Exacerbations Among Patients With Asthma Are Largely Dependent on the Presence of Multimorbidity.

BACKGROUND AND OBJECTIVE: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. METHODS: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. RESULTS: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. CONCLUSION: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Improvement in Olfaction in Patients With CRSwNP and Severe Asthma Taking Anti-IgE and Anti-IL-5 Biologics: A Real-Life Study.

BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), which is characterized by partial loss of smell (hyposmia) or total loss of smell (anosmia), is commonly associated with asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). CRSwNP worsens disease severity and quality of life. The objective of this real-world study was to determine whether biological treatments prescribed for severe asthma can improve olfaction in patients with CRSwNP. A further objective was to compare the improvement in in olfaction in N-ERD and non-N-ERD subgroups. METHODS: We performed a multicenter, noninterventional, retrospective, observational study of 206 patients with severe asthma and CRSwNP undergoing biological treatment (omalizumab, mepolizumab, benralizumab, or reslizumab). RESULTS: Olfaction improved after treatment with all 4 monoclonal antibodies (omalizumab [35.8%], mepolizumab [35.4%], reslizumab [35.7%], and benralizumab [39.1%]), with no differences between the groups. Olfaction was more likely to improve in patients with atopy, more frequent use of short-course systemic corticosteroids, and larger polyp size. The proportion of patients whose olfaction improved was similar between the N-ERD (37%) and non-N-ERD (35.7%) groups. CONCLUSIONS: This is the first real-world study to compare improvement in olfaction among patients undergoing long-term treatment with omalizumab, mepolizumab, reslizumab, or benralizumab for severe asthma and associated CRSwNP. Approximately 4 out of 10 patients reported a subjective improvement in olfaction (with nonsignificant differences between biologic drugs). No differences were found for improved olfaction between the N-ERD and non-N-ERD groups.

Obesity and Asthma: Key Clinical Questions.

Obesity is a common comorbidity of asthma that is associated not only with development of the disease, but also with poorer disease control and greater severity. Recent prospective evidence supports the idea that body weight gain precedes the development of asthma, although the debate is far from over. The objective of this document is to conduct a systematic review of 3 clinical questions related to asthma and obesity: (a) Obesity and asthma: the chicken or the egg? Clinical insights from epidemiological and phenotyping studies. (b) Is obesity a confounding factor in the diagnosis and management of asthma, especially in severe or difficult-to-control asthma? (c) How do obese asthma patients respond to pharmacological treatments and to biological drugs? Do we have effective specific interventions? Revised epidemiological, pathological, and mechanistic evidence combined with data from interventional clinical trials prevent us from clearly stating that obesity causes asthma. However, the complexity and heterogeneity of both illnesses make several clinical scenarios possible. Furthermore, asthma represents an additional clinical challenge in the obese patient. Physicians need to be aware of the confounding effects created by the more marked perception of symptoms, alterations in lung function, and the various comorbidities that obese persons present. Exhaustive phenotyping of the obese asthma patient should enable us to develop a rational therapeutic plan, including both the pharmacological approach and specific antiobesity therapies such as combining diet and exercise and, in extreme cases, bariatric surgery.

Eosinophil-derived exosomes contribute to asthma remodelling by activating structural lung cells.

BACKGROUND: Eosinophils, a central factor in asthma pathogenesis, have the ability to secrete exosomes. However, the precise role played by exosomes in the biological processes leading up to asthma has not been fully defined. OBJECTIVE: We hypothesized that exosomes released by eosinophils contribute to asthma pathogenesis by activating structural lung cells. METHODS: Eosinophils from asthmatic patients and healthy volunteers were purified from peripheral blood, and exosomes were isolated from eosinophils of asthmatic and healthy individuals. All experiments were performed with eosinophil-derived exosomes from healthy and asthmatic subjects. Epithelial damage was evaluated using primary small airway epithelial cell lines through 2 types of apoptosis assays, that is, flow cytometry and TUNEL assay with confocal microscopy. Additionally, the epithelial repair was analysed by performing wound healing assays with epithelial cells. Functional studies such as proliferation and inhibition-proliferation assays were carried out in primary bronchial smooth muscle cell lines. Also, gene expression analysis of pro-inflammatory molecules was evaluated by real-time PCR on epithelial and muscle cells. Lastly, protein expression of epithelial and muscle cell signalling factors was estimated by Western blot. RESULTS: Asthmatic eosinophil-derived exosomes induced an increase in epithelial cell apoptosis at 24 hour and 48 hour, impeding wound closure. In addition, muscle cell proliferation was increased at 72 hours after exosome addition and was linked with higher phosphorylation of ERK1/2. We also found higher expression of several genes when both cell types were cultured in the presence of exosomes from asthmatics: CCR3 and VEGFA in muscle cells, and CCL26, TNF and POSTN in epithelial cells. Healthy eosinophil-derived exosomes did not exert any effect over these cell types. CONCLUSIONS AND CLINICAL RELEVANCE: Eosinophil-derived exosomes from asthmatic patients participate actively in the development of the pathological features of asthma via structural lung cells.

Biologics in the treatment of severe asthma.

Severe asthma is defined as asthma which requires treatment with high dose inhaled corticosteroids and with a second controller drug to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy. Patients with uncontrolled severe asthma require additional treatment options as add-on therapy, including biologics. Biologic therapies in asthma are designed to block key immune regulators, such as IgE, or certain pro-inflammatory cytokines, e.g. interleukin (IL)-5, IL-4, IL-13 or IL-17. Patients with severe asthma and eosinophilic phenotype may benefit from biologic therapies aimed at reducing blood and tissue eosinophils, such as mepolizumab, reslizumab and benralizumab. Patients with Th2-high phenotype may also benefit from therapy with anti-IL-4/anti-IL-13 monoclonal antibodies (dupilumab). The main limitations of asthma treatment with biologic agents are the crossover and overlap of the different pathways in the pathogenesis of asthma which may cause lack of complete success of these therapies, in addition of high costs, which make pharmacoeconomic studies necessary to identify the ideal target patient population to receive these biologic drugs.

Asthma exacerbations in a tertiary hospital: clinical features, triggers, and risk factors for hospitalization.

BACKGROUND: Risk factors for asthma exacerbations are not fully understood. The aim of this study was to determine the epidemiological and clinical characteristics of patients with an asthma exacerbation, potential triggers, and possible predictors of hospitalization. METHODS: A retrospective, non-interventional cohort study was conducted in adult patients who attended the Emergency Department of a tertiary hospital with an asthma exacerbation during 2014. RESULTS: 831 patients (888 events) were included. The highest number of episodes occurred in January and May. Respiratory infection was considered the trigger in 523 events. 34.21% had ≥260 eosinophils/mm3 (20.7%≥400 eosinophils/mm3), significantly associated with allergic asthma (p<0.0001). Risk factors for hospitalization were: older age [OR:1.58 (95% CI 1.46-1.71)]; no previous diagnosis of asthma [OR:1.40(95% CI 1.06-1.86)]; poorly controlled asthma[OR:1.78 (95% CI 1.10-2.88)]; respiratory infection [OR:2.65 (95% CI 1.95-3.62)]; and severe crisis with more treatment requirements. Of those asthmatics with ≥400 eosinophils/mm3, the rate of hospitalization was lower (p<0.001). CONCLUSION: Older age, absence of a previous asthma diagnosis, uncontrolled disease or concomitant COPD are frequent among patients presenting to the ED with asthma exacerbations. There were some features associated with higher risk of admission. Blood eosinophilia should be considered as a marker of asthma, but not as a predictor of hospitalization.

Sputum periostin in patients with different severe asthma phenotypes.

BACKGROUND: Identifying inflammatory phenotypes is relevant in severe uncontrolled asthma. The aim of this study was to identify the different clinical, inflammatory, functional, and molecular phenotypes in patients with severe asthma and to investigate the potential role of sputum periostin as a biomarker of severe asthma phenotypes. PATIENTS AND METHODS: Sputum induction was performed in 62 patients diagnosed with severe asthma. Skin prick testing, lung function tests, exhaled nitric oxide, hematimetry, and total serum IgE were performed. Periostin was measured in sputum supernatants. RESULTS: Patients with asthma were phenotyped and 80% had late-onset asthma, 50% had fixed airflow obstruction, and 66% showed a Th2-high phenotype. With respect to inflammatory phenotypes, 71% were eosinophilic and 25% mixed granulocytic. Periostin levels were higher in patients with fixed as compared to variable airflow limitation (69.76 vs 43.84 pg/ml, P < 0.05) and in patients with eosinophilic as compared to mixed granulocytic phenotype (61.58 vs 37.31 pg/ml, P < 0.05). There was an inverse correlation between postbronchodilator FEV1 /FVC and periostin levels (-0.276, P < 0.05). CONCLUSION: This study demonstrates the utility of periostin in phenotyping severe asthma. Periostin levels in sputum are associated with persistent airflow limitation in asthma patients with airway eosinophilia despite treatment with high-dose inhaled corticosteroids.

Anticholinergics for treatment of asthma.

Asthma management guidelines emphasize the importance of effective treatment to achieve and maintain control of asthma. However, despite widely available and effective treatments, achieving control of asthma is still an unmet need for many patients. Adding a second bronchodilator with a different mechanism of action for the treatment of uncontrolled asthma can be a suitable therapeutic approach. This review focuses on the role of long-acting muscarinic antagonists, particularly tiotropium, in the treatment of asthma. A number of studies have evaluated the efficacy and safety of tiotropium in asthma patients whose disease is poorly controlled with inhaled corticosteroids (ICSs) with or without long-acting ß2-agonists (LABAs). The effect on several clinical and lung function variables of adding tiotropium to an ICS is greater than doubling the dose of the latter and is not inferior to the addition of a LABA (salmeterol). Studies assessing the role of tiotropium as add-on therapy to ICS combined with a LABA have shown modest but clinically significant and dose-dependent improvements in forced expiratory volume in 1 second, as well as a decrease in the risk of exacerbations. In addition, time to the next episode is longer, particularly in patients who experience severe exacerbations. In conclusion, tiotropium proved noninferior to salmeterol and superior to placebo in patients with moderate-severe asthma who were not adequately controlled using ICSs or ICSs combined with a LABA. The major benefits are the increase in lung function and, in the case of severe asthma, the reduction in the frequency of exacerbations. In patients with asthma, tiotropium is usually well tolerated, and no potential safety signals have been observed.

Bendamustine as salvage treatment for patients with relapsed or refractory mantle cell lymphoma patients: a retrospective study of the Spanish experience.

Patients with mantle cell lymphoma (MCL) have an adverse outcome after relapse. Bendamustine has demonstrated a good efficacy and toxicity profile in previously reported trials. In this study, we present a retrospective analysis of the Spanish experience in relapsed/refractory MCL treated with bendamustine in combination or alone with the objective of knowing the efficacy and toxicity profile of this treatment in our current clinical practice. Fifty eight patients were registered: 67 % male with median age of 71 years, and 2 is the median number of previous lines. The most frequent bendamustine regimen was bendamustine plus rituximab (83 %). The median number of cycles was 5 (range 1-8). The overall response rate was 84 % with 53 % of complete response/unconfirmed complete response (CR/uCR). Median progression-free survival (PFS) was 16 months (95 % confidence interval (CI) 13.3-18.8), and for patients who achieved CR/uCR, it was 33 months (95 % CI 11.1-54.2). Median overall survival (OS) was 30 months (95 % CI 25.6-34.9). For PFS, only blastoid histology and not achieving CR after bendamustine had a significant negative impact on the univariate and multivariate analyses (p < 0.05). Nevertheless, for OS, only an elevated lactate dehydrogenase (LDH) had negative impact on both, univariate and multivariate analyses (p < 0.05). Only one case of treatment-related mortality in a 79-year-old patient with very bad performance status was reported. In 280 cycles, 12 (4 %) hospitalizations for febrile neutropenia were reported. In our population, bendamustine has been a good salvage treatment with a favorable toxicity profile in a non selected and heavily pretreated population of patients with MCL.

PSMA PET/CT quick procedure guide.

The application of PET/CT with radiopharmaceuticals targeting PSMA is significantly transforming the diagnostic and therapeutic strategies of patients with prostate cancer. In Spain, the availability and access to positron-emitting radiopharmaceuticals targeting Prostate-Specific Membrane Antigen (PSMA) have significantly changed in recent months. These changes are affecting their use in diagnostic procedures. As a result, its use within diagnostic protocols for patients with prostate cancer is undergoing significant modifications. In this collective and cooperative document, the authors have selected the most robust evidence accumulated to date to generate a clinical guide to achieve appropriate use of this technology. A format that presents the most frequent clinical situations and the patient profiles in which PSMA PET/CT plays a significant role or will do so in the immediate future has been chosen. It should be taken into account that regulatory restrictions mediate the current indications for its use in Spain, as well as its current cost and the production capacity of radiopharmaceuticals. The guideline presents a review of the established methodology for optimized imaging with each of the radiopharmaceutical variants targeting PSMA and recommendations for structured and accurate reporting of metabolic findings in combination with CT.

Phenotypes and endotypes of uncontrolled severe asthma: new treatments.

Severe asthma is a heterogeneous disease that affects only 5%-10% of asthmatic patients, although it accounts for a significant percentage of the consumption of health care resources. Severe asthma is characterized by the need for treatment with high doses of inhaled corticosteroids and includes several clinical and pathophysiological phenotypes. To a large extent, this heterogeneity restricts characterization of the disease and, in most cases, hinders the selection of appropriate treatment. In recent years, therefore, emphasis has been placed on improving our understanding of the various phenotypes of severe asthma and the identification of biomarkers for each of these phenotypes. Likewise, the concept of the endotype has been gaining acceptance with regard to the various subtypes of the disease, which are classified according to their unique functional or pathophysiological mechanism. This review discusses the most relevant aspects of the clinical and inflammatory phenotypes of severe asthma, including severe childhood asthma and the various endotypes of severe asthma. The main therapeutic options available for patients with uncontrolled severe asthma will also be reviewed.