Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Differences in acoustic features of cough by pneumonia severity in patients with COVID-19: a cross-sectional study.

Background: Acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) is characterised by heterogeneous levels of disease severity. It is not necessarily apparent whether a patient will develop severe disease or not. This cross-sectional study explores whether acoustic properties of the cough sound of patients with coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV-2, correlate with their disease and pneumonia severity, with the aim of identifying patients with severe disease. Methods: Voluntary cough sounds were recorded using a smartphone in 70 COVID-19 patients within the first 24 h of their hospital arrival, between April 2020 and May 2021. Based on gas exchange abnormalities, patients were classified as mild, moderate or severe. Time- and frequency-based variables were obtained from each cough effort and analysed using a linear mixed-effects modelling approach. Results: Records from 62 patients (37% female) were eligible for inclusion in the analysis, with mild, moderate and severe groups consisting of 31, 14 and 17 patients respectively. Five of the parameters examined were found to be significantly different in the cough of patients at different disease levels of severity, with a further two parameters found to be affected differently by the disease severity in men and women. Conclusions: We suggest that all these differences reflect the progressive pathophysiological alterations occurring in the respiratory system of COVID-19 patients, and potentially would provide an easy and cost-effective way to initially stratify patients, identifying those with more severe disease, and thereby most effectively allocate healthcare resources.

Challenges for asthma units in response to COVID-19: a qualitative group dynamics analysis.

OBJECTIVE: To develop a set of recommendations for the management of severe asthma during COVID-19 pandemic. METHODS: Eleven pneumologists and allergologists who were staff members of officially accredited asthma units in Catalonia (Spain) participated in a cross-section study based on three 2-hour virtual workshops (first: brainstorming, second: identification of impacts and challenges summarized in 10 topics, third: establishment of final recommendations by consensus). RESULTS: Impacts and challenges identified were improvement of referral protocols between different levels of care; assessment of the minimum number of function tests to be performed and promote the performance of spirometry in primary care; implementation of videoconferencing, mobile apps, telephone calls, or integral virtual platforms for the follow-up of patients, and definition of the model of care (face-to-face, telematics, mixed) according to the patient's individual needs; self-administration of biologics for domiciliary treatment; and empowerment of the role of nursing and hospital pharmacy in particular for follow-up and self-administration of biologics. The main recommendations included coordination between primary care and specialized care consultation, optimization of lung function testing, implementation of telemedicine, and the role of nursing and hospital pharmacy. CONCLUSION: The specific proposals in response to the effect of COVID-19 pandemic focused on four areas of interest (coordination between primary care and specialized care, optimization of lung function testing, implementation of telemedicine, and empowerment of the role of nursing and hospital pharmacy) may be generalized to other health care settings, and help to introduce new ways of caring asthma patients in the COVID-19 context.

Respiratory muscle senescence in ageing and chronic lung diseases.

Ageing is a progressive condition that usually leads to the loss of physiological properties. This process is also present in respiratory muscles, which are affected by both senescent changes occurring in the whole organism and those that are more specific for muscles. The mechanisms of the latter changes include oxidative stress, decrease in neurotrophic factors and DNA abnormalities. Ageing normally coexists with comorbidities, including respiratory diseases, which further deteriorate the structure and function of respiratory muscles. In this context, changes intrinsic to ageing become enhanced by more specific factors such as the impairment in lung mechanics and gas exchange, exacerbations and hypoxia. Hypoxia in particular has a direct effect on muscles, mainly through the expression of inducible factors (hypoxic-inducible factor), and can result in oxidative stress and changes in DNA, decrease in mitochondrial biogenesis and defects in the tissue repair mechanisms. Intense exercise can also cause damage in respiratory muscles of elderly respiratory patients, but this can be followed by tissue repair and remodelling. However, ageing interferes with muscle repair by tampering with the function of satellite cells, mainly due to oxidative stress, DNA damage and epigenetic mechanisms. In addition to the normal process of ageing, stress-induced premature senescence can also occur, involving changes in the expression of multiple genes but without modifications in telomere length.

Asma leve y exacerbaciones de riesgo vital: ¿es hora de que demos un paso adelante? / Mild Asthma and Life-Threatening Exacerbations: Is it Time to Take Action?

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Estudio descriptivo sobre la influencia de la metodología en la medición de la fuerza inspiratoria máxima en nariz (SNIP) en población sana / Descriptive Study of the Effect of Methodology in the Measurement of Sniff Nasal Inspiratory Pressure (SNIP) in a Healthy Population

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Sex differences in function and structure of the quadriceps muscle in chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) is a complex disorder with extrapulmonary manifestations. Even though there is some knowledge regarding sex differences in the lung disease, little is known about extrapulmonary manifestations. Our aim was to analyze the specific profile of muscle dysfunction, structure, and biology in COPD women. Twenty-one women and 19 men with stable COPD as well as 15 controls were included. Nutritional status, physical activity, lung and muscle function, exercise capacity, and quality of life were assessed. In addition, blood, breath condensate, and quadriceps muscle samples were tested for inflammatory markers. Moreover, fiber phenotype, signs of damage-regeneration, and the expression of key genes linked to myogenesis and inflammation were assessed in the muscle. Inflammatory markers were increased in all body compartments but no correlation was found among them. Muscle dysfunction was present in both COPD groups but was more marked in women. The opposite occurred with the increase in the percentage of type II fibers that was lower in women despite a similar level of airway obstruction as in men. Female COPD also showed higher signs of muscle damage than COPD men who, in contrast, exhibited slightly higher signs of regeneration. We conclude that sex influences muscle phenotype and function in COPD.

Quadriceps muscle weakness and atrophy are associated with a differential epigenetic profile in advanced COPD.

Epigenetic mechanisms regulate muscle mass and function in models of muscle dysfunction and atrophy. We assessed whether quadriceps muscle weakness and atrophy are associated with a differential expression profile of epigenetic events in patients with advanced COPD (chronic obstructive pulmonary disease). In vastus lateralis (VL) of sedentary severe COPD patients (n=41), who were further subdivided into those with (n=25) and without (n=16) muscle weakness and healthy controls (n=19), expression of muscle-enriched miRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), growth and atrophy signalling markers, total protein and histone acetylation, transcription factors, small ubiquitin-related modifier (SUMO) ligases and muscle structure were explored. All subjects were clinically evaluated. Compared with controls, in VL of all COPD together and in muscle-weakness patients, expression of miR-1, miR-206 and miR-27a, levels of lysine-acetylated proteins and histones and acetylated histone 3 were increased, whereas expression of HDAC3, HDAC4, sirtuin-1 (SIRT-1), IGF-1 (insulin-like growth factor-1) were decreased, Akt (v-akt murine thymoma viral oncogene homologue 1) expression did not differ, follistatin expression was greater, whereas myostatin expression was lower, serum reponse factor (SRF) expression was increased and fibre size of fast-twitch fibres was significantly reduced. In VL of severe COPD patients with muscle weakness and atrophy, epigenetic events regulate muscle differentiation rather than proliferation and muscle growth and atrophy signalling, probably as feedback mechanisms to prevent those muscles from undergoing further atrophy. Lysine-hyperacetylation of histones may drive enhanced protein catabolism in those muscles. These findings may help design novel therapeutic strategies (enhancers of miRNAs promoting myogenesis and acetylation inhibitors) to selectively target muscle weakness and atrophy in severe COPD.

Oxidative stress, redox signaling pathways, and autophagy in cachectic muscles of male patients with advanced COPD and lung cancer.

Muscle dysfunction and wasting are predictors of mortality in advanced COPD and malignancies. Redox imbalance and enhanced protein catabolism are underlying mechanisms in COPD. We hypothesized that the expression profile of several biological markers share similarities in patients with cachexia associated with either COPD or lung cancer (LC). In vastus lateralis of cachectic patients with either LC (n=10) or advanced COPD (n=16) and healthy controls (n=10), markers of redox balance, inflammation, proteolysis, autophagy, signaling pathways, mitochondrial function, muscle structure, and sarcomere damage were measured using laboratory and light and electron microscopy techniques. Systemic redox balance and inflammation were also determined. All subjects were clinically evaluated. Compared to controls, in both cachectic groups of patients, a similar expression profile of different biological markers was observed in their muscles: increased levels of muscle protein oxidation and ubiquitination (p<0.05, both), which positively correlated (r=0.888), redox-sensitive signaling pathways (NF-κB and FoxO) were activated (p<0.05, all), fast-twitch fiber sizes were atrophied, muscle structural abnormalities and sarcomere disruptions were significantly greater (p<0.05, both). Structural and functional protein levels were lower in muscles of both cachectic patient groups than in controls (p<0.05, all). However, levels of autophagy markers including ultrastructural autophagosome counts were increased only in muscles of cachectic COPD patients (p<0.05). Systemic oxidative stress and inflammation levels were also increased in both patient groups compared to controls (p<0.005, both). Oxidative stress and redox-sensitive signaling pathways are likely to contribute to the etiology of muscle wasting and sarcomere disruption in patients with respiratory cachexia: LC and COPD.

Do epigenetic events take place in the vastus lateralis of patients with mild chronic obstructive pulmonary disease?

Muscle dysfunction is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Several biological mechanisms including epigenetic events regulate muscle mass and function in models of muscle atrophy. Investigations conducted so far have focused on the elucidation of biological mechanisms involved in muscle dysfunction in advanced COPD. We assessed whether the epigenetic profile may be altered in the vastus lateralis of patients with mild COPD, normal body composition, and mildly impaired muscle function and exercise capacity. In vastus lateralis (VL) of mild COPD patients with well-preserved body composition and in healthy age-matched controls, expression of DNA methylation, muscle-enriched microRNAs, histone acetyltransferases (HTAs) and deacetylases (HDACs), protein acetylation, small ubiquitin-related modifier (SUMO) ligases, and muscle structure were explored. All subjects were clinically evaluated. Compared to healthy controls, in the VL of mild COPD patients, muscle function and exercise capacity were moderately reduced, DNA methylation levels did not differ, miR-1 expression levels were increased and positively correlated with both forced expiratory volume in one second (FEV1) and quadriceps force, HDAC4 protein levels were increased, and muscle fiber types and sizes were not different. Moderate skeletal muscle dysfunction is a relevant feature in patients with mild COPD and preserved body composition. Several epigenetic events are differentially expressed in the limb muscles of these patients, probably as an attempt to counterbalance the underlying mechanisms that alter muscle function and mass. The study of patients at early stages of their disease is of interest as they are a target for timely therapeutic interventions that may slow down the course of the disease and prevent the deleterious effects of major comorbidities.

Hospital de día: análisis de resultados, costes y asignación de recursos en neumología / The Day Hospital: Analysis of Results, Costs and Management of Pneumology Resources

Antecedentes: Los hospitales de día de neumología constituyen un instrumento relativamente nuevo de atención al paciente respiratorio complejo. Faltan estudios sobre su eficacia y eficiencia. Objetivo: Estudiar el impacto de la instauración de un hospital de día neumológico en una institución terciaria de 500 camas. Metodología: Análisis de eficacia, eficiencia y calidad. Resultados: En el período analizado (2 años) el hospital de día incrementó progresivamente su actividad. Esto se acompañó de mayor actividad clínica global en neumología, pero también de una reducción en el número de altas hospitalarias, aunque en el período estudiado no varió la presión de pacientes sobre urgencias. Como consecuencia, también se redujo la necesidad de camas en la sala de hospitalización convencional. Por otra parte, aumentó la complejidad de los pacientes ingresados, aunque la eficiencia (razón de funcionamiento estándar) y calidad (reingresos y mortalidad) de la atención en ese dispositivo se mantuvieron estables. Conclusiones: Los hospitales de día neumológicos constituyen un instrumento útil en la gestión de la atención a pacientes respiratorios, ya que reducen las necesidades de hospitalización, manteniendo la calidad asistencial y complementando otros dispositivos(AU)

Background: Day hospital units specialized in pulmonology are a relatively new instrument for providing care to complex respiratory patients. However, the number of studies focused on the efficacy and efficiency of day hospitals is scarce. Aim: Therefore, the aim of the present study was to analyze the effects of implementing a specialized respiratory day hospital in a standard teaching hospital with 500 beds. Methods: An analysis of efficacy, efficiency and quality care. Results: Throughout the study period (2 years) the day hospital progressively increased its activity. Although patient pressure on the emergency department remained constant, this was associated with a parallel increase in the overall medical activity of the Pulmonology Department and a reduction in the number of discharges from the hospital. There was a reduction in the number of admissions, and consequently in the need for beds in the Pulmonology Department. The complexity of the hospitalized patients increased, although the efficiency (standard functioning ratio) and quality (readmissions and mortality) of patient care remained stable. Conclusion: Day hospital pulmonology units are a useful tool in the management of respiratory patient care. They reduce the need for hospitalizations, while maintaining healthcare quality and complementing other care management instruments(AU)

The day hospital: analysis of results, costs and management of pneumology resources.

BACKGROUND: Day hospital units specialized in pulmonology are a relatively new instrument for providing care to complex respiratory patients. However, the number of studies focused on the efficacy and efficiency of day hospitals is scarce. AIM: Therefore, the aim of the present study was to analyze the effects of implementing a specialized respiratory day hospital in a standard teaching hospital with 500 beds. METHODS: An analysis of efficacy, efficiency and quality care. RESULTS: Throughout the study period (2 years) the day hospital progressively increased its activity. Although patient pressure on the emergency department remained constant, this was associated with a parallel increase in the overall medical activity of the Pulmonology Department and a reduction in the number of discharges from the hospital. There was a reduction in the number of admissions, and consequently in the need for beds in the Pulmonology Department. The complexity of the hospitalized patients increased, although the efficiency (standard functioning ratio) and quality (readmissions and mortality) of patient care remained stable. CONCLUSION: Day hospital pulmonology units are a useful tool in the management of respiratory patient care. They reduce the need for hospitalizations, while maintaining healthcare quality and complementing other care management instruments.

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 ß2-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.

Does oxidative stress modulate limb muscle atrophy in severe COPD patients?

Oxidative stress may differentially regulate protein loss within peripheral muscles of severe chronic obstructive pulmonary disease (COPD) patients exhibiting different body composition. Oxidation levels of proteins, myosin heavy chain (MyHC) and myonuclei, superoxide anion, antioxidants, actin, creatine kinase, carbonic anhydrase-3, ubiquitin-proteasome system, redox-signalling pathways, inflammation and muscle structure, and damage were quantified in limb muscles of severe COPD patients with and without muscle wasting, and in sedentary controls. Compared with controls, in the quadriceps of muscle-wasted COPD patients, levels of protein carbonylation, oxidation of MyHC and myonuclei, superoxide anion production, superoxide dismutase, total protein ubiquinitation, E2(14k), atrogin-1, FoxO1 and p65 were higher, while content of MyHC, creatine kinase, carbonic anhydrase-3, myogenin, and fast-twitch fibre size were decreased. Importantly, in nonwasted COPD patients, where MyHC was more oxidised than in controls, its content was preserved. Muscle inflammation and glutathione levels did not differ between patients and controls. In all patients, muscle structure abnormalities were increased, while muscle force and exercise capacity were reduced. In severe COPD, while muscle oxidative stress increases regardless of their body composition, protein ubiquitination and loss of MyHC were enhanced only in patients exhibiting muscle atrophy. Oxidative stress does not seem to directly modulate muscle protein loss in these patients.

Onset of action of formoterol versus salmeterol via dry powder inhalers in moderate chronic obstructive pulmonary disease: a randomized, placebo-controlled, double-blind, crossover study.

BACKGROUND: Bronchodilator therapy is central to the symptomatic management of chronic obstructive pulmonary disease (COPD), and treatment with short-acting bronchodilators is recommended in patients with mild COPD. OBJECTIVE: This study aimed to evaluate the onset of effect of single-dose formoterol 9 µg versus single-dose salmeterol 50 µg in patients with moderate COPD. METHODS: In this multicentre, double-blind, double-dummy, placebo-controlled, three-way single-dose crossover study, patients ≥40 years of age with moderate COPD were randomized to single-dose formoterol 9 µg via Turbuhaler® plus placebo via Diskus®, single-dose salmeterol 50 µg via Diskus® plus placebo via Turbuhaler® or placebo via Turbuhaler® and Diskus® (washout period 2-7 days). Terbutaline 0.5 mg/actuation via Turbuhaler® was used as reliever medication throughout. The primary endpoint was forced expiratory volume in 1 second (FEV1) at 5 minutes post-dose. Secondary endpoints included proportion of patients achieving ≥12% increase in FEV1 at 5 minutes post-dose. RESULTS: 109 patients were randomized, and 108 completed the study. The increase in FEV1 5 minutes post-dose versus pre-dose was 7.2% for formoterol, 4.1% for salmeterol and 0.7% for placebo, and significantly greater for formoterol versus salmeterol (ratio of treatment effects: 1.030; 95% CI 1.008, 1.052; p = 0.009), for formoterol versus placebo (1.064, 95% CI 1.041, 1.087; p < 0.001) and for salmeterol versus placebo (1.033, 95% CI 1.011, 1.056; p = 0.003). The proportions of patients with ≥12% increase in FEV1 5 minutes post-dose were 23.1%, 9.2% and 6.4% for formoterol, salmeterol and placebo, respectively; this was statistically significantly larger after formoterol than salmeterol (p = 0.008) or placebo (p < 0.001). All treatments were well tolerated. CONCLUSION: In COPD patients, formoterol 9 µg has an onset of bronchodilatory effect that is more rapid than salmeterol 50 µg based on FEV1 at 5 minutes post-dose. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01048333; AstraZeneca study code: D5127C00001.

Platelet rich plasma improves the healing process after airway anastomosis.

This study investigated whether platelet-rich plasma (PRP) promotes healing and reduces anastomotic complications following airway surgery in a pig model. PRP was obtained by spinning down the animal's own blood (60 ml) and collecting the buffy coat containing platelets and white blood cells. Fifteen adult pigs were randomized into three groups: (1) sham treatment (cervicotomy), (2) non-PRP group (50% tracheal resection and end-to-end anastomosis), and (3) PRP group (50% tracheal resection, end-to-end anastomosis and PRP application). Blood samples were taken at baseline and at one, six and 24. Animals were monitored for anastomotic complications, infection and local reactivity. Laser Doppler flowmetry was performed intraoperatively and at 30 days to assess differences in pre- and post-anastomotic blood flow. The tensile strength of the anastomosis was also tested. The platelet level was higher in PRP fluid than in the baseline blood sample (P<0.002). Vascular endothelial growth factor, transforming growth factor ß-1 and epidermal growth factor immunoassay readings peaked at one and six hours in the animals that had received PRP (P<0.03); these also showed significantly increased transanastomotic flow and stress-strain resistance (P<0.04) at 30 days than the animals that had not received PRP. PRP therefore, accelerates the onset of healing in airway surgery by promoting an earlier release of platelet-derived growth factors that stimulate transanastomotic angiogenesis.