Pub Date : 2025-11-01DOI: 10.1016/j.waojou.2025.101136
Lili Voloncs-Mindszenthy MD , Hanga Réka Horváth MD , Noémi Andrási MD , Tamás Szilágyi MD , Henriette Farkas MD, PhD, DSc
Background
Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is characterized by sudden subcutaneous and/or submucosal angioedema attacks. C1 inhibitor is a serine protease inhibitor that regulates several enzyme cascade systems. The absence of this control raises concerns about the potential development of comorbidities.
Objective
We aimed to investigate the comorbidities present in the Hungarian HAE-C1INH patient population and to examine the surgical procedures performed on these patients. Additionally, we sought to compare our results to those of the Hungarian general population.
Methods
Demographical, clinical, laboratory, and radiographic data of all 178 adult HAE-C1INH patients followed up at the Hungarian Angioedema Center of Reference and Excellence were used to examine comorbidities and surgical procedures. Information about the general Hungarian population was extracted from national and European statistical databases and individual articles.
Results
At least 1 comorbidity was present in 159 of our patients. From the observed 51 diseases, headache (58%), hypercholesterolemia (52%), hypertension (30%), and liver diseases (26%) were the most prevalent. Hypercholesterolemia and depression/anxiety were at least 3 times more common in the HAE-C1INH population as compared to the Hungarian general population. Tonsillectomy was performed 32, appendectomy 11, and inguinal hernioplasty 2 times more often before the diagnosis of HAE-C1INH was established. Every surgical procedure was more prevalent in the HAE-C1INH population.
Conclusion
Regular, targeted screening is indispensable for the prevention and timely diagnosis of certain diseases found in higher prevalence in the HAE-C1INH population. The early identification and adequate treatment of angioedema attacks help prevent avoidable surgical interventions.
{"title":"Hereditary angioedema: A national investigation of associated comorbidities and surgical procedures","authors":"Lili Voloncs-Mindszenthy MD , Hanga Réka Horváth MD , Noémi Andrási MD , Tamás Szilágyi MD , Henriette Farkas MD, PhD, DSc","doi":"10.1016/j.waojou.2025.101136","DOIUrl":"10.1016/j.waojou.2025.101136","url":null,"abstract":"<div><h3>Background</h3><div>Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is characterized by sudden subcutaneous and/or submucosal angioedema attacks. C1 inhibitor is a serine protease inhibitor that regulates several enzyme cascade systems. The absence of this control raises concerns about the potential development of comorbidities.</div></div><div><h3>Objective</h3><div>We aimed to investigate the comorbidities present in the Hungarian HAE-C1INH patient population and to examine the surgical procedures performed on these patients. Additionally, we sought to compare our results to those of the Hungarian general population.</div></div><div><h3>Methods</h3><div>Demographical, clinical, laboratory, and radiographic data of all 178 adult HAE-C1INH patients followed up at the Hungarian Angioedema Center of Reference and Excellence were used to examine comorbidities and surgical procedures. Information about the general Hungarian population was extracted from national and European statistical databases and individual articles.</div></div><div><h3>Results</h3><div>At least 1 comorbidity was present in 159 of our patients. From the observed 51 diseases, headache (58%), hypercholesterolemia (52%), hypertension (30%), and liver diseases (26%) were the most prevalent. Hypercholesterolemia and depression/anxiety were at least 3 times more common in the HAE-C1INH population as compared to the Hungarian general population. Tonsillectomy was performed 32, appendectomy 11, and inguinal hernioplasty 2 times more often before the diagnosis of HAE-C1INH was established. Every surgical procedure was more prevalent in the HAE-C1INH population.</div></div><div><h3>Conclusion</h3><div>Regular, targeted screening is indispensable for the prevention and timely diagnosis of certain diseases found in higher prevalence in the HAE-C1INH population. The early identification and adequate treatment of angioedema attacks help prevent avoidable surgical interventions.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101136"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.waojou.2025.101135
Daniel K. Lee BA , Arije Ghannam MD, PhD , Nivetha Murugesan PhD , Denis Vincent MD , Micaela Dona MD , Danny M. Cohn MD , Adil Adatia MD , Michael D. Smith PharmD , Paul K. Audhya MD , Sally L. Hampton BSc , Edward P. Feener PhD
Introduction
Plasma kallikrein (PKa) activity is increased in the plasma of patients with hereditary angioedema (HAE) and has been implicated in other kallikrein-kinin system (KKS)–mediated diseases. Exogenous substrates commonly used in PKa assays can be cleaved by multiple plasma proteases, which reduce assay specificity and sensitivity for PKa. We describe a sensitive and specific assay to detect PKa activity in plasma as a candidate biomarker for HAE.
Methods
PKa activity was measured in plasma samples from patients with HAE with decreased C1 inhibitor (C1INH) levels or activity who were not receiving prophylactic medications for HAE (HAE-C1INH; n = 25), from individuals with a presumptive diagnosis of HAE with normal C1INH (HAE-nC1INH; n = 3), and from age-matched controls without HAE (n = 57). Samples were analyzed at baseline and after 6 h of cold incubation at 4 °C. Amidolytic activity was measured in the absence and presence of a PKa-specific inhibitor (KV999272). Specific PKa (sPKa) activity was quantified by the subtraction of amidolytic activity not inhibited by KV999272 from the total measured amidolytic activity.
Results
In control plasma, sPKa activity was 0.69 ± 0.07 nmol/min/mL at baseline and 0.88 ± 0.11 nmol/min/mL after 6 h of cold incubation (mean ± SEM, p = 0.0062); the 95th percentile of sPKa activity was 1.87 nmol/min/mL at baseline and 3.07 nmol/min/mL after cold incubation. In plasma from patients with HAE-C1INH, sPKa activity was 3.43 ± 0.64 nmol/min/mL at baseline and 24.53 ± 8.92 nmol/min/mL after 6 h of cold incubation (p = 0.023). sPKa activity in HAE-C1INH plasma samples was above the 95th percentile for control plasma with assay sensitivity of 84% and specificity of 95%. The area under the receiver operating characteristic curve was 0.98 (p < 0.0001). sPKa activity in all plasma samples from patients with HAE-nC1INH was above the 95th percentile for control plasma after 6 h of cold incubation.
Conclusion
We developed a specific PKa assay that can detect low levels of PKa activity in plasma and can differentiate patients with HAE-C1INH from controls without HAE with high sensitivity and specificity. Using this assay, we demonstrated that sPKa activity is elevated during the intercritical period in patients with HAE-C1INH and in those with HAE-nC1INH compared with controls when measured after 6 h of cold incubation. This sensitive and specific PKa assay could be useful to characterize PKa activity in plasma samples from patients with HAE and could potentially serve as a future candidate biomarker for HAE-nC1INH.
{"title":"A sensitive and specific assay to characterize plasma kallikrein activity in plasma from patients with hereditary angioedema","authors":"Daniel K. Lee BA , Arije Ghannam MD, PhD , Nivetha Murugesan PhD , Denis Vincent MD , Micaela Dona MD , Danny M. Cohn MD , Adil Adatia MD , Michael D. Smith PharmD , Paul K. Audhya MD , Sally L. Hampton BSc , Edward P. Feener PhD","doi":"10.1016/j.waojou.2025.101135","DOIUrl":"10.1016/j.waojou.2025.101135","url":null,"abstract":"<div><h3>Introduction</h3><div>Plasma kallikrein (PKa) activity is increased in the plasma of patients with hereditary angioedema (HAE) and has been implicated in other kallikrein-kinin system (KKS)–mediated diseases. Exogenous substrates commonly used in PKa assays can be cleaved by multiple plasma proteases, which reduce assay specificity and sensitivity for PKa. We describe a sensitive and specific assay to detect PKa activity in plasma as a candidate biomarker for HAE.</div></div><div><h3>Methods</h3><div>PKa activity was measured in plasma samples from patients with HAE with decreased C1 inhibitor (C1INH) levels or activity who were not receiving prophylactic medications for HAE (HAE-C1INH; <em>n</em> = 25), from individuals with a presumptive diagnosis of HAE with normal C1INH (HAE-nC1INH; <em>n</em> = 3), and from age-matched controls without HAE (<em>n</em> = 57). Samples were analyzed at baseline and after 6 h of cold incubation at 4 °C. Amidolytic activity was measured in the absence and presence of a PKa-specific inhibitor (KV999272). Specific PKa (sPKa) activity was quantified by the subtraction of amidolytic activity not inhibited by KV999272 from the total measured amidolytic activity.</div></div><div><h3>Results</h3><div>In control plasma, sPKa activity was 0.69 ± 0.07 nmol/min/mL at baseline and 0.88 ± 0.11 nmol/min/mL after 6 h of cold incubation (mean ± SEM, <em>p</em> = 0.0062); the 95th percentile of sPKa activity was 1.87 nmol/min/mL at baseline and 3.07 nmol/min/mL after cold incubation. In plasma from patients with HAE-C1INH, sPKa activity was 3.43 ± 0.64 nmol/min/mL at baseline and 24.53 ± 8.92 nmol/min/mL after 6 h of cold incubation (<em>p</em> = 0.023). sPKa activity in HAE-C1INH plasma samples was above the 95th percentile for control plasma with assay sensitivity of 84% and specificity of 95%. The area under the receiver operating characteristic curve was 0.98 (<em>p</em> < 0.0001). sPKa activity in all plasma samples from patients with HAE-nC1INH was above the 95th percentile for control plasma after 6 h of cold incubation.</div></div><div><h3>Conclusion</h3><div>We developed a specific PKa assay that can detect low levels of PKa activity in plasma and can differentiate patients with HAE-C1INH from controls without HAE with high sensitivity and specificity. Using this assay, we demonstrated that sPKa activity is elevated during the intercritical period in patients with HAE-C1INH and in those with HAE-nC1INH compared with controls when measured after 6 h of cold incubation. This sensitive and specific PKa assay could be useful to characterize PKa activity in plasma samples from patients with HAE and could potentially serve as a future candidate biomarker for HAE-nC1INH.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101135"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comment on “Characterization of a major house dust mite allergen Der p 22 among Malaysian adult population”","authors":"Patpicha Arunsan PhD , Schawanya K. Rattanapitoon MD , Chutharat Thanchonnang BSc, PhD , Nathkapach K. Rattanapitoon BSc(PH), BSc(OSH), MSc, PhD","doi":"10.1016/j.waojou.2025.101137","DOIUrl":"10.1016/j.waojou.2025.101137","url":null,"abstract":"","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101137"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Response to comments on “Effectiveness of transitioning from omalizumab to dupilumab in chronic spontaneous urticaria patients with inadequate response to omalizumab”","authors":"Koremasa Hayama MD, PhD, Mana Ito-Watanabe MD, PhD, Hideki Fujita MD, PhD","doi":"10.1016/j.waojou.2025.101142","DOIUrl":"10.1016/j.waojou.2025.101142","url":null,"abstract":"","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101142"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.waojou.2025.101123
Stefania Arasi MD, MSc, PhD , Mário Morais-Almeida MD , Bryan L. Martin DO , Gary Wing-Kin Wong MD , Ignacio J. Ansotegui MD, PhD , Motohiro Ebisawa MD, PhD , Adnan Custovic MD, MSc, PhD , Alexandra Santos MD, MSc, PhD , Anna Nowak-Wegrzyn MD , Andrew Stoddart MSc , Antoine Deschildre MD, PhD , Antonella Cianferoni MD, PhD , Antonella Muraro MD, PhD , Audrey DunnGalvin PhD, MSc, HDp, Reg.Psychol. , Brian Vickery MD , Carina Venter PhD, RD , Carla Jones , Carmen Mazzuca MD , Christopher Warren PhD , Daniel Munblit MD, PhD , Lamia Dahdah MD
Background
Data on severity of food allergy across nations are lacking. Building on the World Allergy Organization (WAO) DEFASE (Definition of Food Allergy Severity) score, we aim to explore its global applicability as a grading system for IgE-mediated food allergy (FA) severity.
Methods
An international survey (WAO FASE Project) was conducted using an online questionnaire distributed to WAO members. The survey collected detailed data on diagnostic practices, therapeutic options, characteristics of FA patients, severity of reactions (including anaphylaxis), and eliciting doses of allergenic foods. In addition, FA management costs were examined (medical expenses, medication costs, and impact on quality of life and productivity).
Results
We obtained information from 157 centers in 50 countries. FA management varied significantly across regions. Oral immunotherapy and omalizumab are widely used in Europe and North America. The use of advanced diagnostic tests (molecular diagnostics) vary widely between these regions. Thirty-five percent of patients with anaphylaxis exhibited severe symptoms (respiratory or cardiovascular compromise), with marked regional differences: more frequent in Western Asia (55.83%), Southern Africa (50%), and less frequent in South-Eastern Asia (12.5%) and Central America (21.72%). Approximately 1 in 4 patients reacted to less than half an age-appropriate portion of the allergenic food. Depending on the region, peanut, milk, egg, wheat, hazelnut, and peach allergies varied considerably. Economic resources and healthcare systems play an important role in determining access to diagnostic tests and therapeutic options, which have a direct impact on the severity and management of FA.
Conclusions
With wide global disparities in access to diagnostic and therapeutic tools for food allergies, this condition entails a vast healthcare and economic commitment. The percentage of patients receiving a high severity diagnosis using DEFASE could be around 3%, similar to that of asthma patients diagnosed with severe refractory asthma.
{"title":"Food allergy severity across the world: A World Allergy Organization international survey","authors":"Stefania Arasi MD, MSc, PhD , Mário Morais-Almeida MD , Bryan L. Martin DO , Gary Wing-Kin Wong MD , Ignacio J. Ansotegui MD, PhD , Motohiro Ebisawa MD, PhD , Adnan Custovic MD, MSc, PhD , Alexandra Santos MD, MSc, PhD , Anna Nowak-Wegrzyn MD , Andrew Stoddart MSc , Antoine Deschildre MD, PhD , Antonella Cianferoni MD, PhD , Antonella Muraro MD, PhD , Audrey DunnGalvin PhD, MSc, HDp, Reg.Psychol. , Brian Vickery MD , Carina Venter PhD, RD , Carla Jones , Carmen Mazzuca MD , Christopher Warren PhD , Daniel Munblit MD, PhD , Lamia Dahdah MD","doi":"10.1016/j.waojou.2025.101123","DOIUrl":"10.1016/j.waojou.2025.101123","url":null,"abstract":"<div><h3>Background</h3><div>Data on severity of food allergy across nations are lacking. Building on the World Allergy Organization (WAO) DEFASE (Definition of Food Allergy Severity) score, we aim to explore its global applicability as a grading system for IgE-mediated food allergy (FA) severity.</div></div><div><h3>Methods</h3><div>An international survey (WAO FASE Project) was conducted using an online questionnaire distributed to WAO members. The survey collected detailed data on diagnostic practices, therapeutic options, characteristics of FA patients, severity of reactions (including anaphylaxis), and eliciting doses of allergenic foods. In addition, FA management costs were examined (medical expenses, medication costs, and impact on quality of life and productivity).</div></div><div><h3>Results</h3><div>We obtained information from 157 centers in 50 countries. FA management varied significantly across regions. Oral immunotherapy and omalizumab are widely used in Europe and North America. The use of advanced diagnostic tests (molecular diagnostics) vary widely between these regions. Thirty-five percent of patients with anaphylaxis exhibited severe symptoms (respiratory or cardiovascular compromise), with marked regional differences: more frequent in Western Asia (55.83%), Southern Africa (50%), and less frequent in South-Eastern Asia (12.5%) and Central America (21.72%). Approximately 1 in 4 patients reacted to less than half an age-appropriate portion of the allergenic food. Depending on the region, peanut, milk, egg, wheat, hazelnut, and peach allergies varied considerably. Economic resources and healthcare systems play an important role in determining access to diagnostic tests and therapeutic options, which have a direct impact on the severity and management of FA.</div></div><div><h3>Conclusions</h3><div>With wide global disparities in access to diagnostic and therapeutic tools for food allergies, this condition entails a vast healthcare and economic commitment. The percentage of patients receiving a high severity diagnosis using DEFASE could be around 3%, similar to that of asthma patients diagnosed with severe refractory asthma.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101123"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.waojou.2025.101125
Andrew M. Smith MD , Henry J. Kanarek MD , Jeffrey Rumbyrt MD , Yusaf Hussain DO , Lily M. Lim MD , Shahnaz Fatteh MD , Heidi Memmott PharmD , Teresa Chu PhD , Maunish Patel MD , Ralph Rivera PharmD , Jay M. Kashkin MD , Douglas H. Jones MD
Diagnosis of hereditary angioedema (HAE) with normal C1INH level (HAE-nl-C1INH) is based on several criteria, including either an associated genetic variant identified or family history of recurrent angioedema plus lack of high-dose antihistamine response. A rapid, durable response to bradykinin-targeted medication is considered supportive, and this study aimed to evaluate the use of recombinant human C1 esterase inhibitor (rhC1-INH) in this regard.
A retrospective medical records review was conducted for angioedema/HAE codes. Thirty-one patients with HAE-nl-C1INH were identified (female, 87.1%; mean age, 46.2 years; range, 16–74 years). All patients had experienced recurrent angioedema, with documentation of antihistamine and/or mast cell–targeted therapy ineffectiveness and normal/near-normal laboratory data. Genetic testing (n = 9) found no known pathogenic variants of HAE. Diagnosis of HAE-nl-C1INH was confirmed in the 31 patients via a favorable response after intravenous rhC1-INH (weight-based; maximum, 4200 U) during an angioedema attack. Only 30.0% (9/30) of patients with documented information had been aware of a family history of recurrent angioedema/HAE.
In conclusion, reliance on a family history of recurrent angioedema as a diagnostic criterion may delay accurate diagnosis and access to effective treatment. These results support that responsiveness to C1–INH replacement therapy may also be a useful supportive diagnostic criterion for HAE-nl-C1INH.
{"title":"C1 esterase inhibitor (C1–INH) response as a supportive diagnostic criterion for patients with suspected hereditary angioedema with normal C1–INH","authors":"Andrew M. Smith MD , Henry J. Kanarek MD , Jeffrey Rumbyrt MD , Yusaf Hussain DO , Lily M. Lim MD , Shahnaz Fatteh MD , Heidi Memmott PharmD , Teresa Chu PhD , Maunish Patel MD , Ralph Rivera PharmD , Jay M. Kashkin MD , Douglas H. Jones MD","doi":"10.1016/j.waojou.2025.101125","DOIUrl":"10.1016/j.waojou.2025.101125","url":null,"abstract":"<div><div>Diagnosis of hereditary angioedema (HAE) with normal C1INH level (HAE-nl-C1INH) is based on several criteria, including either an associated genetic variant identified or family history of recurrent angioedema plus lack of high-dose antihistamine response. A rapid, durable response to bradykinin-targeted medication is considered supportive, and this study aimed to evaluate the use of recombinant human C1 esterase inhibitor (rhC1-INH) in this regard.</div><div>A retrospective medical records review was conducted for angioedema/HAE codes. Thirty-one patients with HAE-nl-C1INH were identified (female, 87.1%; mean age, 46.2 years; range, 16–74 years). All patients had experienced recurrent angioedema, with documentation of antihistamine and/or mast cell–targeted therapy ineffectiveness and normal/near-normal laboratory data. Genetic testing (<em>n</em> = 9) found no known pathogenic variants of HAE. Diagnosis of HAE-nl-C1INH was confirmed in the 31 patients via a favorable response after intravenous rhC1-INH (weight-based; maximum, 4200 U) during an angioedema attack. Only 30.0% (9/30) of patients with documented information had been aware of a family history of recurrent angioedema/HAE.</div><div>In conclusion, reliance on a family history of recurrent angioedema as a diagnostic criterion may delay accurate diagnosis and access to effective treatment. These results support that responsiveness to C1–INH replacement therapy may also be a useful supportive diagnostic criterion for HAE-nl-C1INH.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101125"},"PeriodicalIF":4.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145365908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.waojou.2025.101132
Shuang Liu Ph.D. , Zhiwei Lin Ph.D. , Liuyong You M.S. , Jiayong Zhou Ph.D. , Qianyue Yang M.S. , Zhaoming Hu M.S. , Ying Liang MD, M.S. , Baoqing Sun MD. M.S.
Background
Bronchial asthma is a heterogeneous inflammatory airway disease with complex etiology. While the respiratory microbiome and host metabolism are implicated, their integrated roles in defining asthma subtypes remain underexplored.
Methods
This multi-omics study utilized 16S rRNA sequencing and untargeted metabolomics on sputum samples from asthma patients and healthy controls. We characterized airway microbial and metabolic profiles, identified asthma subgroups through unsupervised clustering, and investigated microbe-metabolite interactions.
Results
Asthma patients exhibited typical clinical hallmarks including elevated IgE and impaired lung function. Microbiome analysis revealed significant enrichment of Streptococcus, Veillonella, and Prevotella as key asthma-associated taxa, alongside dysregulation of crucial lipid metabolic pathways (eg, alpha-linolenic and arachidonic acid). Four highly discriminative diagnostic biomarkers (AUC >0.9), including cis-aconitic acid and LPE 20:1, were identified, indicating specific metabolic perturbations. Unsupervised clustering stratified asthma patients into 2 distinct endotypes: a severe Streptococcus-dominant cluster (Cluster 1) with profound systemic and local metabolic disturbances, and a milder cluster (Cluster 2) with microbial and metabolic profiles resembling healthy controls. These endotypes displayed differential lipid and amino acid metabolism, suggesting unique underlying mechanisms.
Conclusion
Our findings precisely delineate asthma endotypes driven by distinct microbiome-metabolome interactions, providing novel diagnostic biomarkers and pathway-specific therapeutic targets. This study critically advances our understanding of asthma heterogeneity, highlighting the importance of integrated multi-omics for personalized precision medicine strategies.
{"title":"Multi-omics identifies severe asthma endotypes linked to Streptococcus dysbiosis and lipid metabolic dysregulation","authors":"Shuang Liu Ph.D. , Zhiwei Lin Ph.D. , Liuyong You M.S. , Jiayong Zhou Ph.D. , Qianyue Yang M.S. , Zhaoming Hu M.S. , Ying Liang MD, M.S. , Baoqing Sun MD. M.S.","doi":"10.1016/j.waojou.2025.101132","DOIUrl":"10.1016/j.waojou.2025.101132","url":null,"abstract":"<div><h3>Background</h3><div>Bronchial asthma is a heterogeneous inflammatory airway disease with complex etiology. While the respiratory microbiome and host metabolism are implicated, their integrated roles in defining asthma subtypes remain underexplored.</div></div><div><h3>Methods</h3><div>This multi-omics study utilized 16S rRNA sequencing and untargeted metabolomics on sputum samples from asthma patients and healthy controls. We characterized airway microbial and metabolic profiles, identified asthma subgroups through unsupervised clustering, and investigated microbe-metabolite interactions.</div></div><div><h3>Results</h3><div>Asthma patients exhibited typical clinical hallmarks including elevated IgE and impaired lung function. Microbiome analysis revealed significant enrichment of <em>Streptococcus</em>, <em>Veillonella</em>, and <em>Prevotella</em> as key asthma-associated taxa, alongside dysregulation of crucial lipid metabolic pathways (eg, alpha-linolenic and arachidonic acid). Four highly discriminative diagnostic biomarkers (AUC >0.9), including <em>cis</em>-aconitic acid and LPE 20:1, were identified, indicating specific metabolic perturbations. Unsupervised clustering stratified asthma patients into 2 distinct endotypes: a severe <em>Streptococcus</em>-dominant cluster (Cluster 1) with profound systemic and local metabolic disturbances, and a milder cluster (Cluster 2) with microbial and metabolic profiles resembling healthy controls. These endotypes displayed differential lipid and amino acid metabolism, suggesting unique underlying mechanisms.</div></div><div><h3>Conclusion</h3><div>Our findings precisely delineate asthma endotypes driven by distinct microbiome-metabolome interactions, providing novel diagnostic biomarkers and pathway-specific therapeutic targets. This study critically advances our understanding of asthma heterogeneity, highlighting the importance of integrated multi-omics for personalized precision medicine strategies.</div></div><div><h3>Clinical trial number</h3><div>Not applicable.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 11","pages":"Article 101132"},"PeriodicalIF":4.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145334793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.waojou.2025.101129
Gian Marco Pace MD , Giulia Mari MD , Francesco Giombi MD , Michele Cerasuolo MD , Camilla Zimello MD , Luca Cerri MD , Giorgio Walter Canonica MD , Enrico Heffler MD PhD , Giovanni Paoletti MD , Francesca Puggioni MD , Barbara Fiamengo MD , Silvia Uccella MD , Giuseppe Mercante MD , Giuseppe Spriano MD , Luca Malvezzi MD
Objective
To evaluate the predictive value of baseline tissue eosinophilic infiltration (cells/high-power field [HPF]) in determining clinical response to dupilumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).
Methods
This retrospective, single-center observational study included patients with severe, refractory CRSwNP treated with dupilumab between December 2020 and December 2024. Based on histopathological analysis of nasal polyp biopsies, patients were stratified into 2 groups according to tissue eosinophil density: <50 cells/HPF and ≥50 cells/HPF. Clinical response was assessed through patient-reported outcomes (SNOT-22) and objective measures including Nasal Polyp Score (NPS), Lund-Kennedy Score (LKS), and Lund-Mackay Score (LMS), evaluated at baseline and after 1, 3, and 12 months of treatment. Repeated-measures ANOVA was used to evaluate within-group and between-group differences over time.
Results
Eighty-six patients were included in the analysis: 57 with low eosinophilic infiltration (<50 cells/HPF) and 29 with high infiltration (≥50 cells/HPF). Patients with high tissue eosinophilia showed significantly greater improvement in SNOT-22 scores across all time points (p = 0.045). No significant between-group differences were found in endoscopic (NPS, LKS) or radiologic (LMS) outcomes throughout the follow-up period.
Conclusions
Dupilumab confirmed high clinical efficacy, rapid symptom improvement, and good tolerability in patients with CRSwNP. Higher tissue eosinophil counts were associated with greater symptom improvement, as measured by SNOT-22. These findings suggest a potential role for tissue eosinophilia as a predictive marker of clinical response.
{"title":"Predictive value of tissue eosinophilia for dupilumab response in chronic rhinosinusitis with nasal polyps: A retrospective monocentric study","authors":"Gian Marco Pace MD , Giulia Mari MD , Francesco Giombi MD , Michele Cerasuolo MD , Camilla Zimello MD , Luca Cerri MD , Giorgio Walter Canonica MD , Enrico Heffler MD PhD , Giovanni Paoletti MD , Francesca Puggioni MD , Barbara Fiamengo MD , Silvia Uccella MD , Giuseppe Mercante MD , Giuseppe Spriano MD , Luca Malvezzi MD","doi":"10.1016/j.waojou.2025.101129","DOIUrl":"10.1016/j.waojou.2025.101129","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the predictive value of baseline tissue eosinophilic infiltration (cells/high-power field [HPF]) in determining clinical response to dupilumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).</div></div><div><h3>Methods</h3><div>This retrospective, single-center observational study included patients with severe, refractory CRSwNP treated with dupilumab between December 2020 and December 2024. Based on histopathological analysis of nasal polyp biopsies, patients were stratified into 2 groups according to tissue eosinophil density: <50 cells/HPF and ≥50 cells/HPF. Clinical response was assessed through patient-reported outcomes (SNOT-22) and objective measures including Nasal Polyp Score (NPS), Lund-Kennedy Score (LKS), and Lund-Mackay Score (LMS), evaluated at baseline and after 1, 3, and 12 months of treatment. Repeated-measures ANOVA was used to evaluate within-group and between-group differences over time.</div></div><div><h3>Results</h3><div>Eighty-six patients were included in the analysis: 57 with low eosinophilic infiltration (<50 cells/HPF) and 29 with high infiltration (≥50 cells/HPF). Patients with high tissue eosinophilia showed significantly greater improvement in SNOT-22 scores across all time points (p = 0.045). No significant between-group differences were found in endoscopic (NPS, LKS) or radiologic (LMS) outcomes throughout the follow-up period.</div></div><div><h3>Conclusions</h3><div>Dupilumab confirmed high clinical efficacy, rapid symptom improvement, and good tolerability in patients with CRSwNP. Higher tissue eosinophil counts were associated with greater symptom improvement, as measured by SNOT-22. These findings suggest a potential role for tissue eosinophilia as a predictive marker of clinical response.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 10","pages":"Article 101129"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.waojou.2025.101126
Changcan Jiang MD, Xiaoqiong Wang MD, Ruoqi Li MD, Liyan Ni MD, Xuejun Liu PhD
Objective
Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) involves extensive tissue remodeling, but its underlying mechanisms remain unclear. This study aimed to identify key regulatory proteins contributing to this process.
Methods
Proteomic analysis was conducted on nasal tissues from 8 eCRSwNP patients, 8 non-eosinophilic CRSwNP (neCRSwNP) patients, and 8 healthy controls. Differentially expressed proteins (DEPs) were selected based on the top 50 overlapping DEPs from both comparison groups. Selected candidates were validated using Western blotting, immunofluorescence, and qRT-PCR in an independent cohort. Correlations with eosinophil infiltration and remodeling markers were assessed. Human nasal epithelial cells (HNECs) were used to explore functional mechanisms in vitro.
Result
Proteomic profiling revealed a distinct protein expression signature in the eCRSwNP group compared to both neCRSwNP and control groups. By intersecting the top 50 DEPs from both comparisons, 4 candidate proteins were identified, among which lysyl oxidase-like protein 2 (LOXL2) exhibited the most prominent upregulation. Validation in an independent cohort confirmed significantly elevated LOXL2 expression in eCRSwNP, predominantly localized to the nasal epithelial region (P < 0.001). LOXL2 mRNA levels were strongly correlated with eosinophil infiltration in nasal tissues (r = 0.349, P = 0.006), and ROC curve analysis supported its high diagnostic utility for eCRSwNP (AUC = 0.746, P = 0.001). Furthermore, the expression of EMT markers including vimentin, α-smooth muscle actin (α-SMA), and N-cadherin was markedly increased in eCRSwNP tissues (all P < 0.01) and positively associated with LOXL2 expression (all P < 0.05). In vitro, stimulation of HNECs with recombinant LOXL2 induced TGF-β1 and EMT marker expression, while co-treatment with the TGF-β1/Smad signaling inhibitor LY364947 significantly attenuated these effects and inhibited Smad2/3 phosphorylation.
Conclusion
Our findings revealed a disease-specific protein profile in eCRSwNP, characterized by selective upregulation of LOXL2 in the nasal epithelium and strong association with eosinophilic inflammation. Functional studies suggest that LOXL2 promotes EMT and may drive tissue remodeling in eCRSwNP via the TGF-β1/Smad signaling pathway.
{"title":"Increased LOXL2 facilitates tissue remodeling in eosinophilic chronic rhinosinusitis with nasal polyps","authors":"Changcan Jiang MD, Xiaoqiong Wang MD, Ruoqi Li MD, Liyan Ni MD, Xuejun Liu PhD","doi":"10.1016/j.waojou.2025.101126","DOIUrl":"10.1016/j.waojou.2025.101126","url":null,"abstract":"<div><h3>Objective</h3><div>Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) involves extensive tissue remodeling, but its underlying mechanisms remain unclear. This study aimed to identify key regulatory proteins contributing to this process.</div></div><div><h3>Methods</h3><div>Proteomic analysis was conducted on nasal tissues from 8 eCRSwNP patients, 8 non-eosinophilic CRSwNP (neCRSwNP) patients, and 8 healthy controls. Differentially expressed proteins (DEPs) were selected based on the top 50 overlapping DEPs from both comparison groups. Selected candidates were validated using Western blotting, immunofluorescence, and qRT-PCR in an independent cohort. Correlations with eosinophil infiltration and remodeling markers were assessed. Human nasal epithelial cells (HNECs) were used to explore functional mechanisms in vitro.</div></div><div><h3>Result</h3><div>Proteomic profiling revealed a distinct protein expression signature in the eCRSwNP group compared to both neCRSwNP and control groups. By intersecting the top 50 DEPs from both comparisons, 4 candidate proteins were identified, among which lysyl oxidase-like protein 2 (LOXL2) exhibited the most prominent upregulation. Validation in an independent cohort confirmed significantly elevated LOXL2 expression in eCRSwNP, predominantly localized to the nasal epithelial region (P < 0.001). LOXL2 mRNA levels were strongly correlated with eosinophil infiltration in nasal tissues (r = 0.349, P = 0.006), and ROC curve analysis supported its high diagnostic utility for eCRSwNP (AUC = 0.746, P = 0.001). Furthermore, the expression of EMT markers including vimentin, α-smooth muscle actin (α-SMA), and N-cadherin was markedly increased in eCRSwNP tissues (all P < 0.01) and positively associated with LOXL2 expression (all P < 0.05). In vitro, stimulation of HNECs with recombinant LOXL2 induced TGF-β1 and EMT marker expression, while co-treatment with the TGF-β1/Smad signaling inhibitor LY364947 significantly attenuated these effects and inhibited Smad2/3 phosphorylation.</div></div><div><h3>Conclusion</h3><div>Our findings revealed a disease-specific protein profile in eCRSwNP, characterized by selective upregulation of LOXL2 in the nasal epithelium and strong association with eosinophilic inflammation. Functional studies suggest that LOXL2 promotes EMT and may drive tissue remodeling in eCRSwNP via the TGF-β1/Smad signaling pathway.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"18 10","pages":"Article 101126"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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