Background There is a considerable diagnostic delay in the diagnosis 'benign acquired subglottic stenosis in adults' (SGS, diagnosed by the reference standard, i.e. laryngo- or bronchoscopy).... Show moreBackground There is a considerable diagnostic delay in the diagnosis 'benign acquired subglottic stenosis in adults' (SGS, diagnosed by the reference standard, i.e. laryngo- or bronchoscopy). Patients are frequently misdiagnosed since symptoms of this rare disease may mimic symptoms of 'asthma.' The 'Expiratory Disproportion Index' (EDI) obtained by spirometry, may be a simple instrument to detect an SGS-patient. The aim of this study was to evaluate the diagnostic accuracy of the EDI in differentiating SGS patients from asthma patients.Methods We calculated the EDI from spirometry results of all SGS-patients in the Leiden University Medical Center (LUMC), who had not received treatment 2 years before their spirometry examination. We compared these EDI results with the EDI results of all true asthma patients between 2011 and 2019, who underwent a bronchoscopy (exclusion of SGS by laryngo- or bronchoscopy).Results Fifty patients with SGS and 32 true asthma patients were included. Median and IQR ranges of the EDI for SGS and asthma patients were 67.10 (54.33-79.18) and 37.94 (32.41-44.63), respectively. Area under the curve (ROC) of the accuracy of the EDI at discriminating SGS and asthma patients was 0.92 (95% CI = 0.86-0.98). The best cut-off point for the EDI was > 48 (i.e. possible upper airway obstruction), with a sensitivity of 88.0%% (95%CI = 77.2-95.0%%) and specificity of 84.4% (95%CI = 69.4-94.1%).Conclusions The EDI has a good diagnostic accuracy discriminating subglottic stenosis patients from asthma patients, when compared to the reference standard. This measurement from spirometry may potentially shorten the diagnostic delay of SGS patients. Further studies are needed to evaluate clinical reproducibility. Show less
Valk, J.P.M. van der; Hekking, P.P.; Rauh, S.P.; Patberg, K.W.; Veen, I.A. van; Huisstede, A. van; ... ; RAPSODI Team 2023
IntroductionSevere asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment.Aims and objectivesThis study aims to relate treatment with... Show moreIntroductionSevere asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment.Aims and objectivesThis study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context.Material and methodsThis is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes.ResultsAt baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (beta = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%.ConclusionsWork productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study. Show less
Hei, S.J. van de; Poot, C.C.; Berg, L.N. van den; Meijer, E.; J.F.M. van boven; Blok, B.M.J.F.D.; ... ; Kocks, J.W.H. 2022
Introduction: Suboptimal asthma control is associated with incorrect inhaler use and poor medication adherence, which could lead to unfavourable clinical and economic outcomes. Smart inhaler... Show moreIntroduction: Suboptimal asthma control is associated with incorrect inhaler use and poor medication adherence, which could lead to unfavourable clinical and economic outcomes. Smart inhaler programmes using electronic monitoring devices (EMDs) could support self-management and increase medication adherence and asthma control. However, evidence on long-term benefits and acceptability is scarce. This study aims to investigate the effectiveness of a smart inhaler asthma self-management programme on medication adherence and clinical outcomes in adults with uncontrolled asthma, to evaluate its acceptability and to identify subgroups who would benefit most based on patient characteristics. Methods and analysis: This open-label cluster randomised controlled trial of 12 months will be conducted in primary care in the Netherlands. General practices will be randomly assigned to either intervention or control group. We aim to include 242 patients. The intervention consists of (1) an EMD attached to the patient's inhaler that measures medication use; (2) a smartphone application to set medication reminders, receive motivational messages and track asthma symptoms; and (3) a portal for healthcare professionals to view data on medication use. The control group is passively monitored by the EMD but cannot view their inhaler data or receive feedback. Eligible patients are adults with suboptimal controlled asthma (Asthma Control Questionnaire score >= 0.75) with evidence of non-adherence established by the EMD during a 6-week run-in period. Primary outcome is the difference in mean medication adherence between intervention and control group. Secondary outcomes include asthma control, asthma-related quality of life, exacerbations, acceptance, cost-effectiveness and whether the effect of the intervention on medication adherence and asthma control is modified by patient characteristics (eg, self-efficacy, medication beliefs and eHealth literacy). Show less
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... Show moreBACKGROUND: 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. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. Show less
Have, P. ten; Hal, P. van; Wichers, I.; Kooistra, J.; Hagedoorn, P.; Brakema, E.A.; ... ; Ossebaard, H.C. 2022
Objectives Dry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurised metered-dose inhalers (pMDIs). To help mitigate climate change, we... Show moreObjectives Dry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurised metered-dose inhalers (pMDIs). To help mitigate climate change, we assessed the potential emission reduction in CO2 equivalents when replacing pMDIs by non-propellant inhalers (NPIs) in Dutch respiratory healthcare and estimated the associated cost. Design We performed a descriptive analysis of prescription data from two national databases of two independent governmental bodies. First, we calculated the number of patients with chronic obstructive pulmonary disease (COPD) and asthma that were using inhalation medication (2020). Second, we calculated the number and total of daily defined doses of pMDIs and NPIs including DPIs and soft mist inhalers, as well as the number of dispensed spacers per patient (2020). Third, we estimated the potential emission reduction in CO2 equivalents if 70% of patients would switch from using pMDIs to using NPIs. Fourth, we performed a budget impact analysis. Setting Dutch respiratory healthcare. Primary and secondary outcome measures The carbon footprint of current inhalation medication and the environmental and financial impact of replacing pMDIs with NPIs. Results In 2020, 1.4 million patients used inhalers for COPD or asthma treatment. A total of 364 million defined daily doses from inhalers were dispensed of which 49.6% were dispensed through pMDIs. We estimated that this could be reduced by 70% which would lead to an annual reduction in greenhouse gas emission of 63 million kg.CO2 equivalents saving at best EUR 49.1 million per year. Conclusions In the Netherlands, substitution of pMDIs to NPIs for eligible patients is theoretically safe and in accordance with medical guidelines, while reducing greenhouse gas emission by 63 million kg.CO2 equivalents on average and saving at best EUR 49.1 million per year. This study confirms the potential climate and economic benefit of delivering a more eco-friendly respiratory care. Show less
Chronic respiratory disease (CRD) is a silent, ongoing pandemic. It disproportionally affects low-resource settings. Tobacco smoke and kitchen smoke (caused by the use of solid fuels and... Show moreChronic respiratory disease (CRD) is a silent, ongoing pandemic. It disproportionally affects low-resource settings. Tobacco smoke and kitchen smoke (caused by the use of solid fuels and inefficient stoves) are major risk factors. Evidence-based solutions to CRD often fail to be effective, as they misalign with local needs and then fail to be implemented. This thesis focused on how lung health solutions can be implemented successfully by capitalising on the local needs.Within the Horizon2020 FRESH AIR implementation research project, we first studied local settings in Kyrgyzstan, Uganda, Greece, and Vietnam. For example, we found that COPD in the highlands of Kyrgyzstan occurred three times more frequently than in the lowlands, partly due to higher levels of kitchen smoke. We discovered the high indirect burden of asthma and COPD, by their impact on work- and daily activities. We also found that many communities and their health workers mistook CRD for infectious disease like tuberculosis. Based on these findings and on implementation literature, we then designed several practical tools addressing critical factors for implementation success of lung health interventions. These evidence-based tools can facilitate implementation success, thereby optimising the use of already scarce resources and benefitting health outcomes. Show less
Primary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and... Show morePrimary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and length of stay. Additionally, biochemical biomarkers in serum are often measured to assess drug effects on a biochemical level. The occurrence of mortality and hospital admissions is rare thanks to the improvements in clinical care that have occurred in the last century, and adopting these as primary endpoints in clinical trials gives disproportional weight to rare events which most patients will not experience. Conversely, length of stay for many clinical conditions is short, and this duration only captures a small part of the clinical recovery trajectory that patients must undergo. This dissertation described the development, technical validation and clinical validation of a new type of clinical endpoints ('value based endpoints') and a new clinical trial paradigm (The remote clinical trial), consisting of digital endpoints and non-invasive pharmacokinetic sampling. Both have the potential to transform pediatric clinical trials and pediatric clinical care. The process towards implementation is challenging and can only proceed after a rigorous validation process. The current work provides a roadmap towards selection, validation, and implementation of digital endpoints, and describes preliminary steps taken for several candidates. The digital endpoints investigated in this work fulfill several validation criteria in a range of clinical conditions and, combined with non-invasive pharmacokinetics, may move the pediatric clinical trial completely towards the home. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
In this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss... Show moreIn this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss interventions in obese asthmatics, we defined the following aimsfor this thesis:1. To gain insight in the effects of exercise training in obese asthmatics and to determine the feasibility and effects of high intensity training in obese subjects2. To design a pulmonary rehabilitation program for obese patients with suboptimalcontrolled asthma and to determine the effectiveness of this program in a randomized controlled trial3. To improve our knowledge on the pathophysiology of obesity related asthma4. To gain insight in the risks and long-term effects of bariatric surgery in morbidlyobese subjects with asthma. Show less
With asthma affecting over 300 million individuals world-wide and estimated to affect 400 million by 2025, developing effective, long-lasting therapeutics is essential. Allergic asthma, where Th2... Show moreWith asthma affecting over 300 million individuals world-wide and estimated to affect 400 million by 2025, developing effective, long-lasting therapeutics is essential. Allergic asthma, where Th2-type immunity plays a central role, represents 90% of child and 50% of adult asthma cases. Research based largely on animal models of allergic disease have led to the generation of a novel class of drugs, so-called biologicals, that target essential components of Th2-type inflammation. Although highly efficient in subclasses of patients, these biologicals and other existing medication only target the symptomatic stage of asthma and when therapy is ceased, a flare-up of the disease is often observed. Therefore, it is suggested to target earlier stages in the inflammatory cascade underlying allergic airway inflammation and to focus on changing and redirecting the initiation of type 2 inflammatory responses against allergens and certain viral agents. This focus on upstream aspects of innate immunity that drive development of Th2-type immunity is expected to have longer-lasting and disease-modifying effects, and may potentially lead to a cure for asthma. This review highlights the current understanding of the contribution of local innate immune elements in the development and maintenance of inflammatory airway responses and discusses available leads for successful targeting of those pathways for future therapeutics. Show less
The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020... Show moreThe European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings.EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. Show less
Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which... Show moreMast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy. Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
Background: An inverse relation between Helicobacter pylori infection and asthma has been shown in epidemiological studies. Infection with H. pylori, or application of an extract of it before or... Show moreBackground: An inverse relation between Helicobacter pylori infection and asthma has been shown in epidemiological studies. Infection with H. pylori, or application of an extract of it before or after sensitization, inhibits allergic airway disease in mice. Objectives: The aim of this study was to investigate the effect of an extract of H. pylori on allergic airway disease induced by repeated allergen exposure in mice that were sensitized and challenged prior to extract application. Method: C57BL/6 mice were intranasally (i.n.) sensitized and challenged with house dust mite (HDM). After a minimum of 4 weeks, mice received the H. pylori extract intraperitoneally and were rechallenged i.n. with HDM. Allergen-specific antibodies were measured by ELISA. Cells present in the bronchoalveolar lavage fluid and dendritic cell (DC) subsets in the lung tissue were analyzed by flow cytometry. Tissue inflammation and goblet cell hyperplasia were assessed by histology. Cells of the mediastinal lymph node (mLN) were isolated and in vitro restimulated with HDM or H. pylori extract. Results: Treatment with H. pylori extract before rechallenge reduced allergen-specific IgE, the DC numbers in the tissue, and goblet cell hyperplasia. Cells isolated from mLN of mice treated with the extract produced significantly more IL-10 and IL-17 after in vitro restimulation with HDM. mLN cells of H. pylori-treated mice that were re-exposed to the H. pylori extract produced significantly more interferon gamma. Conclusions: An extract of H. pylori is effective in reducing mucus production and various features of inflammation in HDM rechallenged mice. (C) 2019 The Author(s) Published by S. Karger AG, Basel Show less
Bousquet, J.; Arnavielhe, S.; Bedbrook, A.; Bewick, M.; Laune, D.; Mathieu-Dupas, E.; ... ; MASK Study Grp 2018
mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and... Show moremHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary. Show less
Bousquet, J.; Arnavielhe, S.; Bedbrook, A.; Bewick, M.; Laune, D.; Mathieu-Dupas, E.; ... ; MASK Study Grp 2018
