The Fractional exhaled Nitric Oxide (FeNO)- test as add-on test in the diagnostic work-up of asthma: a study protocol.

BACKGROUND: Asthma is a common disease characterized by chronic inflammation of the lower airways, bronchial hyperactivity, and (reversible) airway obstruction. The Global Initiative of Asthma Guideline recommends a flowchart to diagnose asthma with first-step spirometry with reversibility and a bronchial challenge test (BPT) with histamine or methacholine as a second step [1]. The BPT is considered burdensome, time-consuming for patients and staff, can cause side effects, and is expensive. In addition, this test strongly encumbers lung function capacity. Elevated Nitric Oxide (NO) is associated with airway eosinophilic inflammation in asthma patients and can be measured in exhaled air with the Fractional exhaled (Fe) NO-test. This low-burden FeNO-test could be used as an 'add-on' test in asthma diagnostics [2, 3]. METHODS AND ANALYSIS: This multi-center prospective study (Trial number: NCT06230458) compares the 'standard asthma diagnostic work-up' (spirometry with reversibility and BPT) to the 'new asthma diagnostics work-up' (FeNO-test as an intermediate step between the spirometry with reversibility and the BPT), intending to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness and reduced burden to the patient and health care. The cost reduction of incorporating the FeNO-test in the new diagnostic algorithm will be established by the number of theoretically avoided BPT. The decrease in burden will be studied by calculating differences in the Visual Analogue Scale (VAS) -score and Asthma Quality of Life Questionnaire (AQLQ) -score after the BPT and FeNO-test with an independent T-test. The accuracy of the FeNO-test will be calculated by comparing the FeNO-test outcomes to the (gold standard) BPTs outcomes in terms of sensitivity and specificity. The intention is to include 171 patients. ETHICS AND DISSEMINATION: The local medical ethics committee approved the proposed study and is considered a low-burden and risk-low study. The local medical ethics committee registration number: R23.005. STRENGTHS AND LIMITATIONS OF THIS STUDY: Strengths: This is the first study that investigates the value of the FeNO-test (cut off ≥ 50 ppb) as an add-on test, to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness, and reduced burden on the patient and health care. LIMITATIONS: High FeNO levels may also be observed in other diseases such as eosinophilic chronic bronchitis and allergic rhinitis. The FeNO-test can be used to rule in a diagnosis of asthma with confidence, however, due to the poor sensitivity it is not suitable to rule out asthma.

Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This 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 METHODS: This 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. RESULTS: At 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 (ß = 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%. CONCLUSIONS: Work 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.

Home-based intravenous treatment with reslizumab for severe asthma in the Netherlands - An evaluation.

The anti-IL-5 biologic reslizumab for the treatment of severe eosinophilic asthma is administered intravenously. In the current study home administration of intravenous reslizumab was evaluated in 24 patients included between 2019 (July) and 2020 (July). This is the first study to show that intravenous reslizumab can be administered safely and successfully in an outpatient setting. Notably, not all patients prefer home administration and severe asthma patients may have different needs when it comes to choosing treatment at home or in the hospital.

Voice bubbling therapy for vocal cord dysfunction in difficult-to-treat asthma - a pilot study.

OBJECTIVE: Dysfunctional breathing often coexists with asthma and complicates asthma control, especially in difficult-to-treat asthma. Voice bubbling therapy (VBT) by a specialized speech therapist may influence the breathing pattern. This pilot study investigated the effect of voice bubbling therapy (VBT) in participants with difficult-to-treat asthma, who fulfilled criteria for dysfunctional breathing pattern. METHOD: Twenty-four patients were randomized between VBT and usual care (UC). VBT is blowing into a glass (resonance) tube (28 cm in length, 0.9 cm inner diameter) which ends in a bowl of water (1.5 litre). Lung function, capillary blood gas and questionnaires were measured at baseline, at 6 and 18 weeks of follow up. RESULTS: No difference in ACQ and quality of life was found after VBT compared to UC group. However, after six weeks of bubbling therapy, pCO2 levels measured in capillary blood gas were higher (baseline median (IQR) pCO2 = 33.00 (17.25 - 38.6) mmHg; week 6 pCO2 = 36.00 (29.00 - 42.3) mmHg) p = 0.01. Moreover, ΔpCO2 (baseline - 18 weeks of follow up) was significantly correlated with ΔAQLQ (rs = 0.78, p = 0.02). CONCLUSION: VBT in participants with difficult-to-treat asthma resulted in a higher average pCO2 level, indicating the treatment may improve hyperventilation. However, this did not improve asthma control or quality of life. VBT may have value for a better management of asthma related symptoms.

Describing fluctuating indoor aerosol dust measurements with application to house dust mite allergens.

Measuring house dust mite aeroallergen concentrations is essential in understanding mite allergen exposure. Physically, the aerolized house dust mite faeces are part of indoor particulate matter. We studied the statistical ways of summarizing measurements of fluctuating mite aeroallergen exposure inside homes through indoor particulate matter. To study emissions from beddings, we measured the time-related airborne dust concentration after shaking a duvet. Analysis was performed both by a method based on the estimated mean and by a non-linear model. Twenty-eight studies reported a sum of concentrations; only one also reported the peak. In our four experiments on shaking a duvet (245 to 275 measurements each), the peak value was two to four times higher than the mean. The mean-based and non-linear models both predicted the sum of concentrations exactly. A 1% upper prediction bound and the non-linear model predicted the peak emission rate moderately well (64 to 92%, and 63 to 93%, respectively). Mean levels of indoor particulate matter measurements differ substantially from peak concentrations. The use of the mean is only sufficient to predict the sum of concentrations. We suggest that, mite aeroallergen measurements should include information on the peak as well as the mean.

High intensity training in obesity: a Meta-analysis.

INTRODUCTION: High Intensity training (HIT) is a time-effective alternative to traditional exercise programs in adults with obesity, but the superiority in terms of improving cardiopulmonary fitness and weight loss has not been demonstrated. OBJECTIVE: to determine the effectiveness of HIT on cardiopulmonary fitness and body composition in adults with obesity compared to traditional (high volume continuous) exercise. METHODS: A systematic search of the main health science databases was conducted for randomized controlled trials comparing HIT with traditional forms of exercise in people with obesity. Eighteen studies were included in the meta-analysis. The (unstandardized) mean difference of each outcome parameters was calculated and pooled with the random effects model. RESULTS: HIT resulted in greater improvement of cardiopulmonary fitness (VO2max) (MD 1.83, 95% CI 0.70, 2.96, p<0.005; I2=31%) and a greater reduction of %body fat (MD -1.69, 95% CI -3.10, -0.27, p=0.02, I2=30%) compared to traditional exercise. Overall effect for BMI was not different between HIT and traditional exercise. CONCLUSION: Training at high intensity is superior to improve cardiopulmonary fitness and to reduce %body fat in adults with obesity compared to traditional exercise. Future studies are needed to design specific HIT programs for the obese with regard to optimal effect and long-term adherence.

4-month omalizumab efficacy outcomes for severe allergic asthma: the Dutch National Omalizumab in Asthma Registry.

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 < 0.001). 75.3% of the responders showed more than 0.5 points improvement in the ACQ. The mean FEV1 increased from 71.58 to 79.06 (p < 0.001). There was no relationship between patients with a FEV1 <80 and ≥80% at baseline and response (p = 0.981). Most of the responders had a considerable improvement of FEV1 either/or ACQ or OCS use (88.3%). While 86.7% of the responders had an improvement of either ACQ or FEV1. 75.4% of the responders had an improvement of ACQ, while 50.4% had an improvement of FEV1. Finally 11.7% of the patients with no improvement of FEV1, ACQ or OCS use were considered to have a good response. CONCLUSIONS: This registry of 403 inadequately controlled severe allergic asthma patients in the Netherlands showed a good or excellent response of 65.5% to omalizumab after 16 weeks, in accordance with previous studies. The assumption that careful registration would lead to higher response rates could not be supported by the data from this registry. Improvement of ACQ appears to be a useful additional assessment tool to measure response in omalizumab treated patients.

Targeted Therapy for Older Patients with Uncontrolled Severe Asthma: Current and Future Prospects.

Severe asthma in the elderly places a high burden on affected individuals and society. Emerging therapies target specific phenotypes of the asthma disease spectrum, and can be beneficial for older asthmatics, albeit their response might be altered due to age-related characteristics. Paradoxically, these characteristics are often ground for exclusion from clinical trials. The question thus arises how the senior asthmatic population can successfully enter the era of targeted therapy. Therefore, we highlight characteristics of this population relevant to effective treatment, and review the evidence for targeted therapy in elderly patients. For targeted therapy it is important to account for aging, as this affects the distribution of phenotypes (e.g. late-onset asthma, non-eosinophilic asthma) and may alter biomarkers and drug metabolism. Elderly asthmatics suffer from age-related comorbidities and subsequent polypharmacy. A systematic search into targeted asthma therapy yielded no randomized clinical trials dedicated to older asthmatics. Post hoc analyses of the anti-immunoglobulin E agent omalizumab indicate similar efficacy in both younger and older adults. Conference abstracts on anti-interleukin-5 and anti-interleukin-13 therapy suggest even more pronounced effects of targeted treatments in late-onset disease and in asthmatic patients 65 years or older, but full reports are lacking. For non-eosinophilic asthma in the elderly, there is not yet high-level evidence for targeted therapy, but macrolides may offer a viable option. In conclusion, there is a gap in knowledge regarding the effect of older age on the safety and efficacy of targeted asthma therapy. Further investigations in the elderly are needed, with special emphasis on both late-onset asthma and therapeutics for non-eosinophilic asthma.

Evaluation of new laboratory tests to discriminate bacterial from nonbacterial chronic obstructive pulmonary disease exacerbations.

INTRODUCTIONS: Discriminating bacterial from nonbacterial acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is difficult, causing antibiotics overuse and bacterial resistance. Sputum cultures are of limited use because results take time. In our hospital, only leukocyte concentration and CRP are laboratory parameters evaluated in AECOPD. We evaluated additional tests to discriminate bacterial vs. nonbacterial AECOPD: 5-part leukocyte differentiation (hematology analyzer), leukocyte differentiation using flow cytometry (Leukoflow, Cytodiff), Leuko64 kit, and procalcitonin. METHODS: Retrospectively, patients were classified as bacterial or nonbacterial AECOPD. ROC analyses tested how the additional tests discriminate these groups. RESULTS: Twenty-two AECOPD were classified as bacterial and 23 as nonbacterial. From the additional tests, basophil percentage (Cytodiff) has superior AUC (0.800). At a cutoff resulting in ≥90% sensitivity, neutrophil/lymphocyte ratio (AUC:0.755) and CD4-positive T cells (Leukoflow, AUC:0.747) have the highest specificity (57%). Both neutrophil mean volume and standard deviation (Cell Population Data, DxH800 hematology analyzer) had good combined sensitivity and specificity (AUC:0.846/0.804, 91% sensitivity, 69% specificity). Addition of leukocyte populations and procalcitonin to CRP in regression models (AUC: 0.907/0.876/0.890) increased specificity compared to CRP alone (71% or 73% vs. 39%). CONCLUSION: No additional test has sufficient accuracy on its own to predict bacterial AECOPD. Combining CRP with several parameters from the additional tests may improve this.

Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo.

BACKGROUND: α-melanocyte-stimulating hormone (α-MSH) was shown to inhibit allergic airway inflammation and exert suppressive effects on human basophils. OBJECTIVE: This study aims to extend our current knowledge on the melanocortin 1 receptor (MC1R) expression in nasal tissue of patients with allergic rhinitis (AR) and functional effects of α-MSH in human basophils especially from patients with allergic rhinitis. METHODS: MC1R expression before and after nasal allergen provocation was studied in nasal mucosal tissue of AR patients and in a mouse model of allergic airway inflammation using immunofluorescence. In vitro regulation of the MC1R and CD203c surface expression on whole-blood basophils of patients with AR and controls was assessed with flow cytometry. Functional effects of α-MSH on isolated basophils were analysed regarding apoptosis with flow cytometry and chemotaxis using a Boyden chamber assay. RESULTS: We detected an accumulation of MC1R-positive basophils in nasal mucosa tissue of patients with AR 24 h after nasal allergen provocation. Such accumulation was not present in mucosa sections from healthy controls. In mice with allergic airway inflammation, we found a clear accumulation of MC1R-positive basophils in the nasal tissue compared to control mice. MC1R expression was inducible in AR patients and controls by stimulation with anti-IgE. α-MSH inhibited anti-IgE and grass pollen induced upregulation of CD203c, but had no effect on chemotaxis or apoptosis of basophils in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: MC1R-positive basophils accumulate in the nasal mucosa of patients with AR after nasal allergen provocation. Since α-MSH suppresses proinflammatory effector functions in human basophils via the MC1R, it constitutes an interesting novel target for modulating the allergic inflammatory response.

In vivo diagnosis of allergic diseases--allergen provocation tests.

The allergen challenge test has been the mainstay of diagnosis of allergic diseases for a long time since it offers a direct proof of the clinical relevance of a particular allergen for the allergic disease symptoms and severity. Standardisation and availability for daily practice (including safety issues) are still to be refined but most of the challenge tests have safely crossed the border from research tools to diagnostic tests available for daily practice for a well trained clinical staff.

Recommendations for the allergy management in the primary care.

The majority of patients seeking medical advice for allergic diseases are first seen in a primary care setting. Correct diagnosis with identification of all offending allergens is an absolute prerequisite for appropriate management of allergic disease by the general practitioner. Allergy diagnostic tests recommended for use in primary care are critically reviewed in accordance with the significant workload in a primary care setting. Simplified pathways for recognition and diagnosis of allergic diseases are proposed, that should be further adapted to local (national) conditions.

The eXpeRience registry: the 'real-world' effectiveness of omalizumab in allergic asthma.

Omalizumab has demonstrated therapeutic benefits in controlled clinical trials. Evaluation of outcomes in real-world clinical practice is needed to provide a complete understanding of the benefits of omalizumab treatment. eXpeRience was a 2-year, international, single-arm, open-label, observational registry that evaluated real-world effectiveness, safety and use of omalizumab therapy in 943 patients with uncontrolled persistent allergic asthma. Effectiveness variables (physician's Global Evaluation of Treatment Effectiveness [GETE], and change from baseline in exacerbation rate, symptoms, rescue medication use, and oral corticosteroid [OCS] use) were evaluated at pre-specified time-points. Safety data were also recorded. By physician's GETE, 69.9% of patients were responders to omalizumab after 16 (±1) weeks. The proportion of patients with no clinically significant exacerbations increased from 6.8% during the 12-month pre-treatment period to 54.1% and 67.3% at Months 12 and 24, respectively. Symptoms and rescue medication use at Month 24 were reduced by >50% from baseline. Maintenance OCS use was lower at Month 24 (14.2%) compared with Month 12 (16.1%) and baseline (28.6%). Overall, omalizumab had an acceptable safety profile. The results from eXpeRience indicate that omalizumab was associated with improvements in outcomes in patients with uncontrolled persistent allergic asthma; these improvements were consistent with the results of clinical trials.

Obesity and asthma: co-morbidity or causal relationship?

There is substantial evidence that obesity and asthma are related. "Obese asthma" may be a unique phenotype of asthma, characterized by decreased lung volumes, greater symptoms for a given degree of lung function impairment, destabilization or lack of asthma control, lack of eosinophilic inflammation and a different response to controller medication. Whether this relationship between obesity and asthma is causal or represents co-morbidity due to other factors is unclear. In previous reviews concerning the relationship between obesity and asthma, five hypotheses were put forth. One of these hypotheses is that a low grade systemic inflammation caused by adipokines from the fat tissue causes or enhances bronchial inflammation. In animal models, there is an increasing amount of evidence for the role of adipokines derived from fat tissue in the relationship between obesity and asthma. The data are conflicting in humans. Since obesity is a component of the metabolic syndrome and the metabolic syndrome is also a form of systemic inflammation, it is to be expected that there is a relationship between metabolic syndrome and asthma. The few data that are available show that there is no relationship between metabolic syndrome and asthma, but there is one between the metabolic syndrome and asthma-like symptoms. Further research is needed to confirm the relationship between obesity and asthma in humans, where a rigorous approach in the diagnosis of asthma is essential.

[Diagnostic image (371). A man with a swollen face]. / Diagnose in beeld (371). Een man met een opgezwollen gelaat.

A 65-year-old man with a history of recurrent pneumothorax and bullous emphysema presented with acute dyspnoea and a swollen face due to subcutaneous emphysema.