Prevalence and management of severe asthma in the Nordic countries: findings from the NORDSTAR cohort.

Background: Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care. Methods: This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged ≥18 years) and in children (aged 6-17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland). Results: Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively. Conclusion: In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care.

A register-based study: cough - a frequent phenomenon in the adult population.

BACKGROUND: Chronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry. MATERIAL AND METHODS: Inclusion criteria were patients 18-90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study's chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC. RESULTS: Of the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p < 0.0001). Both genders were around 2 years older in RCC than UCC (p < 0.0001) Spirometry was performed in 69 and 57%, X-ray in 73 and 58% and asthma challenge test performed in 13 and 5% (UCC and RCC, respectively, p < 0.0001). The frequency of co-morbidities such as heart failure, rheumatologic disease, pulmonary embolism, and diabetes was < 10%. CONCLUSION: Many patients suffer from chronic cough or cough requiring medications, with or without co-morbidity; frequently found among menopausal women. Most patients had a substantial work-up performed. The high frequency and the resources consuming work-up program call for systematic coding of disease, systematic patient evaluation and more specific treatment options. The study was approved (ID: no. P-2019-191).

[Cocaine-induced asthma exacerbation].

Asthma is one of the most common chronic diseases in children and adults. Cocaine is associated with asthma exacerbations. In Denmark, the prevalence of cocaine use has been increasing in recent years. This is a case report of a 47-year-old male with acute asthma exacerbation after cocaine use. Cocaine use is probably an underestimated reason for acute asthma exacerbations.

[Rational use of systemic corticosteroid in the treatment of obstructive lung disease, asthma, and allergic rhinitis].

The anti-inflammatory effect of systemic corticosteroid (CS) on obstructive lung diseases and seasonal allergic rhinitis is well known. So are the physiological side-effects of CS. A major development in inhalation and biologic treatment as well as hyposensibilisation has taken place in recent years and evidence of personalized use of CS in acute exacerbations increases. We review the side effects of CS and the rationale for use of systemic CS in treatment of obstructive lung diseases as asthma and COPD, as well as seasonal allergic rhinitis.

Oral corticosteroid sparing effects of anti-IL5/ anti-IL5 receptor treatment after 2 years of treatment.

INTRODUCTION: Clinical trials have shown oral corticosteroid (OCS) sparing effects of anti-IL5/anti-IL5-receptor treatments. The generalisability of these clinical trials may be limited, due to the rigid inclusion and exclusion criteria, and the short tapering duration. Real-world evidence is needed to bridge the gap between the clinical trials and the clinical practice. With this study we present real-life data on the OCS sparing effects of anti-IL5/anti-IL5-receptor treatments after 12 and 24 months of treatment. METHODS: Severe, eosinophilic asthma patients treated with mepolizumab, reslizumab or benralizumab for 24 months were included in this observational study. Data on OCS-dose, FEV1, ACT/ACQ score and blood eosinophils were obtained from the patients records before anti-IL5/anti-IL5-receptor treatment, and after 12 and 24 months of treatment. RESULTS: At baseline 75% of patients were on daily OCS. This number was reduced to 50% after one year of treatment, p < 0.001, and 28% after two years of treatment, p < 0.001. Within the group on daily OCS the median daily dose was reduced from 10 mg of Prednisolone at baseline (IQR 5-20) to 3.75 mg Prednisolone (IQR 0-10) after 12 months, and 0 mg Prednisolone (IQR 0-7.5) after 24 months, p < 0.001. CONCLUSIONS: The findings in this study add to the generalisability of the clinical studies, showing significant OCS sparing effects of anti-IL5/anti-IL5-receptor treatment in a real-life setting. Furthermore, these findings add to the understanding of the long-term effects of anti-IL5/anti-IL5-receptor treatment, showing an even further and persistent OCS reduction after two years of treatment.

Intralymphatic immunotherapy improves grass pollen allergic rhinoconjunctivitis: A 3-year randomized placebo-controlled trial.

BACKGROUND: Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed. OBJECTIVE: In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT). METHODS: Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). A novel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen. RESULTS: A total of 36 patients were included. Log10-transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P = .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P < .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found. CONCLUSIONS: ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. A booster injection had no additional effect.

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression.

BACKGROUND: MicroRNAs (miRNAs) represent important post-transcriptional regulators with a dynamic expression profile during health and disease. OBJECTIVES: We explored the miRNA profile of human mast cells (MCs) during sen-sitization with IgE, during activation through IgE, and relat ed it to prostaglandin D2 synthesis and histamine release. METHOD: We investigated the expression pattern of 762 miRNAs during the IgE-mediated sensitization and activation of MCs cultured from CD133+ stem cells that were isolated from allergic asthmatic patients and nonatopic controls. RESULTS: IgE-mediated sensitization increased the expression of miRNA-210 eight-fold. This increase was sustained during IgE-mediated MC activation. Furthermore, we confirmed the increase of the miRNA-132/212 cluster after MC activation. Predicted target genes of miRNA-210/132/212 were enriched in several pathways known to be involved in MC activation. Histamine release was significantly higher in MCs from allergic patients when compared to controls, and a number of miRNAs correlated with histamine release and prostaglandin D2 synthesis during MC activation. CONCLUSION: The miRNAs and analysis presented here can help to elucidate the role of miRNAs in mediator release during MC activation. We speculate that miRNA-210 could be important in MC sensitization that leads to allergic symptoms.

Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults.

Although a minority of asthma patients suffer from severe asthma, they represent a major clinical challenge in terms of poor symptom control despite high-dose treatment, risk of exacerbations, and side effects. Novel biological treatments may benefit patients with severe asthma, but are expensive, and are only effective in appropriately targeted patients. In some patients, symptoms are driven by other factors than asthma, and all patients with suspected severe asthma ('difficult asthma') should undergo systematic assessment, in order to differentiate between true severe asthma, and 'difficult-to-treat' patients, in whom poor control is related to factors such as poor adherence or co-morbidities. The Nordic Consensus Statement on severe asthma was developed by the Nordic Severe Asthma Network, consisting of members from Norway, Sweden, Finland, Denmark, Iceland and Estonia, including representatives from the respective national respiratory scientific societies with the aim to provide an overview and recommendations regarding the diagnosis, systematic assessment and management of severe asthma. Furthermore, the Consensus Statement proposes recommendations for the organization of severe asthma management in primary, secondary, and tertiary care.

The level of diagnostic assessment in severe asthma: A nationwide real-life study.

INTRODUCTION: Systematic assessment of patients with severe asthma is pivotal to decide which patients are eligible to new biological therapies. However, the level of diagnostic work-up in patients with severe asthma is only poorly investigated. AIMS & OBJECTIVES: To describe the diagnostic work-up in a complete population of patients with severe asthma including: objective confirmation of the asthma diagnosis, and identification of potential treatment barriers, such as poor adherence and poor inhaler technique. METHODS: A retrospective cross-sectional multicenter study was performed in 2013. We evaluated patient record forms of all patients (aged 18-65 years) consecutively referred with asthma to one of five respiratory outpatient clinics over two years. Patients were included in the study, if they fulfilled ERS/ATS guidelines for having severe asthma. RESULTS: Among 1563 patients with asthma, 98 (6.3%) patients fulfilled the criteria for having severe asthma. The diagnosis of asthma was confirmed objectively in 53/98 patients (54.1%). In total, 83.7% underwent at least one diagnostic test for asthma: reversibility test: 63.3%, PEF: 52% and bronchial challenge test: 21.4%. Among patients eligible for a bronchial challenge test (FEV1 ≥ 70%; negative PEF measurement/reversibility test), only 23.1% had such a test performed. Inhalation technique and adherence were assessed in 19.4 and 30.6% of patients, respectively. CONCLUSION: Among patients managed for severe asthma in a specialist setting, only half had the asthma diagnosis confirmed objectively, and adherence and inhaler technique were infrequently assessed.

Increasing time interval and decreasing allergen dose interval improves ex vivo desensitization of human blood basophils.

BACKGROUND: Desensitization is a method for inducing temporary tolerance to allergen. The mechanism underlying desensitization is yet to be established. METHODS: Basophil granulocytes in whole blood from grass pollen allergic subjects were desensitized ex vivo by sequential addition of increasing allergen concentrations. At each step basophil activation (CD193 + CD63+ ) was monitored with and without (background activation) allergen challenge at optimal concentration. The sequential desensitization protocol was compared to two single-dose desensitization protocols with threshold and subthreshold allergen concentrations. Incubation intervals and allergen concentrations were varied in order to optimise the protocol. RESULTS: Sequential desensitization effectively reduced basophil response. The single-dose subthreshold protocol and single-dose threshold protocol did not reduce basophil activation with optimal allergen challenge from a mean 57.1 (95% CI: 32.7 - 81.5) to 50.4% (95% CI: 16.3 - 84.4; n = 5; P = 0.43) and 45.0% (95% CI: 23.1 - 66.9; P = 0.14) respectively, while the sequential desensitization protocol reduced activation to a mean 37.2% (95% CI: 16.3 - 58.1; P = 0.018). Reducing incubation time from 10 to 5 minutes increased mean background activation from 22.4 (95% CI: 11.7 - 33.1) to 30.0% (95% CI: 19.7 - 40.3; n = 5; P = 0.026). Increasing time intervals from 10 to 20 minutes reduced background activation from 30.9 (95% CI: 22.8 - 39.0) to 21.9% (95% CI: 16.0 - 27.7; n = 5; P = 0.020). Increasing allergen concentration intervals from 2-fold to 5- and 10-fold did not have significant effect on basophil activation. CONCLUSIONS: Sequential desensitization ex vivo effectively attenuates the basophil response to allergen. Increasing the time spent at each step improves desensitization. This protocol could be valuable for investigation the mechanism of desensitization. © 2016 International Clinical Cytometry Society.

[Occupational asthma caused by maleic anhydride].

Organic acid anhydrides (OAA) are widely used in the chemical industry. They are irritants and can cause sensitization and asthma. We describe the first documented case of occupational asthma caused by the OAA maleic anhydride (MA) in the production of insecticides. A 60-year-old man developed work-related respiratory symptoms after eight years of intermittent exposure to MA. Peak expiratory flow measurements showed greater variance on work days than on days off. Both a basophilic activation test and determination of the MA-specific IgE level in serum showed sensitization to MA.

Allergy in bakers' apprentices and factors associated to non-participation in a cohort study of allergic sensitization.

OBJECTIVE: To describe the prevalence of atopy and respiratory symptoms among baker apprentices at the start of the education and factors associated with non-participation in the study. METHODS: A total of 346 students, 22.1(0.6) years of age, mean (SD), from the food production programme of technical colleges in Denmark were invited to participate in a 3 year study. Of the students, 187 agreed to participate and filled in a physician-administered questionnaire. The presence of atopy was determined by skin prick test (SPT) and serum allergen specific IgE (SpIgE). Bronchial hyper responsiveness to methacholine (PD(20)

Response of respiratory flour allergics in an ingested flour challenge may involve plasmacytoid dendritic cells, CD25+ and CD152+ T cells.

BACKGROUND: A number of occupational respiratory allergens are food related, and little is known about the responses these allergens elicit in sensitized persons that ingest them. METHODS: Nine respiratory flour-allergic volunteers were exposed in a double-blind placebo-controlled food challenge with flour. Responses were monitored by spirometry, acoustic rhinometry, determination of urinary methyl histamine and tryptase and flow cytometric evaluation of basophil, dendritic and T cell numbers and markers. RESULTS: Significant increases in serum tryptase (compared with placebo post-exposure levels) and methyl histamine and a coordinated decrease in blood basophils and nasal volume after ingestion of allergen compared with placebo suggest an allergic response to ingested allergen. There was no change in forced expiratory volume in 1 s. The number of blood plasmacytoid dendritic cells (DC), but not of myeloid DC, decreased after exposure (p = 0.001). DC HLA DR was reduced after both exposures (p < 0.001). Expression of CXCR4 on DC was reduced after allergen (p = 0.033) but not after placebo exposure. CD4+ T cell expression of CD25 was elevated after placebo (p = 0.021) but reduced after allergen provocation. The reduction in CD25 expression after allergen compared with placebo was significant (p = 0.024). CD152 was downregulated on these cells after allergen (p = 0.039) but less so after placebo exposure. CONCLUSION: Persons with respiratory allergy respond after ingestion of the relevant allergen. Response to this allergen challenge may selectively recruit plasmacytoid DC through CXCR4 and T cells expressing CD25 and CD152, which may be a regulatory phenotype.