Sputum Eosinophils Research Articles

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.

Study of blood eosinophils and plasma periostin as biomarkers for response of COPD patients to ICS/LABA treatment

BackgroundEosinophilic airway inflammation has been detected in up to 40% of chronic obstructive pulmonary disease (COPD) patients during stable periods of the disease, and increased sputum eosinophil count was associated with better lung function, more future exacerbations, and symptoms that responded better to treatment with inhaled and oral corticosteroids.The aim of this work was to investigate the relationship of blood eosinophils and plasma periostin with lung function changes related to ICS and long-acting beta2-agonist combination treatment in stable COPD patients for 3 months.MethodsThis prospective experimental study was carried out on 50 COPD patients with post-bronchodilator FEV1/FVC ratio < 70%. Patients collected from outpatient clinics of Chest Department Tanta University Hospitals, Tanta Chest Hospital, and Mansoura Chest Hospital from February 2020 to February 2022. Patients were subjected to complete history taking, and clinical examinations including general and local examinations and laboratory investigations (complete blood count to assess eosinophilic count, arterial blood gases, and plasma periostin) and spirometry were done for all patients pre- and post-treatment. All patients received 3 months of treatment with a fixed dose of combined inhalers of ICS and LABA, and then they were classified into FEV1 responder and FEV1 non-responder according to improvement in FEV1 at least 12% and 200 mL from baseline of 3 months of combined treatment with ICS/LABA.ResultsBlood eosinophil count had a significant positive correlation with smoking index (pack/year), negative correlations with FEV1% of predicted, FEV1 actual value (L), and FEV1/FVC ratio. Plasma periostin concentration had significant positive correlation with blood eosinophil count, COPD grade, and FVC actual value (L) and significant negative correlations with FEV1% of predicted, FEV1 actual value (L), and FEV1/FVC. Cutoff values of blood eosinophil count > 265 cell/µL, plasma periostin concentration > 15.747 ng/mL, and FEV1% < 40.5% were associated with posttreatment FEV1 response.ConclusionsCOPD patients with poor lung functions regarding FEV1/FVC ratio, FEV1 actual value (L), and FEV1% of predicted as well as high blood eosinophil count and high plasma periostin concentration are predicted to have FEV1 response with fixed-dose ICS/LABA combination treatment.

(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.

Antibiotic Therapy in Asthma as One of First Step Treatment, a Phase 3 Randomized Clinical Trial

Background: Focus of this study was on subjects suffering from new onset asthma, but actually, they may involve with an infection. Objectives: The target of this study was to determine the frequency of total control of asthma in new onset asthma. Methods: this is a phase 3 randomized clinical trial. The participants were 50 new onset asthma, who feel suffering from respiratory infection, however the physician diagnosis was asthma according to wheezy chest, spirometry and clear chest roentgenogram. Age less than 18 years and pregnant women were excluded. The subjects were randomly divided into two groups, doxycycline hyclate and the placebo arms. The drugs were repacked in similar in shape container. Primary endpoint was time to first recurrence. Secondary endpoints were frequency of total control of asthma, dyspnea, cough, asthma control test (ACT) score, FEV1, FEV1/FVC, eosinophil and neutrophil in blood and sputum. Results: The difference of clinical findings between two groups before the trial were not significant. Ten percent reported acute attack of asthma during last two months. Treatment with Doxycyline revealed significant improvement of clinical findings, asthma attack and ACT score after two months of treatment, however, complete resolution of clinical findings were significantly higher in Doxycyline group compare to placebo. Clinical findings and FEV1 percent predicted in Doxycyline group T2low asthma group showed significant improvement which were not depicted in T2high group. Eighteen months follow up of the subjects showed complete resolution of asthma symptoms in 12 (48%) on Doxycyline group, which was significantly higher than control group (5 (20%). Time to first exacerbation in doxycycline group was 13.6±5.64 months which was significantly longer than control group (7.49±6.95, P=0.002). Time to first exacerbation in CRP positive was significantly longer (13.64±5.35 months) than CRP negative subjects (9.67±7.76 months, P=0.02). Conclusion: Doxycycline is an effective antibiotic for preventing recurrence of asthma, in selected new subjects who suspicious for respiratory infection.

Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study

IntroductionAsthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive...

Screening, identification and targeted intervention of necroptotic biomarkers of asthma

BackgroundAs a pivotal pathway of programmed cell death, necroptosis significantly contributes to the pathogenesis of respiratory disorders. However, its role in asthma is not yet fully elucidated. Therefore, this study aimed to identify markers associated with necroptosis, evaluate their functions in asthma, and explore potential therapeutic agents targeting necroptosis for the management of asthma. MethodsFirstly, machine learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest, and Support Vector Machine-Recursive Feature Elimination (SVM-RFE), were utilized to identify necroptosis-related differentially expressed genes (NRDEGs) in asthma patients compared to healthy controls. Concurrently, the expression of NRDEGs was validated using external datasets, Western blot, and quantitative real-time polymerase chain reaction (qPCR). Secondly, the clinical relevance of NRDEGs was assessed through Receiver Operating Characteristic (ROC) curve analysis and correlation with clinical indicators. Thirdly, the relationship between NRDEGs and pulmonary immune cell infiltration, as well as the signaling interactions between different cells types, were analyzed through immune infiltration and single-cell analysis. Fourthly, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), were conducted to elucidate the functional roles of NRDEGs. Finally, compounds targeting NRDEGs were screened, and their binding affinities were evaluated using molecular docking studies. ResultsIn asthma, necroptosis is activated, leading to the identification of four NRDEGs: NLRP3, PYCARD, ALOX15, and VDAC3. Among these, NLRP3, PYCARD, and ALOX15 are upregulated, whereas VDAC3 is downregulated in asthma. Comprehensive clinical evaluations indicated that NRDEGs hold diagnostic value for asthma. Specifically, NLRP3 was inversely correlated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), while VDAC3 showed an inverse correlation with sputum neutrophils. Conversely, ALOX15 expression was positively correlated with fractional exhaled nitric oxide (FeNO) levels, as well as sputum eosinophils, blood eosinophils, and blood IgE levels. Subsequent immune infiltration analysis revealed associations between NRDEGs and activated dendritic cells, mast cells, and eosinophils. Single-cell RNA sequencing (scRNA-seq) further confirmed the communication signals between myeloid dendritic cells, fibroblasts, neutrophils, and helper T cells, predominantly related to fibrosis and immune-inflammatory responses. Pathway enrichment analysis demonstrated that NRDEGs are involved in ribosomal function, oxidative phosphorylation, and fatty acid metabolism. Finally, resveratrol and triptonide were identified as potential therapeutic agents targeting the proteins encoded by NRDEGs for asthma treatment. ConclusionsThe necroptosis pathway is activated in asthma, with NRDEGs—namely PYCARD, NLRP3, ALOX15, and VDAC3—correlated with declines in lung function and airway inflammation. These genes serve as reliable predictors of asthma risk and are involved in the regulation of the immune-inflammatory microenvironment. Resveratrol and triptolide have been identified as promising therapeutic candidates due to their potential to target the proteins encoded by these genes.

Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial.

Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma. Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

Severe Eosinophilic Asthma or Eosinophilic Granulomatosis With Polyangiitis: Potential Biomarkers for Novel Diagnostic Strategies

BackgroundSevere Eosinophilic Asthma (SEA) may be the prodromal phase of Eosinophilic Granulomatosis with Polyangiitis (EGPA). Nevertheless, few studies have tried to recognize EGPA in the early stages of the disease. ObjectivesTo identify a panel of clinical and biological markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA and crafting a strategy for diagnostic decision-making. Methods30 patients with EGPA and 49 with SEA were enrolled. A complete pulmonary, ear, nose and Throat (ENT) and rheumatologic assessment were made. Blood (eosinophil count, eosinophilic cationic protein-ECP, IL5, IL4, total-IgE, IgG4, anti-neutrophil cytoplasmic antibody (ANCA), sputum (eosinophils count, periostin, IL8 and GMCSF) and nasal smear (eosinophilia) biomarkers were assessed. Asthma Control Test, Short Form-36, SinoNasalOutcome Test-22, and Asthma Quality of Life Questionnaire were also used. ResultsSEA patients had poorer asthma control (p<0.001) and higher level of sputum eosinophils (p<0.002) while EGPA patients reported higher levels of blood eosinophils in the past. Sputum GMCSF was the only biomarker significantly increased in EGPA patients compared with SEA (p<0.0001). Among SEA patients, those with some suggestive but not diagnostic criteria of EGPA, particularly tissue eosinophilic infiltrates, presented higher levels of sputum GMCSF (p<0.0005), blood and sputum eosinophils (p<0.0006, p<0.011) in comparison with the other patients. ConclusionSputum GMCSF and eosinophils might be useful biomarkers to support early diagnosis and treatment choices in SEA patients, suspected of having EGPA

Endotypes of severe neutrophilic and eosinophilic asthma from multi-omics integration of U-BIOPRED sputum samples.

Clustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi-omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development. To determine whether multi-omics integration of sputum leads to improved granularity of the molecular classification of severe asthma. We analyzed six -omics data blocks-microarray transcriptomics, gene set variation analysis of microarray transcriptomics, SomaSCAN proteomics assay, shotgun proteomics, 16S microbiome sequencing, and shotgun metagenomic sequencing-from induced sputum samples of 57 severe asthma patients, 15 mild-moderate asthma patients, and 13 healthy volunteers in the U-BIOPRED European cohort. We used Monti consensus clustering algorithm for aggregation of clustering results and Similarity Network Fusion to integrate the 6 multi-omics datasets of the 72 asthmatics. Five stable omics-associated clusters were identified (OACs). OAC1 had the best lung function with the least number of severe asthmatics with sputum paucigranulocytic inflammation. OAC5 also had fewer severe asthma patients but the highest incidence of atopy and allergic rhinitis, with paucigranulocytic inflammation. OAC3 comprised only severe asthmatics with the highest sputum eosinophilia. OAC2 had the highest sputum neutrophilia followed by OAC4 with both clusters consisting of mostly severe asthma but with more ex/current smokers in OAC4. Compared to OAC4, there was higher incidence of nasal polyps, allergic rhinitis, and eczema in OAC2. OAC2 had microbial dysbiosis with abundant Moraxella catarrhalis and Haemophilus influenzae. OAC4 was associated with pathways linked to IL-22 cytokine activation, with the prediction of therapeutic response to anti-IL22 antibody therapy. Multi-omics analysis of sputum in asthma has defined with greater granularity the asthma endotypes linked to neutrophilic and eosinophilic inflammation. Modelling diverse types of high-dimensional interactions will contribute to a more comprehensive understanding of complex endotypes. Unsupervised clustering on sputum multi-omics of asthma subjects identified 3 out of 5 clusters with predominantly severe asthma. One severe asthma cluster was linked to type 2 inflammation and sputum eosinophilia while the other 2 clusters to sputum neutrophilia. One severe neutrophilic asthma cluster was linked to Moraxella catarrhalis and to a lesser extent Haemophilus influenzae while the second cluster to activation of IL-22.

Impact of Ongoing Treatment With Inhaled Corticosteroids During Specific Inhalation Challenges for Diagnosing Occupational Asthma

BackgroundSpecific inhalation challenge tests (SIC) are still the reference test for diagnosing sensitizer-induced occupational asthma (SIOA). The European Respiratory Society recommends the cessation of inhaled corticosteroids (ICS) 72h prior to SIC. ObjectiveTo assess the effect of an ongoing ICS treatment during SIC on the maximum fall in FEV1, change in methacholine PC20 as well as sputum eosinophil counts after exposure to the suspected agent. MethodsWe performed a retrospective analysis using a database of cases referred to our center for suspected SIOA from 1999 to 2022. The results of the SIC were compared between subjects treated with ICS during SIC and steroid-naïve subjects. ResultsSix-hundred and seventy-one individuals underwent SIC in the laboratory. Three hundred and eighteen were treated with ICS, whereas 353 were steroid naïve. The proportion of subjects with a positive SIC was greater among ICS treated subjects (39. 6%) compared to steroid-naïve subjects (27.5%, p<0.001). A treatment with ICS did not influence the outcome of the SIC. There was no difference in the change in PC20 or percentage of sputum eosinophils after SIC between steroid-treated and steroid-naïve subjects. ConclusionAn ongoing ICS treatment during a SIC did not affect the occurrence of an asthmatic reaction, the change in airway responsiveness or eosinophilic inflammation after exposure to the suspected agent in subjects who have been treated with ICS for a long period of time.

Discovery and Validation of a Volatile Signature of Eosinophilic Airway Inflammation in Asthma.

Volatile organic compounds (VOCs) in asthmatic breath may be associated with sputum eosinophilia. We developed a volatile biomarker-signature to predict sputum eosinophilia in asthma. VOCs emitted into the space above sputum samples (headspace) from severe asthmatics (n=36) were collected onto sorbent tubes and analysed using thermal desorption gas chromatography-mass spectrometry (TD-GC-MS). Elastic net regression identified stable VOCs associated with sputum eosinophilia ≥3% and generated a volatile biomarker signature. This VOC signature was validated in breath samples from: (I) acute asthmatics according to blood eosinophilia ≥0.3x109cells/L or sputum eosinophilia of ≥ 3% in the UK EMBER consortium (n=65) and U-BIOPRED-IMI consortium (n=42). Breath samples were collected onto sorbent tubes (EMBER) or Tedlar bags (U-BIOPRED) and analysed by gas-chromatography-mass spectrometry (GC×GC-MS -EMBER or GC-MS -U-BIOPRED). The in vitro headspace identified 19 VOCs associated with sputum eosinophilia and the derived VOC signature yielded good diagnostic accuracy for sputum eosinophilia ≥ 3% in headspace (AUROC (95% CI) 0.90(0.80-0.99), p<0.0001), correlated inversely with sputum eosinophil % (rs= -0.71, p<0.0001) and outperformed FeNO (AUROC (95% CI) 0.61(0.35-0.86). Analysis of exhaled breath in replication cohorts yielded a VOC signature AUROC (95% CI) for acute asthma exacerbations of 0.89(0.76-1.0) (EMBER cohort) with sputum eosinophilia and 0.90(0.75-1.0) in U-BIOPRED - again outperforming FeNO in U-BIOPRED 0.62 (0.33-0.90). We have discovered and provided early-stage clinical validation of a volatile biomarker signature associated with eosinophilic airway inflammation. Further work is needed to translate our discovery using point of care clinical sensors.

Investigation of lactotransferrin messenger RNA expression levels as an anti–type 2 asthma biomarker

Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility. We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker. Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n= 155) and longitudinal (n= 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation. Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P< .025), retrospective andprospective asthma exacerbations, and low lung function (P< 8.3×10-3). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P<8.3×10-3) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of TH2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of TH1 and inflammation genes (IL12A, MUC5B, and CC16) and TH17-driven cytokines or chemokines for neutrophils (CXCL1,CXCL6, and CSF3) (P< 3.5×10-6). Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.

Monitoring COPD patients: systemic and bronchial eosinophilic inflammation in a 2-year follow-up

BackgroundHigh blood eosinophils seem to predict exacerbations and response to inhaled corticosteroids (ICS) treatment in patients with chronic obstructive pulmonary disease (COPD). The aim of our study was to prospectively evaluate for 2 years, blood and sputum eosinophils in COPD patients treated with bronchodilators only at recruitment.MethodsCOPD patients in stable condition treated with bronchodilators only underwent monitoring of lung function, blood and sputum eosinophils, exacerbations and comorbidities every 6 months for 2 years. ICS was added during follow-up when symptoms worsened.Results63 COPD patients were enrolled: 53 were followed for 1 year, 41 for 2 years, 10 dropped-out. After 2 years, ICS was added in 12/41 patients (29%) without any statistically significant difference at time points considered. Blood and sputum eosinophils did not change during follow-up. Only FEV1/FVC at T0 was predictive of ICS addition during the 2 year-follow-up (OR:0.91; 95% CI: 0.83–0.99, p = 0.03). ICS addition did not impact on delta (T24-T0) FEV1, blood and sputum eosinophils and exacerbations. After 2 years, patients who received ICS had higher blood eosinophils than those in bronchodilator therapy (p = 0.042). Patients with history of ischemic heart disease increased blood eosinophils after 2 years [p = 0.03 for both percentage and counts].ConclusionsBlood and sputum eosinophils remained stable during the 2 year follow-up and were not associated with worsened symptoms or exacerbations. Almost 30% of mild/moderate COPD patients in bronchodilator therapy at enrollment, received ICS for worsened symptoms in a 2 year-follow-up and only FEV1/FVC at T0 seems to predict this addition. History of ischemic heart disease seems to be associated with a progressive increase of blood eosinophils.

Diagnostic Accuracy of Specific IgE Against Wheat and Rye in Flour-Induced Occupational Asthma

Assessment of IgE-mediated sensitization to flour allergens is widely used to investigate flour-induced occupational asthma. The diagnostic efficiency of detecting specific IgE antibodies (sIgEs) against wheat and rye flour, however, has not been thoroughly compared with other diagnostic procedures. We sought to evaluate the diagnostic accuracy of sIgE against wheat and rye compared with specific inhalation challenge (SIC) with flour as the reference standard. This retrospective multicenter study included 264 subjects who completed an SIC with flour in eight tertiary centers, of whom 205 subjects showed a positive SIC result. Compared with SIC, sIgE levels of 0.35 kUA/L or greater against wheat and rye provided similar sensitivities (84% to 85%, respectively), specificities (71% to 78%), positive predictive values (91% to 93%), and negative predictive values (56% to 61%). Increasing the threshold sIgE value to 5.10 kUA/L for wheat and to 6.20 kUA/L for rye provided a specificity of 95% or greater and further enhanced the positive predictive value to 98%. Among subjects with a positive SIC, those who failed to demonstrate sIgE against wheat and rye (n= 26) had significantly lower total serum IgE level and blood and sputum eosinophil counts and a lesser increase in postchallenge FeNO compared with subjects with a detectable sIgE. High levels of sIgE against wheat and/or rye flour strongly support a diagnosis of flour-induced occupational asthma without the need to perform an SIC. The absence of detectable sIgE against wheat and rye in subjects with a positive SIC seems to be associated with lower levels of TH2 biomarkers.

Domiciliary monitoring of exhaled nitric oxide in the management of asthma: a pilot study.

Whether asthma patients could benefit from home monitoring for fractional exhaled nitric oxide (flow of 50 mL/s, FeNO50) is unknown. We explore the application value of home monitoring FeNO50 in daily asthma management. Twenty-two untreated, uncontrolled asthma patients were selected. Medical history, blood and sputum samples, pulmonary function, Asthma Control Test (ACT), and other clinical data of the subjects were collected. All subjects underwent daily monitoring for four weeks using a FeNO50 monitor and mobile spirometry (mSpirometry). The diurnal differences and dynamic changes were described. Compare the effect-acting time and the relative plateau of treatment between FeNO50 and mSpirometry monitoring. In the first two weeks, the morning median (IQR) level of FeNO50 was 44 (35, 56) ppb, which was significantly higher than the evening median level [41 (32, 53) ppb, P = 0.028]. The median (IQR) effect-acting time assessed by FeNO50 was 4 (3, 5) days, which was significantly earlier than each measure of mSpirometry (P < 0.05). FeNO50 reached the relative plateau significantly earlier than FEV1 (15 ± 2 days vs. 21 ± 3 days, P < 0.001). After treatment, the daily and weekly variation rates of FeNO50 showed a gradually decreasing trend (P < 0.05). The ACT score, sputum eosinophils, and blood eosinophils also significantly improved (P ≤ 0.01). The daily home monitoring of FeNO50 in asthmatic patients showed significant circadian rhythm, and the sensitivity of FeNO50 in evaluating the response to treatment was higher than mSpirometry. The daily and weekly variation rates of FeNO50 change dynamically with time, which may be used to assess the condition of asthma.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma

The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/μL and 42% of participants with blood eosinophil counts between 150 and 299 cells/μL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study.

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Evidence for 2 clusters among patients with noneosinophilic asthma

BackgroundAlthough asthma is often seen as an eosinophilic disease associated with atopy, patients with noneosinophilic asthma represent a substantial part of the population with asthma. ObjectiveTo apply an unsupervised clustering method in a cohort of 588 patients with noneosinophilic asthma (sputum eosinophils < 3%) recruited from an asthma clinic of a secondary care center. MethodsOur cluster analysis of the whole cohort identified 2 subgroups as cluster 1 (n = 417) and cluster 2 (n = 171). ResultsCluster 1 comprised a predominantly female group with late disease onset, a low proportion of atopy (24%), and a substantial smoking history (53%). In this cluster, treatment burden was low (<50% of inhaled corticosteroid users); asthma control and quality of life were poor, with median Asthma Control Test, Asthma Control Questionnaire, and Asthma Quality of Life scores of 16, 1.7, and 4.5, respectively, whereas lung function was preserved with a median postbronchodilation forced expiratory volume in 1 second of 93% predicted. Cluster 2 was a predominantly male group, almost exclusively comprising patients with atopy (99%) with early disease onset and a moderate treatment burden (median inhaled corticosteroids dose 800 µg/d equivalent beclomethasone). In cluster 2, asthma was partially controlled, with median Asthma Control Test and Asthma Control Questionnaire scores reaching 18 and 1.3, respectively, and lung function well preserved with a median postbronchodilation of 95% predicted. Although systemic and airway neutrophilic inflammation was the dominant pattern in cluster 1, cluster 2 essentially comprised paucigranulocytic asthma with moderately elevated fraction exhaled nitric oxide. ConclusionNoneosinophilic asthma splits into 2 clusters distinguishing by disease onset, atopic status, smoking history, systemic and airway inflammation, and disease control and quality of life.

The effects of vitamin D supplementation on inflammatory biomarkers in patients with asthma: a systematic review and meta-analysis of randomized controlled trials.

While the association between vitamin D and several inflammatory biomarkers in asthma patients has been extensively reported, it remains unclear whether supplementation modifies these biomarkers. This review aims to evaluate the impact of vitamin D supplementation on inflammatory biomarkers measured in vivo in individuals with asthma. We conducted a systematic review of randomized controlled trials (RCTs) published until November 2022 in six electronic databases evaluating the impact of vitamin D supplementation (any dose, form, administration route, frequency, or duration) compared to placebo in children or adults. The two co-primary outcomes were serum IgE and blood eosinophils reported at the endpoint. Secondary outcomes included other markers of type 2 inflammation (e.g., sputum eosinophils, fractional exhaled nitric oxide, etc.), anti-inflammatory biomarkers (e.g., interleukin (IL)-10, etc.), markers of non-type 2 inflammation (e.g., high-sensitivity C-reactive protein, etc.), and non-specific biomarkers (e.g., macrophages, etc.). Data were aggregated using fixed or random effect models. Thirteen RCTs (5 in adults, 5 in pediatric patients, and 3 in mixed age groups) testing doses of vitamin D supplementation ranging from 800 to 400,000 IU over periods of 6 weeks to 12 months were included. Eight studies provided data on serum IgE and four on blood eosinophils. As secondary outcomes, three studies reported on sputum eosinophils, four on FeNO, five on serum IL-10, and two on airway IL-10. Compared to placebo, vitamin D supplementation had no significant effect on serum IgE (Mean difference [MD] [95% CI]: 0.06 [-0.13, 0.26] IU/mL), blood eosinophils (MD [95% CI]: - 0.02 [-0.11, 0.07] 103/μL), or FeNO (MD [95% CI]: -4.10 [-10.95, 2.75] ppb) at the endpoint. However, the vitamin D supplementation group showed higher serum IL-10 levels compared to placebo (MD [95% CI]: 18.85 [1.11, 36.59] pg/ml) at the endpoint. Although data could not be aggregated, narrative synthesis suggested no significant effect of supplementation on sputum eosinophils and IL-10 in both sputum and exhaled breath condensate, at the endpoint. Vitamin D supplementation in individuals with asthma was not associated with lower inflammatory biomarkers related to type 2 inflammation. However, it was significantly associated with higher serum IL-10 compared to placebo. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022365666.