Exacerbation Rate Research Articles

The Natural History of Severe Chronic Obstructive Pulmonary Disease: The SPOCCAT Study Protocol

IntroductionPatients with severe chronic obstructive pulmonary disease (COPD) are often underrepresented in cohorts, creating uncertainty about the natural history and prognostic factors of this subgroup. Our goal was to describe the SPOCCAT (Severe COPD: Prospective Observational study of COPD in Catalonia) study protocol. Material and methodsSPOCCAT is a non-interventional, multicenter, prospective cohort study of patients with severe COPD (FEV1% predicted<50%). The study aims to: (1) establish a five-year prospective cohort; (2) identify demographic and clinical characteristics; (3) describe treatment patterns; (4) better understand the natural history of severe COPD, including lung function decline, exacerbation rates, and mortality; and (5) identify prognostic factors for poor outcomes.Recruitment began in January 2024, and the cohort will be followed for a minimum of five years (or until death or lung transplant) with follow-up visits every 12 months. Baseline data include demographics, laboratory analyses, comorbidities, lung function, respiratory symptoms, respiratory disease exacerbations and etiology, quality of life, physical activity, chest computed tomography, and treatment. Annual follow-up visits will assess changes in treatment, exacerbation frequency and severity, microbiological outcomes, complementary tests, and mortality. Participation requires written informed consent from all patients, with data collected in an anonymized electronic Case Report Form. ResultsThe results of the SPOCCAT study will provide relevant information about the characteristics, treatment, and prognostic factors of severe COPD. ConclusionsSPOCCAT has the potential to enhance understanding of severe COPD, exploring innovative aspects and establishing a robust research framework for future COPD-related projects.

Multivariate Cluster Analyses to Characterize Asthma Heterogeneity and Benralizumab Responsiveness

An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions. Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach. In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to analyze 11 clinical characteristics simultaneously. The annualized asthma exacerbation rate, exacerbation incidence, and lung function were analyzed across clusters. Patients (n= 2,281) met criteria for four of five clusters: cluster 2 (early-onset moderate asthma, n= 393), cluster 4 (early-onset severe asthma, n= 386), cluster 3 (late-onset severe asthma, n= 641), and cluster 5 (late-onset severe, obstructed asthma, n= 861); no patients met cluster 1 criteria. Exacerbation rate reductions were significant in late-onset severe asthma (-48% [95% CI, -61% to -31%]; P < .0001) and late-onset severe, obstructed asthma (-50% [95% CI, -59% to -38%]; P < .0001), with nonsignificant reductions in early-onset clusters. These differences could not be fully explained by blood eosinophil count differences. Values for improvements in FEV1 were significant in late-onset severe asthma (+133 mL [95% CI, 66-200]; P= .0001) and late-onset severe, obstructed asthma (+160 mL [95% CI, 85-235]; P < .0001) while maintaining acute bronchodilator responsiveness. Benralizumab reduced exacerbations and improved lung function, primarily in late-onset asthma clusters. This multivariate approach to identify subphenotypes, potentially reflecting pathobiological mechanisms, can guide therapy beyond univariate approaches.

Comparing Glycopyrronium/Formoterol Combination Therapy With Monotherapy in Moderate-to-Severe Chronic Obstructive Pulmonary Disease (COPD): A Narrative Review.

Chronic obstructive pulmonary disease (COPD) imposes a significant burden on individuals and healthcare systems globally. While bronchodilators, such as glycopyrronium and formoterol, are cornerstone therapies for COPD management, combining these agents has gained attention for potentially improving outcomes compared to monotherapy. This comprehensive review aims to assess the efficacy and safety of glycopyrronium/formoterol (GFF) combination therapy versus glycopyrronium monotherapy in patients with moderate-to-severe COPD. Through a systematic evaluation of clinical trials and real-world evidence, we analyze the impact of combination therapy on lung function, symptom control, exacerbation rates, and health-related quality of life (HRQoL). Furthermore, we examine the safety profile of combination therapy, including adverse cardiovascular and respiratory events. Comparative analyses with glycopyrronium monotherapy provide insights into the relative benefits and considerations for treatment selection. Factors influencing treatment choice and future directions in COPD management are also discussed. This review underscores the potential of combination therapy in optimizing COPD treatment outcomes and highlights areas for further research and clinical practice refinement.

Benralizumab efficacy and safety in severe asthma: A randomized trial in Asia

BackgroundBenralizumab is indicated as add-on therapy in patients with uncontrolled, severe eosinophilic asthma; it has not yet been evaluated in a large Asian population with asthma in a clinical trial. ObjectiveTo evaluate the efficacy and safety of benralizumab in patients with severe asthma in Asia. MethodsMIRACLE (NCT03186209) was a randomized, Phase 3 study in China, South Korea, and the Philippines. Patients aged 12–75 years with severe asthma receiving medium- to high-dose inhaled corticosteroid/long-acting β2-agonists, stratified (2:1) by baseline blood eosinophil count (bEOS) (≥300/μL; <300/μL), were randomized (1:1) to benralizumab 30 mg or placebo. Endpoints included annual asthma exacerbation rate (AAER; primary endpoint), change from baseline at Week 48 in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1 is being defined, not BD, which has already been defined) and total asthma symptom score (TASS). Safety was evaluated ≤Week 56. ResultsOf 695 patients randomized, 473 had baseline bEOS ≥300/μL (benralizumab n = 236; placebo n = 237). In this population, benralizumab significantly reduced AAER by 74% (rate ratio 0.26 [95% CI 0.19, 0.36], p <0.0001) and significantly improved pre-BD FEV1 (least squares difference [LSD] 0.25 L [95% CI 0.17, 0.34], p <0.0001) and TASS (LSD −0.25 [−0.45, −0.05], p = 0.0126) versus placebo. In patients with baseline bEOS <300/μL, there were numerical improvements in AAER, pre-BD FEV1, and TASS with benralizumab versus placebo. The frequency of adverse events was similar for benralizumab (76%) and placebo (80%) in the overall population. ConclusionsMIRACLE data reinforces the efficacy and safety of benralizumab for severe eosinophilic asthma in an Asian population, consistent with the global Phase 3 results.

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

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. 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. 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. 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.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting β2-agonist reliever or ICS/formoterol reliever only in mild asthma

Introduction/backgroundMild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting β2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. Aims/objectivesTo assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. ResultsThe SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. ConclusionsThis is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Long-Term Impacts of COVID-19 on Severe Exacerbation and Mortality in Adult Asthma: A Nationwide Population-Based Cohort Study

BackgroundIn adults with asthma, the long-term impact of previous coronavirus disease 2019 (COVID-19) on severe exacerbations and mortality is unclear. ObjectiveWe evaluated the long-term risk of severe exacerbation and mortality in adults with asthma who recovered from COVID-19. MethodsUsing the Korean National Health Insurance claim-based database, we compared the risk of severe exacerbations (emergency room visits or hospitalization) and mortality in adults with asthma aged >20 years recovered from COVID-19 between October 8, 2020, and December 16, 2021 (COVID-19 cohort, n=10,739) with 1:1 propensity score-matched controls (n=10,739). ResultsDuring a median follow-up of 87 (range, 15–448) days, the incidence rate of severe exacerbation in the COVID-19 cohort and matched cohort was 187.3 and 119.3 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of severe exacerbation compared to the matched cohort (hazard ratio=1.57; 95% confidence interval [CI]=1.06–2.32). During a median follow-up of 360 (range, 15–721) days, the incidence rate of death in the COVID-19 and matched cohort was 128.3 and 73.5 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of death (hazard ratio=1.76; 95% CI=1.33–2.30) compared to the matched cohort. When further analyzed by COVID-19 severity, severe COVID-19 was associated with a 5.12-fold (95% CI=3.27–8.01) and 7.31-fold (95% CI=5.41–9.88) increased risk of severe exacerbation and death, respectively, but non-severe COVID-19 was not. ConclusionOur study heightens that severe COVID-19 is associated with increased long-term risk of severe exacerbation and mortality among individuals with asthma.

Dupilumab Reduces Exacerbations Independent of Changes in Biomarkers in Moderate-to-Severe Asthma

Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. This post hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at week 52 were performed as a function of the fold change in FeNO at week 52 and the maximum fold change in Eos over weeks 0-12 (also change from baseline in pre-BD FEV1 at week 12). The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by week 2 and then gradually to week 52 in patients treated with dupilumab versus placebo; Eos, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with the change in biomarkers in either treatment group. The change from baseline in pre-BD FEV1 at week 52 was inversely associated with the fold change in FeNO in both groups, with a significant difference between the dupilumab and placebo curves (P= .014), and was positively associated with the fold change in Eos in both groups (P= .022). Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed a predictive value for lung function improvement; for FeNO, this was specific to the dupilumab treatment arm.

Vessel and Airway Characteristics in One-Year Computed Tomography-defined Rapid Emphysema Progression: SPIROMICS.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n = 188, 1-year ΔEI > 1%), nonprogressors (n = 301, 1-year ΔEI ± 0.5%), and never-smokers (n = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAARseg]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAARseg (0.73 ± 0.29 vs. 0.67 ± 0.23; P = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P = 5.0 × 10-12), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P = 6.1 × 10-13), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P = 1.9 × 10-7). In adjusted analyses, an increment of 1 standard deviation in PAARseg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

The impact of insomnia and depression on asthma control

Background Poor sleep quality is often reported by individuals with asthma, particularly by those who have poor asthma control overall. However, there is little understanding of how underlying sleep disorders such as insomnia may impact asthma control. Furthermore, given the frequent overlap of depression and insomnia, the incremental impact of mood disorders and insomnia on asthma control remains unclear. Methods We conducted a retrospective analysis of patients at a large asthma center to further elucidate connections between these disease processes. Asthma patients with and without a diagnosis of insomnia were matched by age, sex, Charlson comorbidity index, and biologic therapy. We evaluated the presence of concurrent obstructive sleep disorder, mood disorders, exacerbation frequency, and asthma control test (ACT) scores. Results From a cohort of 659 patients with an asthma diagnosis, 89 subjects with insomnia (13.5%) were matched 1:1 to patients without insomnia. Compared to those without insomnia, patients with insomnia were more likely to have a concurrent diagnosis of obstructive sleep apnea (57.3% vs. 18%, p < 0.001) and to have a diagnosis of depression or anxiety (68.5% vs. 11.4%, p < 0.001). Among insomnia patients, there was an average of 0.93 asthma exacerbations per year, compared to 0.59 exacerbations per year for those without insomnia (p = 0.039). Conclusion Our data reveal a considerable interaction between insomnia, depression, and obstructive sleep apnea in individuals with asthma. The increased exacerbation rate suggests that underlying sleep and mood disorders negatively affect asthma control.

Suboptimal Response to Biologics in Severe Asthma—A Marker of Humoral Immunodeficiencies

BackgroundAsthmatic patients with antibody deficiencies (AD) have more severe disease and higher risk of exacerbations. No data exists about the efficacy of biologics in severe asthma (SA) patients with AD.The objective of this study was to evaluate the efficacy of biologics in SA patients with and without AD. MethodsA case-control real-life study was conducted including 68 patients divided in two groups: group 1 with SA-AD and group 2 with SA. ResultsTreatment by biologics for 6 months was effective to decrease the number of exacerbations, hospitalizations, and emergency department (ED) visits, to improve the Asthma Control Questionnaire (ACQ) score and proved a systemic corticosteroid sparing effect. Despite benefits, the number of exacerbations, hospitalizations, and ED visits, the mean ACQ score, and the cumulative dose of systemic corticosteroids remain higher in group 1 vs 2, with lower lung function parameters. The rates of responses were inferior in group 1 vs 2 with a decrease by ≥50% of exacerbation rate in 76% vs 97% of patients (p=.006), no hospitalization in 44% vs 91% of patients (p<.001), no ED visit 56% vs 82% of patients (p=.018), significant improvement of ACQ score by ≥0.5 in 68% vs 100% of patients (p<.001), and increase of forced expiratory volume in the first second by >10% in 32% vs 65% of patients (p=.007). ConclusionDespite evident benefits, SA patients with AD have suboptimal responses to biologics compared to those immunocompetent. A multidisciplinary approach is necessary to optimize the management of these patients in practice.

Long-term multicenter comparison shows equivalent efficacy of monoclonal antibodies in severe asthma therapy

BackgroundMonoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months.Methods280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published “Biologic Asthma Response Score” (BARS).ResultsAll biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months.ConclusionsAll biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment.

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany

PurposeMyasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates.MethodsRetrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany.ResultsOverall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each).ConclusionsMaternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children.

Differential decline of lung function in COPD patients according to structural abnormality in chest CT

BackgroundDifferent progressions or prognoses of chronic obstructive pulmonary disease (COPD) have been reported according to structural abnormalities based on chest computed tomography (CT). This study aimed to investigate whether different structural abnormalities independently affect annual lung function changes and clinical prognosis in patients with COPD. MethodsThis longitudinal multicenter observational study was conducted using the KOCOSS cohort (NCT02800499) database in Korea from January 2012 to December 2019. For COPD patients with chest CT findings at baseline enrolment and longitudinal spirometric data, annual forced expiratory volume in 1 s (FEV1) decline rate (mL/year) and clinical outcomes were compared according to structural abnormalities, including emphysema, bronchiectasis (BE), and tuberculosis-destroyed lung (TDL). We estimated the adjusted annual FEV1 changes using a mixed-effect linear regression model. ResultsAmong the enrolled 237 patients, 152 showed structural abnormalities. Emphysema, BE, and TDL were observed in 119 (78.3%), 28 (18.4%), and 27 (17.8%) patients, respectively. The annual decline in FEV1 was faster in COPD patients with structural abnormalities than those without (β = −70.6 mL/year, P-value = 0.039). BE/TDL-dominant or emphysema-dominant structural abnormality contributed to an accelerated annual FEV1 decline compared to no structural abnormality (BE/TDL-dominant, β = −103.7 mL/year, P-value = 0.043; emphysema-dominant, β = −84.1 mL/year, P-value = 0.018). Structural abnormalities made no significant differences in acute exacerbation rate and mortality. ConclusionThe lung function decline rate in COPD differed according to structural abnormalities on CT. These findings may suggest that more focus should be placed on earlier intervention or regular follow-up with spirometry in COPD patients with BE or TDL on chest CT.

Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial.

The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. ClinicalTrials.gov, identifier NCT05578222.

New Drug for Management of Severe Uncontrolled Asthma: Tezepelumab

Abstract: Tezepelumab is a first-in-class human IgG2λ monoclonal antibody used to treat severe, uncontrolled asthma. Tezepelumab acts by hindering the action of thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine that triggers an immunological response by binding to TSLP and thereby preventing its binding with the TSLP receptor complex. TSLP has a critical role in Th2 immunity and plays an important role in the pathogenesis of asthma because it stimulates the production of Th2-associated inflammatory mediators, such as interleukin-4, interleukin-5, interleukin-9, and interleukin-13. It is the first biologic with no phenotypic or biomarker restrictions that has been approved for use in severe asthma. Tezepelumab is indicated in severe, uncontrolled asthma patients due to its safety, tolerability, and efficacy. Adults with severe, uncontrolled asthma experienced considerably lower annualised asthma exacerbation rates (AAERs) when administered with tezepelumab compared to a placebo. These preliminary results indicated that the TSLP-induced release of T2 inflammatory mediators may be reduced, and the sustained inhibition was maintained over a 52-week treatment period. In this review, we have summarised various phase III clinical trials and the mechanism of action of tezepelumab in severe, uncontrolled asthma.

Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. ClinicalTrials.gov-ID: NCT04305405.

Clinical outcomes of functional endoscopic sinus surgery in cystic fibrosis patients - a single centre experience.

Endoscopic sinus surgery (ESS) is an established surgical option for cystic fibrosis (CF) patients with chronic rhinosinusitis that is refractory to conventional medical management. Objective and subjective evidence of benefit of ESS in this cohort of patients is currently conflicting in the literature. A single center retrospective study was undertaken of all CF patients (transplanted and non-transplanted) over the age of 16 who underwent an ESS over a six-year period from 2015 to 2021. Patients on triple-therapy CFTR modulators were excluded. Data was collected on demographics, clinical management, and outcome measures. The objective outcome measures were lung function (%predicted FEV1), pulmonary exacerbations (total number of days of IV antibiotics- both ambulatory and in hospital). The subjective outcome measure was SNOT-22 scores pre and 6 months post-operatively. A minimally clinical important difference (MCID) in SNOT-22 scores of 9 points was used. 55 patients were included in our study, with a median age of 31 and 53% females. Median Lund-Mackay scores for the cohort was 13 (3-24). There was a significant improvement in lung function at 1-year post-surgery, and a significant MCID reduction in SNOT-22 scores at 6 months post-surgery across the cohort. Sub-group analysis revealed a sustained MCID reduction in SNOT-22 scores in both lung-transplanted and native lung groups, and in patients with primary ESS or previous ESS. However, there was no post-operative pulmonary function improvement in lung transplanted patients and patients with previous ESS. There was no impact on the rate of pulmonary exacerbations across the cohort. 2 patients in the cohort died secondary to pulmonary disease. There was a demonstrated clinical and symptomatic benefit of ESS in CF patients in this study. Stricter guidelines for indications for ESS need to be established with regards to CF patients who will undergo ESS in the future.

Acute Exacerbation of Chronic Obstructive Pulmonary Disease Due to Carbapenem-Resistant Klebsiella pneumoniae-Induced Pneumonia: Clinical Features and Prognostic Factors.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is closely related to respiratory tract infection. The aim of this study was to investigate the clinical features and prognostic factors of CRKP-induced pneumonia in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients. A single-centre, retrospective case-control study on COPD patients hospitalized for acute exacerbation and CRKP-induced pneumonia was conducted from January 1, 2016, to December 31, 2022. The mortality rate of acute exacerbation due to CRKP-induced pneumonia was investigated. The patients were divided into the CRKP-induced pneumonic acute exacerbation (CRKPpAE) group and the non-CRKP-induced pneumonic acute exacerbation (non-CRKPpAE) group, and the clinical characteristics and prognostic factors were compared using univariate analysis and multivariate analysis. A total of 65 AECOPD patients were included, composed of 26 patients with CRKPpAE and 39 patients with non-CRKPpAE. The mortality rate of CRKPpAE was 57.69%, while non-CRKPpAE was 7.69%. Compared with non-CRKPpAE, a history of acute exacerbation in the last year (OR=8.860, 95% CI: 1.360-57.722, p=0.023), ICU admission (OR=11.736, 95% CI: 2.112-65.207, p=0.005), higher NLR levels (OR=1.187, 95% CI: 1.037-1.359, p=0.013) and higher D-dimer levels (OR=1.385, 95% CI: 1.006-1.905, p=0.046) were independently related with CRKPpAE. CRKP isolates were all MDR strains (26/26, 100%), and MDR strains were also observed in non-CRKP isolates (5/39, 12.82%). Compared with non-CRKPpAE, CRKPpAE affects the COPD patient's condition more seriously and significantly increases the risk of death.

Real-World Effectiveness of Mepolizumab in Patients with Allergic and Non-Allergic Asthma.

Real-world data on mepolizumab in patients with severe asthma and allergic and non-allergic phenotypes are limited. This study investigated the effectiveness of mepolizumab treatment in patients with severe asthma with allergic and non-allergic phenotypes. This retrospective cohort study (GSK ID: 214148) used administrative claims data from the Optum Research Database. Eligible patients were ≥6 years of age with asthma and had ≥2 mepolizumab claims post-index. Index date was the first mepolizumab claim/administration (January 2016-December 2018). Patients were divided into two cohorts: allergic and non-allergic asthma, based on diagnosis codes, medication use and lab test results. Outcomes included the rate of asthma-related exacerbations and oral corticosteroid (OCS) use during the 12 months before (baseline period) and 12 months after (follow-up period) mepolizumab initiation. Study ended in December 2019. Overall, 240 (44.6%) and 298 (55.4%) patients were included in the allergic and non-allergic asthma cohorts, respectively. Mean (standard deviation [SD]) counts of asthma-related exacerbations were significantly reduced from baseline to follow-up in both the allergic and non-allergic asthma cohorts (3.2 [2.5] to 2.1 [2.1], p < 0.001 and 2.5 [2.2] to 1.7 [1.9], p < 0.001, respectively). The mean number of OCS pharmacy claims was significantly decreased by 33.3% and 41.4% from baseline to follow-up in the allergic and non-allergic cohorts, respectively (p < 0.001); mean daily OCS dose significantly decreased by 30.6% and 45.4%, respectively (p < 0.001) as well as the mean number of OCS bursts, which decreased by 44.9% and 41.8%, respectively (p < 0.001). No significant differences were observed between cohorts in reductions in asthma exacerbations, counts of OCS pharmacy claims or OCS bursts (baseline to follow-up). Mepolizumab significantly reduced asthma exacerbations and OCS use in patients with allergic and non-allergic asthma, suggesting that mepolizumab provides real-world benefit in severe asthma irrespective of whether a patient has an allergic phenotype.