related to weight change. METHODS: Real-world data on weight and cumulative OCS dose from adults included in the Dutch Registry of Adult Patients with Severe asthma for Optimal DIsease management before and at least 2 years after starting anti-IL-5/5Ra were analyzed using linear mixed models and linear regression analyses. RESULTS: For the included 389 patients (55% female; mean body mass index, 28 ± 5 kg/m2; 58% maintenance OCS), mean weight decreased -0.27 kg/y (95% CI, -0.51 to -0.03; P = .03), with more weight loss in patients with maintenance OCS use than in those without maintenance OCS use (-0.87 kg/y [95% CI, -1.21 to -0.52; P < .001] vs +0.54 kg/y [0.26 to 0.82; P < .001]). Greater weight loss at 2 years was associated with higher cumulative OCS dose in the 2 years before anti-IL-5/5Ra initiation (ß = -0.24 kg/g; 95% CI, -0.38 to -0.10; P < .001) and, independently, greater reduction in cumulative OCS dose during follow-up (ß = 0.27 kg/g; 95% CI, 0.11 to 0.43; P < .001). CONCLUSIONS: Anti-IL-5/5Ra therapy is associated with long-term weight reduction, especially in patients with higher OCS exposure before treatment and those able to reduce OCS use during treatment. However, the effect is small and does not apply to all patients, and so additional interventions seem necessary if weight change is desired.

Real-World Effectiveness of IL-5/5Ra Targeted Biologics in Severe Eosinophilic Asthma With Comorbid Bronchiectasis.

BACKGROUND: Bronchiectasis is a common comorbidity in patients with asthma and is associated with increased disease severity. In patients with severe eosinophilic asthma, biologics targeting IL-5/5Ra have beneficial effects on oral corticosteroid (OCS) use and exacerbation frequency. However, how coexisting bronchiectasis affects the response to such treatments is unknown. OBJECTIVE: To evaluate the real-world effectiveness of anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma and comorbid bronchiectasis on exacerbation frequency and daily maintenance and cumulative OCS dose. METHODS: This real-world study evaluated data from 97 adults with severe eosinophilic asthma and computed tomography-confirmed bronchiectasis from the Dutch Severe Asthma Registry, who initiated anti-IL5/5Ra biologics (mepolizumab, reslizumab, and benralizumab) and had follow-up data for 12 months or greater. The analysis was performed for the total population and subgroups with or without maintenance OCS use. RESULTS: Anti-IL-5/5Ra therapy significantly reduced exacerbation frequency in patients with maintenance OCS use as well as in those without it. In the year before biologic initiation, 74.5% of all patients had two or more exacerbations, which decreased to 22.1% in the follow-up year (P < .001). The proportion of patients on maintenance OCS decreased from 47% to 30% (P < .001), and in the OCS-dependent patients (n = 45) maintenance OCS dose decreased from median (interquartile range) of 10.0 mg/d (5-15 mg/d) to 2.5 mg/d (0-5 mg/d) after 1 year (P < .001). CONCLUSIONS: This real-world study shows that anti-IL-5/5Ra therapy reduces exacerbation frequency and daily maintenance as well as the cumulative OCS dose in patients with severe eosinophilic asthma and comorbid bronchiectasis. Although it is an exclusion criterion in phase 3 trials, comorbid bronchiectasis should not preclude anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma.

Airway Inflammation Before and After Bronchial Thermoplasty in Severe Asthma.

Background: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma, of which the working mechanism and responder profile are partly unknown. The aim of this study is to analyse whether BT alters airway inflammation by epithelial gene expression, inflammatory cell counts and cytokines, and whether this relates to treatment response. Methods: In this clinical trial, 28 severe asthma patients underwent bronchoscopy before and after treatment to obtain bronchial brushes and bronchoalveolar lavage fluid (BALF) from treated and untreated airways. RNA was extracted from bronchial brushes for transcriptome analysis, and BALF cells and cytokines were analysed. Asthma quality of life questionnaires were used to distinguish responders from non-responders. We compared results before and after treatment, between treated and untreated airways, and between responders and non-responders. Results: Gene expression of airway epithelium related to airway inflammation gene set was significantly downregulated in treated airways compared to untreated airways, although this did not differ for patients before and after treatment. No differences were observed in cell counts and cytokines, neither from the untreated compared to treated airways, nor before and after treatment. At baseline, compared to non-responders, the expression of genes related to glycolysis in bronchial epithelium was downregulated and both BALF and blood eosinophil counts were higher in responders. Conclusion: Local differences in gene sets pertaining to epithelial inflammatory status were identified between treated and untreated airways after treatment, not resulting in changes in differential cell counts and cytokine analyses in BALF. Secondly, baseline epithelial glycolysis genes and eosinophil counts in BALF and blood were different between responders and non-responders. The observations from this study demonstrate the potential impact of BT on epithelial gene expression related to airway inflammation while also identifying a possible responder profile.

Real-World Effectiveness of Reslizumab in Patients With Severe Eosinophilic Asthma - First Initiators and Switchers.

BACKGROUND: Reslizumab, a biologic targeting IL-5, has been shown to reduce asthma exacerbations and maintenance oral corticosteroid use in randomized controlled trials and pre-post studies in patients with severe eosinophilic asthma. However, real-world effectiveness data of reslizumab are scarce, and it is unknown whether reslizumab has added value after switching from another type 2 biologic. OBJECTIVE: To evaluate (1) the real-world effectiveness of reslizumab on severe asthma exacerbations, maintenance oral corticosteroid use, and overall treatment response, both in biologic-naive patients who initiated reslizumab and in those who switched from another type 2 biologic; and (2) physicians' experience with reslizumab treatment. METHODS: This observational real-world study evaluated data from 134 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI), who initiated reslizumab treatment (4-weekly infusions, 0.3 mg/kg) before April 2020 and had follow-up data for 6 months and greater. Clinical asthma experts completed surveys on their experience with reslizumab treatment. RESULTS: Overall, reslizumab reduced the exacerbation rate (odds ratio [95% CI] = 0.10 [0.05-0.21]; P < .001), oral corticosteroid use (OR [95% CI], 0.2 [0.0-0.5]; P < .001), and maintenance dose (median [CI], 5.0 [0.0-10.0] to 0.0 [0.0-5.0]; P < .001), with comparable results in biologic-naive reslizumab initiators and switchers. The overall response to reslizumab was graded good or excellent in 59.2% of patients. The additive effectiveness of reslizumab after switching from another biologic was reflected in physicians' surveys. CONCLUSIONS: Real-world data show that reslizumab reduces severe asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma, both in biologic-naive reslizumab initiators and in those who switched from another type 2 biologic. This additional value of reslizumab was recognized by clinical asthma experts.

Alpine altitude climate treatment for severe and uncontrolled asthma: An EAACI position paper.

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution. These combined factors seem to have immunomodulatory effects controlling pathogenic inflammatory responses and favoring less neuro-immune stress in patients with different asthma phenotypes. The extensive multidisciplinary treatment program may further contribute to the observed clinical improvement by AACT in asthma control and quality of life, fewer exacerbations and hospitalizations, reduced need for oral corticosteroids (OCS), improved lung function, decreased airway hyperresponsiveness (AHR), improved exercise tolerance, and improved sinonasal outcomes. Based on observational studies and expert opinion, AACT represents a valuable therapy for those patients irrespective of their asthma phenotype, who cannot achieve optimal control of their complex condition despite all the advances in medical science and treatment according to guidelines, and therefore run the risk of falling into a downward spiral of loss of physical and mental health. In the light of the observed rapid decrease in inflammation and immunomodulatory effects, AACT can be considered as a natural treatment that targets biological pathways.

Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RATIONALE: Cystic 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). METHODS: We 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. RESULTS: FIS 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; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC. CONCLUSION: This 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.

Exhaled Metabolite Patterns to Identify Recent Asthma Exacerbations.

Asthma is a chronic respiratory disease that can lead to exacerbations, defined as acute episodes of worsening respiratory symptoms and lung function. Predicting the occurrence of these exacerbations is an important goal in asthma management. The measurement of exhaled breath by electronic nose (eNose) may allow for the monitoring of clinically unstable asthma and exacerbations. However, data on its ability to perform this is lacking. We aimed to evaluate whether eNose could identify patients that recently had asthma exacerbations. We performed a cross-sectional study, measuring exhaled breath using the SpiroNose in adults with a physician-reported diagnosis of asthma. Patients were randomly divided into a training (n = 252) and validation (n = 109) set. For the analysis of eNose signals, principal component (PC) and linear discriminant analysis (LDA) were performed. LDA, based on PC1-4, reliably discriminated between patients who had a recent exacerbation from those who had not (training receiver operating characteristic (ROC)-area under the curve (AUC) = 0.76,95% CI 0.69-0.82), (validation AUC = 0.76, 95% CI 0.64-0.87). Our study showed that, exhaled breath analysis using eNose could accurately identify asthma patients who recently had an exacerbation, and could indicate that asthma exacerbations have a specific exhaled breath pattern detectable by eNose.

Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients.

RATIONALE: Targeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs. OBJECTIVES: To investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract. METHODS: This was a single-centre longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample, were collected before and every 3 months after starting therapy, for up to 12 months. RESULTS: Twenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that Pseudomonas aeruginosa was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow-up. CONCLUSIONS: After starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in the lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

Poor outcome of SARS-CoV-2 infection in patients with severe asthma on biologic therapy.

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.

Bronchial Thermoplasty Induced Airway Smooth Muscle Reduction and Clinical Response in Severe Asthma. The TASMA Randomized Trial.

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT, but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important.Objectives: First, to assess the effect of BT on ASM mass, and second, to identify patient characteristics that correlate with BT response.Methods: Patients with severe asthma (n = 40) were randomized to immediate (n = 20) or delayed (n = 20) BT treatment. Before randomization, clinical, functional, blood, and airway biopsy data were collected. In the delayed control group, reassessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analysis software. Associations between baseline characteristics and Asthma Control Questionnaire and Asthma Quality of Life Questionnaire (AQLQ) improvement were explored.Measurements and Main Results: Median ASM mass decreased by >50% in the immediate BT group (n = 17) versus no change in the delayed control group (n = 19) (P = 0.0004). In the immediate group, Asthma Control Questionnaire scores improved with -0.79 (interquartile range [IQR], -1.61 to 0.02) compared with 0.09 (IQR, -0.25 to 1.17) in the delayed group (P = 0.006). AQLQ scores improved with 0.83 (IQR, -0.15 to 1.69) versus -0.02 (IQR, -0.77 to 0.75) (P = 0.04). Treatment response in the total group (n = 35) was positively associated with serum IgE and eosinophils but not with baseline ASM mass.Conclusions: ASM mass significantly decreases after BT when compared with a randomized non-BT-treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass.

Treatment Eligibility of Real-Life Mepolizumab-Treated Severe Asthma Patients.

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, real-life 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 ≤5 mg prednisone/day. CONCLUSIONS: A large proportion of the real-life, mepolizumab-treated population with severe asthma would be excluded from trial participation, and significant differences in population characteristics exist. Regardless, a large fraction of ineligible patients in clinical care can reduce maintenance OCS dosage under mepolizumab therapy.

Identification of recent exacerbations in COPD patients by electronic nose.

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.

Characteristics and treatment regimens across ERS SHARP severe asthma registries.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.