Elevated Blood Eosinophil Levels Research Articles

Eosinophils promote pulmonary matrix destruction and emphysema via Cathepsin L

Patients with chronic obstructive pulmonary disease (COPD) who exhibit elevated blood eosinophil levels often experience worsened lung function and more severe emphysema. This implies the potential involvement of eosinophils in the development of emphysema. However, the precise mechanisms underlying the development of eosinophil-mediated emphysema remain unclear. In this study, we employed single-cell RNA sequencing to identify eosinophil subgroups in mouse models of asthma and emphysema, followed by functional analyses of these subgroups. Assessment of accumulated eosinophils unveiled distinct transcriptomes in the lungs of mice with elastase-induced emphysema and ovalbumin-induced asthma. Depletion of eosinophils through the use of anti-interleukin-5 antibodies ameliorated elastase-induced emphysema. A particularly noteworthy discovery is that eosinophil-derived cathepsin L contributed to the degradation of the extracellular matrix, thereby leading to emphysema in pulmonary tissue. Inhibition of cathepsin L resulted in a reduction of elastase-induced emphysema in a mouse model. Importantly, eosinophil levels correlated positively with serum cathepsin L levels, which were higher in emphysema patients than those without emphysema. Expression of cathepsin L in eosinophils demonstrated a direct association with lung emphysema in COPD patients. Collectively, these findings underscore the significant role of eosinophil-derived cathepsin L in extracellular matrix degradation and remodeling, and its relevance to emphysema in COPD patients. Consequently, targeting eosinophil-derived cathepsin L could potentially offer a therapeutic avenue for emphysema patients. Further investigations are warranted to explore therapeutic strategies targeting cathepsin L in emphysema patients.

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.

Literature reviews of stroke with hypereosinophilic syndrome.

Hypereosinophilic syndrome (HES) is defined by persistently elevated blood eosinophil levels and is associated with evidence of organ damage. Cardiovascular involvement in HES is most commonly associated with Loffler endocarditis (cardiac HES). Cardiac HES is typically characterized by progressive subendocardial fibrosis with overlying mural thrombus formation, leading to restrictive dysfunction of the left ventricle. The thrombus from cardiac HES could result in cardiogenic stroke; however, most of the stroke cases with HES were not associated with huge thromboembolism rather multiple infarcts in the watershed area. The major clinical features of 97 previously reported cases of stroke with HES are as follows: the median age was 52 years, of which 61 (63%) were men; the initial presenting symptoms were neurological (73%), followed by headache (16%), respiratory symptoms (9%), and visual symptoms (9%). Almost half of the cases were diagnosed with cardiac HES. The characteristics of cardiac findings were mural thrombi, endomyocardial fibrosis, and a restrictive pattern of heart failure. Cerebral findings revealed 78 cases (80%) were described as multiple infarctions and 55 cases (57 %) were involved with watershed areas, whereas 11 cases (11％) were described as embolic stroke for one proximal large-vessel occlusion. Regarding treatment, 71 (73%), 28 (29%), and 16 (16%) patients were treated with steroids, anticoagulants, and antiplatelets, respectively. The overall mortality and recovery rates were 11% and 89%, respectively. Physicians should know most cases of stroke with HES are characterized by multiple infarctions in the watershed area, and cardiac HES is not always associated with stroke.

Inflammatory patterns in fixed airflow obstruction are dependent on the presence of asthma.

Fixed airflow obstruction (FAO) can complicate asthma. Inflammation is a proposed underlying mechanism. Our aim in this cross-sectional investigation was to evaluate the blood leucocyte pattern and level of exhaled nitric oxide in asthmatics and non-asthmatics with or without FAO. A total of 11,579 individuals aged ≥20 years from the US National Health and Nutrition Examination Survey were included. They were grouped as: controls without asthma and FAO (n = 9,935), asthmatics without FAO (n = 674), asthmatics with FAO (n = 180) and non-asthmatics with FAO (n = 790). FAO was defined as post-bronchodilator FEV1/FVC < lower limit of normal. Exhaled nitric oxide ≥ 25ppb, blood eosinophil levels ≥300 cells/μL, and blood neutrophil levels ≥5100 cells/μL were defined as elevated. Stratified analyses for smoking and smoking history were performed. Elevated blood eosinophil levels were more common in all groups compared to the controls, with the highest prevalence in the group with asthma and fixed airflow obstruction (p<0.01). In a multiple logistic regression model adjusted for potential confounders including smoking, the asthma groups had significantly higher odds ratios for elevated B-Eos levels compared to the control group (odds ratio 1.4, (confidence interval: 1.1-1.7) for the asthma group without fixed airflow obstruction and 2.5 (1.4-4.2) for the asthma group with fixed airflow obstruction). The group with fixed airflow obstruction without asthma had higher odds ratio for elevated blood neutrophil levels compared to the controls: 1.4 (1.1-1.8). Smoking and a history of smoking were associated to elevated B-Neu levels. Fixed airflow obstruction in asthma was associated with elevated blood eosinophil levels, whereas fixed airflow obstruction without asthma was associated with elevated blood neutrophil levels.

Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD.

Inhaled corticosteroid/long-acting β2-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) versus formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations.In this phase 3, randomised, double-blind, parallel-group, 12–52-week, variable length study, patients received twice-daily BFF MDI 320/10 µg or 160/10 µg, or FF MDI 10 µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety.The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10 µg, n=619; BFF MDI 160/10 µg, n=617; and FF MDI, n=607). BFF MDI 320/10 µg and 160/10 µg improved morning pre-dose trough FEV1 at week 12 versus FF MDI (least squares mean differences 34 mL [p=0.0081] and 32 mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ≥150 cells·mm−3. The incidence of adverse events was similar, and pneumonia rates were low (≤2.4%) across treatments.SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10 µg and 160/10 µg in patients with moderate-to-very severe COPD at increased risk of exacerbations.

Blood Eosinophil Counts, Withdrawal of Inhaled Corticosteroids and Risk of COPD Exacerbations and Mortality in the Clinical Practice Research Datalink (CPRD)

Although recently introduced in the pharmacological treatment algorithm of chronic obstructive pulmonary disease (COPD), there is a need for more data supporting the use of blood eosinophil counts as a biomarker to guide inhaled corticosteroids (ICS) therapy. The aim of this study was to evaluate the risk of moderate and/or severe exacerbations and all-cause mortality in a large primary care population after withdrawal of ICS compared to continued users stratified by elevated blood eosinophil counts. In this population based cohort study, we used data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom. We included subjects’ aged 40 years or more who had a diagnosis of COPD. We excluded subjects with a history of asthma, pulmonary fibrosis, cardiac arrhythmia and bronchiectasis, COPD exacerbations occurring within 6 weeks prior to index date, or with a myocardial infarction within 3 months prior to index date. Continuous users were subjects who received their most recent ICS prescription within 3 months before the start of an interval. ICS withdrawals were those who discontinued ICS for more than 3 months. We evaluated the risk of moderate and/or severe exacerbations and all-cause mortality among subjects with various blood eosinophil thresholds who withdrew from ICS compared to continuous ICS users with elevated blood eosinophil levels using Cox regression analysis adjusted for potential confounders. We identified 48,157 subjects diagnosed with COPD between 1 January 2005 to 31 January 2014. Withdrawal of ICS was not associated with an increased risk of moderate-to-severe exacerbations among subjects with absolute blood eosinophil counts ≥0.34 × 109 cells/L [adjusted hazard ratio (adj. HR) 0.72; 95% confidence interval (CI) 0.63–0.81] or relative counts ≥ 4.0% (adj. HR 0.72; 95% CI: 0.66–0.78). Similarly, withdrawal of ICS was not associated with an increased risk of severe exacerbations among subjects with absolute blood eosinophil ≥0.34 × 109 cells/L (adj. HR 0.82; 95% CI: 0.61–1.10) or relative blood eosinophil counts ≥4.0% (adj. HR 0.80; 95% CI: 0.61–1.04). No increased risk of all-cause mortality was observed among subjects who withdrew from ICS irrespective of elevated absolute or relative blood eosinophil counts. In a real-world primary care population, we did not observe an increased risk of moderate and/or severe COPD exacerbations or all-cause mortality among subjects with eosinophilia who withdrew their use of ICS.

Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma: A Systematic Literature Review and Network Meta-Analysis

The interaction of IL-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials. To indirectly compare reslizumab with benralizumab in similar patient populations using a network meta-analysis. A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte-Carlo simulation method and a Bayesian statistical framework. Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels of greater than or equal to 300 cells/μL (n= 1537) and a reslizumab subgroup in Global Initiative for Asthma step 4/5 with 2 or more previous exacerbations and greater than or equal to 400 eosinophils/μL (n= 318). Safety was analyzed in the full population (N= 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab once every 4 weeks and there were reasonably high posterior probabilities that reslizumab is superior to benralizumab once every 4 weeks and once every 8 weeks for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations. This indirect comparison suggests that reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/μL; reslizumab, ≥400/μL) and 2 or more exacerbations in the previous year.

Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps

An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/μL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Relationship of Inhaled Corticosteroid Adherence to Asthma Exacerbations in Patients with Moderate-to-Severe Asthma

Patients with asthma and elevated blood eosinophils are at increased risk of severe exacerbations. Management of these patients should consider nonadherence to inhaled corticosteroid (ICS) therapy as a factor for increased exacerbation risk. The objective of this study was to investigate whether poor adherence to ICS therapy explains the occurrence of asthma exacerbations in patients with elevated blood eosinophil levels. This historical cohort study identified patients within the Optimum Patient Care Research Database, aged 18 years or more, at Global Initiative for Asthma step 3 or 4, with 2 or more ICS prescriptions during the year before the clinical review. Patient characteristics and adherence (based on prescription refills and patient self-report) for ICS therapy were analyzed for those with elevated (>400 cells/μL) or normal (≤400 cells/μL) blood eosinophils. We studied 7195 patients (66% female, mean age 60 years) with median eosinophil count of 200 cells/μL and found 81% to be not fully adherent to ICS therapy. A total of 1031 patients (14%) had elevated blood eosinophil counts (58% female, mean age 60 years), 83% of whom were not fully adherent to ICS. An increased proportion of adherent patients in the elevated blood eosinophil group had 2 or more exacerbations (14.0% vs 7.2%; P= .003) and uncontrolled asthma (73% vs 60.8%; P= .004) as compared with non-fully adherent patients. Approximately 1 in 7 patients had elevated eosinophils. Adherence to ICS therapy was not associated with decreased exacerbations for these patients. Additional therapy should be considered for these patients, such as biologics, which have been previously shown to improve control in severe uncontrolled eosinophilic asthma.

Burden of asthma with elevated blood eosinophil levels.

BackgroundAsthma is a common chronic condition with an economic burden of almost $56 billion annually in the US. Biologic markers like blood eosinophils, that help predict the risk of exacerbation could help guide more optimal treatment plans and reduce cost. The purpose of this study was to determine whether healthcare resource use and expenditures vary by eosinophil level among patients with asthma.MethodsPatients with a diagnosis of asthma defined by ICD-9-CM code 493.xx between January 2004 and July 2011 were extracted from EMRClaims + database (eMAX Health, White Plains NY). Patients were classified as mild, moderate, or severe by medication use following diagnosis, based on recommendations of National Institutes of Health Expert Panel Report 3. Patients were classified as those with elevated eosinophils (≥400 cells/μL) and normal eosinophil level (<400 cells/μL). Patients were followed for resource use, defined as hospitalizations, ER visits and outpatient visit and associated costs were calculated to assess whether an economic difference exists between eosinophil groups. Non-parametric tests were used to compare resource use and associated cost between elevated and normal eosinophil groups. Multivariate modeling was performed to assess the contribution of eosinophil level on the likelihood of study outcomes among patients with severe asthma.ResultsAmong the 2,164 patients meeting eligibility criteria, 1,144 had severity designations. Of these, 179(16 %) of patients had severe asthma of which 20 % (n = 35) had elevated eosinophils. Seventeen percent of patients with elevated eosinophils were admitted to the hospital during the follow-up period, significantly greater than patients with normal eosinophil levels (12 %; p = 0.011). Overall, compared to patients with normal eosinophil levels (n = 1734), patients with elevated eosinophil levels (n = 430) had significantly greater mean annual hospital admissions (0.51 vs. 0.21/year, p = 0.006) and hospital costs (2,536 vs. $1,091, p = 0.011). Logistic regressions showed that elevated eosinophil level was associated with 5.14 times increased odds of all cause admissions (95 % CI:1.76–14.99, p = 0.003) and 4.07 times increased odds of asthma related admissions (95 % CI: 1.26–13.12, p = 0.019).ConclusionEosinophil elevation was associated with greater healthcare resource use in patients with asthma.

Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study

This phase 3 study further characterizes the efficacy and safety of reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count≥ 400 cells/μL. Patients were randomized to receive reslizumab 0.3 or 3.0mg/kg or placebo administered once every 4weeks for 16weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV1 over 16weeks. Secondary end points included FVC, forced expiratory flow at 25%to 75%of FVC (FEF25%-75%), patient-reported control of asthma symptoms, short-acting β-agonist (SABA) use, blood eosinophil levels, and safety. Reslizumab significantly improved FEV1 (difference vsplacebo [reslizumab 0.3 and 3.0mg/kg], 115mL [95%CI, 16-215; P= .0237] and 160mL [95%CI, 60-259; P= .0018]). Clinically meaningful increases in FVC (130mL) and FEF25%-75% (233mL/s) were observed with reslizumab 3.0mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vsplacebo (greater effects seen with 3.0mg/kg; P<.05). The minimally important difference was reached for the AQLQ (reslizumab 3.0mg/kg) but not on the ACQ. Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab. The most common adverse events were worsening of asthma, headache, and nasopharyngitis; most events were mild to moderate in severity. Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vsthe 0.3-mg/kg dose, with comparable safety. ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.

WATERSHED INFARCTION DUE TO ACUTE HYPEREOSINOPHILIA

Hypereosinophilia typically results from a parasitic, neoplastic, vasculitic, or allergic cause. However, when elevated blood eosinophil levels (≥1500/μL) persist beyond 6 months and show evidence of organ involvement (other than skin) without identifiable cause, the criteria for idiopathic hypereosinophilia are met. Idiopathic hypereosinophilia can affect multiple organ systems. Up to 65% of patients have neurologic manifestations, including peripheral neuropathy, encephalopathy, or thromboembolic infarction.1 Previously reported thromboembolic events have involved large, intracranial vessels2 and were attributed to the hyperviscous, hypercoaguable state, often accompanied by cardiac dysfunction. We report a patient with acute, severe hypereosinophilia complicated by extensive watershed infarction. Possible mechanistic causes include (1) local thrombus formation from a hyperviscous state or (2) distant microthromboemboli. ### Case report. A 16-year-old, previously healthy male was hospitalized after 2 weeks of cough and 4 days of fever. The initial examination revealed decreased air entry bilaterally. Blood work noted leukocytosis 77.4 × 109/L, with eosinophils 55.3 × 109/L, neutrophils 6.6 × 109/L, and no blasts. Hemoglobin was 115 g/L, and platelets were 154,000 × 109/L. His electrolytes, calcium, phosphorus, uric acid, and renal and liver function tests were normal. Neck and chest CT revealed lymph nodes (≤1.5 cm) and patchy “ground-glass” areas in the …

WATERSHED INFARCTION DUE TO ACUTE HYPEREOSINOPHILIA

Hypereosinophilia typically results from a parasitic, neoplastic, vasculitic, or allergic cause. However, when elevated blood eosinophil levels (≥1500/μL) persist beyond 6 months and show evidence of organ involvement (other than skin) without identifiable cause, the criteria for idiopathic hypereosinophilia are met. Idiopathic hypereosinophilia can affect multiple organ systems. Up to 65% of patients have neurologic manifestations, including peripheral neuropathy, encephalopathy, or thromboembolic infarction.1 Previously reported thromboembolic events have involved large, intracranial vessels2 and were attributed to the hyperviscous, hypercoaguable state, often accompanied by cardiac dysfunction. We report a patient with acute, severe hypereosinophilia complicated by extensive watershed infarction. Possible mechanistic causes include (1) local thrombus formation from a hyperviscous state or (2) distant microthromboemboli. ### Case report. A 16-year-old, previously healthy male was hospitalized after 2 weeks of cough and 4 days of fever. The initial examination revealed decreased air entry bilaterally. Blood work noted leukocytosis 77.4 × 109/L, with eosinophils 55.3 × 109/L, neutrophils 6.6 × 109/L, and no blasts. Hemoglobin was 115 g/L, and platelets were 154,000 × 109/L. His electrolytes, calcium, phosphorus, uric acid, and renal and liver function tests were normal. Neck and chest CT revealed lymph nodes (≤1.5 cm) and patchy “ground-glass” areas in the …