Exacerbation Rate Research Articles

Bronchial rheoplasty for chronic bronchitis: 2-year results from a US feasibility study with RheOx

IntroductionChronic bronchitis (CB), a phenotype of chronic obstructive pulmonary disease (COPD) characterised by persistent cough and mucus hypersecretion, is associated with poor outcomes despite guideline-based treatment. Bronchial rheoplasty (BR) with...

Efficacy and Safety of Mepolizumab in the Management of Severe Eosinophilic Asthma: A Systematic Review.

Severe eosinophilic asthma (SEA) is characterized by persistent airway inflammation and frequent exacerbations despite standard treatments. Mepolizumab, a monoclonal antibody that reduces eosinophil levels by targeting interleukin-5, has emerged as an add-on therapy for patients with SEA. This systematic review evaluated mepolizumab's efficacy and safety for treating SEA. A comprehensive literature search was conducted across major databases. Thirty-two studies with over 6,000 patients were included, comprising randomized controlled trials, open-label extensions, and real-world observational analyses. Study quality and risk of bias were assessed using standard tools. Meta-analysis was deemed inappropriate due to heterogeneity. Instead, a narrative synthesis was performed. Mepolizumab significantly reduced exacerbation rates by around 50% and improved symptoms and lung function compared to placebo in pivotal trials. Long-term open-label studies showed sustained reductions in exacerbations and stable lung function for up to 4.5 years. Real-world data demonstrated consistent 50%-90% exacerbation decreases across diverse patient populations over 6-24 months. Mepolizumab exhibited an acceptable safety profile, with mild injection site reactions and headaches as most common adverse events. While specific subgroups may show enhanced responses, mepolizumab displayed broad efficacy regardless of patient demographics or phenotypes. The extensive evidence provides robust support for mepolizumab as an efficacious and safe add-on treatment option for patients with severe, refractory eosinophilic asthma. Further high-quality comparative effectiveness research is warranted to optimize patient selection and positioning among emerging biologics.

Real-World Study of Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol on Asthma Control in the US.

Real-world asthma control data among patients initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) are limited. This study assessed rescue medication use and asthma-related exacerbations in patients with asthma before and after initiating single-inhaler FF/UMEC/VI using administrative claims data. This retrospective, pre-post cohort study analyzed data from the IQVIA PharMetrics Plus database (September 18, 2016‒March 31, 2020). Patients aged ≥18 years that had ≥1 dispensing of single-inhaler FF/UMEC/VI 100/62.5/25 mcg (first dispensing = index date), ≥12 months of continuous health insurance enrollment prior to (pre-treatment) and following (post-treatment) FF/UMEC/VI initiation and ≥1 diagnosis of asthma during the pre-treatment period or on the index date were included. The primary endpoint was the number of oral corticosteroid (OCS) dispensings per patient per year during pre- and post-treatment periods. Secondary endpoints included asthma-related exacerbation rates and short-acting β2-agonist (SABA) use. Comparisons between pre- and post-treatment periods were made using risk and rate ratios. Overall, 890 patients with asthma initiating treatment with FF/UMEC/VI were included. The most recently dispensed controller medications prior to FF/UMEC/VI initiation were inhaled corticosteroids/long-acting β2-agonists (33.5%) and leukotriene modifiers (33.0%). Patients had a 29% reduction in the number of OCS dispensings (rate ratio [95% confidence interval (CI)]: 0.71 [0.65, 0.77], P < 0.001) during post-treatment versus pre-treatment, with a 23% reduction in the proportion of patients with ≥1 OCS dispensing post-treatment (risk ratio [95% CI]: 0.77 [0.73, 0.82], P < 0.001). Significant reductions in rates (rate ratio [95% CI]) of asthma-related exacerbations (0.59 [0.52, 0.67], P < 0.001) and SABA use (0.80 [0.74, 0.86], P < 0.001) were also observed. In this real-world study, patients with asthma had significantly lower OCS use, asthma-related exacerbations, and SABA use following treatment initiation with FF/UMEC/VI compared with their pre-treatment period. These results suggest better asthma control following initiation of FF/UMEC/VI in a routine clinical practice setting.

The Role of the Cumulative Illness Rating Scale (CIRS) in Estimating the Impact of Comorbidities on Chronic Obstructive Pulmonary Disease (COPD) Outcomes: A Pilot Study of the MACH (Multidimensional Approach for COPD and High Complexity) Study.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous systemic syndrome that often coexists with multiple comorbidities. In highly complex COPD patients, the role of the Cumulative Illness Rating Scale (CIRS) as a risk predictor of COPD exacerbation is not known. The objective of this study was determine the effectiveness of the CIRS score in detecting the association of comorbidities and disease severity with the risk of acute exacerbations in COPD patients. In total, 105 adults with COPD (mean age 72.1 ± 9.0 years) were included in this prospective study. All participants at baseline had at least two moderate exacerbations or one leading to hospitalization. The primary outcome was a composite of moderate or severe COPD exacerbation during the 12 months of follow-up. The CIRS indices (CIRS total score, Severity Index and Comorbidity Index) showed a positive correlation with modified Medical Research Council (mMRC), COPD assessment test (CAT) and a negative correlation with forced expiratory volume in the first second (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC. The three CIRS indices were able to predict the 12-month rate of moderate or severe exacerbation (CIRS Total Score: Hazard Ratio (HR) = 1.12 (95% CI: 1.08-1.21); CIRS Severity Index: HR = 1.21 (95% CI: 1.12-1.31); CIRS Comorbidity Index = 1.58 (95% CI: 1.33-1.89)). Among patients with COPD, the comorbidity number and severity, as assessed by the CIRS score, influence the risk in moderate-to-severe exacerbations. The CIRS score also correlates with the severity of respiratory symptoms and lung function.

Effect of Caplacizumab in the Recovery of ADAMTS13 Level in Patients with Autoimmune Thrombotic Thrombocytopenic Purpura. Analysis from the Spanish Registry (REPTT)

INTRODUCTION Treatment of immune thrombotic thrombocytopenic purpura (iTTP) includes plasma exchanges (PEX) and immunosuppressive treatment with steroids with or without rituximab (RTX). Actually, caplacizumab (CPZ) has been included in this scheme of treatment, because of its effect in decreasing clinical response time, exacerbations and refractoriness. A longer time to recovery of ADAMTS13 levels has recently been described in a group of patients from United Kingdom in subjects treated with caplacizumab. We analysed the behaviour of ADAMTS13 recovery in patients from the Spanish TTP registry (REPTT). METHODS Retrospective, multicentre, non-interventional study. Data collected by the Spanish PTT Registry (REPTT) from September-2018 to February-23. The objective is to describe the efficacy of standard therapy with and without CPZ with regard to recovery of ADAMTS13 levels higher than 20%. Episodes evaluable for ADAMTS13 &amp;gt;20% recovery were those with data available 48 hours or more after last PEX. Data about clinical response, clinical remission, exacerbations and relapses will be described. Qualitative variables described in percentages, quantitative in median and interquartile range (IQR). RESULTS We included 178 patients from REPTT, but only 164 were analysed. Reasons for exclusion were 5 were congenital TTP, 3 patients were younger than 16 years-old, and 6 patients because of lack of data. The 164 patients presented 172 episodes whose characteristics are described in Table 1. Clinical remission rate did not differ between groups, 95% CPZ vs 97% no CPZ, with a median time of 41 days (36-50) vs 43 days (38-50), respectively. A median of 11 PEX (IQR:6-20) were required to get clinical remission, lower in CPZ group (CPZ 10 PEX, IQR:5-18 vs no CPZ 12 PEX, IQR: 7-23, p=0.044). In 49 of the 103 CPZ episodes, CPZ was introduce in the 3 first days from diagnosis (CPZ3). In this group, number of PEX was critically reduced (CPZ 6 PEX, IQR: 4-9 vs no CPZ 12 PEX, IQR: 7-23; p&amp;lt;0.001). Exacerbation rate was lower CPZ group (12.5% vs 23.2%, p. 0.033), as refractoriness rate(4.1% vs 8.7%, p = 0.038). With a median follow-up of 188.5 days (110.5-354.5), relapse rate was 10.5%, lower in subjects treated with CPZ (4% vs 25.5%, p &amp;lt; 0.001). Mortality before reaching clinical remission was 1.9% in the CPZ group and 4.3% in the non-CPZ group (p. 0.177). Adverse events (AEs) rate was 10.5% in the non-CPZ group, most related to plasma infusion, all mild. Incidence of AEs related to CPZ was 24.5%, with 12 bleeding events: 11 WHO grade 1 (3 metrorrhagia, 2 pericatheter bleeds, 6 mucosal bleeds) and one grade 2 (1 gastrointestinal in a patient with intestinal polyposis). Regarding patients reaching ADAMTS13 &amp;gt;20%, we found no differences with regard to CPZ use (Fig 1). There were 114 evaluable episodes (66% of serie): 39 No-CPZ (56.5% of No CPZ group) and 75 CPZ group (72.8% CPZ group). The 93% achieved ADAMTS13 levels &amp;gt;20%, with no difference between groups(CPZ 93.3% vs No CPZ 94.9%, p. 0.082). In the 107 episodes who reached ADAMTS13 &amp;gt;20%, time from start of PEX to ADAMTS13 &amp;gt; 20% was 27 days (IQR:17-51),(CPZ 26.5 days, IQR:17.75-39, vs no CPZ 22 days, IQR:14.75-33.5, p.0.077). ADAMTS13 levels at that time were 51% (IQR: 36-80%),(CPZ 50%, IQR: 33-71% vs No CPZ 59%, IQR: 37-89%, p. 0.437). Time from last PEX to ADAMTS13 levels &amp;gt;20% was similar in both groups (CPZ 15.5 days, IQR: 7.75-29.25 vs No CPZ 13 days, IQR: 8-22 days, p. 0.063). In patients treated with CPZ in the 3 first days from diagnosis, there is no difference in time from start PEX and ADMATS13 &amp;gt;20%, but we found longer time from last PEX to ADAMTS13 &amp;gt;20% (CPZ3 18 days, IQR: 12-43 days vs No CPZ 13 days, IQR: 8-22 days, p. 0.026). The 81.3% of the episodes who reached ADAMTS13 levels &amp;gt;20% received RTX and 71.4% (2/7) of the non-responders (p. 0.385). We found no differences in time to ADAMTS13 &amp;gt; 20% in none of both groups with regard of RTX used. CONCLUSIONS CPZ is safe and effective in the treatment of iTTP. Its use in the first 3 days of diagnosis shortens clinical response times. Exacerbation and refractoriness are lower in patients treated with CPZ. In our series, the use of CPZ did not extend time to ADAMTS13 levels greater than 20%, neither from the start of PEX nor from PEX stop evaluation. Only in the group of patients treated with CPZ in the first 3 days of diagnosis, time from last PEX to ADAMTS13 &amp;gt;20% is longer, probably because they need less PEX, but time from PEX start to ADAMTS13 &amp;gt;20% is the same than in the rest of patients.

Cost-Effectiveness of Caplacizumab in the Warranty Program in Immune Thrombotic Thrombocytopenic Purpura in the USA

Background Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy. Caplacizumab is a humanized nanobody that inhibits formation of microthrombi in iTTP by disrupting binding of von Willebrand factor to platelets. It is the only treatment approved in combination with plasma exchange therapy (PEX) and immunosuppression (IS) for the treatment of iTTP. The United Kingdom National Institute for Health and Care Excellence (NICE) committee reviewed cost-effectiveness of caplacizumab. The committee concluded that addition of caplacizumab to PEX+IS is cost-effective and recommended that the drug be reimbursed in the UK. The Sanofi Promise Warranty Program ® (SPWP) was introduced in January 2023 in the US. It refunds the full cost of caplacizumab to the hospital when treatment is discontinued due to non-response defined as refractoriness (patient with platelet counts &amp;lt;50 × 10 9/L after 4 days of combined treatment with caplacizumab and PEX+IS; up to 6 doses are refunded), or exacerbation (new drop in platelet count after initial platelet count normalization [&amp;gt;150 × 10 9/L], necessitating re-initiation of PEX after ruling out any causes for the drop in platelet count other than iTTP pathophysiology, up to 12 pre-exacerbation doses are refunded). Objectives To evaluate the cost-effectiveness of adding caplacizumab to PEX+IS from a US perspective within the context of SPWP. Methods The NICE model was adapted to the US setting by replacing UK costs with US costs and discount rates. All clinical assumptions and structure remain unchanged. Clinical inputs were derived from the HERCULES trial (NCT02553317) intent-to-treat population (mean age: 46 years; females: 69%, exacerbation rates: 4.17% during double blind phase and 12.50% in total; refractoriness: 0%). The model consisted of a 3-month decision tree, which captured patient treatment and outcomes over the acute iTTP episode, followed by a long-term Markov model (time horizon: up to 55 years; 3-monthly cycles; Figure 1). An annual discount rate of 3% was applied for both costs and quality-adjusted life-years (QALYs). Under the SPWP, the cost of caplacizumab was assumed to be $0 for refractory patients and those who exacerbate early, no discount was applied for patients who experience exacerbations after drug discontinuation, however, clinical outcomes were captured. Results Prior to the SPWP, caplacizumab addition to PEX+IS delivered a gain of 1.75 QALYs (2.96 life-years [LYs]) as compared with PEX+IS alone, at an increased lifetime cost of $256,000. The incremental cost effectiveness ratio (ICER) was $146,350 per QALY and $86,420 per LY gained ( Table 1). An estimated 4.17% of treated patients qualified for the SPWP. With this outcomes-based program, the ICER improved to $138,480 per QALY and $81,780 per LY gained, respectively ( Table 1). Conclusion Based on these analyses using the UK NICE model adapted with US costs, caplacizumab is cost-effective considering WTP threshold of $150,000 to $200,000 and has improved cost-effectiveness when the warranty program is taken into account. Outcomes based programs can improve the cost effectiveness of a treatment in addition to mitigating concerns of perceived uncertainty of efficacy in treating patients with iTTP in the US.

Real World Practices of Thrombopoietin Receptor Agonist Use and Discontinuation in Pediatric Patients with Immune Thrombocytopenia (ITP): A Single Center Retrospective Review

Introduction Thrombopoietin Receptor Agonists (TPO-RAs) are becoming widely used as second-line treatment in patients with immune thrombocytopenia (ITP). These can be weaned/discontinued in adults. There is a paucity of literature on weaning and discontinuation practices in pediatric ITP. Methods We performed a retrospective review of pediatric patients aged 0-18 years with ITP treated with TPO-RAs at our institution over an eight-year period (2015-2022). Weaning and discontinuation practices were compared between patients based on timing of TPO-RA initiation: &amp;lt;3 months from diagnosis (group A), ≥3 to &amp;lt;12 months from diagnosis (group B), &amp;lt;12 months from diagnosis (group AB) or ≥12 months from diagnosis (group C). Results There were 11, 12 and 32 patients in group A, B, and C respectively (table 1). As of last follow up, 10 patients successfully weaned and discontinued their TPO-RA. Eighteen patients were weaning their TPO-RA monotherapy and 15 continued a TPO-RA at maximal dose or required the addition of another agent, such as an immunosuppressant, to permit TPO-RA weaning. Five patients discontinued their TPO-RA due to poor response. Seven patients had stopped the TPO-RA due to an alternate reason (family preference, side effects, etc.). There was no difference in any of these outcomes based on timing of TPO-RA initiation. In patients whose platelet count responded to TPO-RAs, the dose was weaned at the provider's discretion. The dose was generally not weaned for a platelet count &amp;lt;50k. Among only patients in which the TPO-RA monotherapy was weaned, patients in group AB had a shorter duration of TPO-RA treatment than patients in group C (IQR 12.1-48.9 months vs 37.5-88.0 months; p=0.019). While not statistically significant, after the start of the TPO-RA dose weaning, patients in group A weaned their TPO-RA at a faster rate (IQR 4.7-20.5% of maximal dose per month) compared to patients in groups B and C (IQR 1.8-5.1% of maximal dose per month and 1.5-5.5% of maximal dose per month). The 10 patients who fully weaned their TPO-RA had a shorter duration of TPO-RA use compared to the 18 patients who partially weaned their TPO-RA monotherapy (IQR 11.5-38.6 months vs 27.6-82.1 months; p=0.018). Once the wean of TPO-RA dose was started, patients who fully weaned their TPO-RA did so at a faster rate than patients who partially weaned (IQR 5.6-29.6% of maximal dose per month vs 1.0-3.4% of maximal dose per month; p=0.017; figure 1). Seven patients who fully weaned their TPO-RA had follow up CBCs between one and three months after discontinuation. Of these, five patients had platelet counts &amp;gt;100k, while the other two had platelet counts &amp;gt;40k that continued to rise to &amp;gt;80k within a year of discontinuation without further treatment. Of the remaining three patients, two had CBCs more than three months post TPO-RA discontinuation with platelet counts &amp;gt;100k without additional treatment and one had no follow up CBC after TPO-RA discontinuation. Two patients with follow-up had transient ITP exacerbations with platelet counts &amp;lt;10k at 14 and 31 months after TPO-RA discontinuation that were treated with anti-D/steroids and IVIG respectively with subsequent sustained improvement in platelet counts that did not require any further intervention. There was no difference in the number of rescue medications (IVIG, anti-D, steroids) required between patient groups based on timing of TPO-RA initiation or type of agent used. Patients who were treated with both romiplostim and eltrombopag required adjunctive therapies (such as immunosuppressants) more than patients treated with either agent alone (p=0.022). Conclusion TPO-RAs were weaned and successfully discontinued in 10 of 55 (18.2%) pediatric patients with ITP in our small cohort with a low rate of subsequent ITP exacerbation. There was no difference in TPO-RA discontinuation rate in patients with a good platelet response based on timing of TPO-RA initiation. Patients who started a TPO-RA within 12 months of their ITP diagnosis had a shorter duration of TPO-RA use than patients who started a TPO-RA more than 12 months after diagnosis. Patients who started a TPO-RA within three months of diagnosis were able to wean their TPO-RA dose at a faster rate than patients who started a TPO-RA more than three months after diagnosis. TPO-RA dose was weaned at a faster rate in patients who fully weaned their TPO-RA compared to patients who were partially weaned. This data should be validated in a larger study.

Pregnancy and Immune Mediated Thrombotic Thrombocytopenic Purpura (iTTP); A Descriptive Analysis from the U.S. Thrombotic Microangiopathy (USTMA) Registry

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation, confirmed by severely deficient ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) to &amp;lt;10%. It is caused by autoantibodies against the ADAMTS13 protease. Pregnancy can precipitate iTTP, but the diagnosis and treatment are challenging, since it is often difficult to differentiate from other TMAs associated with pregnancy The aim of this study was to describe the clinical presentation, treatment, and outcomes of pregnancy related iTTP. Methods: Data was obtained from the USTMA retrospective database, including 15 large USTMA referral centers. Patients were identified based on the diagnosis of iTTP provoked by pregnancy between 9/6/1990 and 6/18/2018. The study cohort included participants with a clinical diagnosis of iTTP, confirmed by ADAMTS13 activity &amp;lt;10% who had a pregnancy or recent delivery within 30 days of presenting with iTTP. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX (plasma exchange) discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX. Maternal and fetal outcomes were additionally collected from 7/15 sites. Results: 42 patients had 55 iTTP episodes provoked by pregnancy. Median age for patients was 29. Sixteen (38.1%) were white, 20 (47.6%) were black. The most common presenting symptoms were headache and fatigue in 11/55 (20%) episodes. Thirty nine (70.9%) episodes had a platelet count &amp;lt;30 x10 9/L, and 46 (83.6%) had laboratory findings concerning for hemolysis as evidenced by elevated lactate dehydrogenase (LDH) and/or schistocytes present on peripheral smear. Only 5 (9%) episodes presented with a creatinine &amp;gt;2 mg/dL. ADAMTS13 activity was documented in 33 (60%) episodes and was &amp;lt;10% in 30 (90.9%) (Table 1). Treatment with PLEX was described in 30 (54.5%) episodes with a median duration of 6 days (2-26 days). Further immunosuppression included prednisone in 38 (69.1%) episodes and rituximab in 11 (20%), of which 7 (63.6%) had no future exacerbations or relapses during the study period.Seventeen (40.5%) patients had a prior diagnosis of iTTP. There were 10 exacerbations in 8 patients (19%), and 34 relapses in 13 (30%) patients after the 55-pregnancy provoked iTTP episodes. Five of those relapses were triggered again by pregnancy. Pregnancy related outcomes were obtained in 16 patients. Twenty five percent (4/16) of patients had a prior history of iTTP; median time of last iTTP to current presentation was 34 months (10-108). Of 16 patients, iTTP occurred with first pregnancy in 8 patients. Of the remaining eight patients, iTTP occurred in the eleventh (n=1), ninth (n=1), sixth (n=1), fifth (n=1), fourth (n=2), and unknown (n=2) pregnancy. Only 13 of 16 patients had further pregnancy specific outcomes available (Table 2). Preeclampsia was noted in 3 patients. Seven and 1 patients, presented with iTTP within 30 days postpartum or after miscarriage, respectively. The remaining patients (n=5) developed iTTP during the antepartum period. Of these, 2 pregnancies were terminated due to iTTP (second trimester and third trimester). One of the three remaining pregnancies resulted in fetal demise at 24 weeks. The latter two patients delivered healthy infants. There were no maternal deaths in our cohort. Conclusions: This is first multicenter descriptive analysis of pregnancy related iTTP from the USTMA registry. The clinical presentation of this cohort is consistent with iTTP triggered by other causes, and the low rate of acute kidney injury is helpful in identifying iTTP from other TMAs in pregnancy. We observed that pregnancy is a risk not only for acute episodes of iTTP in first pregnancy, but also in subsequent pregnancies and in the relapse setting of those with previous diagnosis of iTTP. While there was a 20% and 30% exacerbation and relapse rate respectively, maternal mortality was not observed. Rituximab did not affect maternal mortality. Fetal mortality was affected by iTTP in the antepartum period. These findings will serve as bases of prospective USTMA study for standardize management of this population.

Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting β2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy

IntroductionAsthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting β2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted. MethodsSearches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998–2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis. ResultsThe SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs. ConclusionA systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs.

Prospective direct comparison of biologic treatments for severe eosinophilic asthma: Findings from the PRISM study

BackgroundAlthough various monoclonal antibodies have been used as add-on therapy for severe eosinophilic asthma (SEA), to the best of our knowledge, no direct head-to-head comparative study has evaluated their efficacy. ObjectiveTo compare the efficacy of reslizumab, mepolizumab, and dupilumab in patients with SEA. MethodsThis was a multicenter, prospective observational study in patients with SEA who had received 1 of these biologic agents for at least 6 months. Cox proportional hazard models were used to compare the risk of the first exacerbation event, adjusting for sputum or blood eosinophils and common asthma-related covariates. The annual exacerbation rate was analyzed using a negative binomial model, and a mixed-effect model was used to analyze changes in forced expiratory volume in 1 second and asthma control test score over time. ResultsA total of 141 patients with SEA were included in the analysis; 71 (50%) received dupilumab; 40 (28%) received reslizumab, and 30 (21%) received mepolizumab. During the 12-month follow-up, 27.5%, 43.3%, and 38.0% of patients in the reslizumab, mepolizumab, and dupilumab groups, respectively, experienced at least 1 exacerbation. However, after adjusting for confounding factors, the dupilumab and mepolizumab groups showed similar outcomes in time-to-first exacerbation, exacerbation rate, forced expiratory volume in 1 second, and asthma control test score to those of the reslizumab group. ConclusionIn patients with SEA, treatment with reslizumab, mepolizumab, and dupilumab resulted in comparable clinical outcomes within a 12-month period. Trial RegistrationThe cohort protocol was sanctioned by the Institutional Review Board of each study center (clinicaltrial.gov identifier NCT05164939).

Comprehensive Observational Study in a Large Cohort of Asthma Patients after Adding LAMA to ICS/LABA.

Adding LAMA to LABA/ICS is recommended to improve control in patients with persistent asthma. This observational, retrospective, before-and-after study considered patients diagnosed with asthma who started LABA/ICS + LAMA treatment (triple therapy, TT) between 1 January 2017 and 31 December 2018 and had been treated with LABA/ICS (dual therapy, DT) in the year before. Changes in lung function and exacerbation rates, healthcare resource utilization, and healthcare and non-healthcare costs (€2019) were estimated in patients with asthma in clinical practices in Spain. Data from computerized medical records from seven Spanish regions were collected ±1 year of LAMA addition. 4740 patients (64.1 years old [SD: 16.3]) were included. TT reduced the incidence of exacerbations by 16.7% (p < 0.044) and the number of patients with exacerbations by 8.5% (p < 0.001) compared to previous DT. The rate of patients with severe exacerbations requiring systemic corticosteroids and their hospitalization rates significantly decreased by 22.5% and 29.5%. TT significantly improved FEV1, FVC, and FEV1/FVC, saving €571/patient for society. Younger patients with asthma (18-44 years old) and patients with severe asthma (FEV1 < 60%) performed better upon the initiation of TT. TT reduced asthma exacerbations, improved lung function and reduced healthcare costs vs. DT, particularly in patients requiring systemic corticosteroids to treat severe exacerbations.

Real-world effectiveness of dupilumab in patients with asthma: Findings from the US ADVANTAGE study

BackgroundDupilumab is approved as an add-on maintenance therapy for patients (≥6 years) with moderate-to-severe asthma. Better understanding of real-world effectiveness is needed. ObjectiveTo characterize the real-world effectiveness of dupilumab in asthma management. MethodsThis retrospective study included patients (≥12 years of age) diagnosed with asthma, initiating dupilumab between November 2018 and September 2020. The study used a US electronic medical record database (TriNetX Dataworks, Cambridge, Massachusetts). Asthma exacerbation rates before and after the initiation of dupilumab were analyzed using generalized estimating equations models with Poisson probabilistic link to estimate incidence rate ratios (IRRs). Sensitivity analyses were conducted based on previous exacerbation data, eosinophil levels, history of atopic dermatitis or chronic rhinosinusitis with nasal polyps, previous use of biologics, and presence of SARS-CoV-2 (COVID-19). ResultsA total of 2400 patients initiating dupilumab met all study criteria. After initiation of dupilumab, risk of asthma exacerbation was reduced by 44% (IRR, 0.56; 95% CI, 0.47-0.57; P = <0.0001) and systemic corticosteroid prescriptions by 48% (IRR, 0.52; 95% CI, 0.48, 0.56; P = <0.0001) compared with those before initiation of dupilumab. Adjustment for COVID-19 showed a greater reduction in asthma exacerbations (IRR, 0.50; 95% CI, 0.45-0.55; P = <0.0001). ConclusionCurrent real-world efficacy evidence indicates that dupilumab reduces asthma exacerbations and total systemic corticosteroid prescriptions in clinical practice. The effectiveness of dupilumab was observed independent of exacerbation history, eosinophil levels, or COVID-19 impact.

Abstract 17053: Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Mortality in Hypertrophic Cardiomyopathy: A Retrospective Study

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to improve outcomes in congestive heart failure (HF). However, their effect in hypertrophic cardiomyopathy (HCM) is unknown. Research Question: Can SGLT2i improve clinical outcomes in HCM patients? Methods: Using TriNetX Global Research Network from March 2013 to February 2021, patients diagnosed with HCM (ICD-10 codes I42.1, I42.2) were identified and categorized into 2 groups: those on SGLT2i vs. those who are not. To avoid inclusion of other causes of left ventricular hypertrophy, patients with aortic stenosis or systemic hypertension were excluded. Propensity score matching (PSM) was used to limit confounders. Primary outcome was all-cause mortality and secondary outcomes were HF exacerbation, all-cause hospitalization, and documented cardiovascular symptoms (chest pain, dyspnea, palpitations, or leg edema) over a 2-year follow-up period. Results: A total of 27,561 HCM patients were identified; 408 (1.5%) on SGLT2i and 27,153 (98.5%) were not. Patients on SGLT2i were older (55 ± 15 vs. 48 ± 19, p&lt;0.01) and had more comorbidities, including a nearly 6-fold higher prevalence of diabetes mellitus (44% vs. 7%, p&lt;0.01) and congestive HF (65% vs. 10%, p&lt;0.01). After PSM, each group consisted of 355 patients. HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.22 [95% CI: 0.12, 0.39]; p&lt;0.01), hospitalizations (OR 0.72 [95% CI: 0.53, 0.98]; p=0.04), and cardiovascular symptoms (OR 0.71 [95% CI: 0.52, 0.97]; p=0.029) when compared to patients not on SGLT2i. There was no statistical difference in the rate of HF exacerbation (OR 0.82 [95% CI: 0.54, 1.24]; p=0.3). Conclusion: In this large dataset, SGLT2i use in a select subset of HCM patients was associated with improved survival, less hospitalizations, and fewer cardiovascular symptoms. These data support future randomized trials to evaluate the efficacy and safety of SGLT2i in more diverse HCM patient populations.

Tezepelumab: a new option for the treatment of severe asthma

In Latin America, asthma is a public health problem with a significant impact on both patients and health systems. The greater understanding of the pathophysiology and the recognition of the central role that inflammation has in the severity of asthma has favored the development of monoclonal antibodies that have IL-5, IL-4, IL-13 and IgE as therapeutic targets. Although these therapeutic alternatives promote better control of the disease, not all patients respond favorably to these treatments. Therefore, it is of particular interest to explore monoclonal antibodies such as Tezepelumab, directed against thymic stromal lymphopoietin (TSLP), an alarmin (epithelial cytokine) that participates in the initiation and perpetuation of inflammation in Asthma. Therefore, in this review, we will show the clinical efficacy of tezepelumab in reducing the annual rate of exacerbations, improving lung function, and reducing bronchial hyperreactivity, regardless of the patient's baseline biomarker levels. Therefore, this new molecule is a highly effective therapeutic option for patients with severe asthma.

Structural understanding of SARS-CoV-2 virus entry to host cells.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health concern associated with millions of fatalities worldwide. Mutant variants of the virus have further exacerbated COVID-19 mortality and infection rates, emphasizing the urgent need for effective preventive strategies. Understanding the viral infection mechanism is crucial for developing therapeutics and vaccines. The entry of SARS-CoV-2 into host cells is a key step in the infection pathway and has been targeted for drug development. Despite numerous reviews of COVID-19 and the virus, there is a lack of comprehensive reviews focusing on the structural aspects of viral entry. In this review, we analyze structural changes in Spike proteins during the entry process, dividing the entry process into prebinding, receptor binding, proteolytic cleavage, and membrane fusion steps. By understanding the atomic-scale details of viral entry, we can better target the entry step for intervention strategies. We also examine the impacts of mutations in Spike proteins, including the Omicron variant, on viral entry. Structural information provides insights into the effects of mutations and can guide the development of therapeutics and vaccines. Finally, we discuss available structure-based approaches for the development of therapeutics and vaccines. Overall, this review provides a detailed analysis of the structural aspects of SARS-CoV-2 viral entry, highlighting its significance in the development of therapeutics and vaccines against COVID-19. Therefore, our review emphasizes the importance of structural information in combating SARS-CoV-2 infection.

Effect of the COVID-19 pandemic on asthma exacerbations in New Zealand: An interrupted time series analysis.

New Zealand (NZ) implemented some of the strictest restrictions during the novel coronavirus pandemic (coronavirus disease 2019 [COVID-19]), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How this impacted asthma exacerbation rates in NZ is unknown. We sought to explore the effects of the COVID-19 restrictions on asthma exacerbations in NZ during 2020. We used a population-based, interrupted time series to examine the impact of the first COVID-19 lockdown in NZ on asthma exacerbation rate. The primary outcome measure was change in the monthly exacerbation rate, defined as hospitalization and/or course of corticosteroids, before and after the first lockdown. In a secondary analysis, we quantified the number of patients with asthma, the actual asthma exacerbation rate from March to December 2019 versus March to December 2020, and the number of asthma hospitalizations. There was a significant drop in the exacerbation rate immediately after lockdown (-3.02; P< .0001) followed by a significant and sustained increasing trend; the rate postlockdown increased relative to that prelockdown (0.27; P< .0001). Similar patterns were observed in all sociodemographic groups. In our secondary analysis, we identified 507,622 people with asthma; this reduced to 458,023 in 2020 postlockdown. The overall asthma exacerbation rate was 33.3% less in 2020 than in 2019 (reduction from 48.6/1000 patients to 32.4/1000 patients). The rate of asthma hospitalizations decreased from 9.5 per 1000 patients in 2019 to 6.2 per 1000 patients in 2020; this decrease was observed across all demographic groups. The first COVID-19 lockdown in 2020 in NZ significantly reduced asthma exacerbation rates across all sociodemographic groups. Whether these reductions are sustained requires further investigation.

Exploring the impact of varying definitions of exacerbations of chronic obstructive pulmonary disease in routinely collected electronic medical records.

Validity of exposure and outcome measures in electronic medical records is vital to ensure robust, comparable study findings however, despite validation studies, definitions of variables used often differ. Using exacerbations of chronic obstructive pulmonary disease (COPD) as an example, we investigated the impact of potential misclassification of different definitions commonly used in publications on study findings. A retrospective cohort study was performed. English primary care data from the Clinical Practice Research Datalink Aurum database with linked secondary care data were used to define a population of COPD patients ≥40 years old registered at a general practice. Index date was the date eligibility criteria were met and end of follow-up was 30/12/19, death or end of data collection. Exacerbations were defined using 6 algorithms based on definitions commonly used in the literature, including one validated definition. For each algorithm, the proportion of frequent exacerbators (≥2 exacerbations/year) and exacerbation rates were described. Cox proportional hazard regression was used to investigate each algorithm on the association between heart failure and risk of COPD exacerbation. A total of 315,184 patients were included. Baseline proportion of frequent exacerbators varied from 2.7% to 15.3% depending on the algorithm. Rates of exacerbations over follow-up varied from 19.3 to 66.6 events/100 person-years. The adjusted hazard ratio for the association between heart failure and exacerbation varied from 1.45, 95% confidence intervals 1.42-1.49, to 1.01, 0.98-1.04. The use of high validity definitions and standardisation of definitions in electronic medical records is crucial to generating high quality, robust evidence.

Impact of COVID-19 measures on exacerbation rates and healthcare visits in US asthma patients.

Objective: To compare exacerbation rates and healthcare resource utilization (HCRU) in real-world patients in the United States who had moderate-to-severe asthma on medium- or high-dose inhaled corticosteroid/long-acting β₂-agonist therapy at different stages before and after the pandemic. Methods: This noninterventional, retrospective study described demographics, exacerbations, HCRU, and medication use in patients from a US-wide healthcare claims database in 4 consecutive years anchored around March 15, 2020 (start date of the first emergency health measures against coronavirus disease 2019 [COVID-19], or the first lockdown, in the United States, termed "restriction onset" hereafter). Four cohorts of patients potentially eligible for moderate-to-severe asthma clinical trials at the beginning (index) of each of four 1-year periods (March 15, 2018, 2019, 2020, 2021, respectively) were built. Exacerbations, healthcare visits, and asthma medication use were counted in the 1-year period after the index for each cohort. Results: The prevalence of patients with one or more exacerbation per year decreased by 10.00% in the first year after the restriction onset compared with the year before and attenuated over time to 6.37% in the second year. The proportion of inpatient, emergency department, and physician's office visits remained stable over the time periods evaluated for all patients and those patients who experienced one or more exacerbations. Asthma treatment of patients who experienced one or more exacerbations also remained stable over the 4 years. Conclusion: The effect of COVID-19 public health measures on asthma exacerbation rates might have affected clinical trials being run during this period and should be considered in their analysis. Asthma clinical trials run under pandemic hygiene restrictions should consider lower exacerbation frequency in their study design, while treatment and healthcare visits seem unchanged.

Beta-blockers reduce severe exacerbation in patients with mild chronic obstructive pulmonary disease with atrial fibrillation: a population-based cohort study

Background and objectiveBeta-blockers (BBs) decrease mortality and acute exacerbation (AE) rates in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular disease; however, information on their effects in patients with...

Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis: An exploratory randomized controlled trial

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an important occurrence in the natural history of idiopathic pulmonary fibrosis (IPF), associated with high hospitalization rates, high mortality and poor prognosis. At present, there is no effective treatment for AE-IPF. Chinese herbal medicine has some advantages in treating IPF, but its utility in AE-IPF is unclear. ObjectiveThe treatment of AE-IPF with Kangxian Huanji Granule (KXHJ), a compound Chinese herbal medicine, lacks an evidence-based justification. This study explores the efficacy and safety of KXHJ in patients with AE-IPF. Design, setting, participants and interventionsWe designed a randomized, double-blind, placebo-controlled, exploratory clinical trial. A total of 80 participants diagnosed with AE-IPF were randomly assigned to receive KXHJ or a matching placebo; the treatment included a 10 g dose, administered twice daily for 4 weeks, in addition to conventional treatment. Participants were followed up for 12 weeks after the treatment. Main outcome measuresThe primary endpoints were treatment failure rate and all-cause mortality. Secondary endpoints included the length of hospitalization, overall survival, acute exacerbation rate, intubation rate, the modified British Medical Research Council (mMRC) score, and the St George’s Respiratory Questionnaire for IPF (SGRQ-I) score. ResultsThe rate of treatment failure at 4 weeks was lower in the intervention group compared to the control group (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.051 to 0.965, P = 0.023). There was no significant difference in all-cause mortality at 16 weeks (RR: 0.75; 95% CI: 0.179 to 3.138; P > 0.999) or in the acute exacerbation rate during the 12-week follow-up period (RR: 0.69; 95% CI: 0.334 to 1.434; P = 0.317). The intervention group had a shorter length of hospitalization than the control group (mean difference [MD]: –3.30 days; 95% CI, –6.300 to –0.300; P = 0.032). Significant differences in the mean change from baseline in the mMRC (between-group difference: –0.67; 95% CI: –0.89 to –0.44; P < 0.001) and SGRQ-I score (between-group difference: –10.36; 95% CI: –16.483 to –4.228; P = 0.001) were observed after 4 weeks, and also in the mMRC (between-group difference: –0.67; 95% CI: –0.91 to –0.43; P < 0.001) and SGRQ-I (between-group difference: –10.28; 95% CI, –15.838 to –4.718; P < 0.001) at 16 weeks. The difference in the adverse events was not significant. ConclusionKXHJ appears to be effective and safe for AE-IPF and can be considered a complementary treatment in patients with AE-IPF. As a preliminary exploratory study, our results provide a basis for further clinical research. Trial registrationChinese Clinical Trial Registry (ChiCTR1900026289).Please cite this article as: Li JS, Zhang HL, Guo W, Wang L, Zhang D, Zhao LM, Zhou M. Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis: an exploratory randomized controlled trial. J Integr Med. 2023; Epub ahead of print.