Uncontrolled Severe Asthma Patients Research Articles

Early response to Tezepelumab in type-2 severe asthma patients non-responders to other biological treatments: a real-life study

Background Biologic therapies play a crucial role in the treatment of severe asthma. Tezepelumab, a human monoclonal antibody (mAb), inhibits thymic stromal lymphopoietin, a pivotal factor in the pathophysiology of asthma. Although randomized clinical trials have demonstrated the efficacy of Tezepelumab, evidence gaps remain in real-world scenarios. Objective We sought investigate Tezepelumab’s response in a clinical setting, focusing on patients who previously failed to other asthma mAbs. Methods Real-life study with severe uncontrolled asthma patients despite mAb treatment, requiring a switch to Tezepelumab. Follow-up was done four to six months after initiation of Tezepelumab. The primary endpoint was to evaluate the response in patients with poor response or intolerance to other mAbs. Results Nine patients were followed up during 7 months. Patients were predominantly middle-aged females with eosinophilic or eosinophilic-allergic phenotypes. Patients had a median failure rate of 2 mAbs (IQR 2–3), with an uncontrolled asthma (median of 2 severe exacerbations the previous year, airflow obstruction and 78% corticosteroid dependence). Tezepelumab demonstrated after 4 to 6 months of treatment reduce corticosteroid dependence (complete withdrawal in 2/7 patients), no exacerbations in 6/9, symptoms control improvement (Asthma Control Test score improved in 5/9) and modulate lung function (improving in 3/9 patients). These findings align with clinical trial results, suggesting Tezepelumab’s potential in real-world settings. Conclusion In real-world scenarios, despite the study’s limitations, our results underscore Tezepelumab’s promise as a therapeutic option for uncontrolled severe asthma, and may be useful for non-responders to other mAbs. Further studies are needed to corroborate these findings.

Gaps in Care Among Uncontrolled Severe Asthma Patients in the United States

Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease. To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators. Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment. Patients with SA without EUD served as controls. Eligibility included age 12 or greater, 12 months enrollment before and after index, no biologic use, and no other major respiratory disease during the pre-period. Escalation of care in the form of specialist visits and medication escalation, health care resource use, costs, and disease exacerbations were assessed during follow-up. We identified 180,736 patients with SA (90,368 uncontrolled and 90,368 controls). Between 35% and 51% of patients with SA with an EUD had no specialist visit or medication escalation. Follow-up exacerbations ranged from 51% to 4% across EUD cohorts, compared with 13% in controls. Among uncontrolled patients with SA who were Black or Hispanic/Latino, 41% and 38%, respectively, had no specialist visit or medication escalation after EUD, compared with 33% of non-Hispanic White patients. A substantial proportion of uncontrolled patients with SA had no evidence of specialist visits or medication escalation after uncontrolled disease, and there was a clear relationship between uncontrolled disease and subsequent health care resource use and exacerbations. Findings highlight the need for improved guideline-based care delivery to patients with SA, particularly for those facing social disparities.

Best practices for interdisciplinary care of uncontrolled severe asthma patients (TEAM project)

As one of the most prevalent chronic respiratory diseases, asthma imposes a heavy health and socioeconomic burden on society, particularly in the case of patients who fail to appropriately control the disease. For this reason, improving the clinical management of patients with severe uncontrolled asthma should be a priority for any healthcare system.At a time when healthcare models for chronic disease management and personalized medicine are undergoing a major overhaul, the project presented in this study seeks to lay the foundations for an interdisciplinary care model for patients with severe uncontrolled asthma. The work carried out reinforces the general perception that it is paramount to optimize coordination between different levels of care, encourage collaboration and an interdisciplinary approach, and promote an integrated care model that makes it possible to adapt the care of patients with severe uncontrolled asthma in a more personalized manner. Under this project, a series of interdisciplinary working groups were created, made up of specialist hospital pharmacists, pneumologists and allergists, to identify and prioritize a number of best practices, and classify them in terms of their potential impact on the improvement of the quality of care and the health outcomes of patients with severe uncontrolled asthma, and their feasibility. The authors’ ambition is that the conclusions drawn from this study should help other interdisciplinary teams improve the care provided to patients suffering from severe uncontrolled asthma.

Retrospective Analysis of Biologic Agent Utilization in Severe Asthma: Impact on Exacerbation Rates, Forced Expiratory Volume in the First Second (FEV1), Eosinophils, and IgE Levels.

Introduction Severe uncontrolled asthma is challenging to manage and impacts lung function and symptoms. Biologic agents targeting inflammatory pathways have transformed asthma management. This retrospective chart review aimed to assess biologic therapy in severe uncontrolled asthma patients and evaluate outcomes. Methods The study analyzed medical records of 30 patients receiving biologic therapy for severe asthma at a tertiary care center in Peshawar, Pakistan, from December 2022 to Jun 2023. Ethical approval was obtained, and patient demographics, biologic agent usage, and clinical parameters were collected. Clinical outcomes were evaluated after six months, including forced expiratory volume in the first second (FEV1), eosinophil count, IgE levels, and exacerbation rates. Results After six months, biologic treatment significantly improved FEV1 (48.7% to 62.4%), reduced eosinophils (540 cells/μL to 290 cells/μL) and IgE levels (410 IU/mL to 280 IU/mL), and decreased exacerbations (4.6 to 1.9). Subgroup analysis based on age and sex showed consistent lung function improvements. Conclusion Biologic agents effectively targeted inflammatory pathways, improving asthma control in severe uncontrolled asthma patients. This study provides valuable insights into biologic therapy for severe asthma, offering new possibilities for patient outcomes. Larger studies are needed to validate findings and optimize personalized treatment strategies.

Redefining the Role of Bronchoscopy in the Workup of Severe Uncontrolled Asthma in the Era of Biologics: A Prospective Study

Severe uncontrolled asthma (SUA) is frequently treated with biologic therapy if a T2 phenotype is found. Bronchoscopy is not routinely recommended in these patients unless a specific indication to rule out comorbidities is present. Is routine bronchoscopy safe and useful in phenotyping and endotyping SUA patients prior to the indication of a biologic therapy?. Prospective study of consecutive SUA patients who were referred to a specialized asthma clinic to assess the indication of a biologic therapy. Patients were clinically phenotyped as T2-allergic, T2-eosinophilic and non-T2. All patients underwent bronchoscopy and systematic data collection of endoscopic findings, microbiology of bronchial aspirate (BAS) and presence of eosinophils in bronchial biopsy were recorded and compared between asthma phenotypes. Cluster analysis was performed accordingly. One-hundred patients were recruited and classified as T2-allergic (28%), T2-eosinophilic (64%) and non-T2 (8%). On bronchoscopy, signs of gastroesophageal reflux disease were detected in 21%, vocal cord dysfunction in 5% and tracheal abnormalities in 3%. BAS culture isolated bacteria in 27% of patients, and fungi in 14%. Three clusters were identified: non-specific, upper airway, and infection being the latter less frequently associated to submucosal eosinophilia. Eosinophils were detected in 91% of bronchial biopsies. Despite a correlation to blood eosinophils, five patients with T2-phenotypes showed no eosinophils in bronchial biopsy, and 3 patients with non-T2 showed eosinophils in bronchial biopsy. Only one patient had a moderate bleeding. Routine bronchoscopy in SUA eligible for biologic therapy is a safe procedure that can help to better phenotype and personalize asthma management.

Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma

Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P< .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.

The Italian severe/uncontrolled asthma registry (RItA): A 12-month clinical follow-up

Backgroundfollow-up studies on registries of severe/uncontrolled asthma (SUA) patients are scanty. Objectiveto analyze baseline and follow-up characteristics of SUA patients and their longitudinal patterns. Methods180 adult patients (age ≥15 yrs) were investigated at baseline and 12-month follow-up through the Italian SUA registry (RItA).Latent transition analysis (LTA) was performed to detect cross-sectional SUA phenotypes and longitudinal patterns. Risk factors for longitudinal patterns were assessed through logistic regression. Resultsa significant/borderline improvement of asthma control outcomes in the last 2–4 weeks emerged at follow-up with respect to baseline for: daily activities limitations (Δ −16%), frequent diurnal symptoms (Δ −25%), uncontrolled asthma symptoms according to ACT (Δ −26%). Last 12-month use of oral corticosteroids was less frequent at follow-up than at baseline (Δ −25%). Health status improvement was confirmed by lung function test results.Through LTA, two longitudinal patterns were detected considering last 12-month control outcomes: “persistence/worsening” (53.9%), “under control/improvement” (46.1%). A lower likelihood of having “persistence/worsening” SUA was exhibited by patients under anti-IgE (OR 0.38, 95% CI 0.17–0.84) and inhaled corticosteroids-bronchodilator association treatment (OR 0.13, 95% CI 0.01–1.26, borderline value), while a higher likelihood was shown by older age at first asthma diagnosis (OR 1.04, 95% CI 1.01–1.07). Conclusionthe implementation of a SUA registry, the availability of patient-level data and the application of an innovative longitudinal analysis allowed to observe a general improvement in asthma control, one year after baseline, and a lower risk of SUA “persistence/worsening” in patients under anti-IgE and regular ICS-bronchodilator association use.

Real-World Response To Anti-Eosinophil Biologics For Severe Eosinophilic Asthma

GINA guidelines indicate use of biologics for uncontrolled severe asthma patients. Targeted anti-eosinophil biologic therapies have been studied in clinical trials and FDA-approved for severe eosinophilic asthma. We sought to evaluate our “real-world” experience on their efficacy in improving asthma control.

Underuse of Biomarkers May Contribute to an Inability to Phenotype Severe Uncontrolled Asthma Patients and Diminish Oral Corticosteroid Burden

Underuse of Biomarkers May Contribute to an Inability to Phenotype Severe Uncontrolled Asthma Patients and Diminish Oral Corticosteroid Burden

Development of a Tool to Measure the Clinical Response to Biologic Therapy in Uncontrolled Severe Asthma: The FEV1, Exacerbations, Oral Corticosteroids, Symptoms Score

There is a lack of tools to quantify the response to monoclonal antibodies (mAbs) holistically in severe uncontrolled asthma patients. To develop a valid score to assist specialists in this clinical context. The score was developed in four subsequent phases: (1) elaboration of the theoretical model of the construct intended to be measured (response to mAbs); (2) definition and selection of items and measurement instruments by Delphi survey; (3) weight assignment of the selected items by multicriteria decision analysis using the Potentially All Pairwise RanKings of All Possible Alternatives methodology using the 1000minds software; and (4) face validity assessment of the obtained score. Four core items, with different levels of response for each, were selected: severe exacerbations, oral corticosteroid use, symptoms (evaluated by Asthma Control Test), and bronchial obstruction (assessed by FEV1 percent predicted). Severe exacerbations and oral corticosteroid maintenance dose were weighted most heavily (38% each), followed by symptoms (13%) and FEV1 (11%). Higher scores in the weighted system indicate a better response and the range of responses runs from 0 (worsening) to 100 (best possible response). Face validity was high (intraclass correlation coefficient of 0.86). The FEV1, exacerbations, oral corticosteroids, symptoms score allows clinicians to quantify response in severe uncontrolled asthma patients who are being treated with mAbs.

PRS16 Results of the Hercules Study: Economic Evaluation of the Healthcare Resources Utilization and Description of the Patient with Severe Uncontrolled Asthma in Italy Based on Real-World DATA

Severe asthma is a subtype of asthma that is difficult to treat and control. It affects 5-10% of patient with asthma and has an important burden on healthcare systems. The analysis of the disease through real-world data is a fundamental tool for knowing and managing these critical issues. Based on national real-world data (SANI national registry, Severe Asthma Network in Italy), a cross-sectional observational study was developed to describe characteristics, treatment patterns, morbidity, co-morbidity, the healthcare resource utilization and costs of uncontrolled severe asthma patients in Italy. Data extracted were processed, analyzed and economically valued. Finally, the mean annual cost per patient, not including the therapies, and the mean cost per patient associated with treatments were obtained to estimate the economic impact of the disease on the NHS. The study included and analyzed data of 459 patients with severe uncontrolled asthma, according to the ERS/ATS classification. The main demographic and clinical characteristics of the population were described, and the economic impact of the disease were analyzed trough the valorization of the health care resources related to visits, diagnostic tests, comorbidities management, therapies and quality of life. The mean annual cost per patient, not including therapies, was estimated at € 5,331. Regarding the mean annual cost per patient of the therapies, it was equal to a maximum of respectively € 138 for rhinitis therapy, € 383 for oral therapy, €469 for inhalation therapy, €960 for immunotherapy, and €17.182 for monoclonal antibodies. This study provided real-world data about the patient with severe uncontrolled asthma in Italy, making possible clinical and economic assessments relating to the management of the disease.

Prevalence, disease burden, and treatment reality of patients with severe, uncontrolled asthma in Japan

BackgroundThe severe asthma and severe, uncontrolled asthma (SUA) populations in Japan are not well-studied. We investigated the prevalence of continuously treated severe asthma and SUA patients, their disease burden, and the treatment reality via a Japanese health insurance claims database. MethodsContinuously treated asthma patients (patients prescribed inhaled corticosteroids for asthma ≥4 times in the past year) aged ≥17 years at the index date (latest visit between April 2014 and March 2015 for asthma treatment) were included in this analysis (KEIFU study, UMIN000027695). Asthma severity and control status at the index date were defined using modified criteria of ERS/ATS guidelines. Asthma hospitalization, oral corticosteroid (OCS) use, and total medical expenses were calculated using data up to 12 months post–index date. ResultsWe identified 10,579 patients as continuously treated asthma patients. Of these, 823 (7.8%) had severe asthma; 267 (2.5%) and 556 (5.3%) patients had SUA and severe, controlled asthma (SCA), respectively. Compared with SCA and mild to moderate asthma patients, a greater percentage of SUA patients required hospitalization (13.7%, 6.2%, and 3.0%, respectively) and were prescribed OCSs (67.4%, 45.9%, and 16.2%, respectively). Yearly total medical expenses were also greater for SUA patients (mean [standard deviation]: 8346 [12,280], vs 5989 [10,483] and 3422 [8800] USD, respectively). ConclusionsThe percentages of severe asthma and SUA patients continuously treated in Japan were obtained through this large-scale analysis using a health insurance claims database. SUA patients had greater medical and economic burdens, suggesting more appropriate treatment is required according to the treatment guidelines.

FACTORS ASSOCIATED WITH THE INITIATION OF BIOLOGIC DRUGS IN MEDICAID PATIENTS WITH SEVERE UNCONTROLLED ASTHMA

Introduction Severe Uncontrolled asthma is associated with high health care costs, yet guidance is lacking on how early to initiate biologic drugs. Few studies have examined the factors associated with the transition from nonbiologic drugs to biologics. Objective To examine patient sociodemographics, medication use patterns, and clinical characteristics associated with lack of initiation of biologic drugs in the treatment of severe uncontrolled asthma. Methods This was a prospective study using the Wisconsin Medicaid patients that were seen in an entirely Medicaid clinic in an underserved area of Milwaukee, Wisconsin. 31 consecutive Medicaid patients with severe uncontrolled asthma were interviewed. Either a physician or an experienced nurse did all interviews and evaluations. Results Data on 31 consecutive severe uncontrolled asthma (GINA and NAEPP guideline criteria) patients aged 9-76 were included; five were under the age of 12. Average age was 42. On average, ACT score was 17, s2agonists were used 2.3 times a day, FEV1 was 68% predicted, FeNO was 52, and the number of ED visits plus hospitalizations was 4.3 in the year prior to the interview. None of the first 30 patients had ever been offered biologic therapy or bronchial thermoplasty for their asthma even through they are recommended as alternatives in Step 5 GINA guidelines. Conclusions Recognizing these potential problems that drive the initiation of biologics for severe uncontrolled asthma therapy in this patient population, health care providers and Wisconsin Medicaid should take measures to achieve optimal therapy for all severe uncontrolled asthma patients, through shared decision-making.

RItA: The Italian severe/uncontrolled asthma registry.

The Italian severe/uncontrolled asthma (SUA) web-based registry encompasses demographic, clinical, functional, and inflammatory data; it aims to raise SUA awareness, identifying specific phenotypes and promoting optimal care. Four hundred and ninety three adult patients from 27 Italian centers (recruited in 2011-2014) were analyzed. Mean age was 53.8years. SUA patients were more frequently female (60.6%), with allergic asthma (83.1%). About 30% showed late onset of asthma diagnosis/symptoms (>40years); the mean age for asthma symptoms onset was 30.2years and for asthma diagnosis 34.4years. 97.1% used ICS (dose 2000 BDP), 93.6% LABA in association with ICS, 53.3% LTRAs, 64.1% anti-IgE, 10.7% theophylline, and 16.0% oral corticosteroids. Mean FEV1 % pred of 75.1%, median values of 300/mm3 of blood eosinophil count, 323kU/L of serum total IgE, and 24ppb of FENO were shown. Most common comorbidities were allergic rhinitis (62.4%), gastroesophageal reflux (42.1%), sinusitis (37.9%), nasal polyposis (30.2%), and allergic conjunctivitis (30.2%). 55.7% of SUA patients had exacerbations in the last 12months, 9.7% emergency department visits, and 7.3% hospitalizations. Factors associated with exacerbation risk were obesity (OR, 95% CI 2.46, 1.11-5.41), psychic disorders (2.87, 0.89-9.30-borderline), nasal polyps (1.86, 0.88-3.89-borderline), partial/poor asthma treatment adherence (2.54, 0.97-6.67-borderline), and anti-IgE use in a protective way (0.26, 0.12-0.53). Comparisons to severe asthma multicenter studies and available registries showed data consistency across European and American populations. An international effort in the implementation of SUA patients' registries could help to better understand the clinical features and to manage severe asthma, representing a non-negligible socioeconomic burden for health services.

Eligibility for treatment with omalizumab in Italy and Germany

Omalizumab is an add-on therapy for patients with uncontrolled severe allergic asthma. In Europe, patients must fulfil a number of additional criteria to become eligible for omalizumab therapy, creating a challenge for epidemiology studies to quantify the potential patient pool. Thus, and in the absence of robust data, the number of omalizumab-eligible patients has remained unclear. To assess eligible patient numbers, a chart-audit design approach was employed to measure epidemiology variables based on patient-level data. 770 patient charts were reviewed in designated towns in Germany and Italy, in collaboration with >200 primary care physicians (PCPs) and respiratory specialists (RS). This study sample represents >50% and >70% of local RS in these designated towns of Germany and Italy, respectively. Of patient charts evaluated, 4 patients were currently receiving omalizumab. A further 31 patients (12 PCP; 19 RS) were evaluated as omalizumab-eligible (i.e. fulfilled all product label criteria) but were not receiving the drug. Extrapolating to a national level, this yields >6500 eligible patients in Germany, and >3200 in Italy. Furthermore, this study sample revealed a significant number of PCPs treating uncontrolled severe asthma patients without referral to RS; these patients are not consistently evaluated for FEV1, aero-allergen sensitivity, a qualitative understanding of severe exacerbations, and day and night-time symptoms. This study suggests that significant numbers of omalizumab-naïve severe allergic asthma patients in Germany/Italy are eligible for omalizumab therapy. Despite proven benefits in uncontrolled severe allergic asthma, adjunctive omalizumab therapy is underutilized.

Omalizumab Therapy in Severe Asthma: Experience from the Spanish Registry—Some New Approaches

Objective. The efficacy of omalizumab in severe asthma has been widely demonstrated. The main objective of this study was to evaluate the efficacy and tolerability of omalizumab in a real-life setting in Spain, particularly in those patients with immunoglobulin E (IgE) levels out of range. Methods. Totally 266 uncontrolled severe asthma patients receiving high-dose inhaled corticosteroids (ICSs) plus long-acting β2-agonist (LABA) were recruited. Main efficacy outcomes were asthma exacerbation rate (AER), asthma control test (ACT), and global evaluation of treatment effectiveness (GETE). Results. AER was reduced from 3.6 (3.6) in previous year to 0.67 (1.2) at 4 months (p < .05) and to 1.04 (1.8) at 2 years (p < .05). ACT increased significantly from 14.3 (4.7) at baseline to 18.4 (4.4) at 4 months (p < .05) and to 20.3 (4.0) (p < .05) at 2 years. After 4 months, 74.6% of patients had reached a good or excellent rate on the GETE scale (p < .05). This rate continued increasing up to 81.6% at 2 years. These efficacy results were similar for patients with “off-label” IgE > 700 IU/ml. At follow-up, maintenance treatment with oral steroids was discontinued in a considerable number of patients: from 89 to 19 (p < .05). Omalizumab was discontinued because of lack of efficacy only in 28/266 (10.5%) patients. Overall, 30 patients (11.4%) reported adverse events. Severe adverse events were not observed. Conclusion. This real-life study confirms that omalizumab is very efficacious and very well tolerated in patients with uncontrolled severe asthma. Results did not vary in the subgroup of patients with IgE levels >700 IU/ml.

Airway Obstruction Correlates with Collagenase-2 (MMP-8) Expression and Activation in Bronchial Asthma

Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degradation in asthma. The present study analyzed molecular forms and degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients, and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in situ hybridization. Immunohistochemistry and in situ hybridization revealed a prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed, but not in intact bronchial epithelial cells of asthma patients. In BALF cytospins, both MMP-8 protein and mRNA expression were observed in epithelial cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active non-PMN–type forms. BALF MMP-8 was significantly converted to active form only in BALFs from steroid-naive and uncontrolled severe asthma patients, but not in BALFs from well-controlled asthma patients or healthy controls. A significant inverse correlation between BALF MMP-8 levels and FEV1 (r = −0.283, p = 0.04), and BALF activated MMP-8 forms and FEV1(r = −0.427, p = 0.001) was detected. Overall, these data suggest that MMP-8 and its activation has an important role in the airway destruction, healing, remodeling, and treatment response in asthma.