Eosinophilic Inflammation Research Articles

The anti-inflammatory role of therapeutic ultrasound and low-level laser in chronic rhinosinusitis: A fractional exhaled nitric oxide outcome hypothesis

Chronic rhinosinusitis is defined as a complex of disorders whose main feature is nasal and paranasal sinus mucosal inflammation for at least three months. Inflammation plays a key role in chronic rhinosinusitis. Fractional exhaled nitric oxide is used to monitor eosinophilic airway inflammation in the human lower airways. Fractional exhaled nitric oxide levels are paradoxically low in some chronic rhinosinusitis patients. This has been attributed to sinus ostia obstruction. However, a recent study has demonstrated that fractional exhaled nitric oxide levels could serve as a chronic rhinosinusitis inflammation biomarker independent of lower airway inflammatory disease and could be used as a treatment response biomarker. Therapeutic ultrasound and low-level laser therapy have been used in chronic rhinosinusitis management. Through a variety of mechanisms, ultrasound enhances bacterial killing. Low level laser therapy increases nitric oxide release and ATP levels. It also reduces inflammation and accelerates tissue repair. Fractional exhaled nitric oxide levels could be used to evaluate the anti-inflammatory actions of therapeutic ultrasound and low-level laser therapy in chronic rhinosinusitis patients. A hypothesis that fractional expired nitric oxide measurements could be a useful biomarker to evaluate their potential anti-inflammatory mechanisms and monitor their treatment efficacy is proposed. This could contribute to a better understanding of these therapies in chronic rhinosinusitis management. An improved understanding of treatment efficacy could lead to improved management strategies.

Integrative Cross-Talk in Asthma: Unraveling the Complex Interactions Between Eosinophils, Immune, and Structural Cells in the Airway Microenvironment

Asthma is a chronic inflammatory process that leads to airway narrowing, causing breath loss followed by spasms, wheezing, and shortness of breath. Within the asthmatic lungs, interaction among various immune cells and structural cells plays a significant role in orchestrating an inflammatory response in which eosinophils hold central importance. In these settings, allergens or other environmental exposures commonly drive the immune response to recruit eosinophils to the airways. The appearance of eosinophils in the airways indicates a dynamic interplay of various cell types within lung tissue and does not represent a passive effect of inflammation. The cellular cross-talk causes the persistence of eosinophilic inflammation, and if left untreated, it results in long-term damage to the airway structure and function. Further exacerbation of the condition occurs because of this. We discuss how this complex interplay of eosinophils, immune, and structural cells within the airway microenvironment leads to the distinct pathophysiological features in asthma, the variability in disease severity, and the response to biological treatments.

Examining the effect of salbutamol use in ozone air pollution by people with exercise-induced bronchoconstriction.

Previous studies based on animal models have raised concerns about salbutamol use in ozone air pollution with regard to ozone related lung injury. We conducted a double-blind, randomized, placebo-controlled crossover study including 18 subjects diagnosed with EIB by a eucapnic voluntary hyperpnea (EVH) test. Participants completed 30 min of standardized moderate to vigorous exercise in four conditions: ozone plus salbutamol; room air plus salbutamol; ozone plus placebo medication; and room air plus placebo medication. Spirometry, fraction of exhaled nitric oxide, and symptoms were measured before, immediately after, 30 min after and 1 h after exercise. Measurements between the four conditions were compared using percent change from pre to post exercise. There was a statistically significant difference between the salbutamol and placebo medication groups for spirometric variables including FEV1 (Estimate = 6.3, 95% CI: 4.23-8.37, p < 0.001). No differences were observed between ozone and room air exposures. There were no significant differences in FeNO response between experimental conditions. We found that salbutamol improved pulmonary function in individuals with EIB when exercising in ozone and did not increase eosinophilic airway inflammation as indicated by FeNO. This evidence suggests that it is safe for people with EIB to continue to use salbutamol as proscribed when ozone levels are elevated.

Long-Term Exposure to Nitrogen Dioxide and Ozone and Respiratory Health in Children.

Further evaluation of the impact of long-term exposure to the gaseous air pollutants nitrogen dioxide (NO2) and ozone (O3) on child lung function, and of NO2 or O3 on eosinophilic airway inflammation, is needed. To determine whether NO2 and O3 are associated with lung function and FeNO in children. We measured lung function (FEV1 and FVC) at mid-childhood (mean age 7.9 years, n=703), early teens (13.2 years, n=976), and mid-teen (17.6 years, n=624) study visits, and fractional exhaled nitric oxide (FeNO) at the early and mid-teen study visits in Project Viva, a cohort of mother-child pairs in the Boston, MA area. Long-term exposure to NO2 and O3 was estimated at home address using geospatial models. We examined associations of home address NO2 and O3 exposure and proximity to roadway with lung function and FeNO using linear regression models, adjusting for age, sex, height, weight, season, relative humidity, temperature, parental smoking, and measures of socioeconomic status. We examined for effect modification of the mid-teen associations by blood eosinophil level, physical activity, aeroallergen sensitization, and parental atopy. Median exposure to NO2 was 33.1 ppb (interquartile range [IQR] 10.4 ppb) and to O3 was 35.3 ppb (IQR 3.4) in the first year of life. Exposure to NO2 was associated with lower FEV1 and FVC across all age groups and exposure time intervals: e.g. an IQR increment of NO2 exposure from birth through the early teen visit was associated with 189.9 mL lower FEV1 (95% CI -273.3, -106.5) at the mid-teen visit. Lifetime NO2 exposure at was associated with higher FeNO at the early teen visit: e.g. 16.2% higher FeNO [95% CI 7.1-26.4%) per IQR of lifetime NO2 through the early teen visit. O3 exposure was not associated with lung function or FeNO. Aeroallergen sensitization (measured in a subset of participants) modified associations of NO2 and O3 with FeNO. Exposure to NO2 was associated with lower lung function and higher FeNO among generally healthy children and teenagers. As NO2 exposure levels were within the annual EPA standard, these findings suggest a need to reduce exposure to this pollutant to optimize child respiratory health.

Rank correlation between atopic comorbidity and laboratory parameters in allergic rhinitis

One of the current cutting-edge problems in allergy and ENT is the study of comorbidity in allergic rhinitis, which is the most common atopic disease among all other atopies. Two decades ago, a new endotype of the disease, local allergic rhinitis, was discovered. In the past, some patients with typical complaints of chronic nasal congestion, persistent runny nose, and other similar symptoms, did not display such characteristic diagnostic criteria as positive allergy skin tests and an increased value of serum total IgE and specific IgE antibodies. They were qualified by allergists and ENT specialists as individualists with non-allergic rhinitis and, accordingly, did not receive adequate treatment. However, their symptoms remained, prompting them to abuse decongestants and resulting in an increased burden on the cardiovascular system. This, along with the burden of concomitant pathology, including other atopies, can be considered a significant medical and social problem. With the purpose to study rank correlation between comorbidity and three laboratory biomarkers, 46 patients with allergic rhinitis were examined. The list of parameters included two routine items such as serum total IgE and eosinophilic cationic protein, and rarely studied IL-4 in skin exudate. Clinical analysis showed that significantly more often allergic rhinitis in patients was combined with bronchial asthma (in 39.1%, p 0.05), less often with food allergy (in 19.6%), atopic dermatitis (in 10.9%), insect allergy (in 8.7%), and allergic urticaria (in 4.5%). In one case, local perennial rhinitis was identified, accompanied by conventional seasonal rhinitis with a high content of serum total IgE and positive allergic skin tests with pollen allergens. Skin tests with household allergens, including house dust mite products, showed a negative result. This case was regarded as a manifestation of the so-called “double” allergic rhinitis. The Spearman correlation demonstrated a negative mean strength relationship between comorbidity and serum IgE and eosinophilic cationic protein (p 0.05). The seemingly paradoxical result can be interpreted quite logically, taking into account immunopathogenetic mechanisms of allergic inflammation. In particular, with an increase in the frequency of atopic comorbidity, the migration of eosinophils from the blood to sites of eosinophilic inflammation increases.

Enhanced immunomodulatory properties of ovalbumin through transglutaminase and tyrosinase/caffeic acid-catalyzed crosslinking plus galactomannan conjugation alleviates allergic asthma

Ovalbumin (OVA) is the primary allergenic protein, associated with T helper 2 (Th2)-mediated allergy reactions. Here, we studied OVA’s conformational structure, digestibility, and allergenic potency upon galactomannan (Man) conjugation along with transglutaminase-catalyzed crosslinking (TG-Man/OVA) and tyrosinase/caffeic acid-catalyzed crosslinking (Tyr-Man/OVA). Enzymatic glycosylation altered OVA’s conformation and enhanced the gastrointestinal digestibility. Stimulation of bone marrow-derived dendritic cells (BMDCs) with enzymatically glycosylated OVA reduced the expression of CD40, CD80, CD86 and MHC class II molecules. Furthermore, glycosylated OVA increased IL-10 production while suppressing proinflammatory cytokine production in BMDCs. In an OVA-induced mouse asthma model, TG-Man/OVA and Tyr-Man/OVA upregulated IFN-γ and IL-10 expression and downregulated IL-4, IL-5, and IL-13 in lungs. Crosslinked OVA diminished infiltrated cells in bronchoalveolar lavage fluid and lung and attenuated eosinophilic airway inflammation. These findings offer valuable insights into the development of a novel product with improved hypoallergenic and immunomodulatory properties and hold promise in attenuating allergic diseases.

Role of Thymic Stromal Lymphopoietin in the Pathophysiology of Asthma and Clinical and Biological Effects of Blockade With Tezepelumab.

The airway epithelium is the first line of defense of the respiratory system against the external environment. It plays an active role in the initiation of immune and allergic responses against potential hazards. Among the various specialized cells and cytokines that participate in epithelium-induced responses, alarmins are particularly interesting, given their ample role in mediating T2 and non-T2 inflammatory mechanisms involved in the pathogenesis of asthma. Thymic stromal lymphopoietin (TSLP) is an alarmin with broad effects in asthma that result from its widespread action on multiple cell types, including eosinophils, mast cells, dendritic cells, and group-2 innate lymphoid cells. Its role in allergy-mediated responses, eosinophilic inflammation, airway hyperresponsiveness, mucus hyperproduction, viral tolerance, and airway remodeling is of the utmost importance, as more comprehensive asthma assessments have been developed to explore these pathogenic features. Therefore, blockade with targeting molecules, such as monoclonal antibodies, has emerged as a promising therapeutic option, particularly in patients with multiple pathogenic pathways. In this review, we examine the roles of alarmins (mainly TSLP) in the pathogenesis of asthma and clinical expression and discuss the effects of inhibiting TSLP on several inflammatory and clinical outcomes. We also review the literature supporting treatment with anti-TSLP biologics and the unanswered questions and unmet needs associated with targeting alarmins in asthma.

Correlation between Lund-Mackay computed tomography score and subjective symptoms in Chinese patients with nasal polyps.

The association between objective imaging findings and subjective symptoms remains undefined. To investigate the correlation between objective imaging findings and symptom severity in the overall chronic rhinosinusitis with nasal polyps (CRSwNP) population as well as its subendotypes according to the eosinophilic inflammation. Patients with CRSwNP undergoing endoscopic sinus surgery were included. All participants completed the Sino-Nasal Outcome Test (SNOT-22) questionnaire. The Lund-Mackay (LM) CT scores was also obtained. Spearman correlation analysis was performed to evaluate the correlation between CT scores and SNOT-22 scores. Forty-four non-eosinophilic CRSwNP(neCRSwNP) and 93 eosinophilic CRSwNP (eCRSwNP) patients were recruited. There was significant association between LM total score and nasal subdomain of SNOT-22 in the overall CRSwNP patients. The nasal symptom of SNOT-22 was significantly associated with maxillary, frontal, sphenoid, anterior drainage, and posterior drainage in all CRSwNP patients. In eCRSwNP and neCRSwNP patients, the sense of smell/taste was associated with sphenoid and posterior drainage. Thick nasal discharge was positively correlated with maxillary, frontal, and anterior drainage only in eCRSwNP patients. The high score of sphenoid and posterior drainage may suggest the occurrence of loss of sense of smell/taste, while high score of maxillary sinus may indicate suffering from thick nasal discharge in eCRSwNP patients.

Expression of Epithelial Alarmin Receptor on Innate Lymphoid Cells Type 2 in Eosinophilic Chronic Obstructive Pulmonary Disease.

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5+ILC2s and TSLPR+ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5+ILC2s, IL-17RB+ILC2s and ST2+ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

Blood eosinophil count correlates with alveolar damage in emphysema-predominant COPD

BackgroundAlthough blood eosinophil count is recognized as a useful biomarker for the management of chronic obstructive pulmonary disease (COPD), the impact of eosinophils in COPD has not been fully elucidated. Here we aimed to investigate the relationships between the blood eosinophil count and various clinical parameters including lung structural changes.MethodsNinety-three COPD patients without concomitant asthma were prospectively enrolled in this study. Blood eosinophil count, serum IgE level, serum periostin level, and chest computed tomography (CT) scans were evaluated. Eosinophilic COPD was defined as COPD with a blood eosinophil count ≧ 300/µL. We examined the correlation between the blood eosinophil count and structural changes graded by chest CT, focusing specifically on thin airway wall (WT thin) and thick airway wall (WT thick) groups. In a separate cohort, the number of eosinophils in the peripheral lungs of COPD patients with low attenuation area (LAA) on chest CT was assessed using lung resection specimens.ResultsThe mean blood eosinophil count was 212.1/µL, and 18 patients (19.3%) were categorized as having eosinophilic COPD. In the whole group analysis, the blood eosinophil count correlated only with blood white blood cells, blood basophils, C-reactive protein level, and sputum eosinophils. However, the blood eosinophil count positively correlated with the percentage of LAA and negatively correlated with the diffusing capacity for carbon monoxide in the WT thin group. Lung specimen data showed an increased number of eosinophils in the peripheral lungs of COPD patients with LAA on chest CT scans compared to normal controls.ConclusionsSome COPD patients without concomitant asthma showed a phenotype of high blood eosinophils. Alveolar damage may be related to eosinophilic inflammation in patients with COPD without asthma and thickening of the central airway wall.

Additive Effect of Blood and Tissue Eosinophilia on ChronicRhinosinusitis With Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with varied clinical features and treatment effects. This study aimed to investigate the additive effect of blood and tissue eosinophilia on patients with CRSwNP. Based on the blood eosinophil (Beos) count and tissue eosinophil (Teos) count, we divided 144 CRSwNP patients into four groups, analysed their clinical features and histopathologic changes, and investigated their postoperative control. Patients in the Beos+Teos+ (blood eosinophil count > 0.3 × 109/L, tissue eosinophil count > 10/HPF) group had a higher incidence of allergic rhinitis (AR) and asthma. Lund-Mackay (LM) scores, hyposmia visual analogue scale (VAS) scores and Global Osteitis Scoring Scale (GOSS) scores were higher in the Beos+Teos+ group than those in the other groups. Tissue remodelling, such as connective tissue oedema and basement membrane thickening was more severe in the Beos+Teos+ group compared with other groups. There were more uncontrolled patients after surgery in Beos+Teos+, Beos+Teos- (blood eosinophil count > 0.3 × 109/L, tissue eosinophil count ≤ 10/HPF)and Beos-Teos+ (blood eosinophil count ≤ 0.3 × 109/L, tissue eosinophil count > 10/HPF)groups compared with the Beos-Teos- group. Eosinophilic inflammation both in blood and tissue was accompanied by more severe clinical features and tissue remodelling. Eosinophilia in blood or tissue indicated poorer disease control after surgery.

Efficacy and safety of benralizumab in eosinophilic granulomatosis with polyangiitis: A meta-analysis of eight studies.

Eosinophilic granulomatous polyangiitis (EGPA) is a rare autoimmune disease characterized by multisystemic inflammation, with eosinophils playing a central role in its pathogenesis. Traditional management relies heavily on corticosteroids and immunosuppressants, which are associated with significant side effects. The emergence of biologic agents, such as benralizumab, offers targeted therapeutic options by inhibiting the interleukin-5 receptor α, thereby reducing eosinophilic inflammation. This systematic review and meta-analysis comprehensively evaluate the efficacy and safety of benralizumab in EGPA patients, focusing on its ability to reduce oral corticosteroid (OCS) use, facilitate remission and spare immunosuppressants. We searched MEDLINE, LILACS and ISI Web of Science databases for relevant studies up to July 2024. Eight studies, including both randomized controlled trials (RCTs) and observational studies, were included in the meta-analysis, involving a total of 396 EGPA patients. The pooled analysis demonstrated a significant reduction in OCS dose, with an overall estimated effect of -8.25 mg/day (95% CI, -9.39 to -7.10). Complete remission was achieved in 56.8% of patients, and immunosuppressants were reduced or discontinued in 28.1% of cases. Adverse events (AEs) were reported in 21.9% of patients, with only one discontinuation due to an AE. These findings provide robust evidence supporting the use of benralizumab as an effective and well-tolerated treatment option for EGPA, significantly reducing OCS requirements and offering promising remission rates. Future research should focus on larger, multicentre RCTs to confirm these findings and further elucidate the long-term benefits and safety profile of benralizumab in EGPA.

Phenotypic Shift of an Inflammatory Eosinophil Subset into a Steady-State Resident Phenotype after 2 Years of Vaccination against IL-5 in Equine Insect Bite Hypersensitivity

Eosinophils play a key role in allergic diseases such as insect bite hypersensitivity (IBH). Together with Th2 cells, they shape the course of inflammation in associated type I/IVb allergies. Therefore, a virus-like particle (VLP)-based vaccine targeting equine interleukin-5 (eIL-5), eIL-5-CuMV-TT, was developed to interfere with the IL-5 dependency of eosinophils by inducing the production of anti-self-IL-5 antibodies and alleviating clinical signs in IBH-affected horses. A previous study highlighted the presence of two eosinophil subsets, steady-state resident eosinophils (rEos) and inflammatory eosinophils (iEos), circulating in the blood of healthy and IBH-affected horses, distinguishable by the expression of integrin CD49f. Furthermore, eIL-5-CuMV-TT 1st year vaccination showed a significant decrease of total eosinophils and, in particular, iEos. Nevertheless, the very few remaining eosinophils still shared an iEos phenotype, reflected by bigger size and higher granularity. The aim of this study was to follow up on the phenotype of eosinophils in the 2nd year of vaccination of IBH-affected horses with eIL-5-CuMV-TT. Using flow cytometry analysis of the blood of healthy, IBH, IBH-placebo, and IBH-vaccinated horses, the percentage and count of cells were compared between groups with a focus on pair analysis of eosinophils in 1st and 2nd year vaccinated horses. Our data showed comparably low levels of iEos and a significant increase of rEos in 2nd year compared to 1st year vaccinated horses, suggesting a phenotypic shift toward a resident-like eosinophil population, primarily associated with the phenotype of healthy horses. The reduction of size, granularity, and expression of integrin CD49f in the 2nd year suggests a benefit of long-term treatment with the eIL-5-CuMV-TT vaccine.

Blood transcriptomics reveal systemic eosinophilic and neutrophilic inflammation patterns in patients with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic sinonasal disease characterized by heterogeneous inflammation. However, the presence of systemic inflammation heterogeneity in CRSwNP patients remains unknown. This study aims to profile transcriptomic alterations in the blood of CRSwNP patients and characterize the CRSwNP heterogeneity based on blood transcriptomic biomarkers. Patients with CRSwNP were prospectively recruited from three hospitals and chronologically divided into exploratory (n=123) and independent validation (n=46) cohorts. Transcriptomic profiles were generated by whole blood mRNA sequencing and subjected to patient clustering, differential expression, and pathway analysis. Differences in immune pattern and clinicopathologic features between clusters were assessed. A transcriptomic signature was defined and applied to an independent cohort to validate the findings. CRSwNP patients showed diverse blood transcriptomic profiles versus healthy controls, or when stratified by tissue and blood eosinophils and asthma comorbidity. Transcriptome-wide correlation analysis revealed a transcriptional signature associated with blood eosinophil levels, consisting of nine T2-related genes (CLC, SIGLEC8, ALOX15, IL5RA, PTGDR2, CCL23, CCR3, EPX and IL1RL1). Three distinct clusters with differing systemic eosinophilic and neutrophilic inflammation patterns and asthma comorbidity were identified based on transcriptomic profiling of T2 and T1/3-related blood biomarkers. A 36-gene signature was developed by machine learning and accurately predicted the three CRSwNP subtypes. Validation on an independent cohort confirmed the prediction robustness. There is heterogeneous systemic inflammation associated with eosinophilic and neutrophilic patterns in patients with CRSwNP. Endotyping based on blood transcriptomic biomarkers might lead to more personalized treatment strategies for CRSwNP in the future.

NFATc1 in CD4+ T cells and CD11c+ dendritic cells drives TH2-mediated eosinophilic inflammation in allergic asthma

BackgroundAsthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased Th2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells (ILCs), B cells, and effector cells. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood. ObjectiveExplore NFATc1’s role in T cells and dendritic cells in modulating Th2 immune responses within the pathophysiology of allergic asthma. MethodsMice lacking Nfatc1 in CD4+T cells or CD11c+ dendritic cells, were induced with asthma using house dust mite (HDM), enabling investigation into NFATc1's role in both cell types in experimental allergic asthma. Additionally, the study examined NFATc1 expression in these cells and its correlation with blood eosinophil levels in an adult asthma cohort. ResultsIn HDM-induced asthma model, we found that Nfatc1 deficiency either in CD4+ T cells or CD11c+ dendritic cells resulted in reduced Th2-driven eosinophilic inflammation, immunoglobulin E (IgE) levels, and mast cell presence in the lung of asthmatic mice. Nfatc1's absence in CD4+ T cells directly hampered Th2 cell polarization and functionality, whereas in CD11c+ dendritic cells, it affected DC differentiation and maturation, thereby weakening T cell priming, proliferation and subsequent Th2 differentiation. Correspondingly, translational research indicated significant correlations between CD4+NFATc1+ and CD11c+NFATc1+ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls. ConclusionNFATc1 in T cells and dendritic cells modulate Th2-mediated eosinophilic inflammation in allergic asthma, which offering insights into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.

(FEV3-FEV1)/FVC: A Terminal-Airflow Variable for Airway Hyperresponsiveness and Inflammation Prediction in Patients With Symptoms Despite Preserved Spirometry

BackgroundSmall-airway function assessment is crucial for asthma diagnosis and management. Abnormalities in terminal airflow deserve attention. ObjectiveThis study investigated whether the ratio of forced expiratory volume in the second and third seconds to forced vital capacity ([FEV3-FEV1]/FVC) correlates with airway hyperresponsiveness (AHR) and inflammation in patients with preserved spirometry. MethodsThis cross-sectional study enrolled patients with FEV1 ≥ 80% predicted, FEV1/FVC ≥ 0.7, and recurring asthma-like symptoms. Data included demographics, fractional exhaled nitric oxide (FeNO), impulse oscillometry, and spirometry. Univariate and combined models predicting AHR was analyzed in 553 patients and validated in 561. Correlations between sputum inflammation and spirometrics were also assessed. ResultsAHR+ patients exhibited higher (FEV3-FEV1)/FVC ratios compared to AHR-. This ratio showed the strongest association with the methacholine dose causing a 20% FEV1 decrease (PD20) and the response dose ratio (RDR)(r = -0.26 and 0.39, respectively; P < .001, both). The area under the receiver operating characteristic curve for AHR diagnosis using (FEV3-FEV1)/FVC was 0.751, increasing to 0.821 when combined with FeNO, confirmed in the validation cohort. (FEV3-FEV1)/FVC was superior to maximal expiratory flow at 50% of forced vital capacity for identifying eosinophilic airway inflammation characterized by elevated FeNO levels. It correlated better with sputum eosinophil count than with the other spirometrics. ConclusionElevated (FEV3-FEV1)/FVC were evident in AHR+ patients with preserved FEV1/FVC ratios. It serves as a sensitive marker of AHR and airway inflammation correlating with RDR, PD20, and sputum eosinophils, suggesting its utility in monitoring patients at risk for uncontrolled asthma.

Transcriptional profiles of peripheral eosinophils in chronic obstructive pulmonary disease and asthma-An exploratory study.

The role of eosinophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains ambiguous and likely differs from its role in asthma. The molecular processes underlying the differences between eosinophils from asthma and COPD have not been sufficiently studied. The objective of this study was to compare the transcriptomic profiles of blood eosinophils in COPD and asthma. Eosinophils were isolated from peripheral blood drawn from stable mild-to-moderate COPD and asthma patients. RNA was isolated from eosinophils and sequenced using an NGSelect RNA. The prepared libraries were sequenced on an Illumina platform. The study group included five patients with asthma and four patients with COPD. The RNA-Seq data analysis identified 26 differentially expressed genes between COPD and asthma (according to adjusted p-value). In total, 6 genes were upregulated (e.g. CCL3L1, CCL4L2, GPR82) and 20 were downregulated (e.g. JUN, IFITM3, DUSP1, GNG7) in peripheral eosinophils of COPD patients compared to asthma. The genes associated with signalling of IL-4 and IL-13 pathways were downregulated in COPD eosinophils compared to asthma. In conclusion, blood eosinophils from COPD and asthma patients present different transcriptomic profiles suggesting their different function in pathobiology of both obstructive airway diseases. These differences might indicate the direction of the search of targeted therapy in COPD.

Long-term efficacy of mepolizumab on eosinophilic granulomatosis with polyangiitis: a retrospective study

Aim: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Patients with EGPA are treated with systemic glucocorticoids and immunosuppressive drugs to induce and maintain remission. However, most patients relapse after tapering glucocorticoids, and there are refractory cases with inadequate response to glucocorticoids. Mepolizumab, a humanized anti-IL-5 antibody, is approved for relapsing or refractory EGPA. Furthermore, recent studies have reported the efficacy of benralizumab, a humanized anti-IL-5 receptor α antibody, in EGPA. Here, we investigate the efficacy of biologics on consecutive cases of EGPA. Methods: We retrospectively collected patients with EGPA treated with mepolizumab in addition to glucocorticoids at the Department of Pulmonary Medicine in Kagoshima University Hospital and Imakiire General Hospital. In this study, we compared the effects of biologics on inflammatory parameters between pre- and post-treatment of biologics in patients with EGPA. Results: Ten patients were included in the study. All patients were treated with mepolizumab, and one was switched to benralizumab later. Treatment with biologics markedly reduced EGPA relapse from 70% (pre-treatment) to 20% (post-treatment), Birmingham Vasculitis Activity Score from 8.4 to 4.0, peripheral blood eosinophil counts from 470.3 /µL to 40.5 /µL, and glucocorticoid doses from 7.3 mg/dL to 1.6 mg/dL. In contrast, lung function and fractional exhaled nitric oxide levels were not affected by treatment with biologics. Furthermore, the duration of biologics was positively correlated with symptom improvement. Conclusions: Treatment with mepolizumab for EGPA was effective in glucocorticoid sparing, symptom reduction, and relapse prevention. Mepolizumab is expected to reduce the risk of glucocorticoid-related adverse events. Therefore, continued administration as well as early intervention with mepolizumab for EGPA might be important to conserve future medical resources and control the disease.

Interleukin-33-activated basophils promote asthma by regulating Th2 cell entry into lung tissue.

Asthma is characterized by lung eosinophilia, remodeling, and mucus plugging, controlled by adaptive Th2 effector cells secreting IL-4, IL-5, and IL-13. Inhaled house dust mite (HDM) causes the release of barrier epithelial cytokines that activate various innate immune cells like DCs and basophils that can promote Th2 adaptive immunity directly or indirectly. Here, we show that basophils play a crucial role in the development of type 2 immunity and eosinophilic inflammation, mucus production, and bronchial hyperreactivity in response to HDM inhalation in C57Bl/6 mice. Interestingly, conditional depletion of basophils during sensitization did not reduce Th2 priming or asthma inception, whereas depletion during allergen challenge did. During the challenge of sensitized mice, basophil-intrinsic IL-33/ST2 signaling, and not FcεRI engagement, promoted basophil IL-4 production and subsequent Th2 cell recruitment to the lungs via vascular integrin expression. Basophil-intrinsic loss of the ubiquitin modifying molecule Tnfaip3, involved in dampening IL-33 signaling, enhanced key asthma features. Thus, IL-33-activated basophils are gatekeepers that boost allergic airway inflammation by controlling Th2 tissue entry.

Clinical characteristics analysis of persistent airflow limitation in asthmatic children

Objective: To analyze the clinical characteristics of asthmatic children with persistent airflow limitation (PAL) in order to improve understanding of PAL and improve asthma management. Methods: The clinic data of asthmatic children aged 6 to 18 years with and without PAL, who visited the Department of Allergy at Children's Hospital of the Capital Institute of Pediatrics between January 2021 and June 2023, were analyzed retrospectively. The study included a total of 197 patients (153 males and 44 females), with a median age of 9.0 (7.0, 12.0) years. The analysis encompassed demographic features, disease-related factors, laboratory tests, and spirometry parameters. Quantitative data differences between the two groups were assessed using the Student's t-test or the Mann-Whitney U test. Qualitative data comparisons were made using the Chi-square test or Fisher's exact test. Results: This study included 100 non-PAL and 97 PAL patients. The female-to-male ratio in the two groups was 27/73 and 17/80, respectively. Age and BMI were 11.0 (10.0, 13.0) years and 20.3 (17.7, 24.1) kg/m2 in the PAL group, which was significantly higher than in the non-PAL group (P<0.001). Among the PAL group, 49.5% fell within the 9-12 age group. The PAL group had a higher percentage of patients with an asthma duration of more than 3 years (89.7% vs. 62.0%, P<0.001) and a history of pneumonia (13.4% vs. 4.0%, P=0.036) compared to the non-PAL group. Regarding laboratory tests, a higher percentage of patients in the PAL group had an elevated FeNO level (60.9% vs. 37.6%, P=0.002) and animal sensitization (50.7% vs. 30.7%, P=0.022) compared to the non-PAL group. Of the 69 patients who underwent spirometry before and after PAL development, FEV1%pred, FEV1/FVC, and MMEF%pred values gradually decreased, with a significant decline in the year preceding PAL development. Conclusions: Asthmatic children with PAL had characteristics such as relatively older age, higher BMI, longer duration of asthma, eosinophilic inflammation, and atopy. Lung function decline occurred several years before PAL development. Long-term follow-up should focus on the evolving trend of spirometry parameters.