The influence of smoking status on exhaled breath profiles in asthma and COPD patients

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and neversmokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease

Optimizing treatment for airways diseases: Using exhaled biomarkers and real world data

Airways diseases are complex and difficult to treat due to the heterogeneity of their etiology. Treatment is typically based on clinical characteristics, and best treatment practices may not necessarily be beneficial for individual patients. Better stratification and timing of medical interventions is possible by adopting an approach that utilizes biological information and disease biomarkers. The identification of differences between patient groups holds potential to improve treatment. This thesis has two main aims: further developing methods that explore the use of biomarkers in (chronic) airway diseases, and exploring the feasibility and application of strategies to collect real-world evidence in patients with severe asthma. Current most well-known biomarkers in chronic airways diseases have predictive value for treatment response to corticosteroid drugs, but their use is limited. We explored the ability of exhaled breath measurement to detect recent exacerbations in COPD and asthma patients using electronic nose (eNose) devices. The studies showed that exhaled breath analysis could identify COPD and asthma patients who recently had an exacerbation with high accuracy, suggesting a possible role in monitoring. In the second part, we found differences between eligibility criteria for anti-IL5 drug trial participation and registry data of patients who started this therapy, however 50% of OCS-dependent patients were able to reduce their dose to ≤5 mg prednisone per day. Within the SHARP consortium we found a large variation in characteristics and lifestyle-associated factors in different severe asthma registries across Europe. Suggesting the severe asthma population and their treatment are heterogenous across Europe and diagnosis in clinical practice differs across countries

Optimizing treatment for airways diseases: Using exhaled biomarkers and real world data

Airways diseases are complex and difficult to treat due to the heterogeneity of their etiology. Treatment is typically based on clinical characteristics, and best treatment practices may not necessarily be beneficial for individual patients. Better stratification and timing of medical interventions is possible by adopting an approach that utilizes biological information and disease biomarkers. The identification of differences between patient groups holds potential to improve treatment. This thesis has two main aims: further developing methods that explore the use of biomarkers in (chronic) airway diseases, and exploring the feasibility and application of strategies to collect real-world evidence in patients with severe asthma. Current most well-known biomarkers in chronic airways diseases have predictive value for treatment response to corticosteroid drugs, but their use is limited. We explored the ability of exhaled breath measurement to detect recent exacerbations in COPD and asthma patients using electronic nose (eNose) devices. The studies showed that exhaled breath analysis could identify COPD and asthma patients who recently had an exacerbation with high accuracy, suggesting a possible role in monitoring. In the second part, we found differences between eligibility criteria for anti-IL5 drug trial participation and registry data of patients who started this therapy, however 50% of OCS-dependent patients were able to reduce their dose to ≤5 mg prednisone per day. Within the SHARP consortium we found a large variation in characteristics and lifestyle-associated factors in different severe asthma registries across Europe. Suggesting the severe asthma population and their treatment are heterogenous across Europe and diagnosis in clinical practice differs across countries

Breathomics in Chronic Airway Diseases

Chronic airway diseases cause a large burden for patients and caregivers and have large economic impact. Moreover, the burden is expected to increase with an increasing life expectancy of the world population. Therefore, there is a need for new biomarkers that can guide diagnosis, monitoring and the treatment of chronic airway diseases. Exhaled breath contains a complex mixture of volatile organic compounds (VOC) that can reflect local, systemic and exogenous (patho)physiological processes in the airways and alveoli and may thus be a promising target for biomarker discovery. Furthermore, breathomics holds the potential for non-invasive, easy, safe and point-of-care analysis. Several techniques for exhaled breath analysis exist that can be distinguished by three main aspects; the ability to detect individual VOCs or VOC patterns, real-time or offline measurements, and targeted or untargeted approaches. Available techniques have different advantages and limitations regarding sensitivity, specificity, costs and complexity. Multiple clinical studies already show the many opportunities of exhaled breath analysis regarding disease diagnosis, monitoring and prediction in diseases like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). To allow for implementation of exhaled breath in clinical practice, limitations of current detection techniques (e.g., the need for highly specialized personnel and machinery or sensitivity to detect very low concentrations of molecules in exhaled breath) should be overcome and results should be validated. Breathomics has large potential to make more personalized treatment possible in chronic airway diseases

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, 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 <= 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. (C) 2020 American Academy of Allergy, Asthma & Immunology.Analysis and support of clinical decision makin

Precision medicine for more oxygen (P4O2): study design and first results of the Long COVID-19 extension

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies.Pathogenesis and treatment of chronic pulmonary disease

Imatinib in patients with severe COVID-19: a randomised, doubleblind, placebo-controlled, clinical trial (vol 9, pg 957, 2021)

Pathogenesis and treatment of chronic pulmonary disease