Benralizumab in Severe Eosinophilic Asthma and Chronic Rhinosinusitis with Nasal Polyps: The Real-World, Multi-Country RANS Observational Study.

Purpose: Real-world evidence of benralizumab effectiveness on nasal polyps (NP) and asthma outcomes in patients with severe eosinophilic asthma (SEA) and comorbid chronic rhinosinusitis with NP are limited. The objective of this study was to assess NP and asthma outcomes in benralizumab-treated patients with SEA and comorbid NP in a real-world setting. Patients and Methods: RANS was a retrospective, multi-country observational study (ClinicalTrials.gov: NCT05180357) using medical chart reviews of adults with SEA and comorbid NP. Total NP Score (NPS), SinoNasal Outcome Test-22 (SNOT-22) total score, annualized exacerbation rate (AER), and 6-item Asthma Control Questionnaire (ACQ-6) and Asthma Control Test (ACT) scores during the 12 months pre-index (baseline) and post-index (follow-up) were measured. Clinically meaningful improvement from baseline following treatment, in terms of total NPS (≥1-point reduction), SNOT-22 total (≥8.9-point reduction), ACQ-6 (≥0.5-point reduction) or ACT (≥3-point increase) scores, were reported. Results: A total of 233 patients were included. Baseline mean (standard deviation [SD]) NPS and SNOT-22 total scores were 3.8 (2.4) and 47.5 (22.6), respectively. The mean change (95% confidence interval [CI]) from baseline was -1.2 (-1.7, -0.6) for NPS, and -19.8 (-23.6, -15.9) for SNOT-22. The AER (95% CI) was 1.2 (0.96, 1.41) at baseline and 0.2 (0.13, 0.28) at follow-up. Mean (SD) ACQ-6 and ACT scores were 1.6 (1.3) and 15.0 (5.2) at baseline and 0.8 (1.0) and 22.0 (3.9) at follow-up, respectively. The proportion of patients who achieved clinically meaningful improvements in NPS, SNOT-22 total, ACQ-6, and ACT scores was 49.1%, 67.6%, 56.6%, and 81.1%, respectively. Conclusion: In this real-world study, improvements in NP and asthma outcomes in patients with SEA and comorbid NP were observed during the 12 months following benralizumab initiation.

Benralizumab in severe eosinophilic asthma by previous biologic use and key clinical subgroups: real-world XALOC-1 programme.

BACKGROUND: Pivotal Phase 3 trials and real-world studies have demonstrated benralizumab's overall efficacy and safety in severe eosinophilic asthma (SEA). Additional large-cohort data are needed to confirm its real-world effectiveness in SEA according to previous biologic use and key baseline characteristics important for treatment selection. METHODS: XALOC-1 is a large, multinational, retrospective, observational, real-world study programme of benralizumab in adults with SEA. This 48-week integrated analysis assessed annualised exacerbation rate (AER), maintenance oral corticosteroid (mOCS) use, asthma symptom control and lung function during a 12-month baseline period and up to 48 weeks after benralizumab initiation. Subgroup analyses were based on previous biologic use and key baseline clinical characteristics (mOCS use, blood eosinophil count, exacerbation history, age at asthma diagnosis, fractional exhaled nitric oxide level and presence of atopy and chronic rhinosinusitis with nasal polyps). RESULTS: Of 1002 patients analysed, 380 were biologic-experienced. At Week 48, 71.3% were exacerbation-free (versus 17.2% at baseline); relative reduction in AER was 82.7% overall and 72.9% in biologic-experienced patients; rates were maintained across all key clinical characteristic subgroups. Of patients using mOCS at baseline (n=274), 47.4% (130/274) eliminated their use by Week 48; the mean reduction from baseline in daily dose was 51.2% and, notably, 34.9% in biologic-experienced patients (n=115). Clinically significant improvements in asthma symptom control and lung function were observed. CONCLUSION: In this large, real-world programme, SEA patients treated with benralizumab had substantial improvements in clinical outcomes irrespective of previous biologic use and key clinical characteristics important to therapeutic decision-making in clinical practice.

Association Between Elevated Blood Eosinophils and Chronic Kidney Disease Progression: Analyses of a Large United States Electronic Health Records Database.

Background: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting. Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] <60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3-4. The primary outcomes were CKD progression and all-cause mortality. Results: We found that high eosinophilic levels (bEOS ≥300 cells/µL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥300 cells/µL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with <300 cells/µL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression. Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.

Real-World Investigation of Eosinophilic-Associated Disease Overlap (REVEAL): Analysis of a US Claims Database.

PURPOSE: The epidemiology of eosinophil-associated diseases (EADs) is not yet fully understood. While some studies have been conducted on stand-alone eosinophilic diseases, there is scarce evidence on the degree of overlap among rarer conditions. METHODS: The retrospective Real-world inVestigation of Eosinophilic-Associated disease overLap (REVEAL) study used data from the Optum® Clinformatics® insurance claims database to describe and characterize disease overlap among 11 EADs: allergic bronchopulmonary aspergillosis, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic gastritis/gastroenteritis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bullous pemphigoid, chronic obstructive pulmonary disorder, chronic spontaneous urticaria, and non-cystic fibrosis bronchiectasis. Patient records with EADs of interest were identified between January 1, 2015, and June 30, 2018. RESULTS: Overall, 1,326,645 patients were included; 74.4% had 1 EAD, 20.5% had ≥ 2 EADs, and 5.1% had ≥ 3 EADs. Higher rates of disease overlap were associated with older age. Higher blood eosinophil counts were also observed in patients with a greater number of overlapping conditions, suggesting a common role for eosinophilic inflammation in the pathogenesis of multiple diseases. Furthermore, greater disease overlap was associated with higher disease severity in most cohorts. CONCLUSIONS: Results from this study have implications for quantifying unmet needs and can be used to inform treatment guidelines and raise the awareness of eosinophilic inflammation and EAD overlap among healthcare professionals from a range of disease specialties.

Clinical and economic burden of chronic rhinosinusitis with nasal polyposis: A U.S. administrative claims analysis.

Background: Limited data exist on the clinical and economic burden of chronic rhinosinusitis with nasal polyposis (CRSwNP). Objective: To describe patient characteristics, health-care resource utilization (HCRU), and health-care costs among patients with CRSwNP with and without comorbid asthma (primary analysis) and with surgical management of nasal polyps (secondary analysis). Methods: This was a retrospective study of patients diagnosed with CRSwNP conducted using administrative claims data from January 1, 2013, through March 31, 2019. Study outcomes were assessed over a 2-year follow-up. Results were stratified by baseline asthma status (primary analysis) and presented separately for patients with surgically managed CRSwNP (secondary analysis). Results: The primary analysis included 10,999 patients with CRSwNP (2649 with asthma, 8350 without asthma). Patients with versus without asthma had higher medication use, HCRU, and all-cause medical costs (mean ± standard deviation $34,667 ± $42,234 versus $27,122 ± $45,573; p < 0.001) across the full follow-up period. CRSwNP-related medical costs were significantly higher for patients with versus without asthma in year 2 of follow-up. In the surgical management analysis (n = 4943), most categories of medication use and CRSwNP-related HCRU declined from baseline levels during follow-up, and CRSwNP-related pharmacy costs in year 2 were less than half of baseline levels. Conclusion: Patients diagnosed with CRSwNP and asthma had a greater burden of illness than those without asthma. Higher CRSwNP-related medical costs in year 2 of follow-up for patients with asthma may indicate worsening symptoms over time. Among patients with surgically managed CRSwNP, HCRU and costs increased in year 1 of follow-up but decreased below baseline levels in year 2, potentially reflecting improved symptom severity.

Systemic Corticosteroid-related Adverse Outcomes and Health Care Resource Utilization and Costs Among Patients with Chronic Rhinosinusitis with Nasal Polyposis.

PURPOSE: Nasal polyps (NPs) develop in 20% to 30% of patients with chronic rhinosinusitis. Severe forms of chronic rhinosinusitis with nasal polyposis (CRSwNP) may be treated with systemic corticosteroids (SCSs), which increase the risk for adverse clinical outcomes. This study compared the incidence of SCS-related adverse outcomes and health care resource utilization and costs between patients with CRSwNP who had SCS exposure and those who did not have SCS exposure. METHODS: This retrospective cohort study used health care claims data from adult patients with CRSwNP identified in the IBMⓇ MarketScanⓇ Databases between January 2003 and June 2019. The first SCS prescription date in SCS users or a matched date in SCS nonusers (controls) represented the index date. Enrollment for ≥1 year before and after the index date was required. SCS-related adverse outcomes and costs were compared between all SCS users and controls, and among subgroups of patients who had claims for 1-3 and ≥4 SCS prescriptions in the 12-month postindex period. Comparisons were also made among SCS users and controls who previously had and did not have NP surgery, and those with and without comorbid asthma. Inverse probability of treatment weights was applied to all comparisons, which were evaluated for a variable-length follow-up period. FINDINGS: SCS users (n = 37,740) had a greater risk for any adverse outcome than controls (n = 7032) (incidence rate ratio [IRR] = 1.10; 95% CI, 1.05-1.16). The risk for adverse outcomes was highest in the subgroups that did not have NP surgery and that had ≥4 SCS claims (n = 2993) versus controls who did not have NP surgery (n = 5078) (IRR = 1.30; 95% CI, 1.18-1.44). Similarly, patients with asthma and ≥4 SCS claims (n = 4195) had a greater risk for SCS-related outcomes versus controls with asthma (n = 1226) (IRR = 1.36; 95% CI, 1.19-1.55). SCS users incurred 60% higher all-cause costs versus non-SCS users (P < 0.001). IMPLICATIONS: In patients with CRSwNP, SCS use was associated with a higher risk for adverse outcomes and with increased health care costs compared with controls without SCS exposure. Alternative treatment strategies that avoid and/or reduce SCS use may decrease health care costs and the risk for adverse outcomes among patients with CRSwNP.

Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab.

INTRODUCTION: Consensus definitions for clinical remission and super-response were recently established for severe asthma. Benralizumab is an interleukin-5 (IL-5) receptor α-directed monoclonal antibody for severe, uncontrolled asthma; efficacy and safety were demonstrated in previous pivotal phase 3 trials (SIROCCO, CALIMA, ZONDA). This analysis applied a composite remission definition to characterize individual responses to benralizumab after 6 and 12 months. METHODS: In previous phase 3 studies, eligible patients were those with severe, uncontrolled asthma receiving medium- or high-dosage inhaled corticosteroids plus long-acting ß2-agonists. This post hoc analysis included patients randomized to the approved benralizumab dose and not receiving oral corticosteroids (OCS) at baseline (SIROCCO/CALIMA) or OCS ≤ 12.5 mg per day (ZONDA). Individual remission components were zero exacerbations; zero OCS use; Asthma Control Questionnaire-6 (ACQ-6) score < 1.5 or ≤ 0.75; and pre-bronchodilator forced expiratory volume in 1 s (FEV1) increase ≥ 100 mL; clinical remission incorporated zero exacerbations, zero OCS use, ACQ-6 score ≤ 0.75, and pre-bronchodilator FEV1 increase ≥ 100 mL after 6 or 12 months. RESULTS: Overall, 609 patients (N = 301 and N = 308) and 586 patients (N = 293 and N = 293) receiving benralizumab in SIROCCO and CALIMA were included at 6 and 12 months, respectively; 40 ZONDA patients were included after 6 months. In SIROCCO/CALIMA, similar to 6-month findings, approx. 83% and approx. 49% receiving benralizumab, and 77% and 37% on placebo achieved ≥ 2 and ≥ 3 remission components after 12 months; 14.5% (85/586) on benralizumab and 7.7% (48/620) on placebo achieved clinical remission at 12 months. Among ZONDA patients, 75% and approx. 48% on benralizumab and 35% and 20% on placebo achieved ≥ 2 and ≥ 3 remission components at 6 months, respectively; 22.5% (9/40) on benralizumab and 7.5% on placebo achieved clinical remission. CONCLUSIONS: This analysis demonstrates clinical remission is achievable by targeting the underlying drivers of inflammation. Precision medicines can help shift treatment paradigms toward treat-to-target, with clinical remission as the ultimate therapeutic goal in severe asthma. CLINICAL TRIAL REGISTRATION: SIROCCO (NCT01928771); CALIMA (NCT01914757); ZONDA (NCT02075255).

Widely accepted definitions for disease remission are already established for the treatment of rheumatoid arthritis, ulcerative colitis, and cancer, among others. Two separate expert groups recently collaborated to discuss clinical remission/super-response to treatment in patients with severe asthma. Both groups developed separate, yet similar ways to determine whether a patient should be considered "in remission." In this study, we used the results from three previous trials (SIROCCO, CALIMA, and ZONDA) that were conducted to assess a therapy called benralizumab in patients with severe asthma to identify patients who met some or all of the criteria for disease remission in severe asthma. These criteria included zero asthma exacerbations; zero oral steroid (OCS) use; asthma control score; and improvement in lung function. Across all three trials, about three quarters of the patients achieved two or more remission components and about half achieved three or more remission components after 6 months of treatment; furthermore, these rates were generally similar to the numbers of patients who achieved two or more components and three or more components of remission after 12 months of treatment. Overall, 15­23% of patients achieved clinical remission in 6 months, and approximately 15% achieved remission within 12 months. The results show that biologic therapies like benralizumab help improve the symptoms of severe asthma and allow patients to achieve disease remission.

Safety of Reslizumab in Uncontrolled Asthma with Eosinophilia: A Pooled Analysis from 6 Trials.

BACKGROUND: Intravenous reslizumab, a monoclonal IL-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of reslizumab in larger populations. OBJECTIVE: To investigate the safety profile of intravenous reslizumab 3.0 mg/kg by analyzing data from 6 asthma clinical trials: 5 placebo-controlled (duration ≤52 weeks) and 1 open-label extension (up to 2 years of treatment). METHODS: Patients were aged 12 to 75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 received reslizumab 3.0 mg/kg. RESULTS: Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than in the reslizumab group (67% and 6%). Asthma, nasopharyngitis, and upper respiratory tract infection were the most common AEs with placebo and reslizumab. Three cases of anaphylaxis, related to reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with more than 12 months of reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for more than 12 months was no higher than in patients with shorter treatment durations. CONCLUSIONS: This analysis confirms that treatment with intravenous reslizumab for more than 12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Mechanisms of Benefit with Aspirin Therapy in Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by severe persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and an intolerance to aspirin and other NSAIDs that preferentially inhibit COX-1. For more than 30 years, aspirin desensitization has proven to be of significant long-term benefit in carefully selected patients with AERD. Despite this, the exact mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. In this article, we review the current understanding of the mechanisms of aspirin desensitization and discuss future areas of investigation.

Chronic Rhinosinusitis and Aspirin-Exacerbated Respiratory Disease.

Patients with severe asthma and concomitant chronic rhinosinusitis often have severe, refractory upper and lower airway inflammation. This inflammation has been proposed to be similar throughout the upper and lower airways leading to the unified airways concept. This article reviews chronic rhinosinusitis with and without nasal polyps, and the subgroup with aspirin-exacerbated respiratory disease, while focusing on the relationship with asthma. Additionally, diagnosis and treatment with current and newer therapies are discussed.

Clinical Examination of Tissue Eosinophilia in Patients with Chronic Rhinosinusitis and Nasal Polyposis.

OBJECTIVE: (1) Describe clinical and histopathologic findings in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). (2) Determine if tissue and serum eosinophilia predicts disease severity in CRSwNP. STUDY DESIGN: Case series with chart review. SETTING: Academic hospital specializing in respiratory and allergic disease. SUBJECTS: Patients with CRSwNP treated from 2008 to 2010. METHODS: Clinical data were collected; sinus computed tomography (CT) scans were scored according to the Lund-Mackay system; and surgical specimens were evaluated for degree of tissue eosinophilia. Statistical analysis was performed to compare eosinophilia with indicators of disease severity. RESULTS: Seventy CRSwNP patients were included, with a mean Lund-Mackay score of 16.7; 62.1% of patients had severe asthma, and 62.9% were aspirin sensitive. Elevated tissue eosinophil level did not correlate with medication usage, olfactory symptoms, or Lund-Mackay scores, nor did it correlate with presence of asthma or aspirin-sensitivity (P = .09). Patients with mild asthma had significantly more tissue eosinophils versus patients with severe asthma, possibly because of the high amount of chronic corticosteroid use in severe asthmatics. There was no correlation between tissue and serum eosinophil counts (P = .97), but there was a significant positive correlation between CT score and peripheral eosinophil level (P < .05). CONCLUSIONS: Higher serum eosinophil levels may indicate more extensive mucosal disease as measured on CT scan. Neither serum nor tissue eosinophilia predicted disease severity in our retrospective analysis of CRSwNP patients, and serum eosinophil level did not serve as a marker of tissue eosinophilia.

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

Characterization and treatment of patients with chronic rhinosinusitis and nasal polyps.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs) may be subdivided into aspirin-sensitive (AS) and aspirin-tolerant (AT) populations. These cohorts are not well characterized. OBJECTIVE: To examine phenotypic characteristics and determine the extent of medical/surgical interventions in patients with CRS+NP and to compare the AS with the AT subset in the CRS+NP sample. METHODS: Retrospective chart review was performed at a tertiary academic respiratory hospital. Data included patient demographics, asthma severity, peripheral eosinophilia, Lund-Mackay computed tomographic score, symptomatic dysosmia, and therapeutic interventions. RESULTS: Of the 182 patients included, 81 had aspirin sensitivity (45%) and 101 had aspirin tolerance (55%). Asthma was present in 94% of patients with CRS+NP (100% in AS subgroup vs 89% in AT subgroup, P = .001). Eighty-eight percent of the CRS+NP sample had moderate to severe persistent asthma. In the AS and AT subgroups, asthma severity was similar (P > .6). The CRS+NP sample showed a mean computed tomographic score of 14.0 (44% with eosinophilia and 46% with dysosmia). More severe sinus disease was noted in the AS group (Lund-Mackay computed tomographic scores, P = .002; olfactory symptoms, P = .001). Serum eosinophil levels were not statistically different between groups (51% in AS group, 39% in AT group, P > .1). CONCLUSION: This study is one of the broadest reviews of patients with CRS+NP, with unique findings in the high prevalence of asthma in AS and AT patients, greater olfactory dysfunction in AS patients, and a minority of patients with CRS+NP and circulating eosinophils. Most AS patients do not have increased circulating eosinophils, as is often believed. These results shed further light on the association between asthma and upper respiratory tract disease in those with nasal polyposis.

Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia.

BACKGROUND: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. OBJECTIVES: We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. METHODS: In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. RESULTS: The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. CONCLUSION: Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.

Mechanisms of aspirin desensitization.

Aspirin-exacerbated respiratory disease is a clinical syndrome characterized by severe, persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and reactions to aspirin and other nonsteroidal antiinflammatory drugs that preferentially inhibit cyclooxygenase 1. The mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. Recent studies suggest that the clinical benefits may occur through direct inhibition of tyrosine kinases and the signal transducer and activator of transcription 6 signaling pathway, which results in inhibition of interleukin 4 production. In this article, the current understanding of the mechanisms of aspirin desensitization is reviewed and future areas of investigation are discussed.

Variations in expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in nasal mucosa of aspirin-sensitive versus aspirin-tolerant patients with nasal polyposis.

BACKGROUND: Matrix metalloproteinases (MMPs) are key enzymes responsible for extracellular matrix degradation contributing to the progressive histological changes seen in lower airway disease, including asthma. MMP-9 and TIMP-1 have also shown some role in the pathogenesis of chronic rhinosinusitis (CRS) and nasal polyposis (NP). OBJECTIVE: We aim to determine variability in expression of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in sinus tissue from distinct patient populations presenting with nasal polyposis. METHODS: The expression of MMP-9 and TIMP-1 was investigated in nasal polyp tissue from 6 aspirin-sensitive (AS) and 6 aspirin-tolerant (AT) patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis (CRSwNP). Sinus mucosa from 6 patients with chronic rhinosinusitis without nasal polyposis (CRSsNP) was used as control. The MMP-9 and TIMP-1 expression was measured using immunofluorescence technique and graded using manual and computerized methods. RESULTS: Expression of TIMP-1 was significantly reduced in the AS group when compared with both the AT and CRSsNP (control) groups (P < .001). The MMP-9/TIMP-1 ratio was significantly increased in the AS group when compared with other patient groups (P < .001). The MMP- 9 expression was similar between study and control groups. CONCLUSION: These results support the importance of MMP-9 and TIMP-1 expression in nasal polyp formation. The decreased expression of TIMP-1 in AS patients may promote the effects of MMP-9 expression and thus contribute to tissue remodeling and inflammatory changes. This finding may lead to further understanding of disease severity and resistance to treatment in this group of patients, as well as the pathogenesis of nasal polyps.

The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear. OBJECTIVE: The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months. METHODS: Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment. RESULTS: There was a significant elevation in both the exhaled nitric oxide level (P = .03) and sputum tryptase level (P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 (P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated (r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated (r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) (r = -0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months. CONCLUSION: Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while T(H)1 marker FLT3-L increases.