Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients.

BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.

Clinical and functional characteristics, possible causes, and impact of chronic cough in patients with cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome (CANVAS).

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is an hereditary autosomal recessive disease. Recent studies propose including chronic cough (CC) as a symptom of CANVAS. For 10 patients with CANVAS as genetically confirmed by biallelic expansion of the AAGG repeat motif (AAGGGexp) in intron 2 of replication factor C subunit 1 (RFC1), our aim was, as a multidisciplinary team, to describe clinical and functional characteristics and possible causes of CC following European Respiratory Society (ERS) recommendations, and to evaluate CC impact on quality of life (QoL) using self-administered questionnaires (Cough Severity Diary, Leicester Cough Questionnaire, Discrete Emotions Questionnaire, and EQ-5D-5L). In all 10 patients, the CC was a dry cough that developed several years prior to the neurological symptoms (mean 14.2 years); 7 patients had symptoms compatible with gastroesophageal reflux (GER), 5 with pathological GER diagnosed by 24-h esophageal pH testing, and 6 patients had impaired esophageal motility diagnosed by high-resolution esophageal manometry, most frequently ineffective peristalsis. Although further studies are required for confirmation, we conclude that CC may be a characteristic prodrome of CANVAS and may be related to GER and esophageal disorders. Furthermore, CC affects patients' QoL, especially in the psychosocial sphere.

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

INTRODUCTION: Adding LAMA to LABA/ICS is recommended to improve control in patients with persistent asthma. METHODS: 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. RESULTS: 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. CONCLUSIONS: TT reduced asthma exacerbations, improved lung function and reduced healthcare costs vs. DT, particularly in patients requiring systemic corticosteroids to treat severe exacerbations.

Chronic rhinosinusitis with nasal polyps and allergic rhinitis as different multimorbid treatable traits in asthma.

Background: Respiratory multimorbidities are linked to asthma, such as allergic rhinitis (AR) with early allergic asthma and chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) with late nonallergic asthma. Objective: Our aim was to investigate the association of asthma severity and control with specific upper airway phenotypes. Method: Patients with asthma were prospectively recruited from 23 pulmonology and ear, nose, and throat clinics. Asthma severity and control, as well as upper airway comorbidities (AR and non-AR [NAR], CRSwNP, and CRS without nasal polyps [CRSsNP]) were assessed according to international consensus guidelines definitions. Results: A total of 492 asthmatic patients were included. Half of the asthmatic patients (49.6%) had associated rhinitis (37.0% had AR and 12.6% had NAR) and 36.2% had CRS (16.7% had CRSsNP and 19.5% had CRSwNP), whereas 14.2% had no sinonasal symptoms. Most cases of AR (78%) and NAR (84%) were present in patients with mild-to-moderate asthma, whereas CRSwNP was more frequent in patients with severe asthma (35% [P < .001]), mainly nonatopic asthma (44% [P < .001]). Patients with severe asthma with CRSwNP had worse asthma control, which was correlated (r = 0.249 [P = .034]) with sinus occupancy. Multiple logistic regression analysis showed that late-onset asthma, intolerance of aspirin and/or nonsteroidal anti-inflammatory drugs, and CRSwNP were independently associated with severe asthma. Conclusion: Severe asthma is associated with CRSwNP, with sinus occupancy affecting asthma control. This study has identified 2 main different upper airway treatable traits, AR and CRSwNP, which need further evaluation to improve management and control of patients with asthma.

Efficacy and Potential Positioning of Tezepelumab in the Treatment of Severe Asthma.

The excellent results for monoclonal antibodies in the treatment of severe uncontrolled asthma (SUCA) represent a milestone in current treatment of asthmatic disorders. Remaining, however, are several subsidiary areas for improvement in which new biologics are expected to make a decisive contribution. These biologics include tezepelumab, a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-release cytokine (alarmin) that plays a key role in initiating both the innate (group 2 innate lymphoid cell (ILC) pathway) and the acquired (T helper 2 (Th2) pathway) immune responses by activating the type 2 (T2) asthma inflammatory pathway through both. It is also thought that it may additionally intervene in the neutrophilic non-T2 inflammatory pathway (via interaction with ILC3 and interleukin-17). Six clinical trials that included 2187 patients with uncontrolled asthma, with 2 or more exacerbations in the previous year, on medium/high-dose inhaled corticosteroids and at least 1 other controller, have demonstrated - irrespective of T2 endotype (and possibly also non-T2 endotype) - the efficacy and safety of tezepelumab, as it significantly reduces exacerbations (61.7%-66%) and bronchial hyperresponsiveness, and improves lung function, disease control, and quality of life. Tezepelumab could be indicated for the treatment of patients with, independently of the T2 phenotype (eosinophilic and non-eosinophilic), and may even be the only biologic available for treatment of non-T2 SUCA.

Los excelentes resultados de los anticuerpos monoclonales en el tratamiento del asma grave no controlada (AGNC) constituyen un hito en el tratamiento actual de los trastornos asmáticos. Sin embargo, aún quedan varios aspectos complementarios susceptibles de mejorar para los que se esperan contribuciones decisivas de los nuevos biofármacos, entre los cuales se encuentra el tezepelumab, un anticuerpo monoclonal que bloquea la linfopoyetina estromal tímica (TSLP). La TSLP es una citocina de liberación epitelial (alarmina) que desempeña una función clave en el inicio de las respuestas inmunitarias tanto innata (vía de las células linfocíticas innatas [ILC] del grupo 2) como adaptativa (vía de los linfocitos T cooperadores 2 [Th2]), activando la vía inflamatoria del asma del tipo 2 (T2) mediante ambas. También se cree que puede intervenir en la vía inflamatoria neutrofílica con T2 baja (mediante la interacción con los ILC3 y la interleucina 17). En seis ensayos clínicos que incluyeron a 2.187 pacientes con asma no controlada, dos o más exacerbaciones en el año anterior, a tratamiento con corticosteroides inhalados en dosis medias o altas y con un mínimo de un tratamiento preventivo adicional, se ha demostrado la eficacia y seguridad del tezepelumab sin importar el endotipo T2 (y posiblemente tampoco el endotipo no T2), ya que reduce significativamente las exacerbaciones (61,7-66%) y la hiperreactividad bronquial y mejora la función pulmonar, el control de la enfermedad y la calidad de vida. El tezepelumab puede estar indicado para tratar a pacientes con asma grave, independientemente del fenotipo T2 (eosinofílico y no eosinofílico), y tal vez sea incluso el único biofármaco existente para el tratamiento del AGNC no T2.

[A Study of the Prevalence of Asthma in the General Population in Spain]. / Estudio de prevalencia de asma en población general en España.

Introduction: Asthma is a disease with high prevalence, which affects all age groups and generates high health and social care costs. Studies carried out in a number of populations show great variability in its prevalence, even in geographically close populations, with data suggesting a relevant influence of socio-economic factors. At present, we do not have reliable data on the prevalence of this disease in the adult population of Spain. The objectives of this study are to estimate the prevalence of asthma in the Spanish population for those aged 18-79, to describe the variability between autonomous communities, to estimate the prevalence of under and overdiagnosis, to analyse the prevalence of uncontrolled asthma and steroid-dependent asthma, to evaluate the health care cost, to identify the most frequent phenotypes and to establish a starting point to evaluate the temporal trend with subsequent studies. Methods: A cross-sectional, two-stage study will be carried out, including patients from 50 catchment areas. The study will be carried out in 3 phases: 1) screening and confirmation in the clinical history, in which patients with a previously correctly established diagnosis of asthma will be identified; 2) diagnosis of asthma to evaluate patients without a confirmed or excluded diagnosis; 3) characterization of asthma, where the characteristics of the asthmatic patients will be analysed, identifying the most frequent phenotypes. Discussion: It seems necessary and feasible to carry out an epidemiological study of asthma in Spain to identify the prevalence of asthma, to optimize healthcare planning, to characterize the most frequent phenotypes of the disease, and to evaluate inaccurate diagnoses.

Disposition of Work-Related Asthma in a Spanish Asthma Cohort: Comparison of Asthma Severity Between Employed and Retired Workers.

BACKGROUND: Exposure to certain agents in the workplace can trigger occupational asthma or work-exacerbated asthma, both of which come under the heading of work-related asthma (WRA). Understanding the burden that WRA represents can help in the management of these patients. OBJECTIVE: To assess the influence of occupation on asthma in real life and analyze the characteristics of patients with WRA included in an asthma cohort. METHODS: This was a prospective multicenter study of a cohort of consecutive patients with asthma. A standardized clinical history was completed. Patients were classified as having WRA or non-WRA. All patients underwent respiratory function tests, FeNO test, and methacholine challenge (methacholine concentration that causes a 20% drop in FEV1) at the beginning of the study. They were classified into two groups, depending on their employment status: employed (group 1) or unemployed (group 2). RESULTS: Of the 480 patients included in the cohort, 82 (17%) received the diagnosis of WRA. Fifty-seven patients (70%) were still working. Mean age (SD) was 46 (10.69) years in group 1 and 57 (9.91) years in group 2 (P < .0001). Significant differences were observed in adherence to treatment (64.9% in group 1 vs 88% in group 2; P = .0354) and in severe asthma exacerbations (35.7% in group 1 vs 0% in group 2; P = .0172). No significant differences were observed in the rest of the variables analyzed. CONCLUSIONS: The burden of WRA in specialized asthma units is not negligible. The absence of differences in the severity of asthma, the treatment administered, alterations in lung function, and the number of exacerbations in those working versus not working may support the idea that advice regarding changing jobs should be customized for individual patients.

The ATLAS ASMA Study: Assessing the Impact of Asthma on Patients' Life - The Spanish Patients' Perspective.

Purpose: ATLAS ASMA described the psychosocial impact of asthma on patients' daily life from patients' perspectives (in terms of impaired personal and intimate relationships, sleep quality, leisure time, daily activities, and others) in Spain. Secondary objective includes description of time since diagnosis, expectations, and satisfaction of patients about disease, treatment and medical assistance received, adherence to treatment, perceived control of asthma, and health-related quality of life. Patients and Methods: This was a cross-sectional, observational study, based on a self-administered online survey for adult patients (≥18 years) with asthma. Patients with asthma diagnosis of any type and severity who voluntarily participated in the survey through a web link were included consecutively. In the present manuscript, only adult patients' data are included. Results: A total of 132 adults with asthma were included. Moderate/severe asthma constituted 59.1% of the patients (females 71.2%). Overall, most relevant areas affected due to asthma were leisure activities (67.0%) and the quality/quantity of sleep (52.3%). Moderate/severe patients perceived some degree of impairment in work, school, or at home due asthma more frequently vs mild patients (55.2% vs 10.9%). Poorly controlled asthma (ACT≤19) was reported in 41 (70.7%) and 10 (21.7%) moderate/severe and mild patients (p<0.000), respectively. Mild patients obtained higher mean (SD) Mini-AQLQ score than moderate/severe asthma patients (5.6 [1.0] vs 4.3 [1.1], p<0.000), likewise higher significant results for every individual dimension. Most patients cited little limitation to intense efforts (20.5%). Half of the patients mentioned needing more information about asthma. Topics those patients like to have more information were difficulties that may can have and legal topics (78.6%), asthma evolution (78.6%), secondary effects or issues related to the treatment (61.9%) and legal topics (61.9%). Conclusion: The study reported important insights on psychosocial impact of asthma on patients' daily life from patients' perspectives along with health determinants in asthma-related health outcomes, sociodemographic and psychosocial factors.

Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.

Clinical Impact of Electronic Monitoring Devices of Inhalers in Adults with Asthma or COPD: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to gain insight into the characteristics and clinical impact of electronic monitoring devices of inhalers (EMDs) and their clinical interventions in adult patients with asthma or COPD. The search included PubMed, Web of Science, Cochrane, Scopus and Embase databases, as well as official EMDs websites. We found eight observational studies and ten clinical trials, assessing a wide range of clinical outcomes. Results from the meta-analysis on adherence to inhalers in a period over three months were favourable in the EMD group (fixed effects model: SMD: 0.36 [0.25-0.48]; random effects model SMD: 0.41 [0.22-0.60]). An exploratory meta-analysis found an improvement in ACT score (fixed effect model SMD: 0.25 [0.11-0.39]; random effects model: SMD: 0.47 [-0.14-1.08]). Other clinical outcomes showed mixed results in the descriptive analyses. The findings of this review highlight the benefits of EMDs in the optimization of adherence to inhaled therapy as well as the potential interest in other clinical outcomes.

Identification of Asthma Phenotypes in the Spanish MEGA Cohort Study Using Cluster Analysis.

INTRODUCTION: The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes. METHODS: We performed a multicentre prospective cohort study, including adult patients with asthma (N=512) from the MEGA study (Mechanisms underlying the Genesis and evolution of Asthma). A standardised clinical history was completed for each patient. Cluster analysis was performed using the kernel k-groups algorithm. RESULTS: Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities. CONCLUSION: We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps.

Characteristics of Induced-Sputum Inflammatory Phenotypes in Adults with Asthma: Predictors of Bronchial Eosinophilia.

Purpose: The objectives of this study were, for patients attending a specialist asthma clinic at a tertiary care hospital, to determine, from sputum induction (SI), proportions of bronchial inflammatory phenotypes, demographic, clinical and functional characteristics of each phenotype, and the most accessible non-invasive inflammatory marker that best discriminates between phenotypes. Patients and Methods: Included were 96 patients with asthma, attending a specialist asthma clinic at a tertiary care hospital, who underwent testing as follows: SI, spirometry, fractional exhaled nitric oxide (FeNO), blood eosinophilia, total immunoglobulin E (IgE), and a skin prick test. Results: SI phenotypes were 46.9% eosinophilic, 33.3% paucigranulocytic, 15.6% neutrophilic, and 4.2% mixed. No significantly different clinical or functional characteristics were observed between the phenotypes. A positive correlation was observed between SI eosinophilia and both emergency visits in the last 12 months (p = 0.041; r = 0.214) and FeNO values (p = 0.000; r = 0.368). Blood eosinophilia correlated with SI eosinophilia (p = 0.001; r = 0.362) and was the best predictor of bronchial eosinophilia, followed by FeNO, and total blood IgE (area under the receiver operating characteristic curve (AUC-ROC) 72%, 65%, and 53%, respectively), although precision was only fair. Conclusion: In consultations for severe asthma, the most frequent phenotype was eosinophilic. Peripheral blood eosinophilia is a reliable marker for discriminating between different bronchial inflammatory phenotypes, is useful in enabling doctors to select a suitable biologic treatment and so prevent asthma exacerbation, and is a better predictor of bronchial eosinophilia than FeNO and IgE values.

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.