Including Blood Eosinophil Research Articles

Digitally monitored inhaled therapy: a ‘smart’ way to manage severe asthma?

Introduction One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a ‘smart’ inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. Methods Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics Results 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). Conclusions In severe asthma patients, ‘smart’ inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Phenotyping of Severe Asthma in the Era of Broad-Acting Anti-Asthma Biologics

Severe asthma is associated with significant morbidity and mortality despite maximal use of inhaled corticosteroids and additional controller medications, and has a high economic burden. Biologic therapies are recommended for the management of severe, uncontrolled asthma to help prevent exacerbations and to improve symptoms and health-related quality of life. Effective management of severe asthma requires consideration of clinical heterogeneity that is driven by varying clinical and inflammatory phenotypes, which are reflective of distinct underlying disease mechanisms. Phenotyping patients using a combination of clinical characteristics such as age of onset or comorbidities and biomarker profiles, including blood eosinophil counts, and levels of fractional exhaled nitric oxide and serum total immunoglobulin E, is important for the differential diagnosis of asthma. Additionally, phenotyping is beneficial for risk assessment, selection of treatment, and monitoring of treatment response in patients with asthma. This review describes the clinical and inflammatory phenotypes of asthma, provides an overview of biomarkers routinely used in clinical practice and those that have recently been explored for phenotyping, and aims to assess the value of phenotyping in severe asthma management in the current era of biologics.

Phenotyping the Responses to Systemic Corticosteroids in the Management of Asthma Attacks (PRISMA): protocol for an observational and translational pilot study

IntroductionAsthma and its associated exacerbation are heterogeneous. Although severe asthma attacks are systematically prescribed corticosteroids and often antibiotics, little is known about the variability of response to these therapies. Blood...

Machine learning-based prediction of in-hospital mortality in patients with pneumonic chronic obstructive pulmonary disease exacerbations

Objective While linear regression and LASSO models have been established for predicting in-hospital mortality, there is currently no validated clinical prediction algorithm to predict in-hospital mortality for patients with chronic obstructive pulmonary disease (COPD) exacerbations using machine learning. Thus, we will evaluate the BAP-65 and CURB-65, and construct a novel prediction model using the random forest (RF) technique. Methods A dataset of 1,418 patients with COPD exacerbations was collected. Age, gender, mental status, vital signs, and laboratory results were all taken into account for predictors. The categorical outcome variable was hospital-based mortality of people over 65 years. The dataset was divided randomly into a training dataset (70%) and a testing dataset (30%). We trained three prediction models, BAP-65, CURB-65, and the RF model, estimated the area under the receiver operating characteristic curve (AUROC) for the entire dataset. We also conducted a comparison of the AUROC values using the Delong test. Results A total of 658 individuals with COPD acute exacerbations were enrolled. Our analysis using the receiver operating characteristic curve demonstrated that the RF model exhibited excellent performance, with an AUROC of 0.80 (95% confidence interval: 0.75-0.84). In comparison, the BAP-65 prediction model yielded an AUROC of 0.72 (0.68-0.75), while the CURB-65 prediction model achieved an AUROC of 0.69 (0.67-0.73). Conclusions The RF model demonstrated superior predictive capabilities than the BAP-65 and CURB-65 models in predicting in-hospital mortality. The results further highlighted significant factors for predicting in-hospital mortality, including blood eosinophil count, systolic blood pressure, and prior history of asthma.

High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children

Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P< .0001), C-reactive protein level (P= .0006), and blood neutrophil count (P= .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio= 1.74 [95% CI= 1.10-2.77]; P= .0187) or low (incidence rate ratio=1.83 [95% CI= 1.21-2.77]; P= .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (β= -0.0044 [95% CI= -0.0073 to -0.0015]; pairwise interaction P= .0028) or low IL-6 levels (β= -0.0042 [95% CI= - 0.0070 to -0.0013]; pairwise interaction P= .0039). Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

LONG-TERM SAFETY AND EFFICACY OF DUPILUMAB IN CHILDREN WITH ASTHMA: LIBERTY ASTHMA EXCURSION

<h3>Introduction</h3> Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13. Efficacy and safety of dupilumab in children with asthma have been demonstrated up to 52 weeks in VOYAGE (NCT02948959). <h3>Methods</h3> 365 pediatric participants who completed VOYAGE entered EXCURSION (NCT03560466), a 52-week open-label study of dupilumab 100/200mg (body-weight based) every 2 weeks; a patient subgroup received 300mg every 4 weeks. Treatment-emergent adverse events, blood eosinophil count, total serum IgE, annualized rate of severe asthma exacerbations (AER), and change from VOYAGE baseline in percent predicted forced expiratory volume in 1 second (ppFEV₁) were assessed. <h3>Results</h3> Dupilumab was well tolerated, and the safety profile was consistent with the parent study (<b>Table</b>). Blood eosinophil count decreased from baseline in VOYAGE with median changes (Q1:Q3) of -140 (-410:10) cells/µL at EXCURSION Week 52 for dupilumab/dupilumab (n=191) and -30 (-260:70) cells/µL for placebo/dupilumab (n=105). Total IgE declined substantially throughout EXCURSION with median percent change from VOYAGE baseline to EXCURSION Week 52 of -89.9% for dupilumab/dupilumab (-339.0 IU/mL; n=219) and -80.0% for placebo/dupilumab (-278.0 IU/mL; n=114). Median total IgE at Week 52 was 40.5 and 53.5 IU/mL for dupilumab/dupilumab and placebo/dupilumab, respectively. The low unadjusted AER and improved ppFEV₁ observed in VOYAGE were sustained in patients with type 2 inflammatory phenotype (<b>Table</b>). <h3>Conclusion</h3> Long-term use of dupilumab was well tolerated, with a decline in type 2 biomarkers including blood eosinophils and total serum IgE. Efficacy observed in VOYAGE in patients with type 2 asthma was sustained in EXCURSION over an additional 52 weeks.

Patients with Chronic Obstructive Pulmonary Disease and Evidence of Eosinophilic Inflammation Experience Exacerbations Despite Receiving Maximal Inhaled Maintenance Therapy.

BackgroundSome patients with chronic obstructive pulmonary disease (COPD) experience frequent exacerbations despite maximal inhaled therapy (“triple therapy”), possibly leading to high health care resource utilization (HCRU).AimDescribe characteristics, future HCRU, and mortality of patients with COPD who experience frequent exacerbations despite triple therapy; characterize individuals who may be candidates for biologic therapies.MethodsThis descriptive observational study used primary care data of patients aged ≥40 years in the United Kingdom receiving maintenance therapy for COPD who had ≥1 year of data prior to index date and ≥1 year of follow-up data. We described these patients’ clinical and demographic characteristics, including blood eosinophil counts (BEC), pattern of exacerbations, hospitalizations, and corticosteroid exposure, as well as future exacerbations, hospitalizations, and death.ResultsOf 43,753 patients with maintenance-treated COPD, 6480 experienced exacerbations despite ≥3 months of triple therapy. Of these, 5669 had available BEC: 1287 (22.7%) had BEC ≥250 cells/µL and ≥3 exacerbations in the year prior to the index date; 471 (36.6%) received ≥4 acute courses of oral corticosteroids. Patients with a pattern of high disease burden continued to have high disease burden: 51.1% experienced ≥3 exacerbations and 2.6% experienced ≥3 hospitalizations. Patients who experienced exacerbations despite triple therapy had a significantly higher risk of COPD-related death than other maintenance-treated patients (5.8% vs 2.1%).ConclusionNearly one-quarter of patients receiving triple therapy for COPD who experienced frequent exacerbations had elevated BEC and ≥3 exacerbations, suggesting a potential mechanism of persistent eosinophilic inflammation that could be a target for eosinophil-depleting biologic therapy.

Potential determinants of T helper 2 markers and their distribution in school-aged children

BackgroundThere is growing data on T helper 2 (Th2) biomarker determinants in adult populations. However, the determinants and typical range of these biomarkers have not been well studied in general populations of children. Therefore, we assessed the determinants and typical range of three Th2 biomarkers, including blood eosinophils, FeNO, and serum total IgE in 9-11-year-old children in a prospective birth cohort. MethodsWe examined the pre- and postnatal factors associated with Th2 biomarkers using multivariable logistic regression analysis (n = 428) and extended the results to the original cohort (n = 17,009) using inverse probability weighting. We also measured typical Th2 biomarker distribution in all examined children and healthy participants without allergic diseases (n = 180). ResultsAt age 9–11, wheeze (odds ratio (OR) 7.63), rhinitis (OR 3.14), and eczema (OR 2.46) were significantly associated with increased blood eosinophils. All three allergic conditions were associated with FeNO and total serum IgE, but the ORs were smaller than those for blood eosinophils. Secondhand smoking was inversely associated with the blood eosinophils (OR, 0.38). Similar results were found in the original cohort. Male sex and prenatal factors (maternal smoking and parental history of allergies) were not independent predictors of high Th2 levels. ConclusionsIn addition to wheezing and rhinitis, eczema and secondhand smoke exposure are independent factors for Th2 biomarker interpretation in children. Furthermore, the typical values and cutoff values of blood eosinophils in adults may not be applicable to children.

Integrated systems modeling of severe asthma: Exploration of IL‐33/ST2 antagonism

Asthma is a complex, heterogeneous disease with a high unmet medical need, despite therapies targeting a multitude of pathways. The ability to quantitatively integrate preclinical and clinical data on these pathways could aid in the development and testing of novel targets and therapeutics. In this work, we develop a computational model of asthma biology, including key cell types and mediators, and create a virtual population capturing clinical heterogeneity. The simulated responses to therapies targeting IL‐13, IL‐4Rα, IL‐5, IgE, and TSLP demonstrate agreement with clinical endpoints and biomarkers of type 2 (T2) inflammation, including blood eosinophils, FEV1, IgE, and FeNO. We use the model to explore the potential benefit of targeting the IL‐33 pathway with anti‐IL‐33 and anti‐ST2. Model predictions are compared with data on blood eosinophils, FeNO, and FEV1 from recent anti‐IL‐33 and anti‐ST2 trials and used to interpret trial results based on pathway biology and pharmacology. Results of sensitivity analyses on the contributions of IL‐33 to the predicted biomarker changes suggest that anti‐ST2 therapy reduces circulating blood eosinophil levels primarily through its impact on eosinophil progenitor maturation and IL‐5‐dependent survival, and induces changes in FeNO and FEV1 through its effect on immune cells involved in T2 cytokine production. Finally, we also investigate the impact of ST2 genetics on the conferred benefit of anti‐ST2. The model includes representation of a wide array of biologic mechanisms and interventions that will provide mechanistic insight and support clinical program design for a wide range of novel therapies during drug development.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation

BackgroundJanus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AimTo assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. MethodsThis study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18–65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. ResultsOf 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41–222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: −6 (−43, 32) at 10 mg QD, −26 (−53, 2) at 30 mg QD, −55 (−78, −32) at 40 mg BID and −52 (−72, −32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. ConclusionsIn patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.Australian New Zealand Clinical Trials Registry: ACTRN12619000227190.

ChAracterization of ItaliaN severe uncontrolled Asthmatic patieNts Key features when receiving Benralizumab in a real-life setting: the observational rEtrospective ANANKE study

BackgroundData from phase 3 trials have demonstrated the efficacy and safety of benralizumab in patients with severe eosinophilic asthma (SEA). We conducted a real-world study examining the baseline characteristics of a large SEA population treated with benralizumab in clinical practice and assessed therapy effectiveness.MethodsANANKE is an Italian multi-center, retrospective cohort study including consecutive SEA patients who had started benralizumab therapy ≥ 3 months before enrolment (between December 2019 and July 2020), in a real-world setting. Data collection covered (1) key patient features at baseline, including blood eosinophil count (BEC), number and severity of exacerbations and oral corticosteroid (OCS) use; (2) clinical outcomes during benralizumab therapy. We also conducted two post-hoc analyses in patients grouped by body mass index and allergic status. Analyses were descriptive only.ResultsOf 218 patients with SEA enrolled in 21 Centers, 205 were evaluable (mean age, 55.8 ± 13.3 years, 61.5% females). At treatment start, the median BEC was 580 cells/mm3 (interquartile range [IQR]: 400–850); all patients were on high-dose inhaled controller therapy and 25.9% were on chronic OCS (median dose: 10 mg/die prednisone-equivalent [IQR: 5–25]); 92.9% experienced ≥ 1 exacerbation within the past 12 months (annualized exacerbation rate [AER] 4.03) and 40.3% reported ≥ 1 severe exacerbation (AER 1.10). During treatment (median duration: 9.8 months [IQR 6.1–13.9]; ≥ 12 months for 34.2% of patients), complete eosinophil depletion was observed; exacerbation-free patients increased to 81% and only 24.3% reported ≥ 1 severe event. AER decreased markedly to 0.27 for exacerbations of any severity (− 93.3%) and to 0.06 for severe exacerbations (− 94.5%). OCS therapy was interrupted in 43.2% of cases and the dose reduced by 56% (median: 4.4 mg/die prednisone-equivalent [IQR: 0.0–10.0]). Lung function and asthma control also improved. The effectiveness of benralizumab was independent of allergic status and body mass index.ConclusionsWe described the set of characteristics of a large cohort of patients with uncontrolled SEA receiving benralizumab in clinical practice, with a dramatic reduction in exacerbations and significant sparing of OCS. These findings support benralizumab as a key phenotype-specific therapeutic strategy that could help physicians in decision-making when prescribing biologics in patients with SEA.Trial registration ClinicalTrials.gov Identifier: NCT04272463

Age related non-type 2 inflammation and its association with treatment outcome in patients with chronic rhinosinusitis with nasal polyp in Korea

This study aimed to investigate the effect of age in patients with chronic rhinosinusitis with nasal polyp (CRSwNP). 269 patients were divided into eosinophilic and non-eosinophilic groups based on tissue eosinophilia, defined by eosinophils accounting for more than 20% of the total inflammatory cells. Patients were then further divided into younger and older groups based on the age of 35 years. Clinical characteristics including blood eosinophil, Lund Mackay score, and modified Lund-Kennedy (mLK) scores were compared. Levels of 14 cytokines from nasal tissues of an additional 78 patients were analyzed. Tissue eosinophilia was significantly associated with age and the proportion of non-eosinophilic CRSwNP was significantly higher in younger patients as compared to older patients (79.2% vs 56.6%). There was no difference in clinical characteristics and cytokine levels between the younger and older patients with eosinophilic CRSwNP. In contrast, in patients with non-eosinophilic CRSwNP, younger patients had significantly lower preoperative blood eosinophils and higher mLK scores at three and six months, postoperatively, compared to older patients. Alpha-1 antitrypsin and IL-5 levels were significantly lower in younger patients than in older patients in non-eosinophilic CRSwNP. This study suggests a potential association between age, non-type 2 inflammation and treatment outcome in CRSwNP.

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.

Mucus Plugs and Small Airway Dysfunction in Asthma, COPD, and Asthma-COPD Overlap.

PurposeThere are reports concerning mucus plugs detected on high-resolution computed tomography images and airflow obstruction in asthma and chronic obstructive pulmonary disease (COPD). However, little is known about the associations between mucus plugs and small airway dysfunction (SAD). We evaluated the relationship between mucus plugs and pulmonary function in patients with asthma, COPD, and asthma-COPD overlap (ACO), and investigated the relevance to SAD and type 2 inflammation in a retrospective study.MethodsSubjects included 49 asthmatic, 40 ACO, and 41 COPD patients. ACO was diagnosed based on the Japanese Respiratory Society ACO guidelines. Clinical and laboratory parameters, including blood eosinophil count, serum total IgE levels, fractional exhaled nitric oxide (FeNO), spirometry, and forced oscillation technique (FOT), were compared between patients with and without mucus plugs.ResultsMucus plugs were found in 29 (59%) asthmatic, 25 (65%) ACO, 17 (41%) COPD patients. Patients with mucus plugs had reduced spirometry and larger FOT parameters, especially in COPD patients. Mucus scores correlated positively with IgE in ACO and FeNO in asthmatic patients, but not in COPD patients. Multivariate logistic regression analysis revealed that SAD parameters, including forced vital capacity and resonant frequency, a respiratory reactance parameter, were significantly associated with the presence of mucus plugs in the whole studied population.ConclusionsSAD, rather than large airway dysfunction, was associated with mucus plugs in asthma, ACO, and COPD patients.

Induction of remission in chronic urticaria by immunotherapy using immunoglobulin/histamine complex (Histobulin\u2122): a case report

BackgroundSymptom control is a major concern in chronic urticaria. Histobulin™ is a histamine/immunoglobulin complex that has been approved for allergic rhinitis, bronchial asthma and chronic urticaria in some countries. Not only has the immunoglobulin/histamine complex been reported to be effective in allergic diseases, including chronic urticaria, but recently, the possibility of remission induction in chronic urticaria by the immunoglobulin/histamine complex has been reported.Case presentationHistobulin™ was administered until remission was induced instead of fixing the number of administrations in four cases of chronic urticaria. Two patients showed an early response and finished treatment with 12 injections of Histobulin™, and the other two patients showed a late response and were injected 43 and 46 times. Remission was induced successfully in all four cases.ConclusionsHistobulin™ is not only effective but also induces remission in CSU. The Histobulin™ therapy protocol in CSU may be better if the treatment is continued until remission is achieved. Based on the responses of the patients, early responders and late responders were present. The progression of the disease during treatment consisted of a slow improvement phase and a rapid improvement phase. Uniquely, the appropriate allergy laboratory results, including blood eosinophil fraction, total IgE and eosinophil cationic protein level, were normal in all 4 cases. Further studies concerning the mechanisms of Histobulin™ may be needed.

Ethnic Differences in Severe Asthma Clinical Care and Outcomes: An Analysis of United Kingdom Primary and Specialist Care

Understanding the effects of ethnicity in severe asthma is important for optimal personalized patientcare. To assess ethnic differences in disease control, exacerbations, biological phenotype, and treatment in severe asthma in the United Kingdom. We compared demographics, type 2 biomarkers, lung function, asthma control, medications, and health care use between White and underrepresented ethnic group patients in the UK Severe Asthma Registry (UKSAR) and Optimum Patient Care Research Database (OPCRD). A total of 3637 patients (665 from the underrepresented ethnic group) were included from UKSAR and 10,549 (577 from the underrepresented ethnic group) from OPCRD. Patients in the underrepresented ethnic group had higher levels of uncontrolled disease when measurements were made using the asthma control questionnaire in UKSAR (odds ratio [OR]= 1.47; 95% confidence interval [CI], 1.12-1.93) and the Royal College of Physicians 3 Questions in OPCRD (OR= 1.82; 95% CI, 1.27-2.60). Although exacerbation rates were similar, patients in the underrepresented ethnic group were more likely to have recently attended the emergency department (OR= 1.55; 95% CI, 1.26-1.92) or to have been hospitalized (OR= 1.31; 95% CI, 1.07-1.59) owing to asthma. Inflammatory biomarkers were consistently higher in the underrepresented ethnic group, including blood eosinophils in OPCRD (ratio= 1.12; 95% CI, 1.05-1.20) and in UKSAR blood eosinophils (ratio= 1.16; 95% CI, 1.06-1.27), FeNO (ratio= 1.14; 95% CI, 1.04-1.26), and IgE (ratio= 1.70; 95% CI, 1.47-1.97). Patients in the underrepresented ethnic group were more likely to be atopic in the UKSAR (OR= 1.32; 95% CI, 1.07-1.63) and OPCRD (OR= 1.67; 95% CI, 1.26-2.21), and less likely to be using maintenance oral corticosteroids at referral (OR= 0.75; 95% CI, 0.61-0.92). Severe asthma patients from underrepresented ethnic groups presented with a higher disease burden and were more likely to attend the emergency department. They had a distinct phenotypic presentation and differences in medicine use, with higher levels of type 2 biomarkers.

Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. In phase 2b and 3 studies, tezepelumab significantly reduced exacerbations versus placebo in patients with severe uncontrolled asthma, irrespective of baseline levels of type 2 inflammatory biomarkers. We investigated the mechanism of action of tezepelumab by assessing its effects on airway inflammatory cells, airway remodelling, and airway hyperresponsiveness. CASCADE was an exploratory, double-blind, randomised, placebo-controlled, parallel-group, phase 2 study done in 27 medical centres in Canada, Denmark, Germany, the UK, and the USA. Adults aged 18-75 years with uncontrolled, moderate-to-severe asthma were randomly assigned (1:1) to receive tezepelumab 210 mg or placebo administered subcutaneously every 4 weeks for a planned 28 weeks, extended to up to 52 weeks if COVID-19-related disruption delayed participants' end-of-treatment assessments. Randomisation was balanced and stratified by blood eosinophil count. The primary endpoint was the change from baseline to the end of treatment in the number of airway submucosal inflammatory cells in bronchoscopic biopsy samples. Eosinophils, neutrophils, CD3+ T cells, CD4+ T cells, tryptase+ mast cells, and chymase+ mast cells were evaluated separately. This endpoint was also assessed in subgroups according to baseline type 2 inflammatory biomarker levels, including blood eosinophil count. Airway remodelling was assessed via the secondary endpoints of change from baseline in reticular basement membrane thickness and epithelial integrity (proportions of denuded, damaged, and intact epithelium). Exploratory outcomes included airway hyperresponsiveness to mannitol. All participants who completed at least 20 weeks of study treatment, had an end-of-treatment visit up to 8 weeks after the last dose of study drug, and had evaluable baseline and end-of-treatment bronchoscopies were included in the primary efficacy analysis. All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, NCT03688074. Between Nov 2, 2018, and Nov 16, 2020, 250 patients were enrolled, 116 of whom were randomly assigned (59 to tezepelumab, 57 to placebo). 48 in the tezepelumab group and 51 in the placebo group completed the study and were assessed for the primary endpoint. Treatment with tezepelumab resulted in a nominally significantly greater reduction from baseline to the end of treatment in airway submucosal eosinophils versus placebo (ratio of geometric least-squares means 0·15 [95% CI 0·05-0·41]; nominal p<0·0010), with the difference seen across all baseline biomarker subgroups. There were no significant differences between treatment groups in the other cell types evaluated (ratio of geometric least-squares means: neutrophils 1·36 [95% CI 0·94-1·97]; CD3+ T cells 1·12 [0·86-1·46]; CD4+ T cells 1·18 [0·90-1·55]; tryptase+ mast cells 0·83 [0·61-1·15]; chymase+ mast cells 1·19 [0·67-2·10]; all p>0·10). In assessment of secondary endpoints, there were no significant differences between treatment groups in reticular basement membrane thickness and epithelial integrity. In an exploratory analysis, the reduction in airway hyperresponsiveness to mannitol was significantly greater with tezepelumab versus placebo (least-squares mean change from baseline in interpolated or extrapolated provoking dose of mannitol required to induce ≥15% reduction in FEV1 from baseline: tezepelumab 197·4 mg [95% CI 107·9 to 286·9]; placebo 58·6 mg [-30·1 to 147·33]; difference 138·8 [14·2 to 263·3], nominal p=0·030). Adverse events were reported in 53 (90%) patients in the tezepelumab group and 51 (90%) patients in the placebo group, and there were no safety findings of concern. The improvements in asthma clinical outcomes observed in previous studies with tezepelumab are probably driven, at least in part, by reductions in eosinophilic airway inflammation, as shown here by reduced airway eosinophil counts regardless of baseline blood eosinophil count. Tezepelumab also reduced airway hyperresponsiveness to mannitol, indicating that TSLP blockade might have additional benefits in asthma beyond reducing type 2 airway inflammation. AstraZeneca and Amgen.

COPD in Germany: Use of Diagnostic Measures Including Blood Eosinophil Counts in Daily Practice.

Background Accumulating evidence on the role of blood eosinophils as a biomarker prompted the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee to refine the existing treatment algorithm by incorporating eosinophil counts into treatment recommendations. However, there is a lack of data on when, why and how frequently such blood tests and other measures are being performed by German private respiratory specialists. Methods A questionnaire evaluating doctors’ opinions on the use of diagnostic measures at initial diagnosis and during follow-up, including blood eosinophil count in patients with COPD, was completed by 27 respiratory specialists. Medical records from the past 12 months of 251 patients treated by the same physicians were reviewed retrospectively to investigate the use of these measures. Results Body plethysmography (100 % of doctors) and chest X-ray (96.3 %) were the most commonly used measures according to the doctor’s questionnaire; other measures were COPD assessment test (CAT; 85.2 %) and blood eosinophil count (81.5 %). The evaluation of patients’ medical records revealed that body plethysmography was performed in 72.7 %, the CAT in 61.8 % and chest X-ray in 40.6 % of patients. Blood eosinophil count was measured in 7.2 %. Conclusions In line with the GOLD recommendations, these results confirm that lung function, imaging and patient-reported outcome questionnaires play a crucial role in managing COPD. Our analyses reveal that measurement of the blood eosinophil count gained importance due to physicians’ increased awareness of these cells as a useful biomarker. However, this test seems to be performed mainly for initial diagnosis and not on a regular basis.

Ne 2 tipo sunkios astmos diagnostikos ir gydymo galimybės

Įrodyta, jog 2 tipo astma bei eozinofilinis kvėpavimo takų uždegimas nustatomas dviem trečdaliams sergančių sunkia astma pacientų. Jam būdinga padidėjęs eozinofilų skaičius kraujyje, didesnė serumo imunoglobulino E (IgE) ir frakcinė iškvepiamo azoto oksido (FeNO) koncentracijos. Tačiau trečdaliui sergančiųjų sunkia astma vis dėlto stebimi ne 2 tipo astmai būdingi požymiai.Nepaisant to, kad klinikinėje praktikoje vartojami vis nauji vaistai sunkiai astmai gydyti ir dažnai pabrėžiama individualaus sunkios astmos gydymo parinkimo svarba, šiuo metu specifinis sunkios astmos gydymas biologiniais vaistais yra galimas tik esant 2 tipo astmai (eozinofiliniam fenotipui). Deja, ne 2 tipo astmai būdingiems fenotipams (neutrofilinei ir paucigranuliocitinei astmai) patvirtinto veiksmingo medikamentinio gydymo kol kas nėra.

Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease.

Precision medicine is an approach that combines individual clinical characteristics with additional biological information to distinguish between patients with similar diagnoses, with the aim of predicting disease course and treatment response. Biomarkers have an important role in the practical implementation of precision medicine and enrichment of clinical trial populations. For patients with chronic obstructive pulmonary disease, higher blood eosinophil counts, in combination with clinical characteristics, are associated with increased response to corticosteroids and targeted therapies. A single blood eosinophil count cutoff value is not appropriate for identification of potential treatment response, because often a continuous relationship exists between blood eosinophil counts and treatment response. Response also varies with clinical characteristics such as exacerbation risk and current smoking status. Future incorporation of blood eosinophil counts into clinical trials could potentially reduce drug development costs and trial failures. Including blood eosinophil counts as a biomarker in clinical trials will also provide further opportunities to evaluate aspects of eosinophil testing and standardization of methodology and clinical utility. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).