Asthma Phenotypes Research Articles

A partial loss-of-function variant in STAT6 protects against T2 asthma

BackgroundSignal Transducer and Activator of Transcription 6 (STAT6) is central to Type 2 (T2) inflammation and common non-coding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment. ObjectiveTo test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture. MethodsWe tested association of p.L406P with plasma protein levels, white blood cell counts and the risk of asthma and allergic phenotypes. We tested significant associations in other cohorts using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4+ T-cell responses from carriers and non-carriers of the variant. Resultsp.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2 high asthma. We showed that p.L406P led to lower IL-4-induced activation in luciferase reporter assays and lower levels of STAT6 in CD4+ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype upon IL-4 treatment of CD4+ T cells; the effect was consistent with a weaker IL-4 response in carriers than non-carriers of p.L406P. ConclusionsWe report a partial loss-of-function variant in STAT6, resulting in dampened IL-4 responses and protection from T2 high asthma, implicating STAT6 as an attractive therapeutic target.

Late-Onset Asthma: A Review

Asthma is a chronic respiratory condition with a growing global prevalence, affecting millions of individuals annually. While asthma can develop at any age, late-onset asthma is a specific phenotype that begins in adulthood, as recognized by the Global Initiative for Asthma (GINA) in its 2024 guidelines. This form of asthma is often associated with several predisposing factors, including gender, obesity, occupational exposure, rhinitis, respiratory infections, smoking, stress, and diminished lung function. Unlike early-onset asthma, which frequently involves a history of allergies, late-onset asthma tends to lack allergic triggers, making it a distinct and challenging form of the disease. Managing late-onset asthma is often more complex, as it typically requires higher doses of corticosteroids and demonstrates a reduced responsiveness to standard steroid treatments. The exact mechanisms and pathophysiological processes contributing to the increased severity and poorer clinical outcomes in late-onset asthma remain largely unclear. This uncertainty often leads to underdiagnosis and inadequate management, further complicating patient care. Phenotypic analysis is recommended to improve treatment outcomes. This includes assessing clinical features and utilizing biomarkers, such as inflammatory markers and immunoglobulin E (IgE) levels, to guide targeted therapy when conventional steroid treatments are insufficient. However, there is a significant need for further research to elucidate the underlying mechanisms of late-onset asthma. This literature review is essential to develop more effective, personalized treatment strategies that can address the unique challenges posed by this asthma phenotype, ultimately leading to better management and improved patient outcomes.

Exploring CD26-/lo subpopulations of lymphocytes in asthma phenotype and severity: A novel CD4+ T cell subset expressing archetypical granulocyte proteins.

Asthma pathology may induce changes in naïve/memory lymphocyte proportions assessable through the evaluation of surface CD26 (dipeptidyl peptidase 4/DPP4) levels. Our aim was to investigate the association of asthma phenotype/severity with the relative frequency of CD26-/lo, CD26int and CD26hi subsets within different lymphocyte populations. The proportion of CD26-/lo, CD26int and CD26hi subsets within CD4+ effector T cells (Teff), total CD4- lymphocytes, γδ-T cells, NK cells and NKT cells was measured in peripheral blood samples from healthy (N = 30) and asthma (N = 119) donors with different phenotypes/severities by flow cytometry. We performed K-means clustering analysis and further characterised the CD4+CD26-/lo Teff cell subset by LC-MS/MS and immunofluorescence. Cluster analysis including clinical and flow cytometry data resulted in four groups, two of them with opposite inflammatory profiles (neutrophilic vs. eosinophilic). Neutrophilic asthma presented reduced CD4-CD26hi cells, which negatively correlated with systemic inflammation. Eosinophilic asthma displayed a general expansion of CD26-/lo subsets. Specifically, CD4+CD26-/lo Teff expansion was confirmed in asthma, especially in atopic patients. Proteomic characterisation of this subset with a TEM/TEMRA phenotype revealed upregulated levels of innate (e.g. MPO and RNASE2) and cytoskeleton/extracellular matrix (e.g. MMP9 and ACTN1) proteins. Immunofluorescence assays confirmed the presence of atypical proteins for CD4+ T cells, and an enrichment in 'flower-like' nuclei and MMP9/RNASE2 levels in CD4+CD26-/lo Teff compared to CD4+ T lymphocytes. There is an association between CD26 levels in different lymphocyte subsets and asthma phenotype/severity. CD4+CD26-/loTEMRA cells expressing innate proteins specific to eosinophils/neutrophils could be determinant in sustaining long-term inflammation in adult allergic asthma.

Obesity-related Asthma: A Pathobiology-based Overview of Existing and Emerging Treatment Approaches.

Though obesity-related asthma associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still largely unavailable. This state-of-the-art review article synthesizes evidence for existing and emerging treatment approaches for obesity-related asthma and highlights pathways that offer potential targets for novel therapeutics. Existing treatments targeting insulin resistance and obesity, including metformin and glucagon-like-peptide 1 (GLP-1) receptor agonists, have been associated with improved asthma outcomes, though GLP-1R agonist data in asthma is limited to individuals with co-morbid obesity. Monoclonal antibodies approved for treatment of moderate to severe asthma generally appear to be effective in individuals with obesity, though this is based on retrospective or secondary analysis of clinical trials; moreover, while most of these asthma biologics are approved for use in the pediatric population, the impact of obesity on their efficacy has not been well studied in youth. Potential therapeutic targets being investigated include IL-6, arginine metabolites, nitro-fatty acids, and mitochondrial antioxidants, with clinical trials for each currently underway. Potential therapeutic targets include adipose tissue eosinophils and the GLP-1-Arginine-Advanced glycation end products axis, though data in humans is still needed. Finally, transcriptomic and epigenetic studies of "obese asthma" demonstrate enrichment of interferon-related signaling pathways, Rho-GTPase pathways, and integrins, suggesting that these too could represent future treatment targets. We advocate for further study of these potential therapeutic mechanisms and continued investigation of the distinct inflammatory pathways characteristic of obesity-related asthma, in order to facilitate effective treatment development for this unique asthma phenotype.

Tezepelumab: a promising therapy for severe uncontrolled asthma

Asthma is a complex inflammatory airway disease affecting a significant global population, spanning from childhood through adulthood. Despite advances in treatment modalities, a significant subset of patients, approximately 10%, grapple with severe asthma, characterized by increased healthcare utilization and diminished quality of life. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), offers promising therapeutic potential. TSLP is a protein released by a variety of cells, with a predominance of epithelial cells, in reaction to plenty of stimuli, such examples as viruses, aeroallergens, and others. Its action is upstream and pertains to initiating numerous subsequent innate and adaptive immune reactions, contributing to the continuation of asthma pathophysiological processes. Tezepelumab’s unique efficacy spans diverse severe asthma phenotypes, significantly reducing exacerbation rates across eosinophilic and non-eosinophilic subtypes. Its favorable safety profile and clinically meaningful improvements in asthma control, accompanied by reductions in cytokine levels and baseline biomarkers, underscore its broad impact on asthma inflammation. Its efficacy, irrespective of type 2 (T2) endotype, reinforces the idea that TSLP blockade broadly inhibits pathways crucial to asthma pathophysiology, rather than narrowly focusing on individual downstream factors, as previous biological treatments have. This review discusses the rationale for TSLP blockade and the efficacy of tezepelumab in severe asthma using data from key trials.

Clinical variability of equine asthma phenotypes and analysis of diagnostic steps in phenotype differentiation

BackgroundEquine asthma is a common, non-infectious, chronic lung disease that affects up to 80% of the horse population. Strict phenotyping and identification of subclinically asthmatic horses can be challenging. The aim of this study was to describe equine asthma phenotypes (mild, moderate, and severe asthma) defined by BALF cytology and occurrence of clinical signs in a population of privately owned horses and to identify the variables and examination steps with best discriminative potential. The standardised examination protocol included clinical examinations, blood work, airway endoscopy with bronchoalveolar lavage fluid analysis, arterial blood gas analysis and radiography under clinical conditions performed by one veterinarian.ResultsOut of 26 horses, four were diagnosed with mild (subclinical), seven with moderate, and seven with severe asthma based on clinical examination and BALF cytology. Eight horses served as controls. Cough with history of coughing was the strongest variable in phenotype differentiation. Factor analysis revealed an increasing clinical variability with disease severity and an overlapping of clinical presentations between phenotypes. Elevated mast cell (4/4 horses) and neutrophil counts (3/4 horses) in bronchoalveolar lavage cytology differentiated mild asthmatic horses from healthy horses. Moderate and severe asthmatic horses were characterised by clinical signs and neutrophil counts.ConclusionsThe results indicate that medical history, clinical examination and bronchoalveolar lavage cytology are minimum indispensable steps to diagnose equine asthma and that phenotypes are clinically overlapping. A differentiation of three phenotypes without neutrophil and mast cell counts in bronchoalveolar lavage cytology is not sufficient for clinical diagnostics. A comparably exact diagnosis cannot be achieved by relying on alternative examinations used in this study. Screenings of inconspicuous horses with bronchoalveolar lavage can aid in diagnosing subclinically affected animals, however, group size was small, the procedure is invasive and clinical relevance of slightly elevated cells in bronchoalveolar lavage remains unclear. Clinical relevance could not be clarified in this study, since follow-up examinations or lung function testing were not performed.

The triple radiologic asthma phenotype is associated with worse disease control

BackgroundEfforts have been made to combine radiographical biomarkers such as bronchiectasis or bronchial wall thickness (BWT) to identify asthma sub-phenotypes and their clinical implications. ObjectiveTo assess whether a composite triple radiological phenotype measured by high resolution computed tomography comprising BWT, mucus plug score (MPS) and mediastinal lymph node (MLN) size might provide a better insight into sub-phenotypes in persistent asthma. MethodsOne hundred and twelve patients with moderate-to-severe asthma were included in this retrospective observational study. A binary method was used to classify patients according to median values for: pooled MLN≥3.6mm; BWT as pooled wall area ≥50% of the total airway area; and MPS≥1 where a mucus plug was considered positive if complete bronchial obstruction was imaged more than 2 cm from a pleural surface. ResultsPatients with the triple imaging phenotype exhibited significantly worse asthma control questionnaire scores exceeding minimal clinical important difference, a higher prevalence of concomitant chronic rhinosinusitis with nasal polyposis and a greater total IgE level. ConclusionWe have demonstrated an association between poorer symptom control and the triple radiological asthma phenotype.

Prevalence and CCR3-T51C genotype–phenotype correlation of bronchial asthma among basic education school children: an observational study

BackgroundBronchial asthma (BA) is a chronic inflammatory disorder identified by different endotypes and phenotypes. Chemokine receptor 3 (CCR3) is one of the essential chemokine receptors that have a crucial role in asthma development by activating the migration of eosinophils through eotaxin production. We aimed to determine asthma prevalence among school children and to investigate the association between CCR3-T51C gene polymorphisms and the symptom-based clinical asthma phenotypes.MethodsThis study employed a hybrid design, conducted at a single center in Egypt from 2020 to 2021, to explore the relationship between asthma, its clinical phenotypes, and the CCR3-T51C gene polymorphism. Initially, a cross-sectional analysis was performed, utilizing a modified version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire to determine the prevalence of asthma in a cohort of 60 children, who presented with diverse clinical phenotypes, alongside 100 healthy controls. Subsequently, in the case–control phase of the study, we focused on examining the association between asthma (and its clinical phenotypes) and the CCR3-T51C gene polymorphism. For both groups, serum immunoglobulin E (IgE) levels and eosinophil counts were assessed, and the genotypes and alleles of the CCR3-T51C gene polymorphism were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) technique.ResultsA total of 600 children aged (6 to 16 years old) were enrolled. Out of these, 72 children (12%) were diagnosed with bronchial asthma in the basic education schools in El Manzala City, Egypt. Also, 72 (12%) of the studied children had wheezes, and 48 (8%) had night cough. Children with asthma had significantly higher relative eosinophil count and serum IgE levels than the control group. In terms of CCR3-T51C genotypes analysis, the TT genotype was the most prevalent in both patient and control groups, with 63.3% and 64%, respectively, but the difference was not statistically significant (P > 0.05). Also, there were no significant associations between CCR3-T51C genotypes and laboratory biomarkers among cough, wheezy, and cough and wheezy groups, except for the CT genotype in the cough group that had a lower eosinophil count than the wheezy group (P = 0.04).ConclusionAsthma affects 12% of the school-aged children. The CCR3-T51C genotype or allelic polymorphism frequency did not differ between asthmatics and controls; however, the TT genotype was more frequent in asthmatic children. Eosinophil count, serum IgE and gene polymorphism of CCR3-T51C appeared similar among different asthmatic phenotypes.

Novel insights into the pleiotropic health effects of growth differentiation factor 11 gained from genome-wide association studies in population biobanks

BackgroundGrowth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β (TGF-β) superfamily that has gained considerable attention over the last decade for its observed ability to reverse age-related deterioration of multiple tissues, including the heart. Yet as many researchers have struggled to confirm the cardioprotective and anti-aging effects of GDF11, the topic has grown increasingly controversial, and the field has reached an impasse. We postulated that a clearer understanding of GDF11 could be gained by investigating its health effects at the population level.Methods and resultsWe employed a comprehensive strategy to interrogate results from genome-wide association studies in population Biobanks. Interestingly, phenome-wide association studies (PheWAS) of GDF11 tissue-specific cis-eQTLs revealed associations with asthma, immune function, lung function, and thyroid phenotypes. Furthermore, PheWAS of GDF11 genetic variants confirmed these results, revealing similar associations with asthma, immune function, lung function, and thyroid health. To complement these findings, we mined results from transcriptome-wide association studies, which uncovered associations between predicted tissue-specific GDF11 expression and the same health effects identified from PheWAS analyses.ConclusionsIn this study, we report novel relationships between GDF11 and disease, namely asthma and hypothyroidism, in contrast to its formerly assumed role as a rejuvenating factor in basic aging and cardiovascular health. We propose that these associations are mediated through the involvement of GDF11 in inflammatory signaling pathways. Taken together, these findings provide new insights into the health effects of GDF11 at the population level and warrant future studies investigating the role of GDF11 in these specific health conditions.

Therapeutic efficacy of JEW-M449, an anti-TCTP monoclonal antibody, administered via the nasal route in a BALB/c mouse model of ovalbumin-induced acute asthma

Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.

Association between asthma and IgG levels specific for rhinovirus and respiratory syncytial virus antigens in children and adults

BackgroundViral infections in childhood, especially to rhinovirus (RV) and respiratory syncytial virus (RSV) are associated with asthma inception and exacerbation. However, little is known about the role of RV- and RSV-specific antibodies in childhood versus adult asthma. ObjectiveTo investigate associations between RV- and RSV-specific IgG levels with asthma phenotypes, in children and adults. MethodsThe analysis included 1771 samples from 1501 participants of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) (530 children (mean(sd) age = 11.1 (2.8) and 1241 adults (mean(sd) age = 43.4(16.7), among which 274 and 498 had ever asthma, respectively). RSV- and RV-specific IgG levels were determined using micro-arrayed virus-derived antigens and peptides. Cross-sectional associations between standardized RSV- and RV-specific IgG levels and asthma phenotypes were estimated by multiple regression models. ResultsIn children, ever asthma was associated with higher IgG levels specific to RV, especially to RV-A, RV-C and to RSV (adj-OR for 1-sd increase in IgG levels = 1.52 (95%CI, 1.16;1.99), 1.42 (1.10;1.83) and 1.24 (0.99;1.54), respectively). These associations were stronger for moderate-to-severe asthma than for mild asthma. Conversely in adults, ever asthma was associated with lower RV-A, RV-B and RV-C IgG levels (adjusted OR = 0.86 (0.74;0.99), 0.83 (0.73;0.95) and 0.85 (0.73;0.99), respectively). ConclusionOur results suggest that the association between respiratory virus specific antibody levels and asthma varies during life, with asthma associated with higher levels of IgG to RSV, RV-A and RV-C in children and lower levels of IgG responses to RV-A/B/C in adults.

Intermittent ozone inhalation during house dust mite-induced sensitization primes for adverse asthma phenotype

The ability of air pollution to induce acute exacerbation of asthma is well documented. However, the ability of ozone (O3), the most reactive gaseous component of air pollution, to function as a modulator during sensitization is not well established. C57BL/6 J male mice were intranasally sensitized to house dust mite (HDM) (40 μg/kg) for 3 weeks on alternate days in parallel with once-a-week O3 exposure (1 ppm). Mice were euthanized 24 h following the last HDM challenge. Lung lavage, histology, lung function (both forced oscillation and forced expiration-based), immune cell profiling, inflammation (pulmonary and systemic), and immunoglobulin production were assessed. Compared to HDM alone, HDM + O3 leads to a significant increase in peribronchial inflammation (p < 0.01), perivascular inflammation (p < 0.001) and methacholine-provoked large airway hyperreactivity (p < 0.05). Serum total IgG and IgE and HDM-specific IgG1 were 3–5 times greater in HDM + O3 co-exposure compared to PBS and O3-exposed groups. An increase in activated/mature lung total and monocyte-derived dendritic cells (p < 0.05) as well as T-activated, and T memory lymphocyte subset numbers (p < 0.05) were noted in the HDM + O3 group compared to HDM alone group. Concurrent O3 inhalation and HDM sensitization also caused significantly greater (p < 0.05) lung tissue interleukin-17 pathway gene expression and mediator levels in the serum. Redox imbalance was manifested by impaired lung antioxidant defense and increased oxidants. O3 inhalation during allergic sensitization coalesces in generating a significantly worse TH17 asthmatic phenotype.

Exploring Machine Learning Applications in Pediatric Asthma Management: Scoping Review.

The integration of machine learning (ML) in predicting asthma-related outcomes in children presents a novel approach in pediatric health care. This scoping review aims to analyze studies published since 2019, focusing on ML algorithms, their applications, and predictive performances. We searched Ovid MEDLINE ALL and Embase on Ovid, the Cochrane Library (Wiley), CINAHL (EBSCO), and Web of Science (core collection). The search covered the period from January 1, 2019, to July 18, 2023. Studies applying ML models in predicting asthma-related outcomes in children aged <18 years were included. Covidence was used for citation management, and the risk of bias was assessed using the Prediction Model Risk of Bias Assessment Tool. From 1231 initial articles, 15 met our inclusion criteria. The sample size ranged from 74 to 87,413 patients. Most studies used multiple ML techniques, with logistic regression (n=7, 47%) and random forests (n=6, 40%) being the most common. Key outcomes included predicting asthma exacerbations, classifying asthma phenotypes, predicting asthma diagnoses, and identifying potential risk factors. For predicting exacerbations, recurrent neural networks and XGBoost showed high performance, with XGBoost achieving an area under the receiver operating characteristic curve (AUROC) of 0.76. In classifying asthma phenotypes, support vector machines were highly effective, achieving an AUROC of 0.79. For diagnosis prediction, artificial neural networks outperformed logistic regression, with an AUROC of 0.63. To identify risk factors focused on symptom severity and lung function, random forests achieved an AUROC of 0.88. Sound-based studies distinguished wheezing from nonwheezing and asthmatic from normal coughs. The risk of bias assessment revealed that most studies (n=8, 53%) exhibited low to moderate risk, ensuring a reasonable level of confidence in the findings. Common limitations across studies included data quality issues, sample size constraints, and interpretability concerns. This review highlights the diverse application of ML in predicting pediatric asthma outcomes, with each model offering unique strengths and challenges. Future research should address data quality, increase sample sizes, and enhance model interpretability to optimize ML utility in clinical settings for pediatric asthma management.

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

Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome. 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). 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. 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.

Clinical and pathogenetic features and polymorphic gene variants in various phenotypes of occupational bronchial asthma

Clinical and pathogenetic features and polymorphic gene variants in various phenotypes of occupational bronchial asthma

Characterizing the Asthma Phenotype of Military Personnel.

Asthma is the most common diagnosis in military personnel who endorse chronic dyspnea. Service members have unique occupational risk factors, and there is concern that airborne exposures in the deployed environment as well as other occupational exposures may contribute to the development of asthma or exacerbate pre-existing disease. Asthma phenotyping with clinical biomarkers such as serum immunoglobulin E (IgE) levels and eosinophil (EOS) counts is useful in defining treatment strategies for the management of asthma. This study sought to characterize the phenotype of medically separated military personnel with career-limiting asthma to define potential management strategies and guide future research evaluating the unexplained prevalence of asthma in this population. A retrospective chart review of active duty service members (ADSM) who underwent fitness for duty evaluation via medical evaluation board between 2005 and 2016 and were separated with a minimum 30% conditional disability rating for asthma was performed. Only ADSM who were diagnosed with asthma by a pulmonologist and had spirometry data available were included in the analysis. Demographics, spirometry data, and laboratory data to include IgE levels, radioallergosorbent panels, and EOS counts were analyzed from the DoD electronic medical record. A total of 141 service members were evaluated with a mean age of 42 ± 6.8 years, mean serum EOS count of 300 ± 358 cells/μL, and mean IgE level of 305 ± 363 IU/mL. The patients were further categorized into 4 subgroups based on serum EOS count and IgE level: group A with IgE < 100 IU/mL and EOS < 300 cells/μL (n = 45; 33%), group B with IgE > 100 IU/mL and EOS < 300 cells/μL (n = 44; 32%), group C with IgE < 100 IU/mL and EOS > 300 cells/μL (n = 6; 1%), and group D with IgE > 100 IU/mL, EOS > 300 cells/μL (n = 46; 34%). Among the cohorts, there were no statistically significant differences in demographics, body mass index, spirometry, smoking history, or disability rating. The majority of ADSM with a defined asthma history do not have concordant elevations in serum IgE and blood EOS suggestive of a Th2-high phenotype. Asthma in this population is heterogeneous, and phenotyping using clinical biomarkers may be useful to define optimal treatment strategies.

Pulmonary adaptation to repeated poly(I:C) exposure is impaired in asthmatic mice: an observational study

BackgroundWhile asthma exacerbations remain a major challenge in patient management, few animal models exist to explore the underlying mechanisms. Here, we established an animal model of asthma that can be used to study pathophysiological mechanisms and therapeutic strategies on asthma exacerbation.MethodsFemale BALB/c mice were sensitized and exposed to PBS or Dermatophagoides pteronyssinus (DerP) extract for 11 weeks. Asthmatic phenotype was assessed through lung inflammation, bronchial hyperresponsiveness and bronchial smooth muscle remodeling. Asthmatic and control mice were exposed once or three times to poly(I:C) to simulate virus-induced inflammation.ResultsFourteen days after exposure to DerP, asthmatic mice showed resolution of inflammation with sustained bronchial hyperresponsiveness and bronchial smooth muscle remodeling compared to control. At this stage, when mice were subjected to a single exposure to poly(I:C), control and asthmatic mice were characterized by a significant increase in neutrophilic inflammation and bronchial hyperresponsiveness. When mice were repeatedly exposed to poly(I:C), control mice showed a significant decrease in neutrophilic inflammation and bronchial hyperresponsiveness, while asthmatic mice experienced worsening of these outcomes.ConclusionsThis observational study report an asthmatic mouse model that can undergo exacerbation after repeated exposure to poly(I:C). Our findings on pulmonary adaptation in control mice may also pave the way for further research into the mechanism of adaptation that may be impaired in asthma and raise the question of whether asthma exacerbation may be a loss of adaptation.

Single-cell analysis identifies distinct CD4+ T cells associated with the pathobiology of pediatric obesity-related asthma.

CD4+T cells from obese children with asthma are distinctly programmed for non-allergic immune responses, steroid resistance and inflammasome activation, that underlie the obese asthma phenotype.

The Impact of High-Fructose Diet and Co-Sensitization to House Dust Mites and Ragweed Pollen on the Modulation of Airway Reactivity and Serum Biomarkers in Rats.

The topic of ragweed pollen (RW) versus house dust mites (HDMs) has often been deliberated, but the increasing incidence of co-sensitization between them has been scarcely addressed. Utilizing Sprague Dawley rats, we explored the effects of co-sensitization with the combination of HDMs and RW pollen extracts in correlation with high-fructose diet (HFrD) by in vitro tracheal reactivity analysis in isolated organ bath and biological explorations. Our findings unveiled interrelated connections between allergic asthma, dyslipidemia, and HFrD-induced obesity, shedding light on their compounding role through inflammation. The increased CRP values and airway hyperresponsiveness to the methacholine challenge suggest a synergistic effect of obesity on amplifying the existing inflammation induced by asthma. One of the major outcomes is that the co-sensitization to HDMs and RW pollen led to the development of a severe allergic asthma phenotype in rats, especially in those with HFrD. Therefore, the co-sensitization to these allergens as well as the HFrD may play a crucial role in the modulation of systemic inflammation, obesity, and airway reactivity.

Non-Invasive Detection of Cytokines in Saliva Towards Asthma Phenotyping Using an Electrochemical Sensor

Introduction: Asthma is a complicated and heterogeneous condition of the lungs which is usually associated with the chronic inflammation of the airways. Traditionally, classification of asthma has been based on clinical attributes such as the symptoms observed and response to treatment. However, with the growing understanding of the heterogeneity of asthma as a spectrum with varying underlying causes, asthma phenotyping has been on the horizon. Cytokines are the chemical messengers that play a crucial role in the immune system. They mediate communication between the cells in the immune system and as such have a direct effect on the inflammation process. The role of some cytokines has been established in the pathogenesis of asthma. Due to the involvement of cytokines in the modulation of asthma, they can be excellent target for asthma phenotyping. This is also helpful because identification and quantification of these inflammatory mediators can allow for more precise medicine for more targeted treatment. To aid the identification and quantification of cytokines in the phenotyping of asthma, we have created a customizable (currently for IL-8 and IL-10) multi-marker electrochemical platform for the detection of cytokines non-invasively in saliva. The developed electrochemical platform can detect cytokines rapidly and non-invasively within reported physiological ranges of the given cytokines. Evaluating the presence and quantity of the cytokines will be useful in the phenotyping and treatment plans adopted by physicians.Materials and Methods: The electrochemical sensor consists of 6 multiplexed gold electrodes on a PCB substrate. IL-8 and IL-10 antibodies were immobilized onto the sensor surface using a gold-thiol linker chemistry. Sensor response was evaluated with non- faradaic Electrochemical Impedance Spectroscopy (nf-EIS). Pooled human saliva was spiked with increasing doses of IL-8 and IL-10 in their respective physiological ranges to develop a dose response curve. Spike and recovery experiments were conducted to validate the efficacy of dose response curve.Results and Discussion: Sensor response to both IL-8 and IL-10 spiked doses in pooled saliva showed a dose-dependent response to increasing concentrations of IL-8 and IL-10 respectively as illustrated by the Nyquist plots in Fig.1. The change in impedance with increasing doses of IL-8 and IL-10 in pooled human saliva lends to credence to the establishment of the presence and quantification of cytokines in saliva that can be used by clinicians and scientists alike in the further development of personalized medicine for severe asthmatics unresponsive to traditional asthmatic treatments.Conclusion: This study presents a noninvasive electrochemical sensor for rapid and early detection of cytokines in pooled human saliva towards asthma phenotyping. The sensor exhibits a dose dependent response to IL-8 and IL-10, markers implicated in pathogenesis of asthma. Sensor capability was demonstrated with spike and recovery experiments illustrating the ability of the developed electrochemical sensor to detect and quantify cytokines in human saliva. Figure 1