Higher Blood Eosinophil Levels Research Articles

Genetic Polymorphisms of GP1BA, PEAR1, and PAI-1 May Be Associated with Serum sIgE and Blood Eosinophil Levels in Chinese Patients with Allergic Diseases.

It has been suggested that genetic factors may be substantially linked to allergy disorders. This study aims to investigate the relationship between the serum specific Immunoglobulin E [sIgE], blood eosinophil, and the polymorphisms of glycoprotein Ib alpha gene [GP1BA] rs6065, platelet endothelial aggregation receptor 1 gene [PEAR1] rs12041331, and plasminogen activator inhibitor 1 gene [PAI-1] rs1799762. From the Peking Union Medical College Hospital, this study enrolled 60 healthy participants and 283 participants with allergic diseases. TaqMan-minor groove binder [MGB] quantitative polymerase chain reaction [qPCR] was used to examine the gene polymorphisms in each group. The TaqMan-MGB qPCR results were completely consistent with the DNA sequencing results, according to other studies in this medical center [Kappa =1, p <0.001]. The GP1BA rs6065, PEAR1 rs12041331, and PAI-1 rs1799762 polymorphisms did not show different distribution between allergy patients and healthy individuals. Concerning allergy patients, the CT [n=33] genotype of GP1BA rs6065 had higher blood eosinophil level than the CC [n=250] genotype [0.59, IQR 0.32-0.72 vs 0.31, IQR 0.15-0.61, *109/L, p =0.005]. The serum sIgE of AA [n=46] genotype of PEAR1 rs12041331 was lower [median 3.7, interquartile quartiles [IQR] 0.2-16.8, kU/L] than the GA [n=136] and GG [n=101] genotypes [GA median 16.3, IQR 3.1-46.3, kU/L, p = 0.002; GG median 12.9, IQR 3.0-46.9, kU/L, p =0.003]. The GA genotypes of PEAR1 rs12041331were with higher blood eosinophil levels [median 0.42, IQR 0.17-0.74 *109/L] than the AA genotype [median 0.25, IQR 0.15-0.41*109/L, p =0.012]. The sIgE of the 5G5G [n=44] genotype of PAI-1 rs1799762 was lower [median 5.0, IQR 0.1-22.8, kU/L] than the 4G5G [n=144] [median 17.3, IQR 3.7-46.0, kU/L, p = 0.012]. The GP1BA rs6065, PEAR1 rs12041331, and PAI-1 rs1799762 polymorphisms may be associated with the genetic susceptibility of serum sIgE or blood eosinophil in Chinese allergic disease patients.

Type 2 Biomarkers for the Indication and Response to Biologics in CRSwNP.

Three biologics targeting type 2 inflammation have been approved for the treatment of severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). Nevertheless, around 40-60% of patients do not respond well to these biological treatments. Selecting appropriate patients is crucial to improve treatment outcome of biologics. This review summarizes the literature data on type 2 biomarkers, with a specific focus on the indication to biologics for severe CRSwNP. No consensus has been reached on how to define mucosal type 2 inflammation in CRSwNP. Clinical markers (e.g., 22-item Sino-nasal Outcome Test (SNOT-22) score, Lund-Mackay CT score (LMS), ethmoid/maxillary sinus CT score, and CT-radiomics), nasal secretion biomarkers (e.g., eosinophil cationic protein and interleukin-5), blood and nasal cytology eosinophil counts, and nasal swab eosinophil peroxidase activity have been reported to be associated with type 2 inflammation in CRSwNP. The time duration since the last surgery, SNOT-22 score at 1 week of treatment, and baseline serum osteoprotegerin levels might indicate the response to dupilumab. LMS and asthma control test scores were found to have moderate predictive value for acceptable improvement after 24-week treatment of omalizumab. High blood eosinophil levels at baseline were associated with treatment response to mepolizumab and benralizumab. Although several clinical and biological markers might be associated with type 2 inflammation and response to biologics in patients with CRSwNP, their validity requires further investigation. Identifying clinically applicable biomarkers for biologic treatment holds significant promise for advancing personalized approaches to biologics and optimizing treatment outcomes for patients with CRSwNP.

Dupilumab-induced eosinophilia in patients with diffuse type 2 chronic rhinosinusitis.

Dupilumab, a monoclonal anti-IL-4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy. This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy. Patients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino-Nasal-Outcome-Test Score (SNOT-22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils. Sixty-eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT-22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM-1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down- and IL-4 upregulated in subjects with eosinophil increase. Our findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL-4 at baseline developed dupilumab-induced transient eosinophilia. We identified the downregulation of VCAM-1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab-induced eosinophilia.

Effectiveness and safety of bronchodilators and inhaled corticosteroids in the management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a lung condition marked by restricted lung airflow. It is a globally prevalent condition affecting almost 300 million individuals. COPD is linked to a significant burden of morbidity and mortality thus necessitating early diagnosis and management. Rising COPD treatment options complicate care and necessitate a review of clinical data to guide treatment choices. Corticosteroids and bronchodilators are the mainstay of treatment for COPD due to their safety and efficacy. Compared to inhaled corticosteroids or long-acting β-agonist therapy alone, inhaled corticosteroids plus long-acting β-agonist lower the risk of exacerbations and enhance lung function and health status in patients with COPD. Patients who experience frequent exacerbations despite taking long-acting bronchodilators and those who have evidence of eosinophilic bronchial inflammation, as shown by high blood eosinophil levels and/or a history of asthma or asthma-COPD overlap, may both benefit greatly from inhaled corticosteroids therapy. Although not widespread, inhaled corticosteroid use is linked to an elevated risk of pneumonia and may vary depending on the particular corticosteroid utilized. Recent research on combination therapy of inhaled corticosteroids and long-acting β-agonist has shown significant advantages and supports its widespread use in COPD patients who experience frequent exacerbations however some clinical studies and trials have also demonstrated quite conflicting outcomes to this therefore necessitating the need for further clinical trials to exhibit conclusive results. The purpose of this research is to review the available information about the effectiveness and safety of bronchodilators and inhaled corticosteroids in the management of COPD.

Severe asthma and biologics: managing complex patients.

Bronchial asthma is a chronic airway inflammatory disease of the respiratory tract that varies in terms of clinical presentations (phenotypes) and distinct underling pathophysiological mechanisms (endotypes). The definition of phenotype/endotype is crucial tak-ing into account the availability of novel biologic agent dedicated to patients who do not respond to conventional therapies. Although patients suffering from type 2 severe asthma significantly benefit from treatment with biologics no responders patients have been identified. Comorbidities increase the symptoms of asthma and complicate the overall management of the disease. The assessment and treatment of comorbidities is a crucial step and they the appropriate management may improve asthma symptoms and morbidity. Among comorbidities certainly chronic rhinosinusit with nasal polyps, obesity, bronchiectasis and immune defects represent a group of clinical conditions that negatively impact on asthma control despite a correct treatment. Although asthma is frequently characterized by an increase of blood eosinophils that releasing mediators and cytokines are involved in the inflammatory processes of airways wall, in patients with very high blood eosinophil levels it is opportune to be very careful in discerning whether it is a case of isolated severe eosinophilic asthma or a case of asthma in EGPA disease. In addition, hypereosinophilia can be the consequence of specific biological treatment as in the case of dupilumab. In this paper we have outlined the clinical features of those patients with severe asthma in which the management of the disease can be more complex.

Evaluation of the clinical features and laboratory data of patients with severe asthma classified as super-responder or non super-responder to omalizumab treatment: a single-center real-life study

Introduction Omalizumab is used for the treatment of severe allergic asthma. Objective The aim of this study was to evaluate the clinical features and laboratory data of patients with severe allergic asthma classified as super-responder or non super-responder to omalizumab. Methods Comparisons were made of the laboratory data and clinical features of patients with severe allergic asthma. Patients who had no asthma exacerbation, no oral corticosteroid (OCS) use, asthma control test (ACT) score >20 and forced expiratory volume in 1 s (FEV1) >80% were considered super-responder after omalizumab. Results A total of 90 patients were included in the study, comprising 19 (21.1%) males. The age at onset of asthma, allergic rhinitis rate, number of endoscopic sinus surgeries (ESS), intranasal corticosteroid (INS) use, baseline FEV 1 (%) and ACT score were significantly higher in the omalizumab super-responder group (p = 0.013, p = 0.015, p = 0.002, p = 0.001, p = 0.001 and p < 0.001, respectively). The duration of asthma, rate of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), regular use of OCS, baseline eosinophil count and eosinophil-to-lymphocyte ratio were significantly higher in the omalizumab non super-responder group (p = 0.015, p < 0.001, p = 0.004, p < 0.001 and p < 0.001, respectively). Blood eosinophil count (AUC: 0.187, p < 0.001), eosinophil-to-lymphocyte ratio (AUC: 0.150, p < 0.001) and FEV1 (%) (AUC:0.779, p = 0.001) were determined to have diagnostic value in predicting the treatment response to omalizumab of patients with severe allergic asthma. Conclusion High-blood eosinophil levels, CRSwNP and low pretreatment lung capacity may affect omalizumab treatment response in patients with severe allergic asthma. These results should be supported by further multicenter real-life studies.

Clinical and cytokine patterns of uncontrolled asthma with and without comorbid chronic rhinosinusitis: a cross-sectional study

BackgroundAsthma is significantly related to chronic rhinosinusitis (CRS) both in prevalence and severity. However, the clinical patterns of uncontrolled asthma with and without comorbid CRS are still unclear. This study aimed to explore the clinical characteristics and cytokine patterns of patients with uncontrolled asthma, with and without comorbid CRS.Methods22 parameters associated with demographic characteristics, CRS comorbidity, severity of airflow obstruction and airway inflammation, and inflammation type of asthma were collected and assessed in 143 patients with uncontrolled asthma. Different clusters were explored using two-step cluster analysis. Sputum samples were collected for assessment of Th1/Th2/Th17 and epithelium-derived cytokines.ResultsComorbid CRS was identified as the most important variable for prediction of different clusters, followed by pulmonary function parameters and blood eosinophil level. Three clusters of patients were determined: Cluster 1 (n = 46) characterized by non-atopic patients with non-eosinophilic asthma without CRS, demonstrating moderate airflow limitation; Cluster 2 (n = 54) characterized by asthma patients with mild airflow limitation and CRS, demonstrating higher levels of blood eosinophils and immunoglobulin E (IgE) than cluster 1; Cluster 3 (n = 43) characterized by eosinophilic asthma patients with severe airflow limitation and CRS (46.5% with nasal polyps), demonstrating worst lung function, lowest partial pressure of oxygen (PaO2), and highest levels of eosinophils, fraction of exhaled nitric oxide (FeNO) and IgE. Sputum samples from Cluster 3 showed significantly higher levels of Interleukin (IL)-5, IL-13, IL-33, and tumor necrosis factor (TNF)-α than the other two clusters; and remarkably elevated IL-4, IL-17 and interferon (IFN)-γ compared with cluster 2. The levels of IL-10 and IL-25 were not significantly different among the three clusters.ConclusionsUncontrolled asthma may be endotyped into three clusters characterized by CRS comorbidity and inflammatory cytokine patterns. Furthermore, a united-airways approach may be especially necessary for management of asthma patients with Type 2 features.

The Influence of Peripheral Blood Eosinophil Counts in Asthma Comorbidities in Adults: A Real Life Study

Asthma and eosinophilia are two closely related pathologies whose interaction is key in the era of precision medicine. However, this relationship is rarely taken into account without the influence of therapeutic prescriptions. In this study involving 1296 subjects, the relationship between eosinophilia and asthma was analyzed without taking into account other biases. We observed that rhinitis only appears in non-asthmatic patients with elevated blood eosinophil levels, while atopy was elevated in parallel to eosinophilia regardless of whether the patients were asthmatic or not. In terms of lung function, a decrease was observed for higher blood eosinophil levels, which is especially relevant in the FEV1/FVC ratio. FENO is elevated in relation to higher eosinophilia, but total IgE is only elevated in patients with high peripheral blood eosinophil levels and asthma. Finally, the only feature of asthma that is altered by increased peripheral eosinophilia is persistent asthma, with all other features remaining unchanged.

Association Between Clinical Burden and Blood Eosinophil Counts in Asthma: Findings From a Korean Adult Asthma Cohort.

BackgroundSome reports have suggested that the clinical and economic burdens of asthma are associated with blood eosinophil levels. The association between clinical burden and blood eosinophil counts were evaluated in a Korean adult asthma cohort.MethodsClinical information including blood eosinophil counts that were not affected by systemic corticosteroids were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea database. Clinical burden was defined as 1) asthma control status, 2) medication demand and 3) acute exacerbation (AE) events during 1 consecutive year after enrollment. All patients were divided into atopic and non-atopic asthmatics. The associations between asthma outcomes and the blood eosinophil count were evaluated.ResultsIn total, 302 patients (124 atopic and 178 non-atopic asthmatics) were enrolled. In all asthmatics, the risk of severe AE was higher in patients with blood eosinophil levels < 100 cells/µL than in patients with levels ≥ 100 cells/µL (odds ratio [OR], 5.406; 95% confidence interval [CI], 1.266–23.078; adjusted P = 0.023). Among atopic asthmatics, the risk of moderate AE was higher in patients with blood eosinophil levels ≥ 300 cells/µL than in patients with levels < 300 cells/µL (OR, 3.558; 95% CI, 1.083–11.686; adjusted P = 0.036). Among non-atopic asthmatics, the risk of medication of Global Initiative for Asthma (GINA) steps 4 or 5 was higher in patients with high blood eosinophil levels than in patients with low blood eosinophil levels at cutoffs of 100, 200, 300, 400, and 500 cells/µL.ConclusionThe baseline blood eosinophil count may predict the future clinical burden of asthma.

Predictors of High Sputum Eosinophils in Chronic Obstructive Pulmonary Disease.

Eosinophils are involved in the development of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroid responsiveness. We evaluated clinical predictors of high sputum eosinophil levels in a COPD cohort in China. We conducted an observational, prospective, population-based, cross-sectional study. Participants were tested for COPD and underwent spirometry, computed tomography scans, and a blood test. Participants also produced induced sputum and responded to an information-gathering questionnaire. High sputum eosinophils were defined as ≥3.0%. Multivariate logistic regression was used to identify predictors of high sputum eosinophil levels. We recruited 895 patients with complete and quality control data. The median percentage of sputum eosinophil abundance was 2.00% (interquartile range: 0.75-5.00) and the prevalence of COPD with high sputum eosinophils was 38.0%. Covariance analysis indicated that the high sputum eosinophil group had lower lung function, more severe emphysema, and air trapping. Multivariate logistic regression indicated that high blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases were associated with high sputum eosinophil levels. High blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases may be predictors of high sputum eosinophil levels in Chinese COPD patients. High sputum eosinophils were associated with lower lung function, more emphysema, and gas trapping.

TYPE II INFLAMMATION IN PATIENTS WITH COPD TAKING PROTON PUMP INHIBITORS

TOPIC: Obstructive Lung Diseases TYPE: Original Investigations PURPOSE: To examine if (chronic obstructive pulmonary disease) COPD patients taking proton pump inhibitors (PPI's) are more likely to be admitted and if a significant difference in eosinophil levels exist when compared to COPD patients not taking PPI's. METHODS: A retrospective case control analysis comparing clinically diagnosed COPD patients on PPI's to those who were not in terms of demographics, spirometry, eosinophilia, and admissions. We considered p<0.05 statistically significant. Risk factors for admissions were sought using both univariate and multivariate analyses. They were selected for a multivariate analysis if their p<0.05 or if clinically significant. RESULTS: A total of 314 clinically diagnosed COPD patients had obstruction on PFT's, completed a CBC with differential and met our matching algorithm. Baseline characteristics showed no significant difference between the PPI and non-PPI groups in; percent predicted FEV1(PPI 46.8 non-PPI 46.5 p=0.917), FEV1/FVC(PPI 45.5 non-PPI 45.2 p=0.795), age(PPI 68.4 non-PPI 68.8 p=0.695), male gender(PPI 75/157 non-PPI 75/157 p=1.0), BMI(PPI 28.0 non-PPI 26.6 P=0.079) and smoking history(PPI 84/157 non-PPI 79/157 p=0.572).A significant difference was found between the PPI and non-PPI groups in eosinophil %(E%) (PPI 3.6 non-PPI 3.0 p=0.008), maximum eosinophil count(MEC) (PPI 0.300K/µL non-PPI 0.244K/µL p=0.008), being above the GOLD eosinophil benefit threshold(GEBT) (PPI 74/157, non-PPI 52/157 p=0.011), and admissions(PPI 46/157, non-PPI 26/157 p=0.007).Using admission as the outcome variable, the following variables were significant in a univariate analysis: PPI use(Admitted 46/72 not 111/242 p=0.01), MEC(Admitted 0.333K/µL Not 0.254K/µL p=0.018), E%(Admitted 3.8 Not 3.2 p=0.037), GEBT(Admitted 37/72 Not 89/242 p=0.029), age(Admitted 65.9 Not 69.4 p=0.011), history of smoking(Admitted 45/72 Not 118/242 p=0.044). In our multivariate model PPI use(p=0.019, OR=1.96), GEBT(p=0.041 OR 1.78) and age(p=0.034 OR=0.97) were significant while smoking history(p=0.079 OR 1.65) and FEV1(p=0.287 OR 0.991) were not. CONCLUSIONS: Our study was the first to show a significant difference with higher blood eosinophil levels in COPD patients on PPI's versus not taking PPI's. We also found PPI's were associated with admissions. While PPI's are an effective treatment for GERD, reflux likely still occurs due to changes in pressure dynamics augmented in COPD. In addition, during reflux a vagally mediated acid induced bronchospasm reflex may be triggered by the presence of acid in the esophagus. This reflex persists even after acid clearance and is thought to initiate an inflammatory cascade and bronchospasm. Our findings suggest this inflammation may be eosinophilic in nature and warrants further research evaluating eosinophilia in COPD patients with GERD. CLINICAL IMPLICATIONS: COPD patients on PPI's are more likely to be admitted and to have higher eosinophil levels. DISCLOSURES: Grant for research relationship with Sanofi Please note: January 2021 Added 04/20/2021 by Daniel Ouellette, source=Web Response, value=Grant/Research No relevant relationships by Jovica Veljanovski, source=Web Response

Prevalence and screening of specific aeroallergens in Chinese male patients with chronic obstructive pulmonary disease: A retrospective cross-sectional observational study.

Sensitization to aeroallergens was linked to severe symptoms and frequent exacerbations in chronic obstructive pulmonary disease (COPD) patients. Elevated serum total immunoglobulin E (tIgE) level is a hallmark of allergic COPD patients. Phadiatop test exhibited high sensitivity for predicting specific aeroallergens (SAs) sensitization. However, the prevalence of aeroallergens, the value of Phadiatop test, alone or combined with tIgE, for predicting aeroallergens sensitization in male COPD patients have not been explored in China. To explore the prevalence and predictors of aeroallergens in the context of COPD. The predictive value of Phadiatop test for SAs sensitization in male COPD patients was analyzed via the area under receiver operating characteristic curves (AUCs). The top five SAs in the context of COPD were d2, mx2, i6, d1, and tx5, of which the seasonal distribution showed no significant differences. Allergic group showed higher levels of blood eosinophils, total Phadiatop IgE and tIgE than the nonallergic group (all P ≤ 0.001). The AUCs of total Phadiatop IgE and tIgE for predicting the sensitization to SAs, SAs excluding mx2 (AEM) and mx2 were ((0.921 vs. 0.879, P=0.2522), (0.967 vs. 0.807, P = 0.0003), and (0.780 vs. 0.883, P<0.05)) (AUCPhadiatop vs AUCtIgE ), respectively. The combined application of these two parameters (model) increased the AUC of SAs, significantly higher than the single parameter used (P<0.05 for all). d2, mx2, i6, and d1 were the top four SAs sensitized in male COPD patients; Phadiatop test was valuable for predicting the sensitization to SAs when it was > 0.13 kAU/L.

Anti-IL-5 therapies for chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospital admissions, disease-related morbidity and mortality. COPD is a heterogeneous disease with distinct inflammatory phenotypes, including eosinophilia, which may drive acute exacerbations in a subgroup of patients. Monoclonal antibodies targeting interleukin 5 (IL-5) or its receptor (IL-5R) have a role in the care of people with severe eosinophilic asthma, and may similarly provide therapeutic benefit for people with COPD of eosinophilic phenotype. To assess the efficacy and safety of monoclonal antibody therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) compared with placebo in the treatment of adults with COPD. We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, clinical trials registries, manufacturers' websites, and reference lists of included studies. Our most recent search was 23 September 2020. We included randomised controlled trials comparing anti-IL-5 therapy with placebo in adults with COPD. Two review authors independently extracted data and analysed outcomes using a random-effects model.The primary outcomes were exacerbations requiring antibiotics or oral steroids, hospitalisations due to exacerbation of COPD, serious adverse events, and quality of life. We used standard methods expected by Cochrane. We used the GRADE approach to assess the certainty of the evidence. Six studies involving a total of 5542 participants met our inclusion criteria. Three studies used mepolizumab (1530 participants), and three used benralizumab (4012 participants). The studies were on people with COPD, which was similarly defined with a documented history of COPD for at least one year. We deemed the risk of bias to be generally low, with all studies contributing data of robust methodology. Mepolizumab 100 mg reduces the rate of moderate or severe exacerbations by 19% in those with an eosinophil count of at least 150/μL (rate ratio (RR) 0.81, 95% confidence interval (CI) 0.71 to 0.93; participants = 911; studies = 2, high-certainty evidence). When participants with lower eosinophils are included, mepolizumab 100 mg probably reduces the exacerbation rate by 8% (RR 0.92, 95% CI 0.82 to 1.03; participants = 1285; studies = 2, moderate-certainty evidence). Mepolizumab 300 mg probably reduces the rate of exacerbations by 14% in participants all of whom had raised eosinophils (RR 0.86, 95% CI 0.70 to 1.06; participants = 451; studies = 1, moderate-certainty evidence); the evidence was uncertain for a single small study of mepolizumab 750 mg. In participants with high eosinophils, mepolizumab probably reduces the rate of hospitalisation by 10% (100 mg, RR 0.90, 95% CI 0.65 to 1.24; participants = 911; studies = 2, moderate-certainty evidence) and 17% (300 mg, RR 0.83, 95% CI 0.51 to 1.35; participants = 451; studies = 1, moderate-certainty evidence). Mepolizumab 100 mg increases the time to first moderate or severe exacerbation compared to the placebo group, in people with the eosinophilic phenotype (hazard ratio (HR) 0.78, 95% CI 0.66 to 0.92; participants = 981; studies 2, high-certainty evidence). When participants with lower eosinophils were included this difference was smaller and less certain (HR 0.87, 95% CI 0.75 to 1.0; participants = 1285; studies 2, moderate-certainty evidence). Mepolizumab 300 mg probably increases the time to first moderate or severe exacerbation in participants who all had eosinophilic phenotype (HR 0.77, 95% CI 0.60 to 0.99; participants = 451; studies = 1, moderate-certainty evidence). Benralizumab 100 mg reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high-certainty evidence). Benralizumab 10 mg probably reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.68, 95% CI 0.49 to 0.94; participants = 765; studies = 1, moderate-certainty evidence). There was probably little or no difference between the intervention and placebo for quality of life measures. Where there were differences the mean difference fell below the pre-specified minimum clinically significant difference. Treatment with mepolizumab and benralizumab appeared to be safe. All pooled analyses showed that there was probably little or no difference in serious adverse events, adverse events, or side effects between the use of a monoclonal antibody therapy compared to placebo. We found that mepolizumab and benralizumab probably reduce the rate of moderate and severe exacerbations in the highly selected group of people who have both COPD and higher levels of blood eosinophils. This highlights the importance of disease phenotyping in COPD, and may play a role in the personalised treatment strategy in disease management. Further research is needed to elucidate the role of monoclonal antibodies in the management of COPD in clinical practice. In particular, it is not clear whether there is a threshold blood eosinophil level above which these drugs may be effective. Studies including cost effectiveness analysis may be beneficial given the high cost of these therapies, to support use if appropriate.

Mepolizumab effectiveness and identification of super-responders in severe asthma

Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.

Eosinophils in chronic obstructive pulmonary disease: are they just another biomarker?

Interest in blood eosinophils as a biomarker of responsiveness to therapy in chronic obstructive pulmonary disease (COPD) continues to grow, with recommendations regarding their adjunctive use incorporated into the GOLD 2019 treatment algorithm. The present review summarizes some key recent papers referencing differential treatment effects based on blood eosinophil counts. Post-hoc analyses of trials of inhaled corticosteroids in COPD have shown greater treatment responses in patients with higher blood eosinophil levels, with some exceptions. Eosinophil-directed treatment with oral corticosteroids showed equivalent benefits to noneosinophil-directed therapy, with reduced corticosteroid exposure. Prespecified analyses of recent prospective trials of therapies incorporating inhaled corticosteroids were generally supportive of previous findings, so evidence for the use of blood eosinophils as biomarkers is gathering. Nonetheless, the anti-interleukin (IL)-5 receptor antagonist benralizumab, which depletes blood eosinophils, showed no treatment benefit in patients with COPD selected for eosinophilic phenotype and treatment of COPD with the IL-5 antagonist, mepolizumab showed inconsistent results. The 2019 GOLD COPD Strategy document embraced the use of the blood eosinophil to guide ICS therapy in management of patients with stable COPD and frequent exacerbations. Although post-hoc and several prospective studies with prespecified subgroup analyses have supported this approach, questions still remain about how to incorporate this new assessment tool into real-life management of COPD and more research is required to validate its adoption into clinical practice. There is an absence of data to support the use of biologic therapy in patients with an eosinophilic COPD phenotype at this stage.

Role of phosphodiesterase-4 inhibitors in chronic obstructive pulmonary disease.

Phosphodiesterase-4 inhibitors (PDE4Is) are potent anti-inf lammatory agents and roflumilast has been used to prevent acute exacerbation of chronic obstructive pulmonary disease (COPD). Roflumilast decreases neutrophil migration, restores cystic fibrosis transmembrane conductance regulator activity, and recovers glucocorticoid effects. A forced expiratory volume in 1 second of < 50%, a chronic bronchitis phenotype, high blood eosinophil levels, and a history of hospitalization are biomarkers for predicting responses to roflumilast. Adverse effects are common in clinical practice. An inhaled PDE4I has recently been developed and is under clinical trial. CHF6001 and RPL554 exhibit promise and may be future treatment options for COPD.

Upper and lower airway inflammation in severe asthmatics: a guide for a precision biologic treatment.

Background and aims:Severe asthma may require the prescription of one of the biologic drugs currently available, using surrogate markers of airway inflammation (serum IgE levels and allergic sensitization for anti-IgE, or blood eosinophils for anti-IL5/IL5R). Our objective: to assess upper and lower airway inflammation in severe asthmatics divided according to the eligibility criteria for one of the target biologic treatments.Methods:We selected 91 severe asthmatics, uncontrolled despite high-dose ICS-LABA, and followed for >6 months with optimization of asthma treatment. Patients underwent clinical, functional and biological assessment, including induced sputum and nasal cytology. They were then clustered according to the eligibility criteria for omalizumab or mepolizumab/benralizumab.Results:Four clusters were selected: A (eligible for omalizumab, n = 23), AB (both omalizumab and mepolizumab, n = 26), B (mepolizumab, n = 22) and C (non-eligible for both omalizumab and mepolizumab, n = 20). There was no difference among clusters for asthma control (Asthma Control Test and Asthma Control Questionnaire 7), pre-bronchodilator forced expiratory volume in 1 s, serum IgE and fractional exhaled nitric oxide levels. Sputum eosinophils were numerically higher in clusters AB and B, in agreement with the higher levels of blood eosinophils. Allergic rhinitis was more frequent in clusters A and AB, while chronic rhinosinusitis with nasal polyps prevalence increased progressively from A to C. Eosinophils in nasal cytology were higher in clusters AB, B and C.Conclusion:Eosinophilic upper and lower airway inflammation is present in the large majority of severe asthmatics, independently from the prescription criteria for the currently available biologics, and might suggest the use of anti-IL5/IL5R or anti IL4/13 also in patients without blood eosinophilia.The reviews of this paper are available via the supplemental material section.

Higher blood eosinophil levels after omalizumab treatment may be associated with poorer asthma outcomes

Higher blood eosinophil levels after omalizumab treatment may be associated with poorer asthma outcomes

Eosinophil levels predict lung function deterioration in apparently healthy individuals.

BackgroundWhile chronic respiratory diseases are among the leading causes of mortality and morbidity worldwide, little is known about the effect of blood eosinophil levels on lung function trajectories among healthy individuals.MethodsWe analyzed data of apparently healthy individuals (n=18,089) recruited for the Tel Aviv Medical Center Inflammation Survey. Blood eosinophil levels were compared between participants with normal and those with abnormal lung function. Multivariate regression was used to assess the OR of forced expiratory volume in 1 second (FEV1) deterioration according to baseline eosinophils in subjects with normal lung function (n=4,141) during a follow-up period of 4 years.ResultsParticipants with an abnormal, as opposed to a normal, pulmonary function test (PFT) (n=1,832, 10.1%) had significantly higher eosinophil levels, expressed as a percentage or count (2.99%±2.00% compared to 2.67%±1.88% and 0.2210e3/µL±0.163/µL compared to 0.1810e3/µL±0.183/µL, respectively; P<0.001 for both). Among participants with a normal PFT at baseline, those with an eosinophil percentage higher than 4% showed a higher risk for FEV1 decline above 60 mL/year (OR=1.199, 95% CI=1.005–1.431, P=0.044).ConclusionOur study suggests that higher blood eosinophil levels can predict PFT deterioration even in apparently healthy subjects, implying that these individuals could benefit from frequent lung function evaluation.

Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Inhaled corticosteroids (ICSs) are a mainstay of COPD treatment for patients with a history of exacerbations. Initial studies evaluating their use as monotherapy failed to show an effect on rate of pulmonary function decline in COPD, despite improvements in symptoms and reductions in exacerbations. Subsequently, ICS use in combination with long-acting β2-agonists (LABAs) was shown to provide improved reductions in exacerbations, lung function, and health status. ICS-LABA combination therapy is currently recommended for patients with a history of exacerbations despite treatment with long-acting bronchodilators alone. The presence of eosinophilic bronchial inflammation, detected by high blood eosinophil levels or a history of asthma or asthma–COPD overlap, may define a population of patients in whom ICSs may be of particular benefit. Prospective clinical studies to determine an appropriate threshold of eosinophil levels for predicting the beneficial effects of ICSs are needed. Further study is also required in COPD patients who continue to smoke to assess the impact of cell- and tissue-specific changes on ICS responsiveness. The safety profile of ICSs in COPD patients is confounded by comorbidities, age, and prior use of systemic corticosteroids. The risk of pneumonia in patients with COPD is increased, particularly with more advanced age and worse disease severity. ICS-containing therapy also has been shown to increase pneumonia risk; however, differences in study design and the definition of pneumonia events have led to substantial variability in risk estimates, and some data indicate that pneumonia risk may differ by the specific ICS used. In summary, treatment with ICSs has a role in dual and triple therapy for COPD to reduce exacerbations and improve symptoms. Careful assessment of COPD phenotypes related to risk factors, triggers, and comorbidities may assist in individualizing treatment while maximizing the benefit-to-risk ratio of ICS-containing COPD treatment.