Background Preschool children with asthma are more susceptible to develop acute life-threatening respiratory distress leading to hospital admissions compared to school children and treatment options are limited for this age group. We evaluated the safety and efficacy of tiotropium as add-on therapy to inhaled corticosteroids (ICS) in preschool children with high-risk, partly controlled or uncontrolled asthma. Methods TIPP was a phase III, prospective, multicentre, randomised, double-blind, placebo-controlled, parallel-group (investigator-initiated) trial conducted at 13 German centres (12 hospitals, one specialised medical practice). Children aged 1–5 years with physician-diagnosed asthma, partly controlled or uncontrolled symptoms despite ICS, and a history of severe exacerbations were randomly assigned to receive once-daily tiotropium (two puffs of 1.25 μg) via Respimat® inhaler or placebo as add-on to ICS therapy over 52 weeks. The primary outcome was time to first severe asthma exacerbation requiring hospitalisation and/or systemic corticosteroid treatment. All randomised participants were included in the intention-to-treat analysis and analysed by treatment received for safety. No primary or safety data were missing; therefore, no imputation was required. The study was registered in the “EU Clinical Trials Registry” (EudraCT 2021-000190-81). Findings Between February 2022 and March 2025, 100 of the planned 204 children were enrolled, of whom 86 were randomised to tiotropium + ICS (n = 44) or placebo + ICS (n = 42). Mean age was 3.3 years (Standard deviation (SD) 1.3). The primary outcome time to first severe asthma exacerbation did not differ between groups (Hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.51–1.92; p = 0.98). At least one adverse event was reported in 41 (93%) of 44 children in the tiotropium + ICS group and 42 (100%) of 42 children in the placebo + ICS group. 397 adverse events were reported with tiotropium + ICS group and 450 with placebo + ICS group. Tiotropium was well tolerated, and no new safety signal was identified. Interpretation Tiotropium did not reduce the risk of a severe asthma exacerbation, but was well tolerated as add-on therapy to ICS in preschool children with high-risk asthma. Funding German Federal Ministry of Education and Research (01KG2030); study medication provided by Boehringer Ingelheim Pharma GmbH & Co. KG (0205-0546).

BACKGROUND:Preschool children with refractory respiratory symptoms often undergo diagnostic bronchoscopy to exclude anatomical and functional abnormalities and to detect suspected chronic lower respiratory tract infections by bronchoalveolar lavage (BAL). The objective of this retrospective analysis was to analyze BAL fluid findings with respect to bacterial colonization and cytology. Additionally, we aimed to determine associations with bacterial colonization of the airways and allergic sensitization status and symptoms as well as to identify comorbidities like gastroesophageal reflux disease (GERD) or eosinophilic esophagitis (EoE). METHODS:In a retrospective analysis, the electronic medical records of 355 children aged 1-5 years who underwent bronchoscopy for refractory respiratory symptoms between 2010 and 2019 were evaluated. Differential cytology and bacterial cultures from BAL, laboratory parameters, oesophagogastroduodenoscopy (OGDS) and histology from esophageal biopsies were analyzed. RESULTS:A positive bacterial culture from BAL fluid was found in 214 children (61.7%). Of these, 105 children (49%) subsequently received antibiotic treatment. The most frequently identified bacteria were Haemophilus influenzae (34%), Streptococcus pneumoniae (25%) and Moraxella catarrhalis (16%). The percentage of neutrophils in differential cell counts from BAL samples was significantly higher with positive bacterial cultures compared to negative cultures (29.2 + 28.1% vs. 21.2 + 25.4%, p = 0.02). Children with insufficient S. pneumoniae antibody titers had significantly more positive cultures for S. pneumoniae in BAL fluid (28.3% vs. 12.8%; p = 0.0024). GERD was identified in 115 children (32%) and EoE was diagnosed in nine children (2.8%). CONCLUSION:Bronchoscopy is a valuable diagnostic tool in the evaluation of persistent respiratory symptoms in preschool children. Bacterial colonization of the airways was common and associated with significantly elevated airway neutrophil counts.

Post-infectious bronchiolitis obliterans (PiBO) is a chronic lung disease that develops after severe lower respiratory infections and leads to persistent inflammation and fibrotic changes in the small airways. In the present study, gene expression analysis was used to identify differentially expressed genes (DEGs) in sputum cells derived from PiBO patients and compare them to healthy controls. Clinical history, lung function parameters, and induced sputum samples were collected from nine patients with PiBO and eight healthy controls. Multiplex immunohistochemistry (mIHC) as well as mRNA sequencing (MACE-Seq) were performed. Evaluation of the biological targets was done by KEGG pathway enrichment analysis. PiBO patients showed significantly reduced lung function parameters, an increased neutrophil count, and an altered macrophage profile in sputum. Transcriptome analysis revealed significant upregulation of the TNFα-dependent NFκB signalling pathway, as well as significant downregulation of the oxidative phosphorylation (OXPHOS). Linear regression analyses and mIHC indicated a shift in macrophage polarisation that may contribute to the dysregulated gene expression. Notably, expression of these DEGs significantly correlated with FEV1 lung function. These findings indicate a central role of macrophages in the immunopathology of PiBO and contribute to our understanding of the molecular mechanisms involved in the disease process.

BACKGROUND:Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS:NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS:Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION:The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING:Quince Therapeutics.

Asthma is the most common chronic respiratory disease in children and adolescents. While most patients achieve good control with guideline-based treatment, a significant proportion experience persistent symptoms, frequent exacerbations, and impaired quality of life.This guideline aims to define severe and difficult-to-treat asthma in children and adolescents, support diagnostic precision, and provide practical, evidence-based recommendations for assessment and management, including biological therapies.The S1 guideline was developed under the coordination of the German Society for Pediatric Pulmonology following AWMF procedures. A structured consensus process involving experts from pediatric pulmonology, allergology, and general pediatrics was conducted. Existing national and international guidelines and new evidence were systematically reviewed and adapted.Key elements include a stepwise diagnostic algorithm to distinguish difficult-to-treat from truly severe asthma, guidance on assessing adherence, comorbidities, and inflammation biomarkers, and recommendations for targeted biological treatment. This guideline addresses monitoring tools, transition to adult care, and the role of rehabilitation.Children and adolescents with severe asthma require early referral to specialized centers and a structured, interdisciplinary approach. Personalized treatment strategies-including biologics-should be guided by phenotyping and biomarkers. Registry data are essential to improve care quality and generate real-world evidence.

Purpose:Alternaria alternata (AA) grows on decaying material. Spores occur on hot and dry days in the summer and can trigger asthma and allergic rhinitis. Skin prick test (SPT-AA) and Alternaria alternata-specific IgE (AA-IgE) are used for diagnostic purposes, but their predictive value is unclear. Patients and Methods:A retrospective analysis of electronic medical records to 2011-2021 was performed on symptoms, SPT-AA, AA-IgE, lung function, asthma therapy and bronchial provocation using Alternaria alternata extract (BP-AA). Results:149 children and adolescents (5-18 years) with Alternaria allergy were investigated. Between June and September, 86 Alternaria-sensitized patients had asthmatic symptoms and 113 had nasal symptoms (often outdoors or with mold exposure). SPT-AA and AA-IgE levels did not differ between the symptomatic and asymptomatic patients (SPT-AA, p= 0.23). A weak correlation was observed between the diagnostic tests in 49 patients with bronchial and/or nasal symptoms (r= 0.36, p= 0.01). Nineteen patients received provocation, 16 showed an early asthmatic response and 14 a late asthmatic response. Patients with BP-AA had a medium SPT-AA ≥7 mm or AA-IgE ≥16.8 kU/L. Both tests significantly correlate with PD20-AA (r= -0,49, p< 0.01 and r= 0.26, p< 0.01, respectively). Conclusion:The Diagnosis of Alternaria allergy is still a challenge. The weak to moderate correlation between SPT-AA and AA-IgE seems to be allergen-specific. Typical medical history is a key diagnostic criterion. Allergy profiles and climate may play a role in the manifestation of symptoms. BP-AA help to establish threshold values for SPT-AA and AA-IgE. In unclear cases, nasal or bronchial provocation should be performed before immunotherapy.

BACKGROUND:Patients with allergic rhinitis (AR) and/or mild or moderate asthma derived from birch-family pollen allergy can be treated with liquid sublingual immunotherapy (SLIT-liquid). This study evaluated the impact of two SLIT extracts on AR and asthma progression or onset in these patients. METHODS:This was a sub-analysis of a retrospective, longitudinal comparative cohort study that used a German prescription database. Patients treated with 3-tree (birch/alder/hazel) or birch-only SLIT-liquid and followed up for up to 6 years after treatment were compared with controls dispensed symptomatic medications. Multiple regression analysis compared dispensation data as a proxy for disease status and progression. RESULTS:A total of 493 patients treated with 3-tree SLIT-liquid and 311 treated with birch SLIT-liquid were analysed vs. 44,835 patients included as controls. Overall, 70.5 % of patients presented solely AR, 24.2 % solely asthma, and 5.3 % both diseases. Compared with controls, patients treated with 3-tree SLIT-liquid had reduced risk of AR [odds ratio (OR) = 3.21, 95 % CI 2.54-4.06, p < 0.001], asthma progression (OR = 2.03, 95 % CI 1.43-2.89, p < 0.0001), or asthma onset (OR = 0.592, 95 % CI, 0.408-0.860, p = 0.006). Birch-only SLIT-liquid showed similar effectiveness in reducing AR and asthma medication dispensation but no significant effect in reducing new-onset asthma. CONCLUSIONS:This real-world study demonstrated the effectiveness of treatment with 3-tree SLIT-liquid or birch SLIT-liquid in slowing the progression of birch-family pollen allergy. 3-tree SLIT-liquid covering a broader repertoire of epitopes mimicking natural exposure throughout the year may be valuable for patients sensitised to birch and/or alder and/or hazel pollen suffering from overlapping tree-pollen seasons.

Asthma bronchiale ist die häufigste chronische Atemwegserkrankung im Kindes- und Jugendalter. Während der Großteil der Patient:innen unter leitliniengerechter Therapie gut behandelt werden kann, leidet eine relevante Subgruppe an schwerem oder schwer behandelbarem Asthma mit eingeschränkter Lebensqualität und hoher Krankheitslast. Diese Leitlinie zielt darauf ab, schweres Asthma im Kindes- und Jugendalter klar zu definieren, eine strukturierte diagnostische und therapeutische Herangehensweise zu fördern und konkrete Empfehlungen für das Management, einschließlich des Einsatzes von Biologika, zu geben. Die Leitlinie wurde unter Federführung der Gesellschaft für Pädiatrische Pneumologie (GPP) gemäß dem AWMF-Regelwerk erstellt. Grundlage war ein systematischer Literaturreview relevanter nationaler und internationaler Empfehlungen. Ein multidisziplinäres Expertengremium stimmte alle Empfehlungen konsensbasiert ab. Im Mittelpunkt steht ein mehrstufiges diagnostisches Vorgehen zur Differenzierung zwischen schwer behandelbarem und genuin schwerem Asthma. Es werden Kriterien zu Therapieadhärenz, Komorbiditätserfassung und phänotypspezifischer Auswahl von Biologika dargestellt. Weitere Themen sind Monitoring, Rehabilitation, Transition und zukünftige Therapien. Empfehlungen zur Anwendung bestehender und neuer monoklonaler Antikörper basieren auf aktueller Evidenz. Kinder mit schwerem Asthma benötigen eine strukturierte, interdisziplinäre Versorgung. Eine frühe phänotypbasierte Therapie mit Biologika sowie flächendeckende Registerdaten und patientenorientierte Versorgungspfade sind erforderlich, um die Prognose dieser Patientengruppe zu verbessern.

Objective:Children with preschool asthma suffer disproportionally more often from severe asthma exacerbations with emergency visits and hospital admissions than school children. However, there are only a few reports on characteristics, hospitalization, phenotypes and symptoms in this age cohort. Patients and methods:This analysis of an ongoing prospective trial of Tiotropium bromide in preventing severe asthma exacerbations (the TIPP study) assessed baseline characteristics, hospitalizations and symptoms in 100 children with severe preschool asthma. Children aged 1-5 years were analyzed at study enrollment and daily symptoms were recorded by an electronic diary [Pediatric Asthma Caregiver Diary (PACD)] for the following four weeks until randomization. Results:At enrollment, the total number of severe asthma exacerbations, defined as three days systemic steroid use or hospitalization in the last 24 months, was mean (±SD) 5.8 ± 5.7 and the test for respiratory and asthma control in kids (TRACK) was mean 46.9 ± 19.0. Daily recording of symptoms by the PACD revealed that only 7 patients were controlled at randomization, whereas 35 were partially and 58 were uncontrolled according to GINA. Conclusion:Despite protective therapy with inhaled corticosteroids (ICS), most children of this severe asthma cohort were only partially or uncontrolled according to GINA guidelines.

House dust mites (HDM) are the world’s most important cause of allergic asthma. It is unclear why some patients with HDM allergy develop an early asthmatic reaction (EAR) only, whereas others react with a dual asthmatic reaction—EAR plus late asthmatic reaction (LAR). In patients with LAR, the symptoms and bronchial inflammation are more severe, and the current knowledge suggests that the EAR always precedes the LAR. The aim of the present study was to investigate whether a LAR can occur separately even without a significant EAR. In a pilot study of 20 patients with asthma and HDM allergy, a bronchial allergen challenge (BAC) was performed on three separate occasions with a tapered allergen dose. Before and 24 h later, exhaled NO (eNO), eosinophils and miRNAs were measured as markers of bronchial inflammation. Compared to BAC1, at BAC2 there was a significant decrease in the EAR from mean 39.25 ± 13.37% to mean 33.55 ± 5.25% (p < 0.01), whereas the LAR remained unchanged: mean 28.10 ± 10.95% to mean 30.31 ± 7.77% (n.s.). At BAC3, both the EAR and the LAR were significantly attenuated compared to the first and second BAC. In 3 (15%) patients, even the tapered allergen dose induced a dual asthmatic reaction. In 10 (50%) patients, the allergen dose was too low to trigger a significant EAR and LAR. In 7 (35%) patients, there was no EAR, but a significant LAR (mean max fall FEV1 20.5 + 4.7%) recorded. Significant correlations (p < 0.05) were found between distinct miRNAs (miR-15a-5p, miR-15b-5p and miR-374a-p5), eNO, and the decline in lung function and the presence of a LAR (p < 0.01). We can demonstrate that a LAR is induced in some patients without an EAR to low allergen exposure. This leads to a strong inflammatory reaction with an increase in eNO and a decrease in FEV1 and distinct miRNAs. Accordingly, these individuals are at greater risk of asthmatic symptoms and remodeling with loss of lung function than patients who do not have a LAR.

ABSTRACT Background PQ Grass 27600 SU (PQ Grass) cumulative dose is a pre‐seasonal, six‐injection, aluminium‐free, modified subcutaneous immunotherapy product under development for the treatment of allergic rhinitis (AR). A pivotal Phase III randomised double‐blind, placebo‐controlled clinical trial was performed to evaluate the efficacy and safety of PQ Grass in subjects with seasonal AR. Methods An adaptive group sequential trial PQGrass306 (G306) with one pre‐defined interim analysis was designed, using 2 parallel groups applying a 1:1 active versus placebo randomisation of patients aged 18–65. The primary efficacy endpoint was the EAACI (European Academy of Allergy and Clinical Immunology) Combined Symptom and Medication Score (EAACI‐CSMS 0–6 ) averaged over the peak grass pollen season (GPS). Results 858 subjects were screened and 555 subjects were randomised. Based on the results of the pre‐defined interim analysis, the trial was stopped for success showing superiority in favour of PQ Grass. The primary endpoint EAACI‐CSMS 0–6 (peak GPS) demonstrated a highly significant and clinically meaningful point difference of PQ Grass over placebo of −0.27 points (95% CI: −0.42 to −0.12), corresponding to a relative difference of −20.3% ( p = 0.0005). Highly consistent and beneficial results were obtained for PQ Grass for all key secondary endpoints. Significant induction of blocking IgG4 and IgA antibody subclasses occurred. PQ Grass was well tolerated, and no unexpected safety signals occurred. Conclusions This pivotal Phase III trial demonstrated a significant and clinically meaningful effect on the primary endpoint as well as highly consistent secondary endpoint results and a supportive safety profile.