Eosinophilic Inflammation Research Articles

Fraction of exhaled nitric oxide is higher in liver transplant recipients than in controls from the general population: a cohort study.

Fraction of exhaled nitric oxide with an expiratory flow of 50 mL/s (FENO50) is a biomarker of eosinophilic airway inflammation. Liver transplant recipients have an increased risk of pulmonary infections, but little is known about the burden of chronic pulmonary diseases in this group. We aimed to assess the prevalence of elevated FENO50 in liver transplant recipients and compare it to controls from the general population. FENO50 was measured in 271 liver transplant recipients from The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study and 1,018 age- and sex-matched controls from The Copenhagen General Population Study (CGPS). Elevated FENO50 was defined as ≥25 or ≥50 parts per billion (ppb). The analyses were adjusted for known and suspected confounders. The median age of the liver transplant recipients was 55 years (interquartile range (IQR) 46-64), and 58% were men. The liver transplant recipients had a higher median FENO50 than the controls [16 ppb (IQR 10-26) vs. 13 ppb (IQR 8-18.), p < 0.001]. Furthermore, the liver transplant recipients had a higher prevalence of elevated FENO50 (for FENO50 ≥25 ppb 27% vs. 11%, p < 0.001 and ≥50 ppb 4% vs. 2%, p = 0.02). The results were similar after adjusting for age, sex, smoking status, use of airway medication, and blood eosinophil counts [the adjusted odds ratio (OR) for FENO50 ≥25 ppb was 3.58 (95% CI: 2.50-5.15, p < 0.0001) and the adjusted OR for FENO50 ≥50 ppb was 3.14 (95% CI: 1.37-7.20, p = 0.007)]. The liver transplant recipients had elevated FENO50, implying increased eosinophilic airway inflammation. The clinical impact of this finding needs further investigation.

When sequential use of mepolizumab and dupilumab in a severe atopic eosinophilic asthmatic questions the role of eosinophils in mediating the clinical expression of the disease: a case report

BackgroundThe advent of biologics has resulted in major progress in the treatment of severe T2 high asthmatics. There are currently several classes of biologics approved for severe asthma including anti-immunoglobulin E, anti-interleukin-5/interleukin 5R, anti-interleukin 4/interleukin 13R, and anti-thymic stromal lymphopoietin.Case presentationsHere we report the case of a 55-year-old Caucasian man with severe eosinophilic atopic asthma, who sequentially benefited from a treatment with mepolizumab, an anti-interleukin-5 monoclonal antibody, followed by treatment with dupilumab, an anti-interleukin-4/interleukin-13R antibody, the switch being justified by a flare-up of dermatitis while on mepolizumab. Overall, the patient has been followed for 72 months, including 42 months on mepolizumab and 30 months on dupilumab. Close monitoring of exacerbations, asthma control, lung function, asthma quality of life, and biomarkers shows that both biologics reduced asthma exacerbation and provided an improvement in asthma control and quality of life, with the patient achieving remission after 30 months on dupilumab. However, the effects of the two biologics on the biomarkers were very different, with mepolizumab controlling eosinophilic inflammation and dupilumab reducing serum immunoglobulin E and fractional exhaled nitric oxide levels.ConclusionThe originality of this case resides in the description of clinical status and biomarker evolution after a sequential use of mepolizumab and dupilumab in a severe atopic eosinophilic asthmatic. It shows that mepolizumab reduces exacerbation and improves asthma control by curbing eosinophilic inflammation whereas dupilumab provides asthma remission without controlling airway eosinophilic inflammation.

P571 The Effect of NLRX1 Activation on Eosinophils in Ulcerative Colitis and Inflammation: Translational Learnings Across Diseases and from Mouse to Human

Abstract Background Although the precise role of eosinophils in IBD is debated, elevated eosinophils may influence response to therapy and clinical outcomes1. Thus, therapeutic agents which affect both neutrophil and eosinophil recruitment may provide more robust clinical improvement in patients with UC. NLRX1 is an immunometabolic protein which reduces oxidative stress, shifts cellular metabolism, and decreases inflammation in multiple cell types implicated in ulcerative colitis (UC). Studies of NLRX1 agonists (gut-selective NX-13 &amp; systemic LABP-73) in diverse disease models identified novel cellular targets of NLRX1 activation. We compared NLRX1’s effect on eosinophils in 2 disease states, UC and the more prototypical eosinophilic disease, asthma, and evaluated the findings. Methods In the 4-week NX-13 Phase 1b, a double-blind trial of 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) who were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks, histology was assessed using the Geboes score by a blinded pathologist2. For allergic asthma models, mice were immunized with ovalbumin or house dust mite followed by antigen challenge concurrent with LABP-73 or vehicle. Cells isolated from the lung were analyzed by flow cytometry using the BD FACS Celesta/Diva. Data are represented as means (standard error). Results In the 1b clinical trial, both the Geboes score and neutrophil subscores were reduced in the IR NX-13 group compared to placebo, consistent with the effects seen in preclinical IBD models. Upon examination, eosinophil infiltration was reduced in both the IR dose cohorts compared to placebo (Fig1A). In the subset of patients with active eosinophil infiltration at baseline (defined as Geboes subscore ≥2A.1), eosinophil reduction was seen in all NX-13 doses (Fig1B). Importantly, a numerically increased clinical response rate (decrease in total Mayo score of ≥3 or ≥30%) was seen in patients that demonstrated effective eosinophil reduction, compared to patients without improvement (75% versus 29%; Fisher’s Exact Test, p=0.08). In two allergic asthma models, NLRX1 activation by LABP-73 significantly reduced the fraction of eosinophils within the lung relative to vehicle control (n=7-8; p&amp;lt; 0.05), confirming NLRX1 activation can regulate eosinophilic inflammation in Th2-mediated responses. Conclusion Neutrophil and eosinophil infiltration were reduced in UC patients treated with the gut selective NLRX1 agonist, NX-13, and was coupled with better clinical outcomes. The effect of NX-13 on eosinophils will be evaluated further in the ongoing phase 2 NEXUS trial in patients with UC. 1 A Mookhoek, et al. JCC (16). 2 L Peyrin-Biroulet, et al. JCC (17) Supp

Tuft cells are required for a rhinovirus-induced asthma phenotype in immature mice.

Infection of immature mice with rhinovirus (RV) induces an asthma-like phenotype consisting of type 2 inflammation, mucous metaplasia, eosinophilic inflammation, and airway hyperresponsiveness that is dependent on IL-25 and type 2 innate lymphoid cells (ILC2s). Doublecortin-like kinase 1-positive (DCLK1+) tuft cells are a major source of IL-25. We sought to determine the requirement of tuft cells for the RV-induced asthma phenotype in wild-type mice and mice deficient in Pou2f3, a transcription factor required for tuft cell development. C57BL/6J mice infected with RV-A1B on day 6 of life and RV-A2 on day 13 of life showed increased DCLK1+ tuft cells in the large airways. Compared with wild-type mice, RV-infected Pou2f3-/- mice showed reductions in IL-25 mRNA and protein expression, ILC2 expansion, type 2 cytokine expression, mucous metaplasia, lung eosinophils, and airway methacholine responsiveness. We conclude that airway tuft cells are required for the asthma phenotype observed in immature mice undergoing repeated RV infections. Furthermore, RV-induced tuft cell development provides a mechanism by which early-life viral infections could potentiate type 2 inflammatory responses to future infections.

The problem of choosing a genetically engineered biological drug in a patient with severe bronchial asthma

Severe bronchial asthma (SA) is asthma whose symptoms are not controlled by high doses of inhaled glucocorticosteroids, the main drug in the treatment of asthma. SA is associated with a high economic burden and remains a serious public health problem. Modern advances in understanding the molecular mechanisms underlying respiratory tract inflammation have led to the development of monoclonal antibody therapy. In recent years, the approach to the treatment of patients with SA has undergone significant changes: six biological drugs have shown their effectiveness in phase 3 studies, especially in reducing exacerbations, improving asthma control, quality of life, lung function and the abolition of systemic corticosteroids or at least reducing their daily dose, with some differences between them. Choosing a targeted drug is always a difficult task, involving a thorough assessment of clinical, anamnestic and laboratory parameters. Biologics have different targets of exposure and, therefore, different therapeutic indications should be expected; however, some patients may be shown more than one drug, which makes it difficult to choose. The analysis of markers of eosinophilic inflammation makes it possible to determine the mechanisms of pathogenesis, predict the response to treatment, monitor its effectiveness or disease progression. Other factors that need to be analyzed are the frequency of symptoms, asthma triggers, baseline spirometry, oral corticosteroid intake status, frequency of exacerbations and concomitant diseases. The appointment of targeted therapy without a thorough assessment of clinical, functional and laboratory parameters, as well as the lack of control of these indicators during therapy can lead to insufficient effectiveness of treatment.

Bronchiectasis with Chronic Rhinosinusitis Is Associated with Eosinophilic Airway Inflammation and Is Distinct from Asthma.

Rationale: Bronchiectasis is an airway inflammatory disease that is frequently associated with chronic rhinosinusitis (CRS). An eosinophilic endotype of bronchiectasis has recently been described, but detailed testing to differentiate eosinophilic bronchiectasis from asthma has not been performed. Objectives: This prospective observational study aimed to test the hypotheses that bronchiectasis with CRS is enriched for the eosinophilic phenotype in comparison with bronchiectasis alone and that the eosinophilic bronchiectasis phenotype exists as a separate entity from bronchiectasis associated with asthma. Methods: People with idiopathic or postinfectious bronchiectasis were assessed for concomitant CRS. We excluded people with asthma or primary ciliary dyskinesia and smokers. We assessed sputum and blood cell counts, nasal NO and fractional excreted NO, methacholine reactivity, skin allergy testing and total and specific immunoglobulin (Ig) E, cytokines in the sputum and serum, and the microbiome in the sputum and nasopharynx. Results: A total of 22 people with CRS (BE + CRS) and 17 without CRS (BE - CRS) were included. Sex, age, Reiff score, and bronchiectasis severity were similar. Median sputum eosinophil percentages were 0% (IQR, 0-1.5%) in BE - CRS and 3% (1-12%) in BE + CRS (P = 0.012). Blood eosinophil counts were predictive of sputum eosinophilia (counts ⩾3%; area under the receiver operating characteristic curve, 0.68; 95% confidence interval, 0.50-0.85). Inclusion of CRS improved the prediction of sputum eosinophilia by blood eosinophil counts (area under the receiver operating characteristic curve, 0.79; 95% confidence interval, 0.65-0.94). Methacholine tests were negative in 85.7% of patients in the BE - CRS group and 85.2% of patients in the BE + CRS group (P > 0.99). Specific IgE and skin testing were similar between the groups, but total IgE levels were increased in people with increased sputum eosinophils. Microbiome analysis demonstrated distinct microbiota in nasopharyngeal and airway samples in the BE + CRS and BE - CRS groups, without significant differences between groups. However, interactome analysis revealed altered interactomes in individuals with high sputum eosinophil counts and CRS. Conclusions: Bronchiectasis with CRS is associated with an eosinophilic airway inflammation that is distinct from asthma.

Ym1 protein crystals promote type 2 immunity

Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 (Gal10) protein, an abundant protein in eosinophils. Although mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by Chil3 and Chil4 and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs.

Ym1 protein crystals promote type 2 immunity.

Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 (Gal10) protein, an abundant protein in eosinophils. Although mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by Chil3 and Chil4 and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles

BackgroundAmbient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined.ResultsBlack carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures.ConclusionsDEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

Eosinophilic Inflammation in Chronic Obstructive Pulmonary Disease: A Treatable Trait

Abstract COPD remains to be a giant public health burden and is the third leading cause of death worldwide. The presence of eosinophilic inflammation indicates a distinct pathophysiologic phenotype in COPD with a differential risk profile and response to therapy. Blood eosinophilia, clinical judgement and other patient centred factors helps in developing individualized treatment plans for patients with COPD. Appropriate management of eosinophilic airway inflammation will have an impact on lung function decline and exacerbations, thereby causing significant improvement in morbidity and mortality associated with COPD.

Markers of eosinophilic airway inflammation in patients with asthma and allergic rhinitis.

Background: Measurement of airway inflammation is an important step to determine phenotype of asthma and allergic rhinitis (AR). Objective: To assess the level of nitric oxide in exhaled air (FeNO), nasal fraction of nitric oxide (nasal NO), their relationship with clinical control and blood eosinophils in patients with steroid-naive mild and moderate asthma and AR. Methods: One hundred forty-seven patients (65 men), ages 26-49.5 years (mean age, 32 years) with AR (n = 81) or AR and concomitant asthma (n = 46) and 20 healthy subjects were included in a single-center cohort study. All the patients underwent spirometry with reversibility test. Control of asthma and AR was assessed by using the Asthma Control Questionnaire and the visual analog scale, respectively. Levels of FeNO and nasal NO were measured by chemiluminescent analyzer, peripheral blood eosinophils were counted by automatic analyzer. Results: The FeNO level was significantly elevated in the patients with asthma and concomitant AR compared with the healthy subjects and was associated with control of both asthma and AR. There was no correlation between nasal NO and control of AR. Receiver operating characteristic analysis revealed that the level of eosinophils of 150 cells/μL may be a cutoff for lower airway eosinophilic inflammation. Blood eosinophils count was unable to distinguish eosinophilic and non-eosinophilic upper airway inflammation. Conclusion: We confirm that FeNO but not nasal NO is a marker of eosinophilic airway inflammation in patients with mild-moderate steroid-naive AR and concomitant asthma. A blood eosinophil level of ≥150 cells/µL may be a simple marker of eosinophilic airway inflammation in patients with asthma. However, its low specificity requires repeated measurements and use in combination with other biomarkers.

Monitoring mepolizumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP): Discontinue, change, continue therapy?

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL-5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary. A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries, and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals, and possible therapy breaks as well as discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet. Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

EGPA: Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) as a special presentation of chronic rhinosinusitis with nasal polyps (CRSwNP).

Eosinophilic granulomatosis with polyangiitis (EGPA) was formerly known as Churg-Strauss syndrome. The condition is characterized by disseminated necrotizing vasculitis with extravascular granulomas associated with hypereosinophilia. The vasculitides affect small vessels and are associated with antineutrophil cytoplasmic antibodies (ANCAs) detectable in the blood. Distinguishing between type 2-mediated chronic airway inflammation such as chronic rhinosinusitis with nasal polyps (CRSwNP) without vasculitis can be clinically challenging and should be considered. Immunological background, diagnosis, and therapy of EGPA were identified through literature searches in Medline, PubMed, as well as national and international studies (ClinicalTrials.gov) and the Cochrane Library. Human studies published up to and including 10/2023 on the topic were considered. In cases of deteriorating general health with previously known eosinophilic inflammation of the upper and lower airways, EGPA and its interdisciplinary investigation should be considered. Various types of eosinophilic inflammation and syndromes must be considered differentially. Characterization of mucosal airway inflammation through biomarker determination is meaningful and occasionally makes the difference for targeted therapy.

Pharmacologic Treatment of Type 2-High Severe Asthma

Asthma is a common and heterogeneous disease whose treatment has considerably changed over the last decades. While inhaled therapies based on inhaled corticosteroids and long acting β2 agonists are effective in controlling asthma in the majority of patients, about 5% of asthmatics poorly respond to inhaled steroids or inhaled steroids/long acting β2 agonists combinations. These patients are affected by “severe asthma”, which is associated with need of oral corticosteroids, progression of the disease, increased use of healthcare services, deterioration of quality of life, and a significant economic burden on society. Asthma is no longer considered a single disease, but a respiratory syndrome with complex biological network of distinct and interrelating inflammatory and remodeling pathways (endotypes) that are associated with different clinical manifestations (phenotypes) both in the lungs (asthma) and other organs (e.g. nose and skin). Severe asthma endotypes may be broadly regarded as Type 2-high and Type 2-low, a model that has become central to asthma management with the development of novel treatments for the Type 2-high endotypes. The hallmark feature of Type 2-high asthma is eosinophilic inflammation, often associated with increased serum IgE, increased exhaled nitric oxide (FeNO) and blood eosinophilia. The discovery of the main key drivers of Type 2-high inflammation (IgE, cytokines such as interleukin IL-5, -4 and -13) enabled the development of new biological agents directed towards specific molecular targets. These advances have shifted the existing paradigm “one drug fits all” to “patient-tailored” novel therapies. The monoclonal antibodies direct to IgE (omalizumab), IL-5 and IL-5 receptor (mepolizumab, benralizumab, reslizumab), and to the α chain of the IL-4 and IL-13 combined receptor (dupilumab), and more recently, to the thymic stromal lymphopoietin (tezepelumab) have been shown in both clinical trials and real-life studies to control symptoms, reduce asthma exacerbations and improve lung function in severe asthmatics not controlled by full inhalation therapies. More recently, the Single Inhaler Triple Therapy (SITT) containing inhaled steroids, long acting β2 agonists and muscarinic antagonists has been developed, slightly improving the effectiveness/safety of the inhalation therapy. This report aims to review available therapeutic opportunities for patients with severe asthma focusing on patients with Type 2-high severe asthma and how to position these new therapeutic alternatives in clinical practice.

Potential association between M694V homozygous mutation in familial Mediterranean fever and eosinophilic intestinal inflammation: a pediatric case series.

Familial Mediterranean fever (FMF) is the most common hereditary systemic auto-inflammatory disease. Digestive complaint is a common feature during FMF attacks. Nevertheless, digestive complaint in attack-free period has scarcely been studied. This retrospective monocentric study aimed to describe the clinical, histological, and genetic features of pediatric patients with FMF who underwent endo-colonoscopy in this setting. Out of 115 patients with a diagnosis of FMF, 10 (8, 7%) underwent endoscopy or colonoscopy. All displayed homozygote MEFV M694V mutation and presented chronic abdominal pain, iron deficiency, and/or growth retardation. On the histological level, all patients displayed low-grade mucosal inflammation, characterized by a moderate eosinophilic infiltrate in the lamina propria sometimes associated with increased crypt apoptosis. The proportion of patients explored with endoscopy or colonoscopy was 0.4 patients per year in our center, compared with 5.7 patients per year nationwide. This study identified a specific intestinal phenotype that does not respond to the criteria of classical inflammatory bowel disease: pediatric FMF pediatric patients with homozygous MEFV M694V, abdominal pain, iron deficiency, and growth retardation should benefit from specialized gastroenterological advice.

Sputum Transcriptomics Reveals FCN1+ Macrophage Activation in Mild Eosinophilic Asthma Compared to Non-Asthmatic Eosinophilic Bronchitis.

Eosinophilic asthma (EA) and non-asthmatic eosinophilic bronchitis (EB) share similar eosinophilic airway inflammation. Unlike EA, EB did not present airway hyperresponsiveness or airflow obstruction. We aimed to compare the mechanism underlying the different manifestations between EA and EB via sputum transcriptomics analysis. Induced-sputum cells from newly physician-diagnosed EA, EB patients, and healthy controls (HCs) were collected for RNA sequencing. Bulk RNA sequencing was performed using sputum cells from patients with EA (n = 18), EB (n = 15) and HCs (n = 28). Principal component analysis revealed similar gene expression patterns in EA and EB. The most differentially expressed genes in EB compared with HC were also shared by EA, including IL4, IL5 IL13, CLC, CPA3, and DNASE1L3. However, gene set enrichment analysis showed that the signatures regulating macrophage activation were enriched in EA compared to EB. Sputum cells were profiled using single-cell RNA sequencing. FABP4+ macrophages, SPP1+ macrophages, FCN1+ macrophages, dendritic cells, T cells, B cells, mast cells, and epithelial cells were identified based on gene expression profiling. Analysis of cell-cell communication revealed that interactions between FCN1+ macrophages and other cells were higher in EA than in EB. A wealth of transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) interactions between FCN1+ macrophages and other cells have been shown in EA. The gene expression levels of EREG, TGFBI, and VEGFA in FCN1+ macrophages of EA were significantly higher than those of EB. Furthermore, signatures associated with the response to TGF-β, cellular response to VEGF stimulus and developmental cell growth were enriched in FCN1+ macrophages of EA compared to those of EB. FCN1+ macrophage activation associated with airway remodeling processes was upregulated in EA compared to that in EB, which may contribute to airway hyperresponsiveness and airflow obstruction.

Immune Cell-Mediated Autoimmune Responses in Severe Asthma.

Severe asthma (SA) has heterogeneous inflammatory phenotypes characterized by persistent airway inflammation (eosinophilic and/or neutrophilic inflammation) and remodeling. Various immune cells (eosinophils, neutrophils, and macrophages) become more activated and release inflammatory mediators and extracellular traps, damaging the protective barrier of airway epithelial cells and further activating other immune and structural cells. These cells play a role in autoimmune responses in asthmatic airways, where the adaptive immune system generates autoantibodies, inducing immunoglobulin G-dependent airway inflammation. Recent studies have suggested that adult asthmatics had high titers of autoantibodies associated with asthma severity, although pathogenic factors or diagnostic criteria are not well-defined. This challenge is further compounded by asthmatics with the autoimmune responses showing therapy insensitivity or failure to current pharmacological and biological treatment. This review updates emerging mechanisms of autoimmune responses in asthmatic airways and provides insights into their roles, proposing potential biomarkers and therapeutic targets for SA.

Presence of sputum IgG against eosinophilic inflammatory proteins in asthma.

Sputum immunoglobulin G (Sp-IgG) has been discovered to induce cytolytic extracellular trap cell death in eosinophils, suggesting a potential autoimmune mechanism contributing to asthma. This study aimed to explore the potential origin of Sp-IgG and identify clinically relevant subtypes of Sp-IgG that may indicate autoimmune events in asthma. This study included 165 asthmatic patients and 38 healthy volunteers. We measured Sp-IgG and its five subtypes against eosinophil inflammatory proteins (Sp-IgGEPs), including eosinophil peroxidase, eosinophil major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and Charcot-Leyden Crystal protein in varying asthma severity. Clinical and Mendelian randomization (MR) analyses were conducted. A positive Sp-IgGEPs signature (Sp-IgGEPs+) was defined when any of the five Sp-IgGEPs values exceeded the predefined cutoff thresholds, calculated as the mean values of healthy controls plus twice the standard deviation. The levels of Sp-IgG and Sp-IgGEPs were significantly elevated in moderate/severe asthma than those in mild asthma/healthy groups (all p < 0.05). Sp-IgG levels were positively correlated with airway eosinophil and Sp-IgGEPs. MR analysis showed causality between eosinophil and IgG (OR = 1.02, 95%CI = 1.00-1.04, p = 0.020), and elevated IgG was a risk factor for asthma (OR = 2.05, 95%CI = 1.00-4.17, p = 0.049). Subjects with Sp-IgGEPs+ exhibited worse disease severity and served as an independent risk factor contributing to severe asthma (adjusted-OR = 5.818, adjusted-95% CI = 2.193-15.431, adjusted-p < 0.001). Receiver operating characteristic curve analysis demonstrated that the combination of Sp-IgGEPs+ with non-allergic status, an ACT score < 15, and age ≥ 45 years, effectively predicted severe asthma (AUC = 0.84, sensitivity = 86.20%, specificity = 67.80%). This study identifies a significant association between airway eosinophilic inflammation, Sp-IgG, and asthma severity. The Sp-IgGEPs panel potentially serves as the specific biomarker reflecting airway autoimmune events in asthma.

Abnormal S100A8 expression associates with postoperative recurrence in chronic rhinosinusitis with nasal polyps

ObjectiveTo investigate the role of S100A8 in chronic rhinosinusitis with nasal polyps (CRSwNP) and assess its value in predicting disease recurrence after surgery. MethodsThirty healthy controls (HC), 30 patients with chronic rhinosinusitis without nasal polyp (CRSsNP), and 60 patients with CRSwNP were enrolled. Serum S100A8 concentration was measured by ELISA. Immunohistochemistry (IHC), western blotting (WB), and reverse transcription-polymerase chain reaction (RT-PCR)were performed to examine tissue expression levels of S100A8. The potential values of S100A8 in predicting postoperative recurrence of CRSwNP were assessed by the receiver operating characteristic (ROC)curve. ResultsSerum S100A8 concentrations in the CRSwNP group were higher than the HC group and the CRSsNP group， especially in the recurrent CRSwNP group (P < 0.05). Serum S100A8 levels were positively correlated with peripheral blood eosinophil numbers (r = 0.263, P = 0.043) and percentages (r = 0.336, P = 0.009), tissue eosinophil percentages (r = 0.273, P = 0.035), VAS score (r = 0.385, P = 0.002) and Lund-Kennedy score (r = 0.283, P = 0.029). IHC, WB, and RT-PCR results showed tissue S100A8 expression was significantly enhanced in the CRSwNP group, especially in the recurrence group (P < 0.05). Binary regression analysis showed that serum S100A8 concentration and tissue eosinophil percentage were correlated with postoperative recurrence of CRSwNP. ROC curve analysis showed that compared with tissue eosinophil percentage, the S100A8 level had a higher value for postoperative recurrence of CRSwNP. ConclusionSerum and tissue S100A8 levels were elevated in patients with CRSwNP， especially in the recurrent CRSwNP patients, and were correlated with the degree of peripheral blood and tissue eosinophilic inflammation. S100A8 seemed to be a potential objective biomarker to predict the postoperative recurrence of CRSwNP.