Class III Obesity as a Risk Factor for Persistent Asthma.

BACKGROUND: The burden of asthma remains steady with no decline observed in the past few decades. Obesity prevalence has been steadily increasing with a rate of 41.9% in the United States between 2017-2020. Obesity is an inflammatory chronic condition that may partially contribute to the burden and severity of asthma. This study aimed to examine whether the association between obesity and asthma varies with the categories of obesity (class I, II, and III) and persistent asthma (mild, moderate, and severe asthma). We hypothesized that subjects with elevated body mass index (BMI) are more likely to be diagnosed with persistent asthma than subjects without obesity with asthma. METHODS: As a retrospective and cross-sectional study, this study used a total of 1,977 records of subjects with asthma (age ≥ 19 y) hospitalized in Nevada between 2016-2021. BMI and persistent asthma were evaluated as the main exposure and outcome of interest. Logistic regression was used to estimate the magnitude of the association between obesity and persistent asthma. RESULTS: Among the selected subject records, subjects with obesity were more likely to be diagnosed with persistent asthma compared to subjects without obesity (odds ratio 1.50 [CI 1.10-2.05]). Subgroup analyses revealed that subjects with class III obesity (BMI ≥ 40) were more likely than subjects without obesity to be diagnosed with mild persistent asthma (odds ratio 2.21 [CI 1.18-4.16]) and severe persistent asthma (odds ratio 1.74 [CI 1.12-2.70]). CONCLUSIONS: Obesity was identified as a risk factor for persistent asthma, particularly class III obesity. This in turn increases the potential for greater health care utilization and economic burden. Public health and clinical interventions are necessary among those with comorbid asthma and obesity.

A new Anticalin protein for IL-23 inhibits non-type 2 allergen-driven mouse lung inflammation and airway hyperresponsiveness.

Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of severe asthma patients was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4+ T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23 binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, and lymphocytes, IL-17+ CD4 T cells, mucous cell metaplasia and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19) (αIL-23) also decreased macrophages, IL-17+ CD4 T cells and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness, but did decrease lung neutrophils, macrophages, and IL-17+ CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5+ or IL-13+ CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation, and that these protective actions were broader than blocking only IL-17A or IL-5, which selectively decreased airway neutrophils and eosinophils, respectively.

A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia.

BACKGROUND: Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome. METHODS: Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS). FINDINGS: Fifty-one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation. CONCLUSION: We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics.

Enhancers regulate genes linked to severe and mild childhood asthma.

Background: Children with severe asthma suffer from recurrent symptoms and impaired quality of life despite advanced treatment. Underlying causes of severe asthma are not completely understood, although genetic mechanisms are known to be important. Objective: The aim of this study was to identify gene regulatory enhancers in leukocytes, to describe the role of these enhancers in regulating genes related to severe and mild asthma in children, and to identify known asthma-related SNPs situated in proximity to enhancers. Methods: Gene enhancers were identified and expression of enhancers and genes were measured by Cap Analysis Gene Expression (CAGE) data from peripheral blood leukocytes from children with severe asthma (n = 13), mild asthma (n = 15), and age-matched controls (n = 9). Results: From a comprehensive set of 8,289 identified enhancers, we further defined a robust sub-set of the high-confidence and most highly expressed 4,738 enhancers. Known single nucleotide polymorphisms, SNPs, related to asthma coincided with enhancers in general as well as with specific enhancer-gene interactions. Blocks of enhancer clusters were associated with genes including TGF-beta, PPAR and IL-11 signaling as well as genes related to vitamin A and D metabolism. A signature of 91 enhancers distinguished between children with severe and mild asthma as well as controls. Conclusions: Gene regulatory enhancers were identified in leukocytes with potential roles related to severe and mild asthma in children. Enhancers hosting known SNPs give the opportunity to formulate mechanistic hypotheses about the functions of these SNPs.

In mouse model of mixed granulocytic asthma with corticosteroid refractoriness, Bronchom mitigates airway hyperresponsiveness, inflammation and airway remodeling.

BACKGROUND: Asthma is a heterogeneous, inflammatory disease with several phenotypes and endotypes. Severe asthmatics often exhibit mixed granulocytosis with reduced corticosteroid sensitivity. Bronchom is a newly developed Ayurvedic prescription medicine, indicated for the treatment of obstructive airway disorders. The purpose of the present study was to evaluate the in-vivo efficacy of Bronchom in mouse model of mixed granulocytic asthma with steroidal recalcitrance. METHODS: High-performance thin layer chromatography (HPTLC) and Ultra-high performance liquid chromatography (UHPLC) were employed to identify and quantitate the phytometabolites present in Bronchom. The preclinical effectiveness of Bronchom was assessed in house dust mite (HDM) and Complete Freund's adjuvant (CFA)-induced mixed granulocytic asthma model in mice. High dose of dexamethasone was tested parallelly. Specific-pathogen-free C57BL/6 mice were immunized with HDM and CFA and nineteen days later, they were intranasally challenged with HDM for four consecutive days. Then the mice were challenged with nebulized methacholine to evaluate airway hyperresponsiveness (AHR). Inflammatory cell influx was enumerated in the bronchoalveolar lavage fluid (BALF) followed by lung histology. Additionally, the concentrations of Th2 and pro-inflammatory cytokines was assessed in the BALF by multiplexed immune assay. The mRNA expression of pro-inflammatory cytokines and Mucin 5AC (MUC5AC) was also evaluated in the lung. RESULTS: HPTLC fingerprinting and UHPLC quantification of Bronchom revealed the presence of bioactive phytometabolites, namely, rosmarinic acid, gallic acid, methyl gallate, piperine, eugenol and glycyrrhizin. Bronchom effectively reduced AHR driven by HDM-CFA and the influx of total leukocytes, eosinophils and neutrophils in the BALF. In addition, Bronchom inhibited the infiltration of inflammatory cells in the lung as well as goblet cell metaplasia. Further, it also suppressed the elevated levels of Th2 cytokines and pro-inflammatory cytokines in the BALF. Similarly, Bronchom also regulated the mRNA expression of pro-inflammatory cytokines as well as MUC5AC in mice lungs. Reduced effectiveness of a high dose of the steroid, dexamethasone was observed in the model. CONCLUSIONS: We have demonstrated for the first time the robust pharmacological effects of an herbo-mineral medicine in an animal model of mixed granulocytic asthma induced by HDM and CFA. The outcomes suggest the potential utility of Bronchom in severe asthmatics with a mixed granulocytic phenotype.

Imagining the severe asthma decision trees of the future.

INTRODUCTION: There are no validated decision-making algorithms concerning severe asthma (SA) management. Future risks are crucial factors and can be derived from SA trajectories. AREAS COVERED: The future severe asthma-decision trees should revisit current knowledge and gaps. A focused literature search has been conducted. EXPERT OPINION: Asthma severity is currently defined a priori, thereby precluding a role for early interventions aiming to prevent outcomes such as exacerbations (systemic corticosteroids exposure) and lung function decline. Asthma 'at-risk' might represent the ultimate paradigm but merits longitudinal studies considering modern interventions. Real exacerbations, severe airway hyperresponsiveness, excessive T2-related biomarkers, noxious environments and patient behaviors, harms of OCS and high-doses inhaled corticosteroids (ICS), and low adherence-to-effectiveness ratios of ICS-containing inhalers are predictors of future risks. New tools such as imaging, genetic, and epigenetic signatures should be used. Logical and numerical artificial intelligence may be used to generate a consistent risk score. A pragmatic definition of response to treatments will allow development of a validated and applicable algorithm. Biologics have the best potential to minimize the risks, but cost remains an issue. We propose a simplified six-step algorithm for decision-making that is ultimately aiming to achieve asthma remission.

Asthma severity: the patient's point of view.

Objective: Initiated by the Severe Asthma Network Italy (SANI), this study aims to explore asthma patients' perceptions of disease severity, differentiating between mild and severe asthma. The objective is to identify factors influencing tailored treatment strategies for varying disease severities and to provide insights into asthma care in Italy. Methods: Conducted between November 2020 and January 2021, a survey using Computer-Assisted Personal Interviewing (CAPI) collected data from 308 Italian adults, representing the population. A 25 item multiple choice questionnaire covered asthma diagnosis, symptoms, treatment approaches, associated conditions, and quality of life. Results: Among participants, 83.8% reported having mild asthma, while 16.2% had severe asthma. Severe asthma patients had longer disease durations, more severe symptoms, frequent exacerbations, and higher hospital/ER visits. Although treatment adherence and symptom profiles generally aligned with international guidelines for self reported severe asthma, 22% of self identified mild asthmatics experienced severe respiratory symptoms. Oral corticosteroid (OCS) use was observed in 50% of severe cases and 22% of mild cases. Adherence was higher in severe asthma patients (76%) versus mild asthma patients (28%). Both groups experienced comorbidities, with 96% of severe asthmatics and 72% of mild asthmatics reporting impaired quality of life. Conclusion: This study highlights the disparity between clinical categorization and patient perceptions of asthma severity. The prevalence of self reported severe asthma exceeds literature data. The burden of mild asthma remains significant, with treatment approaches not fully aligned, particularly regarding disproportionate OCS use. Addressing this gap requires enhancing patient education, improving diagnostic practices, and promoting adherence.

Long-term effects of mepolizumab in patients with severe eosinophilic asthma: a 6-year real-life experience.

Background: Severe eosinophilic asthma (SEA) is often linked to a dysregulation in the Interleukin-(IL)-5 axis. Mepolizumab, a humanized monoclonal antibody, reduces eosinophils by directly binging to IL-5, potentially restoring homeostatic eosinophil biology, with a significant impact on quality of life, acute exacerbations and oral corticosteroids (OCS) elimination in SEA patients. While its short- and middle-term effects are well described, no study has so far investigated its long-lasting effects in SEA patients. The aim of our study was therefore to explore the effects of a long-term, six-year continuous treatment with mepolizumab on clinical control and clinical remission in a cohort of SEA patients. Methods: We conducted a retrospective review of clinical records of patients who were prescribed mepolizumab between June 2017 and April 2018. We collected demographical, functional, and clinical data from visits performed at baseline and then at the specified timepoints and checked if patients had reached clinical remission after 6 years. We assessed asthma control test (ACT), exacerbation rate, and OCS elimination dose at 6 years. Clinical Remission (CR) was defined on the basis of the elimination of OCS and the contemporary presence of all the following: 1) stable lung function; 2) no exacerbation in the previous 12 months; 3) acceptable symptom control (ACT ≥ 20). Results: Of 86 patients screened, 62 were included in the final analysis. Our study suggests that mepolizumab is effective and well tolerated after a six-year course of continuous treatment in patients with SEA. We reported a prevalence of 28 (46.8%) patients who reached complete CR at 72 months from the treatment start. 75% of patients eliminated the maintenance OCS already after 1 year of treatment; this proportion reached the 87% within the sixth year of treatment. Conclusion: Mepolizumab proved to be effective in real-life after 6 years of treatment, inducing a complete clinical remission in the 46.8% of patients, with sustained improvements in quality of life, exacerbation rate, OCS intake and lung function.

Profiling severe asthma: Any relevance for age? An analysis from Severe Asthma Network Italy (SANI) cohort.

Background: Aging implies changes in terms of lung function, immune system, and respiratory and extra-respiratory comorbidities. Few studies have specifically addressed the relevance of age on severe asthma burden and control. We aimed to evaluate whether age acts as an independent determinant of asthma severity, in terms of clinical, functional, and inflammatory profile, and to explore potential cofactors that contribute to a more difficult disease control in different age groups. Methods: Patients from Severe Asthma Network Italy (SANI) registry were retrospectively divided in subgroups according to their age. Cutoffs for age were established according to quartiles in order to obtain a comparable number of patients for each group, and then rounded for the sake of simplicity. Results: Overall, 1805 severe asthma patients were analyzed. Lung function represented the most important age-related variable. On the opposite the level of asthma control was not differently distributed among age ranges. In young people the presence of atopy-related comorbidities (allergic rhinitis, atopic dermatitis) predominated, whilst systemic-metabolic and degenerative comorbidities such as diabetes, cardiovascular diseases, anxious-depressive syndrome, and osteoporosis prevailed in elderly. Bronchiectasis and sleep disturbances were significantly associated with age. Conclusions: Despite that it cannot be considered a treatable trait, our study suggests that age should be evaluated within a personalized approach to severe asthma patients, in order to provide a better clinical profiling and a more tailored treatment strategy.

Comparative Effectiveness of Dupilumab and Omalizumab on Asthma Exacerbations and Systemic Corticosteroid Prescriptions: Real-World US ADVANTAGE Study.

BACKGROUND: In the US, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, while omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories. OBJECTIVE: This analysis assessed the real-world effectiveness of dupilumab and omalizumab for asthma among patients in the US. METHODS: In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify asthma patients (age: ≥12 years) who initiated (index) dupilumab or omalizumab between November 2018 and September 2020, and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting (IPTW) was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after IPTW. RESULTS: Overall, 2,138 patients in dupilumab and 1,313 in omalizumab treatment groups met all inclusion and exclusion criteria. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the two groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (p<0.0001) than omalizumab. Additionally, dupilumab treatment significantly (p<0.05) reduced SCS prescriptions by 28% during the follow-up period compared to omalizumab treatment. CONCLUSION: The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared to those prescribed omalizumab during 12 months of follow-up.

Identification of candidate genes and molecular mechanisms related to asthma progression using bioinformatics.

BACKGROUND: Asthma is a heterogeneous disorder. This study aimed to identify changes in gene expression and molecular mechanisms associated with moderate to severe asthma. METHODS: Differentially expressed genes (DEGs) were analyzed in GSE69683 dataset among moderate asthma and its controls as well as between severe asthma and moderate asthma. Key module genes were identified via co-expression analysis, and the molecular mechanism of the module genes was explored through enrichment analysis and gene set enrichment analysis (GSEA). GSE89809 was used to verify the characteristic genes related to moderate and severe asthma. RESULTS: Accordingly, 2540 DEGs were present between moderate asthma and the control group, while 6781 DEGs existed between severe asthma and moderate asthma. These genes were identified into 14 co-expression modules. Module 7 had the highest positive correlation with severe asthma and was recognized to be a key module by STEM. Enrichment analysis demonstrated that the module genes were mainly involved in oxidative stress-related signaling pathways. The expression of HSPA1A, PIK3CG and PIK3R6 was associated with moderate asthma, while MAPK13 and MMP9 were associated with severe asthma. The AUC values were verified by GSE89809. Additionally, 322 drugs were predicted to target five genes. CONCLUSION: These results identified characteristic genes related to moderate and severe asthma and their corresponding molecular mechanisms, providing a basis for future research.

Higher prevalence of dupilumab-induced ocular adverse events in atopic dermatitis compared to asthma: A daily practice analysis.

BACKGROUND: Dupilumab has been shown to be an effective treatment in moderate-to-severe atopic dermatitis (AD) and severe asthma (SA). However, comparative real-world analyses of adverse events (AE), particularly dupilumab-associated ocular surface disease (DAOSD), are lacking. OBJECTIVE: This is the first real-world study to provide insight into the prevalence of AEs associated with dupilumab in AD compared with SA. Secondary objectives were to assess the prevalence, onset and therapeutic strategies of DAOSD and evaluate dupilumab discontinuation rates. METHODS: Data from two daily practice registries including AD and SA patients receiving dupilumab treatment were analyzed. Adverse events, including DAOSD, were evaluated. RESULTS: In total, 322 AD and 148 SA patients were included. Headaches (23.6%), injection site reactions (10.1%), and influenza-like symptoms (13.5%) were more prevalent in SA patients. Interestingly, ocular AEs were significantly more prevalent in AD patients (62.1%, p < 0.001), including conjunctivitis (17.1%, p = 0.004). 88% AD and 47% SA patients with ocular AEs received one or more ophthalmic treatment(s). Additionally, 20% of AD and 17.6% of SA patients discontinued dupilumab treatment due to ocular AEs, while only 65% of these AD and none of these SA patients were referred to an ophthalmologist. CONCLUSION: The higher incidence of DAOSD in AD patients compared with SA patients in this real-world study highlights the importance of physician awareness, especially when prescribing dupilumab to AD patients. Conversely, the findings of this study help alleviate potential concerns about ocular AEs in patients with SA who do not have comorbid AD. Furthermore, the effective management of most ocular AEs with ophthalmic treatments suggests favorable tolerability of dupilumab in daily practice, and multidisciplinary collaboration is essential to proactively manage ocular AEs before discontinuing dupilumab.

iPREDICT: proof-of-concept study to develop a predictive model of changes in asthma control.

BACKGROUND: The individualized PREdiction of DIsease Control using digital sensor Technology (iPREDICT) program was developed for asthma management using digital technology. Devices were integrated into daily lives of patients to establish a predictive model of asthma control by measuring changes from baseline health status with minimal device burden. OBJECTIVES: To establish baseline disease characteristics of the study participants, detect changes from baseline associated with asthma events, and evaluate algorithms capable of identifying triggers and predicting asthma control changes from baseline data. Patient experience and compliance with the devices were also explored. DESIGN: This was a multicenter, observational, 24-week, proof-of-concept study conducted in the United States. METHODS: Patients (⩾12 years) with severe, uncontrolled asthma engaged with a spirometer, vital sign monitor, sleep monitor, connected inhaler devices, and two mobile applications with embedded patient-reported outcome (PRO) questionnaires. Prospective data were linked to data from electronic health records and transmitted to a secure platform to develop predictive algorithms. The primary endpoint was an asthma event: symptom worsening logged by patients (PRO); peak expiratory flow (PEF) < 65% or forced expiratory volume in 1 s < 80%; increased short-acting ß2-agonist (SABA) use (>8 puffs/24 h or >4 puffs/day/48 h). For each endpoint, predictive models were constructed at population, subgroup, and individual levels. RESULTS: Overall, 108 patients were selected: 66 (61.1%) completed and 42 (38.9%) were excluded for failure to respond/missing data. Predictive accuracy depended on endpoint selection. Population-level models achieved low accuracy in predicting endpoints such as PEF < 65%. Subgroups related to specific allergies, asthma triggers, asthma types, and exacerbation treatments demonstrated high accuracy, with the most accurate, predictive endpoint being >4 SABA puffs/day/48 h. Individual models, constructed for patients with high endpoint overlap, exhibited significant predictive accuracy, especially for PEF < 65% and >4 SABA puffs/day/48 h. CONCLUSION: This multidimensional dataset enabled population-, subgroup-, and individual-level analyses, providing proof-of-concept evidence for development of predictive models of fluctuating asthma control.

Outcomes of biological therapy in patients with severe asthma with chronic rhinosinusitis in Saudi Arabia: patients with nasal polyps versus those without nasal polyps.

BACKGROUND: This study's purposes were to evaluate the impact of biological therapies on outcomes in patients with severe asthma (SA) and chronic rhinosinusitis (CRS) and to compare these effects among those with NP (CRSwNP) versus those without NP (CRSsNP) in the "real-world" setting in Saudi Arabian patients. METHODS: From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital-Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of dupilumab therapy. Outcomes were assessed, including clinical outcomes, FEV1, and laboratory findings before and one year after dupilumab. Post-therapy effects were compared between CRSwNP and CRSsNP. RESULTS: Fifty subjects were enrolled, with a mean age of 46.56. There were 27 (54%) females and 23(46%) males. Significant improvements in clinical parameters (frequency of asthma exacerbations and hospitalizations, the use of OCs, anosmia, SNOTT-22, and the ACT), FEV1, and laboratory ones (serum IgE and eosinophilic count) were observed 6 and 12 months after using dupilumab (p < 0.001), respectively. However, after 12 months of dupilumab therapy, there were no significant differences between those with and without NP with regards to clinical (anosmia, ACT, and OCs use), laboratory (eosinophilic count, serum IgE level) parameters, and FEV1%. CONCLUSIONS: Patients with CRS experienced significant improvements in clinical, FEV1, and laboratory outcomes after dupilumab therapy. However, these improvements were not maintained when comparing CRSwNP with CRSsNP. There were no significant differences between those with and without NP regarding ACT and OCs use or laboratory (eosinophilic count, serum IgE level) parameters. Further prospective multicenter studies are warranted.

Type 2 severe asthma: pathophysiology and treatment with biologics.

INTRODUCTION: The hallmark of most patients with severe asthma is type 2 inflammation, driven by innate and adaptive immune responses leading to either allergic or non-allergic eosinophilic infiltration of airways. The cellular and molecular pathways underlying severe type 2 asthma can be successfully targeted by specific monoclonal antibodies. AREAS COVERED: This review article provides a concise overview of the pathophysiology of type 2 asthma, followed by an updated appraisal of the mechanisms of action and therapeutic efficacy of currently available biologic treatments used for management of severe type 2 asthma. Therefore, all reported information arises from a wide literature search performed on PubMed. EXPERT OPINION: The main result of the recent advances in the field of anti-asthma biologic therapies is the implementation of a personalized medicine approach, aimed to achieve clinical remission of severe asthma. Today this accomplishment is made possible by the right choice of the most beneficial biologic drug for the pathologic traits characterizing each patient, including type 2 severe asthma and its comorbidities.

Dupilumab responder types and predicting factors in patients with type 2 severe asthma: A real-world cohort study.

BACKGROUND: Severe asthma (SA) presents a considerable healthcare challenge despite optimal standard treatment. Dupilumab, which is effective in type 2 (T2) SA patients, demonstrates variable responses, categorizing patients as non-responders, partial responders, or those achieving clinical remission. However, real-world response rates remain underexplored. Additionally, understanding the characteristics of patients achieving clinical remission is crucial for predicting favourable responses to dupilumab. OBJECTIVE: To investigate responder types and identify predictors of clinical remission and non-response induced by dupilumab in a real-world cohort of SA patients. METHODS: We analyzed retrospective data from SA patients undergoing dupilumab treatment in a study conducted at Franciscus Gasthuis & Vlietland hospital. Data were collected at baseline and at a 12 to 24-months follow-up (T = 12). Response rates were evaluated at T = 12. Predictors of non-response and clinical remission were investigated using multivariate logistic regression analysis with a stepwise forward variable selection approach. RESULTS: Among the 175 patients screened, 136 met the inclusion criteria. At T = 12, 31.6 % achieved clinical remission, 47.1 % were partial responders and 21.3 % were non-responders. Predictors associated with clinical remission included high baseline blood eosinophil counts (BEC) and male sex. Conversely, younger age at baseline, low baseline total immunoglobin E (IgE) and low baseline fractional exhaled nitric oxide (FeNO) levels were identified as predictors of non-response. CONCLUSIONS: Dupilumab results in clinical disease remission in one-third of the treated patients. Clinical remission is predicted by high BEC and male sex, whereas low total IgE, low FeNO and younger age indicate a lower likelihood of response.

Geographic and economic influences on benralizumab prescribing for severe asthma in Japan.

Benralizumab, a monoclonal antibody targeting IL-5 receptors, reduces exacerbations and oral corticosteroid requirements for severe, uncontrolled eosinophilic asthma. In Japan, geographic disparities in asthma outcomes suggest differential prescribing and access. This study aimed to quantify regional prescribing variations for benralizumab nationwide. Using Japan's National Database (NDB) of insurance claims (2009-2019), benralizumab standardized claim ratios (SCRs) were calculated for 47 prefectures. Correlations between SCRs and other biologics' SCRs, economic variables like average income, and physician densities were evaluated through univariate analysis and multivariate regressions. Income-related barriers to optimal prescribing were examined. Wide variation emerged in benralizumab SCRs, from 40.1 to 184.2 across prefectures. SCRs strongly correlated with omalizumab (r = 0.61, p < 0.00001) and mepolizumab (r = 0.43, p = 0.0024). Average monthly income also positively correlated with benralizumab SCRs (r = 0.45, p = 0.0016), whereas lifestyle factors were insignificant. Respiratory specialist density modestly correlated with SCRs (r = 0.29, p = 0.047). In multivariate regressions, average income remained the most robust predictor (B = 0.74, p = 0.022). Benralizumab SCRs strongly associate with income metrics more than healthcare infrastructure/population factors. Many regions show low SCRs, constituting apparent prescribing gaps. Access barriers for advanced asthma therapies remain inequitable among Japan's income strata. Addressing affordability alongside specialist allocation can achieve better prescribing quality and asthma outcomes.

Machine learning-enhanced HRCT analysis for diagnosis and severity assessment in pediatric asthma.

OBJECTIVES: Chest high-resolution computed tomography (HRCT) is conditionally recommended to rule out conditions that mimic or coexist with severe asthma in children. However, it may provide valuable insights into identifying structural airway changes in pediatric patients. This study aims to develop a machine learning-based chest HRCT image analysis model to aid pediatric pulmonologists in identifying features of severe asthma. METHODS: This retrospective case-control study compared children with severe asthma (as defined by ERS/ATS guidelines) to age- and sex-matched controls without asthma, using chest HRCT scans for detailed imaging analysis. Statistical analysis included classification trees, random forests, and conventional ROC analysis to identify the most significant imaging features that mark severe asthma from controls. RESULTS: Chest HRCT scans differentiated children with severe asthma from controls. Compared to controls (n = 21, mean age 11.4 years), children with severe asthma (n = 20, mean age 10.4 years) showed significantly greater bronchial thickening (BT) scores (p < 0.001), airway wall thickness percentage (AWT%, p < 0.001), bronchiectasis grading (BG) and bronchiectasis severity (BS) scores (p = 0.016), mucus plugging, and centrilobular emphysema (p = 0.009). Using AWT% as the predictor in conventional ROC analysis, an AWT% ≥ 38.6 emerged as the optimal classifier for discriminating severe asthmatics from controls, with 95% sensitivity, specificity, and overall accuracy. CONCLUSION: Our study demonstrates the potential of machine learning-based analysis of chest HRCT scans to accurately identify features associated with severe asthma in children, enhancing diagnostic evaluation and contributing to the development of more targeted treatment approaches.

Impact of comorbidities on EQ-5D quality-of-life index in severe asthma.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients' characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.