Background Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that ...binds IgE with higher affinity than omalizumab. Objective This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. Methods Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. Results QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15 ) that was maximal and approximately 3-fold greater than that of omalizumab ( P = .10) and 16-fold greater than that of placebo ( P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. Conclusion QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.
AbstractPurposeThe goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. MethodsThis multicenter, open-label, ...long-term, Phase IIIb study (COSMEX COSMOS Extension; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. FindingsOf the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. ImplicationsThis study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.
Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a role in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD).
We ...sought to determine the relationship between sputum microbiome at the time of AECOPD hospitalization and 1-year mortality in a COPD cohort.
We used sputum samples from 102 patients hospitalized because of AECOPD. All subjects were followed for 1 year after discharge. The microbiome profile was assessed through sequencing of 16S rRNA gene. Microbiome analyses were performed according to 1-year mortality status. To investigate the effect of α-diversity measures and taxon features on time to death, we applied Cox proportional hazards regression models and obtained hazard ratios (HRs) associated with these variables.
We observed significantly lower values of α-diversity (richness, Shannon index, evenness, and Faith's Phylogenetic Diversity) among nonsurvivors (
= 19, 18.6%) than survivors (
= 83, 81.4%). β-Diversity analysis also demonstrated significant differences between both groups (adjusted permutational multivariate ANOVA,
= 0.010). The survivors had a higher relative abundance of
; in contrast, nonsurvivors had a higher abundance of
. The adjusted HRs for 1-year mortality increased significantly with decreasing α-diversity. We also observed lower survival among patients in whom sputum samples were negative for
(HR, 13.5; 95% confidence interval, 4.2-43.9;
< 0.001) or positive for
(HR, 7.3; 95% confidence interval, 1.6-33.2;
= 0.01).
The microbiome profile of sputum in AECOPD is associated with 1-year mortality and may be used to identify subjects with a poor prognosis at the time of hospitalization.
Asthma is a heterogeneous airways disease with a substantial burden.1 Although major improvements have been made in care, especially with regards to a reduction in admissions to hospital—as ...documented by the Global Initiative for Asthma—and asthma-related deaths, a substantial proportion of patients still have uncontrolled asthma and are prone to exacerbations.2 Because asthma patients tend to be younger adults and likely to be working, this lack of asthma control is associated with a huge economic burden and loss of quality-adjusted life-years.3 Inhaled corticosteroids, alone or if ineffective combined with a long-acting β agonist, are effective for most patients, but asthma in up to 40% of patients remains uncontrolled despite a systematic and structured increase in such therapy.4 Until the 2010s, this population of patients had few treatment options, especially those with more severe asthma. The addition of a long-acting muscarinic agonist has been previously reported in a subgroup with more severe asthma than in Virchow and colleagues' Article, which showed a substantial effect on improving lung function also measured using FEV1 and reducing the rate of exacerbations to a greater extent than in the present Article (ie, >20%).7 The novelty of TRIMARAN and TRIGGER is that they are the first to use a single inhaler with three medications in a broad patient population with uncontrolled asthma. A similar recommendation relates to patients who are prednisone dependent and who should also proceed to a biologic because, unlike the addition of a muscarinic agonist, with the currently available biologics an oral corticosteroid sparing effect is present.11 This new treatment option is to be welcomed because it provides in one inhaler a simpler treatment option for patients with asthma that is uncontrolled on a combination inhaler with a long-acting β agonist and inhaled corticosteroids.
A better understanding of the true burden of chronic obstructive pulmonary disease (COPD) needs to consider the implications of comorbidities. This study comprehensively examined the impact of ...comorbidities on excess direct medical costs in COPD patients.From health administrative data in British Columbia, Canada (1996-2012), we created a propensity-score-matched cohort of incident COPD patients and individuals without COPD. Health services use records were compiled into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2015 Canadian dollars and converted to 2015 Euros; CAD1.000=EUR 0.706) were estimated as the adjusted difference in direct medical costs between the two groups.The sample included 128 424 subjects in each group. COPD patients generated excess costs of CAD5196/EUR3668 per person-year (95% CI CAD3540-8529), of which 26% was attributable to COPD itself and 51% was attributable to comorbidities (the remaining 23% could not be attributed to any specific condition). The major cost driver was excess hospitalisation costs. The largest components of comorbidity costs were circulatory diseases, other respiratory disorders, digestive disorders and psychological disorders (CAD696/EUR491, CAD312/EUR220, CAD274/EUR193 and CAD249/EUR176 per person-year, respectively).These findings suggest that the prevention and appropriate management of comorbidities in COPD patients may effectively reduce the overall burden of COPD.
Numerous studies with varying associations between domestic use of solid biomass fuels (wood, dung, crop residue, charcoal) and respiratory diseases have been reported.
To present the current data ...systematically associating use of biomass fuels with respiratory outcomes in rural women and children.
Systematic searches were conducted in 13 electronic databases. Data were abstracted from original articles that satisfied selection criteria for meta-analyses. Publication bias and heterogeneity of samples were tested. Studies with common diagnoses were analysed using random-effect models.
A total of 2717 studies were identified. Fifty-one studies were selected for data extraction and 25 studies were suitable for meta-analysis. The overall pooled ORs indicate significant associations with acute respiratory infection in children (OR 3.53, 95% CI 1.94 to 6.43), chronic bronchitis in women (OR 2.52, 95% CI 1.88 to 3.38) and chronic obstructive pulmonary disease in women (OR 2.40, 95% CI 1.47 to 3.93). In contrast, no significant association with asthma in children or women was noted.
Biomass fuel exposure is associated with diverse respiratory diseases in rural populations. Concerted efforts in improving stove design and lowering exposure to smoke emission may reduce respiratory disease associated with biomass fuel exposure.
The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local ...circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β
-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β
-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.
Significance Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that presents with a diverse array of clinical symptoms and afflicts over 1.5 million Americans. Current ...treatments involve immunosuppressive regimens associated with debilitating and adverse effects. With the description of a role for innate signaling in SLE, safe and efficient therapies that block Toll-like receptors also have been stymied by the relative short in vivo half lives of known inhibitors and the dangerous outcome of complete MyD88 blockade. Key natural regulators of the disease process are not well described but are more likely to provide disease-specific therapeutics with fewer adverse effects. In this study, we have identified a novel function for Stimulator of interferon genes as a suppressor of disease and a target for future SLE therapeutics.
Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.
Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We ...explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (F eno ) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had F eno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of F eno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of F eno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.
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