Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4-87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis-particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy-and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022-2024 criteria. Prospective studies are needed.

Background The phenotypic nature of multimorbidity in severe asthma is poorly understood. Our aims in this study were to define multimorbidity phenotypes and their characteristics in severe asthma across Europe by identifying and characterising co-aggregation of comorbidities. Methods Cross-sectional patient data were analysed from the pan-European Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) Central database of national severe asthma registries. Patients were grouped by four European regions (North, South, East, and West). Hierarchical clustering of comorbidities was applied to characterise the correlation structure of the ten commonest comorbidities within these geographical regions. Subsequent multimorbidity phenotypes (MMP) and their clinical features were then defined. Findings Data were available for 2690 severe asthma patients and 23 comorbidities from 11 countries. Three comorbidity clusters were consistently seen across the four European regions: 1) osteoporosis plus steroid-induced weight gain, 2) eczema plus rhinitis, and 3) chronic sinusitis plus nasal polyps. Four further comorbidities (obesity, bronchiectasis, gastro-oesophageal reflux disease, psychological factors) showed variable clustering. Multimorbidity was ubiquitous. Patients were assigned multimorbidity phenotypes (MMP) according to comorbidity cluster alignment. MMP sn (sinonasal-associated) and MMP u (no specific cluster alignment) were commonest. MMP ster (steroid-associated multimorbidity) had highest maintenance oral steroid (m-OCS) use, and Body Mass Index, plus worst lung function, asthma control, and asthma exacerbation frequency. MMP max (maximal multimorbidity) showed high prevalence of variably assigned comorbidities, higher m-OCS and biologic treatment needs. Interpretation Multimorbidity is common in severe asthma and can be classified into replicable novel phenotypes with characteristic clinical traits and outcomes. Recognising these phenotypes can guide better care of the ‘whole patient’ with severe asthma. Future clinical guidance should promote such understanding in order to support delivery of more effective personalised asthma care. Funding European Respiratory Society, pharmaceutical industry partners (Sanofi, TEVA, Novartis, GlaxoSmithKline, Chiesi).

BACKGROUND:Severe asthma affects a minority of patients with asthma; however, it substantially impacts morbidity, health-care use, and systemic corticosteroid-related harm. Despite the increasing use of biological treatments, achievement of severe asthma remission remains elusive. Notably, real-world data on the disease burden and remission potential of severe asthma in Europe remain limited. We aimed to close this knowledge gap, offering insights with global relevance. METHODS:Using data from 13 455 adults with severe asthma enrolled in the European Severe Heterogeneous Asthma Registry, Patient-centred Clinical Research Collaboration (SHARP CRC), this cross-sectional observational study evaluated the burden of severe asthma and remission-related clinical domains (exacerbations, asthma control, airflow limitation, and maintenance oral corticosteroid use) across Europe and examined their relationship with disease duration, biological therapy, and type 2 biomarkers (blood eosinophils, fractional exhaled nitric oxide [FeNO], and total IgE). Patients with severe asthma had been enrolled in national registries according to local principles and guidelines and in accordance with the European Respiratory Society/American Thoracic Society guidelines; 3% (430 of 13 885) of patients were excluded due to no consent for the international study and/or missing medication data. FINDINGS:Patients were predominantly female (59%; 7999 of 13 453), with adult-onset asthma (82%; 8751 of 10 711), and a median disease duration of 23 years (95% CI 20-26 years). 59% (4148 of 7006) of patients had FEV1/FVC of 0·7 or less, 62% (4680 of 7568) had FEV1 lower than 80% predicted, and 89% (3519 of 3968) had at least one active disease domain. Despite 79% (10 632 of 13 453) receiving biological therapy, more than 66% (2621 of 3968) still had at least two active domains. Elevation of type 2 biomarkers persisted (89% [2806 of 3153] with at least one elevated biomarker) despite widespread biological and maintenance oral corticosteroid treatment. A subset of biologic-naive patients (35%; 1069 of 3018) exhibited a rapid accumulation of disease burden within less than 10 years, suggesting a potentially accelerated progression trajectory. INTERPRETATION:This pan-European analysis of severe asthma revealed significant clinical heterogeneity and a substantial disease burden despite advanced therapies, highlighting the enduring nature of type 2 inflammation, the potential inadequacy of current remission strategies with available therapeutic approaches, and the necessity for early identification of high-risk patients. FUNDING:SHARP Clinical Research Collaboration and consortium partners: European Respiratory Society, GlaxoSmithKline Research and Development, Chiesi Farmaceutici Società per Azioni, Novartis Pharma Aktiengesellschaft, Sanofi-Genzyme Corporation, and Teva Branded Pharmaceutical Products R&D.

BACKGROUND:Severe asthma imposes a substantial burden on individuals' health-related quality of life (HRQoL), which might not be fully captured by generic instruments. The Severe Asthma Questionnaire (SAQ) is a validated disease-specific HRQoL instrument capturing the unique lived experience of people with severe asthma. However, the SAQ does not generate preference-based utility values required for health economic evaluations. This study aimed to develop and validate mapping algorithms from the SAQ to the EuroQol (EQ)-5D-5L, enabling estimation of utility values when EQ-5D data are unavailable. METHODS:We used baseline and 6-month data from the longitudinal, multicentre SHARP Burden of Asthma study, including adults with severe asthma across 7 European countries. Direct mapping (ordinary least squares and beta-mixture regression models) using the UK value set and indirect mapping (ordered probit regression models) were developed with baseline data to predict EQ-5D-5L utility values from SAQ scores. Performance was assessed via mean absolute error (MAE), root mean square error (RMSE), and R2, with 6-month data used for validation. RESULTS:Data from 327 patients were included. The beta-mixture model using SAQ subscales marginally outperformed the other models in the development set (MAE = 0.090, RMSE = 0.129, R2 = 0.704), whereas in the validation set the ordered probit regression model showed the best predictive performance (MAE = 0.106, RMSE = 0.151, R2 = 0.589). CONCLUSIONS:Direct mapping with beta-mixture regression showed good overall performance, aligning with prior studies. Indirect mapping may be advantageous in settings requiring flexibility across EQ-5D-5L value sets. These findings demonstrate that EQ-5D-5L utility values can be reliably estimated from the SAQ, supporting use of the instrument in health-economic analyses.

Basophil activation test (BAT) is a useful approach for diagnosing hypersensitivity reactions to tocilizumab. BAT offers insight into IgE‐allergenic activity beyond sensitisation, complementing skin tests and IgE measurements.

IntroductionDupilumab, an IL-4Rα antagonist that blocks IL-4/IL-13 signalling, is used in severe eosinophilic asthma to improve clinical control and suppress type 2 inflammation.MethodsWe evaluated the clinical and systemic immunologic effects of dupilumab, focusing on type 2 biomarkers, total and aeroallergen-specific IgE, and FcεRI (High affinity IgE receptor) - expressing cells. Thirty-three adults with severe eosinophilic asthma were enrolled and followed up for 12 months in two Slovenian centres. Clinical assessments, spirometry, FeNO (Fractional exhaled nitric oxide), ACT (Asthma Control Test) scores, complete blood counts, total IgE, aeroallergen-specific IgE, and FcεRI expression on basophils were measured at baseline and at 1.5, 3, 6, and 12 months.ResultsTwenty-seven patients completed follow-up and were included in the final analysis. Dupilumab treatment resulted in significant improvement in ACT (p = 0.0221), FEV1 (p = 0.0139) and reduction in exacerbations requiring OCS (oral corticosteroid) (p < 0.0001). FeNO declined by 78 %, total IgE by 83%, and aeroallergen-specific IgE by 65% with consistent reductions across perennial and seasonal allergens. Circulating eosinophils increased transiently, whereas basophils increased by 39%.ConclusionsDupilumab demonstrated sustained clinical improvement in patients with severe eosinophilic asthma, accompanied by broad immunologic modulation. Concurrent reductions in FeNO, total IgE, and aeroallergen-specific IgE indicate upstream inhibition of IL-4/IL-13-mediated inflammation, suggesting modulation of the underlying type 2 inflammatory network.

BACKGROUND:Chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype is linked to frequent exacerbations and increased oral corticosteroid (OCS) use. Mepolizumab, an anti-IL-5 monoclonal antibody, has shown efficacy in eosinophilic airway disease. This study assessed its real-life effectiveness in COPD patients with frequent OCS-requiring exacerbations. OBJECTIVES:To evaluate the effectiveness of mepolizumab in reducing exacerbations and corticosteroid use in eosinophilic COPD patients in a real-world setting. DESIGN:Retrospective, single-centre cohort study with two-year follow-up. METHODS:The study included 13 consecutive COPD patients treated with mepolizumab (100 mg SC every 4 weeks) from 2020 to 2022 and followed for two years. Inclusion required ⩾2 OCS-treated exacerbations or maintenance OCS use in the prior year and blood eosinophils > 300 cells/µL. Response was defined as a ⩾50% reduction in annual OCS-requiring exacerbations. RESULTS:At one year, 9 of 13 patients (69%) were responders. Median annual moderate-to-severe exacerbations decreased from 4.0 (IQR: 1.5-10.0) to 1.0 (IQR: 0.0-2.0; p = 0.007). COPD-related hospitalizations declined from 2.0 (IQR: 0.0-4.0) to 0.0 (IQR: 0.0-0.0; p = 0.007). Among the eight patients who continued therapy into the second year, moderate-to-severe exacerbations declined from a median of 5.0 (IQR: 3.0-12.0) at baseline to 2.0 (IQR: 1.0-2.8) in year one and 0.5 (IQR: 0.0-2.8) in year two (p = 0.018), representing 60% and 90% reductions, respectively. Hospitalisations dropped from 2.0 (IQR: 0.3-4.0) to 0.0 (IQR: 0.0-0.0) in both years (p = 0.008). Maintenance OCS was discontinued in 2 of 4 patients (50%) after one year. Responders did not differ from non-responders in type 2 markers, but tended to have a higher baseline frequency of exacerbations. CONCLUSION:Mepolizumab significantly reduced exacerbations and hospitalizations in eosinophilic COPD patients with frequent OCS use. A 69% response rate at one year and sustained benefit in the second year support its role in this difficult-to-treat population.

INTRODUCTION:Mas‑related G protein-coupled receptor X2 (MRGPRX2) has emerged as a mediator of mast cell activation in acute and chronic conditions. Exogenous ligands, such as neuromuscular blocking agents (NMBAs) and fluoroquinolones (FQs), can trigger MRGPRX2‑dependent activation and may augment immunoglobulin E (IgE)-mediated pathways. Although investigators have measured serum MRGPRX2 level in asthma, mastocytosis, and chronic urticaria, its role in immediate hypersensitivity reactions (IHRs) to FQs or NMBAs remains unclear. OBJECTIVES:We conducted this study to determine whether increased serum MRGPRX2 concentration is a risk factor for IHRs to NMBAs or FQs, and whether its concentration is related to reaction severity, causative agent, or serum tryptase. PATIENTS AND METHODS:We studied 43 patients with a history of IHRs to NMBAs or FQs, and compared them with 50 patients with IHR to Hymenoptera venom and 40 control individuals. The participants underwent a diagnostic evaluation that included skin testing, specific IgE measurement, and a basophil activation test when indicated. We measured serum MRGPRX2 level with an enzyme‑linked immunosorbent assay. RESULTS:Median serum MRGPRX2 concentrations with interquartile ranges for the drug‑induced reactions group, the Hymenoptera venom-induced reactions group, and the control group were 7.5 (3.73-15.64), 7 (3.96-10.62), and 5.89 (2.43-9.98) ng/ml, respectively (P = 0.32). Serum MRGPRX2 concentration showed no relationship with reaction severity, specific causative agents, or serum tryptase level. CONCLUSIONS:In this cohort, serum MRGPRX2 concentration was not a risk factor for the investigated drug- and venom‑induced IHRs. These findings do not support using serum MRGPRX2 level as a predictor of the reaction occurrence or severity in these settings.

INTRODUCTION:Diamine oxidase (DAO) degrades histamine, the key mediator in anaphylaxis, yet its relationship with clonal mast cell disorder (CMD) in the context of anaphylaxis is unclear. We evaluated whether DAO during anaphylaxis differs by CMD status. METHODS:We enrolled 35 emergency-department patients with acute anaphylaxis to drugs (7 patients), food (2 patients), or Hymenoptera venom (26 patients). Tryptase, DAO, and histamine degradation were measured during anaphylaxis and convalescence. CMD was defined by detecting KIT p.D816V in peripheral blood leukocytes using highly sensitive qPCR. Post-mortem DAO and tryptase were also compared in two fatal Hymenoptera venom-triggered anaphylaxis (HVA) cases with CMD versus 13 non-anaphylaxis controls. RESULTS:KIT p.D816V was detected in 6 (17%); all had severe HVA and normal basal tryptase. During anaphylaxis, DAO increased markedly in CMD (median 1142%), but only modestly in KIT p.D816V-negative patients (median 20%; p < 0.0001), independent of trigger or severity. Acute DAO was ~5-fold higher in CMD (median 101 vs. 18 U/mL), while convalescent DAO was similar (both 14 U/mL). Despite markedly elevated DAO, we observed impaired histamine degradation in acute anaphylaxis plasma. Receiver-operating-characteristic analyses showed strong discrimination for CMD using acute DAO (AUC 0.92; cut-off 53 U/mL; sensitivity 83%; specificity 97%) and percentage increase from convalescence (AUC 0.97; cut-off 223%; sensitivity 83%; specificity 100%). Post-mortem DAO lacked specificity, whereas post-mortem tryptase supported the diagnosis of fatal anaphylaxis and CMD. CONCLUSION:DAO concentrations rise markedly during anaphylaxis in CMD and may help identify individuals at the highest risk. Further studies should refine the diagnostic utility and elucidate the mechanisms by which DAO may amplify anaphylaxis in CMD.

Abstract Introduction Sleep problems are common in individuals with asthma, and several nocturnal symptoms overlap with asthma-related manifestations. Evidence indicates that sleep disorders may contribute to poor asthma control or signal suboptimal disease management. This study aimed to determine the prevalence and spectrum of sleep disorders in patients with difficult-to-treat asthma and to identify sleep-related factors associated with poor disease control. Methods This prospective single-centre study was conducted at the University Clinic Golnik. Consecutive patients with difficult-to-treat asthma were recruited from a multidisciplinary outpatient clinic between August 2022 and February 2024. Polysomnography was performed during clinical stability, and medical records were reviewed. Results A total of 142 patients were enrolled (53% male, mean age 58.5 ± 12.6 years). Sleep disturbances were highly prevalent across multiple domains. Patients reported snoring (33%), breathing pauses (27%), night awakenings (60%), night cough (42%), nocturia (67%), restless leg syndrome symptoms (41%), restless sleep (34%), unrefreshed sleep (34%), and morning headaches (18%). Polysomnography showed prolonged sleep latency in 68%, prolonged wake after sleep onset in 86%, suboptimal sleep efficiency in 78%, an arousal index >15/h in 53%, and a periodic leg movement index >15/h in 44%. Sleep-disordered breathing (SDB) was diagnosed in 70.4 % of patients according to ICSD-3-TR criteria. In univariate logistic regression, poor asthma control (Asthma Control Test < 20) was associated with SDB (OR 2.71, 95% CI 1.28–5.70), breathing pauses (OR 3.84, 95% CI 1.69–8.74), night awakenings (OR 2.85, 95% CI 1.40–5.79), restless sleep (OR 4.11, 95% CI 1.91–8.82), and unrefreshed sleep (OR 3.34, 95% CI 1.55–7.17). In multivariate logistic regression adjusting for these sleep disturbances as well as age, obesity, gastroesophageal reflux disease, smoking status, allergic rhinitis, and cardiovascular disorders, both SDB (OR 3.17, 95% CI 1.27-7.90) and unrefreshed sleep (OR 2.51, 95% CI 1.02-6.19) remained independently associated with poor asthma control. Conclusion Sleep disturbances were highly prevalent in patients with difficult-to-treat asthma, with more than 70% diagnosed with sleep-disordered breathing. While multiple nocturnal symptoms were associated with poor asthma control in univariate analysis, only sleep-disordered breathing and unrefreshed sleep emerged as independent predictors. Support (if any)

Background:Multimorbidity refers to the presence of multiple coexisting conditions, but is often underappreciated in the context of severe asthma (SA) management. We sought to identify differences in approaches to multimorbidity management in SA, variability in access to multidisciplinary team (MDT) resources, and whether physician perspectives on multimorbidity differ between SA specialists and general respiratory physicians. Methods:The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration circulated an online physician survey via European national respiratory societies to assess 1) available resources to address multimorbidity and 2) physician perspectives on multimorbidity in SA. Results:495 responses from 25 European countries included 48% SA specialists and 52% general respiratory physicians. SA specialists had more experience with SA patients (20% were seeing >60 patients per month) compared to general respiratory physicians. SA specialists had greater access to multidisciplinary care - including better access to MDTs, allied health professionals and referrals to external specialists, and therefore more routinely assessed comorbidities and considered them greater influences on their practice. They also considered multimorbidity to a greater degree and rated its impact on their patients' asthma outcomes (and general health outcomes) as more substantial. Conclusions:Alongside more experience of treating SA, SA specialists have increased awareness of multimorbidity and better resources to manage it. However, access to MDTs remains a significant gap for both SA specialists and general respiratory physicians. Furthermore, both groups identified a high need for further education and training about multimorbidity. These findings highlight key areas for improvement in clinical practice, resources and training.

Bronchiectasis is a chronic inflammatory lung disease characterized by acquired permanent dilatation of the large bronchi or bronchioles. It is considered a rare disease with a prevalence of 67 per 100,000 inhabitants. The characteristic symptoms include chronic cough, sputum production, and recurrent respiratory infections. Acute exacerbations are common, during which the patient produces abundant purulent sputum.The purpose of this document is to implement the international guidelines for bronchiectasis in Slovenian health care system. The document is meant to serve as an agreed approach to the management of patients with bronchiectasis at primary and specialist pulmonary levels in Slovenia.

Background: Therapies targeting IL-5 or its receptor (IL-5Ra) are currently used to treat patients with severe eosinophilic asthma. Objective: We sought to investigate the impact of anti-IL-5 and anti-IL-5Ra biological therapies on mast cells (MCs) and their progenitors. Methods: Surface IL-5Ra expression was investigated on MCs and their progenitors in mouse lungs and bone marrow and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma before and after anti-IL-5 (mepolizumab) or anti-IL-5Ra (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Ra therapy. Results: Approximately 50% of the human primary lung MCs and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Ra. In patients with mild to moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Ra1 MC progenitors was elevated. In addition, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Furthermore, patients with severe asthma from 2 independent cohorts demonstrated a reduction in blood MC progenitors after anti-IL-5 or anti-IL-5Ra treatment. This was associated with improved asthma control as well as a decline in both blood eosinophils and TH2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Ra (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. Conclusions: This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Ra in severe asthma may also involve reduction of MC populations. (J Allergy Clin Immunol 2025;155:1310-20.)

Diagnosing and prognosing immune-mediated airway diseases, like hypersensitivity pneumonitis (HP) and sarcoidosis, is complicated due to their overlapping symptoms and the lack of definitive biomarkers. Hence, we wanted to compare bronchoalveolar lavage (BAL) cytokine and chemokine profiles from 92 patients with different immune-mediated and inflammatory airway diseases, namely, HP, sarcoidosis, non-allergic asthma, amiodarone lung, and EGPA. We also compared pulmonary function parameters, BAL’s cellularity, and lymphocyte immunophenotypes. We found significant differences across all measured lung functions (VC, VC%, FEV1, FEV1%, and Tiff%) and in the number of macrophages, lymphocytes, neutrophils, and eosinophils. Furthermore, we showed significant differences in CD4, CD8, and CD4/8 across all included ILDs and OLDs; however, no significant differences were found in CD3, CD19, NK, or NKT. We identified nine biomarkers (IL-1β, IL-6, IL-8, IL-13, VEGF, angiogenin, C4a, RANTES, and MCP-1) that significantly differ in the BAL of patients with HP and sarcoidosis and showed that RANTES and IL-6 are associated with fibrotic outcome. We have demonstrated that interstitial and obstructive lung diseases differ in cytokine and cellular lung imprint, which may, in the future, enable the determination of the disease subtype and thus the identification of targets for the treatment of individuals or subgroups within diseases.