Pre-asthma: a useful concept? A EUFOREA paper. Part 2-late onset eosinophilic asthma.

The concept of pre-diabetes has led to provision of measures to reduce disease progression through identification of subjects at risk of diabetes. We previously considered the idea of pre-asthma in relation to allergic asthma and considered that, in addition to the need to improve population health via multiple measures, including reduction of exposure to allergens and pollutants and avoidance of obesity, there are several possible specific means to reduce asthma development in those most at risk (pre- asthma). The most obvious is allergen immunotherapy (AIT), which when given for allergic rhinitis (AR) has reasonable evidence to support asthma prevention in children (2) but also needs further study as primary prevention. In this second paper we explore the possibilities for similar actions in late onset eosinophilic asthma.

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.

Pre-asthma: a useful concept for prevention and disease-modification? A EUFOREA paper. Part 1-allergic asthma.

Asthma, which affects some 300 million people worldwide and caused 455,000 deaths in 2019, is a significant burden to suffers and to society. It is the most common chronic disease in children and represents one of the major causes for years lived with disability. Significant efforts are made by organizations such as WHO in improving the diagnosis, treatment and monitoring of asthma. However asthma prevention has been less studied. Currently there is a concept of pre- diabetes which allows a reduction in full blown diabetes if diet and exercise are undertaken. Similar predictive states are found in Alzheimer's and Parkinson's diseases. In this paper we explore the possibilities for asthma prevention, both at population level and also investigate the possibility of defining a state of pre-asthma, in which intensive treatment could reduce progression to asthma. Since asthma is a heterogeneous condition, this paper is concerned with allergic asthma. A subsequent one will deal with late onset eosinophilic asthma.

[Pharmacological treatment of asthma during pregnancy]. / Medicamenteuze behandeling van astma tijdens zwangerschap.

- Asthma during pregnancy is associated with an increased risk of preterm delivery, low birth weight and pre-eclampsia.- This condition may be undertreated due to insufficient knowledge and, in particular, concerns about teratogenic effects of asthma medication among treating healthcare professionals and pregnant women.- The risk of teratogenic effects of inhaled medications (ICS, SABA and LABA) is small. These agents have been used by large groups of patients for many years.- Well-controlled asthma with pharmacological therapy during pregnancy is safer and leads to fewer complications then accepting asthma symptoms and exacerbations.- Preconception care for a woman with asthma who is treated with medication is recommended.

Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.

BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD: The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS: All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS: It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.

Lymphomatoid granulomatosis with pulmonary and gastrointestinal involvement.

We present a rare case of grade II lymphomatoid granulomatosis (LYG) with pulmonary and gastrointestinal involvement. LYG is considered an Epstein-Barr virus-driven lymphoproliferative disorder that often presents with multiple nodular lesions in the lungs and sometimes involvement of skin and the central nervous system. Although the aetiology is unknown, it is associated with the use of immunosuppressives. Involvement of other organ systems is very rare. We successfully treated our patients with 6 cycles of R-CHOP and autologous stem cell transplantation with a major response at 20 months follow-up.

Behçet's disease, hospital-based prevalence and manifestations in the Rotterdam area.

INTRODUCTION: Behçet's disease is most prevalent in countries along the former Silk Road. Prevalence varies from 70-420 per 100,000 in Turkey, and 13.5-20 and 1-2 per 100,000 in Asia and Western Europe, respectively. Additionally, disease severity and morbidity might be correlated with ethnicity. We studied demography and morbidity in the Dutch cohort of patients with Behçet's disease and compared those with known figures. PATIENTS AND METHODS: The prevalence of Behçet's patients in the Rotterdam area was determined by comparing the total number of patients within the ethnic population with the number of patients diagnosed with Behçet's disease. Patient files of the Erasmus University Medical Centre (Erasmus MC) were reviewed for morbidity figures and compared with existing data. RESULTS: In total 84 Behçet's patients of Dutch, Turkish or Moroccan descent were identified in the Rotterdam area. Prevalence of Behçet's disease differed per ethnicity: 1, 71 and 39 per 100,000 for Dutch-Caucasians, Turks, and Moroccans, respectively. These figures are comparable with occurrence in West Turkey and Morocco. Within the studied Erasmus MC cohort no significant differences in morbidity appeared between the ethnic groups. However, uveitis and pustules were significantly more common in the Erasmus MC cohort as compared with UK, German, Turkish and Moroccan cohorts. DISCUSSION AND CONCLUSIONS: We present the first epidemiological study of Behçet's disease in the Netherlands. The prevalence of Behçet's disease in the studied Dutch region and in countries of ancestry is similar. Morbidity is equally spread, compared with other countries, but uveitis and pustules seem to be more common in the Netherlands.

Glucocorticoid sensitivity in Behçet's disease.

OBJECTIVE: Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-)inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behçet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity. METHODS: Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-α and GR-ß) were measured. RESULTS: Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9ß minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals. At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-α/GR-ß mRNA expression levels was significantly lower in BD. CONCLUSIONS: Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-ß splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.

Managing Behçet's disease: An update on current and emerging treatment options.

Behçet's disease is an autoinflammatory vasculitis of unknown origin characterized by recurrent oral and genital ulcers, uveitis, arthritis and skin lesions. Additionally, involvement of the gastrointestinal tract, central nervous system and large vessels may occur. The disease is prevalent in countries along the ancient Silk Road from Eastern Asia to the Mediterranean Basin. Many treatment modalities are currently available. The choice of treatment depends on organ involvement and severity of disease. Topical treatment with corticosteroids is often sufficient for mucocutaneous involvement, however for more severe disease with vasculitis or neurological involvement a more aggressive approach is warranted. Newer drugs (biologicals) influencing cytokines and thereby T-cell function are promising with an acceptable side effect profile. Unfortunately, reimbursement of the costs of biologicals for rare disease is still a problem in various countries. In this report we discuss the current treatment modalities for Behçet's disease.