BACKGROUND:Berotralstat is a first-line once-daily oral prophylactic treatment for hereditary angioedema (HAE). Berolife was designed to evaluate the tolerability and effectiveness of berotralstat in real-world conditions. METHODS:Berolife is an open-label, multicenter, observational study conducted in France from September 2021 to January 2024. The primary objective was to assess tolerability, and secondary objectives included characterization of the treated population and assessment of berotralstat effectiveness. HAE attack rate was assessed before and after initiation of berotralstat using the paired Wilcoxon rank-sum test. RESULTS:Altogether, 80 patients were enrolled in the study (75 with HAE-C1INH type 1 or 2 and 5 with HAE-nC1INH) and received at least one dose of berotralstat. At baseline, patients had a mean (standard deviation [SD]) age of 40.0 (17.5) years, and most (67.5%) had received prior long-term prophylaxis treatment. The mean (SD) duration of berotralstat treatment was 11.5 (8.5) months. Treatment-related adverse events (AEs) occurred in 45.0% of patients, with gastrointestinal disorders being the most common (diarrhea: 13.8%, abdominal pain: 12.5%, upper abdominal pain: 7.5%). Importantly, no treatment-related serious AEs were reported. A total of 61 patients were treated with berotralstat for ≥ 6 months and evaluated for effectiveness. At 6 months of treatment, a significant reduction in monthly HAE attack rates was observed (mean [SD]: 0.62 [0.66] vs. mean [SD]: 1.25 [1.10] at baseline; p = 0.001). CONCLUSIONS:Berotralstat was generally well tolerated with a tolerability profile consistent with prior clinical trials. Significant reductions in monthly HAE attack rates were observed, confirming its effectiveness in real-world settings.
Drug hypersensitivity reactions (DHRs) are a global health concern and remain challenging to investigate owing to the heterogeneity of endotypes and phenotypes, as well as the lack of standardized biomarkers. Until recently, strict drug avoidance was the only management strategy for severe DHRs. However, the development of novel therapeutic options, including biologics and drug desensitization protocols, has shown promising results, particularly when no alternatives exist. In parallel, the search for reliable biomarkers for diagnosis and monitoring immunomodulatory strategies is essential to improve patient care. Advances in the algorithms and digital tools also offer opportunities for enhanced risk stratification and more efficient delabeling of patients who may be incorrectly classified as allergic. In this review, we summarize recent advances in the classification of DHRs, discuss current and emerging immunomodulatory strategies for their management, and highlight relevant biomarkers, emphasizing the need to integrate them into clinical practice.
ABSTRACT Background Airway allergies affect 20%–30% of the global population, with pollen and fungal spores representing major environmental triggers. Although fungal spores are far more abundant than pollen, their allergenic role—particularly from phytopathogenic rust fungi such as birch rust (BR)—remains poorly understood. In Northern Norway, where seasonal dispersal of BR spores occurs with minimal overlap from other aeroallergen exposures, we investigated their potential contribution to autumnal airway symptoms by linking spore distribution with clinical outcomes. Methods In this prospective study, 160 patients and 94 controls were followed during BR season (Aug‐Oct) and out of season (Jan‐Feb). Participants reported allergic rhinitis, conjunctivitis, and/or asthma. Symptom scores (Visual Analogue Scale), nasal airflow (Peak Nasal Inspiratory Flow), and lung function (spirometry) were recorded, alongside daily BR spore counts from three monitoring sites. Results During BR season, patients showed significantly higher symptom severity (VAS difference 1.58, p < 0.01) and lower PNIF values (−12.2 L/min, p = 0.01) versus controls. Seasonal increases in symptoms were observed (1.70, p < 0.001), and anti‐allergic medication use was more frequent in patients (62.5% of patients vs. 1.1% of controls ( p < 0.001). Symptom worsening was associated with reported proximity to birch forests (regression coefficient 0.46, p < 0.01, R 2 = 0.48). Conclusions BR spore exposure was associated with increased autumnal airway symptoms, suggesting that BR may represent an underrecognized trigger. These findings highlight the need for further research, including allergen‐specific testing and dispersal modelling, to clarify their clinical relevance. Trial Registration This study is registered at ClinicalTrials.gov (identifier: NCT05661812)
BACKGROUND:Dupilumab is effective for moderate-to-severe atopic dermatitis (AD), but sustained disease control after treatment discontinuation remains challenging. House dust mite allergen immunotherapy (HDM-AIT) may provide disease-modifying effects in sensitized patients, but the added value of combining HDM-AIT with dupilumab remains unclear. OBJECTIVE:To evaluate the efficacy and safety of dupilumab combined with HDM-AIT versus dupilumab monotherapy in patients with AD. METHODS:PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to April 21, 2026. Randomized controlled trials and comparative observational studies evaluating dupilumab plus HDM-AIT versus dupilumab alone were included. Disease severity assessed by EASI or SCORAD was pooled using standardized mean differences (SMDs), Dermatology Life Quality Index (DLQI) using mean differences, and adverse events using risk ratios. Random-effects models were applied. The certainty of evidence was assessed using the GRADE approach. RESULTS:Four studies involving 138 patients were included, comprising one randomized controlled trial and three comparative observational studies. Combination therapy showed no significant improvement in disease severity at 6 months (SMD = -0.02, 95% CI -0.41 to 0.36; I2 = 0%) or 12 months (SMD = 0.53, 95% CI -1.10 to 2.16; I2 = 93%). At 18 months, the pooled estimate suggested a possible benefit of combination therapy for disease severity, although the certainty of evidence was very low (SMD = -0.96, 95% CI -1.76 to -0.17; I2 = 61%), although evidence was limited. At the follow-up closest to 30 months, the effect favored combination therapy but was not significant (SMD = -1.16, 95% CI -2.56 to 0.24; I2 = 87%). No significant differences were observed in DLQI, overall adverse events, or ocular adverse events. CONCLUSION:Current evidence regarding dupilumab combined with HDM-AIT for AD remains limited and inconclusive. Although an exploratory signal of improved disease severity was observed at 18 months, the available data did not demonstrate a statistically significant difference in adverse events, and the certainty of evidence was very low for all evaluated outcomes. Further adequately powered randomized controlled trials with standardized protocols, outcome definitions, and long-term follow-up are needed.
BACKGROUND:Lanadelumab has been approved for hereditary angioedema (HAE) long-term prophylaxis since 2018. The Phase 4, prospective ENABLE Study (NCT04130191) evaluated the long-term effectiveness and safety of lanadelumab in clinical practice across Europe and the Middle East. METHODS:Patients with HAE aged ≥ 12 years initiating lanadelumab treatment (300 mg every 2 weeks) per approved product labeling were recruited from Austria, Germany, Israel, Italy, Kuwait, Spain, and Switzerland and followed for up to 36 months (± 30 days). The primary objective was to evaluate lanadelumab effectiveness for HAE attack prevention. Safety and patient-reported health-related quality of life (HRQoL) were also evaluated. RESULTS:Outcomes were analyzed in 138 patients (mean [range] age: 41.0 [14-79] years; 62.3% female; 92.0% HAE-C1INH-Type1), of whom > 60% extended dosing intervals by Month 12. Over a mean ± SD treatment duration of 28.6 ± 9.8 months, mean ± SD patient-reported HAE attack rate decreased from 3.88 ± 3.43 attacks/month pre-lanadelumab to 0.30 ± 0.53 attacks/month (mean decrease, 84% [median 96%]). The incidence-rate ratio was 0.07 (95% CI: 0.06-0.10), reflecting a 93% reduction from modeled pre-lanadelumab rates. Overall, 95/138 patients reported treatment-emergent adverse events (TEAEs); most were unrelated to lanadelumab (82.3%). Of the 17.7% of TEAEs considered treatment-related, injection-site reactions, headache, fatigue, and asthenia occurred in > 1 patient. Before lanadelumab initiation, most patients reported moderate-to-large HRQoL impairments; clinically meaningful improvements were observed 1 month after lanadelumab initiation and sustained throughout the study. CONCLUSIONS:Real-world data from ENABLE demonstrated long-term effectiveness of lanadelumab in patients with HAE aged ≥ 12 years and a safety profile consistent with previous clinical studies.
NSAID-exacerbated respiratory disease (N-ERD) is a chronic inflammatory disorder characterized by asthma, chronic rhinosinusitis with nasal polyps and respiratory reactions to cyclooxygenase-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAID). Its pathogenesis involves dysregulated arachidonic acid metabolism, epithelial barrier dysfunction and activation of multiple immune cell types, including eosinophils, mast cells, macrophages, basophils, and innate lymphoid cells. Recent genomic and transcriptomic analyses have revealed variants in genes linked to epithelial integrity and cellular interactions, metabolic and epigenetic reprogramming of monocyte-derived macrophages that promotes persistent proinflammatory activity. Emerging biomarkers, such as 15-oxo-eicosatetraenoic acid (15-oxo-ETE), acylcarnitines, apolipoprotein E, oncostatin M, surfactant protein D, retinoic acid and glial cell line-derived neurotrophic factor provide novel mechanistic insights. A recently proposed Aspirin Hypersensitivity Diagnostic Index, integrating urinary leukotriene E4 (LTE4) and 15-oxo-ETE with sinus computed tomography (CT) scoring, may offer a practical noninvasive diagnostic tool. Inflammatory endotyping highlights substantial heterogeneity in N-ERD, encompassing T2-dominant, T1-, T3-related and neutrophilic inflammatory patterns, which may coexist or vary across airway compartments and influence clinical presentation and treatment response. As therapeutic strategies evolve, biologic agents targeting T2 pathways are becoming increasingly central, while aspirin therapy after desensitization may be reserved for selected patients. This review aims to summarize current mechanistic insights into the immune, epithelial, and lipid pathways involved in N-ERD, with a particular focus on emerging biomarkers and inflammatory endotypes relevant to diagnosis and personalized therapy.
ABSTRACT Background Allergic rhinitis, conjunctivitis and asthma are prevalent IgE‐mediated respiratory diseases that frequently coexist and impair quality of life. Allergen immunotherapy (AIT) has clinical benefits and potential disease‐modifying effects. Until recently, standardised definitions of disease control and remission were lacking in routine clinical practice, particularly for allergic rhinitis and conjunctivitis. This study aimed to propose preliminary definitions of control and remission in patients receiving AIT and to assess expert consensus using the Delphi methodology. Methods A scientific committee developed a survey based on a literature review and expert input, addressing symptoms, medication use, quality of life, exacerbations and tools for objective and subjective assessment. Forty allergists participated in a two‐round Delphi study. Consensus was predefined as ≥ 70% agreement on a 9‐point Likert scale. Results Consensus was achieved for all items after two rounds. The panel agreed on proposed definitions of disease control and clinical remission for allergic rhinitis, conjunctivitis and asthma in the context of AIT, integrating symptom severity, medication use, validated questionnaires and objective measures. Conclusions This study presents preliminary expert‐consensus definitions of control and remission in allergic rhinitis, conjunctivitis and asthma in patients undergoing AIT. These definitions should not be interpreted as validated clinical criteria or endpoints. As a preliminary proposal, they aim to provide a structured approach for assessing treatment response in clinical practice by integrating symptom burden, medication use, patient‐reported outcomes and objective measures. They should be regarded as an initial conceptual step, and further prospective studies are needed to validate these criteria and confirm their relevance, feasibility and applicability.
ABSTRACT Background Up to 50% of patients with nonsteroidal anti‐inflammatory drug‐exacerbated respiratory disease (N‐ERD) exhibit a noneosinophilic airway inflammatory phenotype, with paucigranulocytic asthma being the most prevalent. The aim was to identify clusters within N‐ERD and aspirin‐tolerant asthma (ATA) controls with a paucigranulocytic asthma phenotype. Methods Two separate hierarchical cluster analyses were performed using 23 variables in 36 N‐ERD patients and 19 ATA controls. Variables included demographic, clinical, treatment‐related, and hematologic parameters; sputum cytology; sinus computed tomography findings; and eicosanoid levels in induced sputum supernatant (ISS) and urine. Results Two clusters were identified in each group: 1N‐ERD, 2N‐ERD, 1ATA, and 2ATA. Cluster 1N‐ERD patients had less severe asthma and required lower doses of inhaled corticosteroids (ICS) but showed higher blood eosinophil counts, Lund‐Mackay (LM) scores, and ISS leukotriene E4 (LTE4) levels than those in cluster 2N‐ERD. Cut‐off values defining a T2‐high paucigranulocytic asthma profile in N‐ERD included LM score ≥ 18, blood eosinophils ≥ 300 cells/mm3, and ISS LTE4 ≥ 30 pg/mL, with the LM score demonstrating the highest AUC at 0.8. Among ATA controls, cluster 1ATA had more severe asthma, higher ICS doses, more severe sinonasal disease, and increased ISS leukotriene D4 and LTE4 levels compared with cluster 2ATA. Conclusion Two clusters were identified among N‐ERD patients with a paucigranulocytic asthma phenotype. Cluster 1N‐ERD was characterized by milder asthma, more severe sinonasal disease, elevated blood eosinophil counts, and elevated ISS LTE4. This T2‐high‐like cluster may represent a subgroup requiring further evaluation for anti‐T2 biologic therapy targeting chronic rhinosinusitis with nasal polyps, although further validation is required.
ABSTRACT Background A variety of clinical signs and symptoms have been described in patients suspected of having mast cell activation syndrome (MCAS), however, symptom patterns and linked organ systems were not yet described. Methods This cross‐sectional online survey included adults with physician‐diagnosed self‐assessed or suspected MCAS between June and September 2021. Symptoms were collected as free‐text responses, and coded using the Medical Dictionary for Regulatory Activities (MedDRA). These data were then analyzed using an unsupervised machine learning approach to identify distinct participant clusters. Patient‐reported outcome measures (PROMs), including the PHQ‐2, GAD‐7, and SF‐36, were used to assess mental health symptoms and health‐related quality of life. Results A total of 592 patients (mean age 45 years, 90% female) reported 400 symptoms in 58 categories. The hierarchical clustering algorithm failed to identify distinct patient clusters. We identified 256 (43%) patients with signs and symptoms aligning with the diagnostic criteria for MCAS including the most prevalent symptoms. Overall, patients infrequently reported mast cell‐mediated skin symptoms, such as pruritus (13%), wheals (9%), flushing (7%), or angioedema (1%). We identified patients with comorbid signs of depression (39%), general anxiety (34%), and impaired quality of life (28%). Conclusion Patients with suspicion of MCAS exhibit highly heterogeneous symptoms, whereas almost 50% report symptoms corresponding to the first diagnostic criterion for MCAS. Because over a third of the patients were tested positive for other diseases, we recommend considering common and more treatable diagnoses when evaluating patients with suspected MCAS.
ABSTRACT Background As a surrogate for eosinophilic activation, eosinophil‐derived neurotoxin (EDN) is a potential clinical biomarker. However, EDN levels and discriminatory ability in different asthma phenotypes are unknown. We quantified serum and nasal lavage fluid (NLF) EDN levels and assessed the potential to differentiate clinically defined asthma phenotypes in an adult‐representative sample. Methods A total of 1499 serum and 386 NLF samples from individuals with current asthma obtained from the West Sweden Asthma Study were analyzed for EDN. Eosinophilic asthma was defined as blood eosinophil count of ≥ 300 cells/mm3, T2‐high asthma was defined as blood eosinophil count of ≥ 300 cells/mm3 or fractional exhaled nitric oxide (FeNO) levels of ≥ 25 ppb. Other asthma phenotypes were defined based on presence of atopy, chronic rhinosinusitis (CRS), nasal polyposis, and obesity. Results Subjects with eosinophilic asthma had higher serum and NLF EDN levels than those with non‐eosinophilic asthma. In ROC analyses, serum EDN provided excellent discrimination between eosinophilic and non‐eosinophilic asthma (area under curve [AUC] = 0.84, 95% CI = 0.82–0.86); the corresponding AUC for NLF EDN was 0.67 (95% CI = 0.62–0.73). Serum and NLF EDN were higher in atopic asthma, T2‐high asthma, and asthma with nasal polyposis compared to their counterparts, but not in asthma with CRS. The highest absolute values of serum and NLF EDN were observed in the high eosinophil + FeNO group, followed by the high‐eosinophil‐only and high‐FeNO‐only groups. Conclusion Both serum and NLF EDN were higher in those with eosinophilic compared to non‐eosinophilic asthma. However, only serum EDN appears to distinguish eosinophilic asthma in ROC analyses.
BACKGROUND:Multiple routes of allergen immunotherapy (AIT) are approved for several IgE-mediated allergic diseases; however, the use of AIT in eosinophilic esophagitis (EoE) remains controversial and is supported by limited evidence. This review, conducted within the frame of an EAACI Task Force, aims to systematically evaluate the use of AIT as a potential treatment for EoE. METHODS:The protocol was registered and prepared in accordance with PRISMA guidelines. The literature search was conducted across three online databases (PubMed, Embase, and Scopus) and included studies published through January 31st, 2025. Risk of Bias was assessed for each eligible study. RESULTS:Four articles met the inclusion criteria. Three articles evaluated EPIT for milk-induced EoE in pediatric patients, all from the SMILEE (Study of Efficacy and Safety of Viaskin Milk for milk-induced EoE) trial and its extensions. These included a randomized, placebo-controlled trial, its open-label extension, and a pilot immunological study. The SMILEE trial found no statistically significant difference in tissue eosinophilia between the active (EPIT) and control (placebo) arms in the intention-to-treat population, while 47% of treated EoE patients tolerated milk without recurrence of esophageal eosinophilia. This finding was further supported by a subsequent open-label study with a 2-year follow-up. In the third publication, the researchers found that EPIT was associated with decreased Th2-related transcripts and increased regulatory T-cell-associated transcripts. Only one eligible study evaluated the use of SCIT for treating EoE. It was a retrospective case-control study reporting that SCIT had a neutral effect and yielded inconclusive findings regarding the course of EoE. CONCLUSION:There is insufficient high-quality evidence to support the effectiveness of alternative routes of AIT for the treatment of EoE, either as an add-on or a standalone treatment.
ABSTRACT Background Allergic sensitisation is traditionally viewed as a stable trait despite studies suggesting that it may vary across life‐course. This study aims to provide longitudinal evidence of allergic sensitisation and its associated factors in the general population. Methods Aeroallergen sensitisation was assessed in the Austrian population‐based cohort using repeated skin prick testing (SPT) across 3 visits (mean visit interval, 4.25 ± 0.33 years). Longitudinal sensitisation patterns were characterised as stable nonsensitised, stable sensitised, new‐onset, resolution or fluctuating. We examined demographic, metabolic, behavioural, environmental and immunological factors across age strata (< 18, 18 ≤ 40, 40 ≤ and ≥ 60 years). Results Among 5046 individuals with follow‐up and valid SPT in all 3 visits, 54.4% remained stably nonsensitised and 30.6% stably sensitised, 5.6% experienced resolution, 4.8% new onset and 4.6% fluctuating sensitisation. New onset expectedly predominated in < 18 years, fluctuation in 18 ≤ 60 years and resolution in ≥ 60 years, indicating that sensitisation is modifiable and time‐varying. Stable sensitisation was strongly associated with parental allergy and blood eosinophils while cumulative smoking modestly reduced its likelihood. Fluctuation was linked to adiposity (in adults ≥ 40 years old) and environmental exposures. Aeroallergen‐specific analysis showed new‐onset sensitisation was driven by outdoor allergens (ragweed, tree pollens and pets) whereas fluctuation was driven by seasonal pollens. Conclusion Although predominantly stable, allergic sensitisation is dynamic and exhibits substantial temporal variation. Resolution and fluctuation occur across all ages and new sensitisation can emerge well into adulthood. These findings challenge the traditional view of fixed sensitisation and suggest it reflects a modifiable phenotype shaped by age and environmental and lifestyle exposures.
Atopic dermatitis (AD) is a complex chronic inflammatory skin disease driven by skin barrier dysfunction, immune dysregulation, and microbial imbalance. Traditional sampling methods, such as biopsies and blood collection, have provided valuable pathophysiological insights. However, their invasiveness, associated discomfort, and limitations for repeated sampling have constrained a dynamic understanding of disease progression and treatment responses. In recent years, skin tape stripping (STS) has emerged as a minimally invasive or even non-invasive technique that addresses these limitations. STS enables the collection of corneocytes and upper granular layer cells from the epidermis, and when combined with high-throughput multi-omics technologies, such as RNA sequencing, proteomics, lipidomics, and metatranscriptomics, it provides a powerful platform to dissect the molecular mechanisms of AD, identify novel biomarkers, and facilitate stratification in precision medicine approaches.
ABSTRACT Background In Western countries, Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is predominantly associated with a type 2 inflammatory endotype. While nasal secretion analysis shows promise for disease endotyping, current biomarkers remain limited for accurate stratification, disease monitoring, and prediction of treatment response. Objective This study aimed to investigate the inflammatory patterns in nasal secretions of patients with type 2 Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) undergoing treatment with dupilumab, an anti‐IL4Rα antibody. A second objective was to evaluate markers for therapy response and monitoring. Methods Nasal secretions and blood samples were collected at four time points from 23 patients with histological type 2 CRSwNP undergoing dupilumab treatment and compared with 10 healthy controls. Samples were analysed using proximity extension assay method by Olink. Results Proteomic analysis of nasal secretions revealed 50 differentially expressed proteins in type 2 CRSwNP compared to healthy controls. Nasal secretions of most patients revealed a mixed inflammatory endotype. Under dupilumab treatment, cytokines of all different endotypes decreased. The cytokines with the highest mean change (MCP‐4, CCL23, GDNF and CCL11) showed good associations with clinical variables and were effective predictors of dupilumab response and disease control. Conclusion The inflammatory environment of the nasal mucosa in histological type 2 CRSwNP is most often characterized by a mixed type 1, 2, and 3 inflammatory endotype. Targeting type 2 inflammation with dupilumab reduces inflammation markers of all three types of inflammation. GDNF has emerged as a valuable marker for stratifying therapy and monitoring success in type 2 CRSwNP under dupilumab treatment.
ABSTRACT Chronic rhinosinusitis (CRS) is a prevalent upper respiratory condition characterized by a multifaceted etiology involving various cellular and molecular processes. In recent years, researchers have increasingly recognized the significance of different forms of programmed cell death (PCD), such as apoptosis and pyroptosis, in the pathological mechanisms underlying CRS. Studies suggest that these PCD pathways not only influence the disease's progression but may also serve as novel therapeutic targets. Thus, gaining a thorough understanding of how PCD contributes to CRS is crucial for elucidating its pathogenesis and developing new treatment strategies. This article aims to investigate the mechanisms of PCD in CRS, examining its effects on disease progression and potential implications for treatment. We will begin by discussing the background of CRS and its underlying processes, followed by an exploration of the roles played by various types of PCD in CRS, and conclude with a discussion on future research directions and their practical applications.
BACKGROUND:Unverified antibiotic allergy labels lead to suboptimal antimicrobial prescribing and increased antibiotic resistance. Cephalosporins are among the most frequently administered antibiotics and cephalosporin allergy labels increasingly limit optimal therapy. Clinical decision rules that enable delabeling of low-risk patients by non-allergists are emerging as important tools. The PEN-FAST score is a validated rule for identifying low-risk penicillin allergy labels suitable for direct drug challenge. CEPH-FAST is a recently proposed adaptation for cephalosporin allergy. We evaluated the diagnostic performance of PEN-FAST and CEPH-FAST for cephalosporin allergy. METHODS:In this single-center retrospective cohort study, 100 adults with reported cephalosporin allergy labels underwent allergy assessment including skin testing and drug provocation testing at a tertiary allergy clinic in Heidelberg, Germany. Logistic regression was used to identify predictors of confirmed allergy. Diagnostic performance of PEN-FAST and CEPH-FAST scores was assessed using sensitivity, specificity, predictive values, and area under the receiver operating curve (AU-ROC). RESULTS:Cephalosporin allergy was confirmed in 48 of 100 patients. PEN-FAST categorized 20 patients at low risk, of whom one had a positive skin test (NPV 95.0%, sensitivity 97.9%, AU-ROC 0.769). CEPH-FAST classified 42 patients low-risk, but 12 had confirmed allergies (NPV 71.4%, sensitivity 75.0%, AU-ROC 0.667). Higher PEN-FAST and CEPH-FAST scores were significantly associated with confirmed allergy. CONCLUSION:PEN-FAST demonstrated high sensitivity and negative predictive value for identifying low-risk cephalosporin allergy and may support safe delabeling strategies. In contrast, CEPH-FAST showed reduced diagnostic performance in this cohort, highlighting the need for further validation before routine clinical implementation.
ABSTRACT Introduction Chronic rhinosinusitis (CRS) pathophysiology and its link to microbiome is an area of ongoing investigation. Certain pathogens, in particular Staphylococcus aureus described to contribute to recalcitrant CRS. In addition, different species of coagulase negative staphylococci (CoNS) are frequently isolated from the sinonasal cavity of CRS patients. However, the influence of Staphylococcal species coexisting in the same niche on the inflammatory process remains unclear. The aim of this study was to explore the impact of exoproteins from various Staphylococcus species isolated from the same patients on the mucosal barrier. Methods Staphylococcal species isolated from CRS and control patients were cultured from sinus swabs in planktonic and biofilm forms, and their exoproteins extracted. Primary human nasal epithelial cells (HNECs) from CRS patients were cultured at an air‐liquid interface (ALI) and exposed to 20 μg/mL exoproteins or control. Barrier disruption and cytotoxicity were assessed by measuring the transepithelial electrical resistance (TEER), passage of fluorescein labeled dextrans and lactate dehydrogenase (LDH) levels. IL‐ 6 concentration was measured employing ELISA. Patient's matched sinonasal tissue samples were analyzed with flow cytometry to detect and quantify immune cells. Results Forty‐four Staphylococcal species were isolated from 22 CRS and control patients including: 22 S. aureus, 12 S. epidermidis, and 10 S. lugdunensis. 15 out of 22 S. aureus exoproteins significantly enhanced cytotoxicity, reduced TEER values and increased paracellular permeability compared to control (p < 0.05). By contrast, S. epidermidis and S. lugdunensis exoproteins caused either mild or negligible effects on the TEER values, cell viability, and paracellular permeability. However, S. lugdunensis exoproteins induced significantly higher IL‐6 compared to control. Correlation analysis indicated S. aureus and S. lugdunensis from the same patient acted in concert to disrupt the nasal epithelial barrier and induce toxicity. Conclusion This study shows the significant and detrimental impact of the presence of S. aureus exoproteins on nasal epithelial cell barrier function. S. aureus and S. lugdunensis isolated from the same patients acted in concert to affect the nasal barrier and inducing toxicity.
ABSTRACT Background Hereditary Angioedema due to C1‐inhibitor deficiency (HAE‐C1INH) is a rare disease that affects individuals of all ages, however, older adults have never been characterized in terms of disease severity, comorbidities, and treatments. The aim was to identify the clinical characteristics of and therapeutic approaches in HAE‐C1INH patients aged 65 and older. Methods Data from the ITACA (Italian network for Hereditary and Acquired Angioedema) Registry were prospectively collected for 10‐month. Results Data from 647 HAE‐C1INH, patients including 343 females (53%), were collected: 114 patients (17.6%) were aged 65 and older (68 females; 58.6%). Group mean age was 74.3 ± 7.5 years, mean age at first‐symptom‐onset was 19 ± 15 years, and mean age at diagnosis was 45.6 ± 14.3 years. Common comorbidities were: hypertension (59.6%), dyslipidaemia (28.9%), coronary artery disease (14.0%), diabetes (14.0%), endocrinopathies (14.0%), neoplasia (12.3%) and B/C hepatitis (11.4%). Half of the older patients (49%) experienced at least one attack during the study period, and 8 patients (7%) had an attack frequency of > 0.5 attacks/month. Long‐term prophylaxis (LTP) was the treatment of choice in 45 patients (39.5%) and represented 15.9% of overall LTP prescriptions: 60% were treated with lanadelumab, 22.2% with attenuated androgens, 13.3% with berotralstat, and 4.5% with sub‐cutaneous C1INH concentrate. Gender differences were not detected in any of the variables analyzed. Conclusion Older patients with HAE‐C1INH constitute a relevant subgroup, characterized by persistent disease activity and comorbidities. The availability of new therapies and guideline recommendations are driving an increase in LTP use, although shifting from older non‐specific treatments, especially androgens, is still incomplete.
