Marcela Valverde-Monge

Background: Polygenic risk scores (PRS) capture inherited susceptibility to asthma, whereas methylation risk scores (MRS) may reflect disease-associated epigenetic variation. We assessed whether these scores differ in patients requiring biologic therapy and whether MRS change after mepolizumab initiation. Methods: Cross-sectional analyses in the GEMAS study included 699 participants with genotype data (428 with asthma, 271 controls) and 668 with blood DNA methylation data (408 with asthma, 260 controls). We evaluated 35 existing asthma PRS and derived six MRS from published epigenomic asthma studies. Longitudinal MRS changes after mepolizumab initiation were assessed in 16 GEMAS patients and were replicated in 20 patients from the MEGA study. Results: Twenty-eight PRS differentiated biologic-treated patients from controls (areas under the curve [AUC], 0.68-0.75), but none distinguished biologic-treated and non-treated patients after multiple-testing correction. MRS was higher in asthma without biologic than in controls (odds ratio [OR], 1.64; 95% CI, 1.34-1.99) and lower in biologic-treated than in asthma without biologic patients (OR, 0.54; 95% CI, 0.35-0.81). MRS did not differ significantly between biologic-treated patients and controls. Following mepolizumab initiation, MRS decreased at 6 and 12 months in GEMAS ( p =4.81×10 ⁻⁵ and p =2.40×10 ⁻⁵ , respectively). The 6-month decrease was also observed in MEGA ( p =3.25×10 ⁻⁹ ). MRS epigenetic markers were predominantly hypermethylated, opposite to their described pattern in asthma risk. Conclusions: Asthma PRS did not differ significantly between biologic-treated and non-biologic-treated patients, but asthma MRS were lower in biologic-treated patients. The MRS decreased after mepolizumab initiation in two independent cohorts, consistent with a reversal of asthma-associated epigenetic patterns.

Background: Accurate inflammatory phenotyping in asthma remains challenging. Nasal cytology has emerged as a potential non-invasive tool to assess airway inflammation in asthma. However, its relationship with lower airway inflammation and systemic biomarkers remains unclear, particularly in severe asthma (SA). Objective: To evaluate whether a multi-compartment approach could improve the characterisation of type 2 inflammation and the relationship between nasal cytology, induced sputum, and systemic inflammatory biomarkers in patients with severe asthma. Methods: In this cross-sectional exploratory BRISA study, twenty-two patients with SA underwent nasal cytology by mucosal scraping, induced sputum analysis, and serum biomarker assessment (periostin, eosinophil cationic protein, thymic stromal lymphopoietin, dipeptidyl peptidase-4, and total IgE). Patients were stratified according to blood eosinophil count (BEC < 300 vs ≥ 300 cells/μL). Correlations between compartments and associations with clinical and inflammatory variables were analysed. Results: Higher blood eosinophil counts were associated with worse lung function, increased exacerbations, and higher serum periostin levels. Valid induced sputum samples were obtained in 16 patients: 7 eosinophilic, 3 neutrophilic, 2 mixed eosinophilic-neutrophilic and 4 paucigranulocytic. Nasal cytology predominantly showed limited agreement with induced sputum inflammatory phenotypes. Serum TSLP, DPP4, and IgE also showed an upward trend in patients with higher blood eosinophil counts, although these differences were not statistically significant. Correlation analysis demonstrated a significant positive association between sputum and blood eosinophils, as well as between blood eosinophils and serum periostin. A strong positive correlation was also observed between serum eotaxin and TSLP. Conclusion: Nasal cytology alone cannot replace induced sputum for inflammatory phenotyping in SA, although it may provide complementary information on upper airway inflammation. Among the evaluated systemic biomarkers, periostin emerged as the most consistent marker associated with blood eosinophilia, while other biomarkers showed only non-significant trends. Further studies are needed to validate the role of combined biomarkers in predicting airway inflammation.

Background: Anaphylaxis is an acute life-threatening reaction. Research into the vascular endothelium and its components may improve disease management and patient outcomes. Objective: We investigated the endothelial glycocalyx (eGCX) and its pathophysiological role in murine anaphylaxis, aiming to identify novel diagnostic and therapeutic targets. Methods: Active systemic anaphylaxis (ASA) and passive systemic anaphylaxis (IgE-PSA and IgG1-PSA) models were evaluated in mice. Sulodexide (Sdx) was administered as a prophylactic treatment. eGCX structure and N-acetylglucosamine residues in mouse aortic tissue were analyzed by electron microscopy and wheat germ agglutinin (WGA) staining. Endocan (ESM-1) levels in mouse aorta and plasma were determined by immunofluorescence and ELISA. Human sera from beta-lactam-induced anaphylaxis and endothelial cell (EC) secretome samples were also analyzed. Results: ASA, IgE-PSA, and IgG1-PSA models showed reduced eGCX surface area and thickness. N-acetylglucosamine and ESM-1 levels decreased in aortic tissue but increased in plasma, indicating glycocalyx shedding. Consistently, ESM-1 secretion was enhanced in ECs exposed to acute anaphylactic sera. ESM-1 and hyaluronic acid levels differed significantly between anaphylactic patients and non-allergic controls. Sdx reduced reaction severity in ASA and IgE-PSA, increased survival in ASA, and prevented eGCX disruption and ESM-1 release. Conclusions: eGCX shedding, particularly of ESM-1, acts as a key mediator in murine anaphylaxis. Sdx prophylaxis protects against severe reactions and improves survival. Clinical Implication: Therapies based on glycosaminoglycans and proteoglycans may mitigate anaphylaxis severity, and monitoring eGCX dynamics could aid diagnosis. Capsule summary: Endothelial glycocalyx shedding contributes to anaphylaxis pathophysiology; targeting its preservation and measuring HA and ESM1 may offer novel diagnostic and therapeutic strategies for clinicians.

Introduction: Work‐related exposures contribute to one in six new‐onset adult asthma cases and exacerbation of one in five existing cases, which together are termed ‘work‐related asthma’ (WRA). A valid and standardized WRA questionnaire is needed for workplace surveillance and epidemiological studies. This project aimed to review evidence on WRA questionnaires and algorithms to propose a standardized instrument. Methods: A scoping review was conducted using PubMed, Embase, and Cochrane databases up to March 2021. Search terms focused on asthma, occupational diseases, questionnaires, surveys, and algorithms. High‐quality studies were identified and data extracted on instrument construction, validation, and performance. Common questions were used to develop a questionnaire and algorithm for detecting suspected WRA. Results: Six studies were included. The final WRA questionnaire consists of eight questions on general asthma symptoms, diagnosis, and medication; four on WRA symptoms; and two on work‐related ocular‐nasal symptoms. The algorithm calculates a WRA total score (WRATS) based on the general asthma and work‐related symptoms. A score of ≥ 1 triggers a referral for further evaluation. Conclusion: This is the first WRA questionnaire based on validated questionnaires. Evaluation of its performance and validation in diverse geographic and occupational settings are needed for further refinement and translation for broader applications.

Asthma is a chronic and heterogeneous inflammatory airway disease with diverse clinical endotypes and limited curative treatment options. Recent systems biology analyses identified four potential molecular triggers—AKT1, MAPK13, STAT1, and TLR4—as candidate regulators of asthma-associated signaling pathways. This study aimed to validate the expression of these four proteins and their downstream signaling elements in peripheral blood mononuclear cells (PBMCs) from patients with allergic asthma (AA), nonallergic asthma (NA), and healthy controls (HC), to explore their potential as biomarkers or therapeutic targets. For that, PBMC samples were collected from 45 AA patients, 17 NA patients, and 15 HC subjects. Gene and protein expression of AKT1, MAPK13, STAT1, and TLR4 were quantified using RT-qPCR and Western blotting. Expression patterns were compared across groups and stratified by asthma severity. Correlations with clinical parameters (FEV1, FVC, FeNO, IgE, eosinophil counts) and treatment regimens were also assessed. All four target genes showed significantly reduced expression in asthma patients compared to controls (p < 0.001), with the most marked downregulation in NA patients. At the protein level, MAPK13 and TLR4 showed significant differential expression. Stratification by severity revealed a stepwise reduction in gene expression in AA patients, correlating with disease severity, whereas NA patients showed uniformly low expression regardless of severity. Multiple pathway-related genes, including RELA, SMAD3, NFATC1, and ALOX5, were also downregulated, particularly in NA patients. Notably, differential correlations were observed between gene expression and lung function parameters in AA vs. NA groups. In conclusion, this study supports the potential involvement of AKT1, MAPK13, STAT1, and TLR4 in asthma pathogenesis and highlights differences between allergic and nonallergic asthma at the molecular level. These proteins and their associated pathways may serve as future targets for biomarker development or endotype-specific therapies. Further studies in larger and more diverse cohorts, including functional validation, are warranted.

(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/μL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/μL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.

We present the case of a patient with failed desensitisation to paclitaxel that was ultimately successful with omalizumab treatment. Our patient, a female aged between 20–25 and diagnosed with a triple negative breast cancer, received first-line treatment with carboplatin and paclitaxel. During the second cycle of paclitaxel, she experienced heat, dyspnoea, facial angioedema and vomiting. Skin tests for allergic reactions returned negative results, and drug provocation tests showed a positive result (anaphylaxis). Rapid drug desensitisation (RDD) was carried out with two bags of dilutions but at the beginning of the infusion, the patient experienced symptoms again, so the infusion was stopped. Therefore, the use of omalizumab, already reported as a successful adjuvant in desensitisation to other drugs, was considered. The anti-immunoglobulin E (IgE) monoclonal antibody was administered off-label before the first programmed desensitisation with success: total dose of paclitaxel was infused without any reaction. The patient was able to receive the complete chemotherapy treatment.