Add-on inhaled budesonide in the treatment of hospitalised patients with COVID-19 : a randomised clinical trial

SARS-CoV-2 vaccines have been extremely effective to reduce the incidence of severe COVID19 [1-3], but effective and safe treatments of the acute infection are still limited [4, 5]. An uncontrolled pulmonary inflammatory response to SARS-CoV-2 is considered a key pathogenic mechanism of COVID19 progression [6], so systemic dexamethasone is recommended in severe cases [5, 7]. On the other hand, in very mild patients at home inhaled corticosteroids (ICS) may prevent disease progression [8-11]. Whether ICS prevent disease progression too in patients hospitalised because of COVID19 has not been explored before. Accordingly, we designed an investigator-initiated, open-label, randomised clinical trial (RCT) to explore the efficacy of adding inhaled budesonide to usual care to prevent disease progression in patients hospitalised because of COVID19 pneumonia. We also monitored carefully the safety of this intervention since there are concerns about the use of systemic corticosteroids in other viral (influenza) lung infections [12]

Update on metabolomic findings in COPD patients

COPD is a heterogeneous disorder that shows diverse clinical presentations (phenotypes and "treatable traits") and biological mechanisms (endotypes). This heterogeneity implies that to carry out a more personalised clinical management, it is necessary to classify each patient accurately. With this objective, and in addition to clinical features, it would be very useful to have well-defined biological markers. The search for these markers may either be done through more conventional laboratory and hypothesis-driven techniques or relatively blind high-throughput methods, with the omics approaches being suitable for the latter. Metabolomics is the science that studies biological processes through their metabolites, using various techniques such as gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance. The most relevant metabolomics studies carried out in COPD highlight the importance of metabolites involved in pathways directly related to proteins (peptides and amino acids), nucleic acids (nitrogenous bases and nucleosides), and lipids and their derivatives (especially fatty acids, phospholipids, ceramides and eicosanoids). These findings indicate the relevance of inflammatory-immune processes, oxidative stress, increased catabolism and alterations in the energy production. However, some specific findings have also been reported for different COPD phenotypes, demographic characteristics of the patients, disease progression profiles, exacerbations, systemic manifestations and even diverse treatments. Unfortunately, the studies carried out to date have some limitations and shortcomings and there is still a need to define clear metabolomic profiles with clinical utility for the management of COPD and its implicit heterogeneity

Influence of COPD systemic environment on the myogenic function of muscle precursor cells in vitro

Background: Loss of muscle mass and function are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Acute exacerbations, in turn, significantly contribute to upgrade these systemic comorbidities. Involvement of myogenic precursors in muscle mass maintenance and recovery is poorly understood. The aim of the present study was to investigate the effects of the vascular systemic environment from stable and exacerbated COPD patients on the myogenic behavior of human muscle precursor cells (MPC) in vitro. Methods: Serum from healthy controls and from stable and exacerbated COPD patients (before and after Methylprednisolone treatment) was used to stimulate human MPC cultures. Proliferation analysis was assessed through BrdU incorporation assays. MPC differentiation was examined through real-time RT-PCR, western blot and immunofluorescence analysis. Results: Stimulation of MPCs with serum obtained from stable COPD patients did not affect myogenic precursor cell function. The vascular systemic environment during an acute exacerbation exerted a mitotic effect on MPCs without altering myogenic differentiation outcome. After Methylprednisolone treatment of acute exacerbated COPD patients, however, the mitotic effect was further amplified, but it was followed by a deficient differentiation capacity. Moreover, these effects were prevented when cells were co-treated with the glucocorticoid receptor antagonist Mifepristone. Conclusion: Our findings suggest that MPC capacity is inherently preserved in COPD patients, but is compromised after systemic administration of MP. This finding strengthens the concept that glucocorticoid treatment over the long term can negatively impact myogenic stem cell fate decisions and interfere with muscle mass recovery

Bispectral index in hypercapnic encephalopathy associated with COPD exacerbation: a pilot study

Background: Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. Objective: The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. Patients and methods: A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation–Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. Results: BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6–69) for RSS score of 4 to 92.2 (95% CI: 90.1–94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=-0.757, r=0.701, and r=0.615, respectively; P<0.001 for all). In the stable phase after discharge, BIS showed values considered as normal for a wake state (94.6; 95% CI: 91.7–97.9). Conclusion: BIS may be useful for the objective early detection and automatic monitoring of the intensity of hypercapnic encephalopathy in ECOPD, facilitating the early detection and follow-up of this condition, which may avoid management problems in these patients.We are thankful to Jonathan McFarland for his editing aid and to Mireia Admetllo and Camino Fernández for their help in collecting clinical data. This project was funded in part by SAF SAF2014-54371, CIBERES, BRN-Pla Armengol 2014, 2014SGR424, SEPAR 2015, and SEPAR Becario 2015

The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia

Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia.Support for this study was provided by CIBERES, FIS 14/00713 (FEDER), SAF-2014-54371-R, SEPAR 2016, FUCAP 2016 (Spain), and an unrestricted grant from Takeda (Japan). E. Barreiro was a recipient of the ERS COPD Research Award 2008

Bispectral index in hypercapnic encephalopathy associated with COPD exacerbation: a pilot study

Background: Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. Objective: The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. Patients and methods: A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation–Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. Results: BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6–69) for RSS score of 4 to 92.2 (95% CI: 90.1–94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=-0.757, r=0.701, and r=0.615, respectively; P<0.001 for all). In the stable phase after discharge, BIS showed values considered as normal for a wake state (94.6; 95% CI: 91.7–97.9). Conclusion: BIS may be useful for the objective early detection and automatic monitoring of the intensity of hypercapnic encephalopathy in ECOPD, facilitating the early detection and follow-up of this condition, which may avoid management problems in these patients.We are thankful to Jonathan McFarland for his editing aid and to Mireia Admetllo and Camino Fernández for their help in collecting clinical data. This project was funded in part by SAF SAF2014-54371, CIBERES, BRN-Pla Armengol 2014, 2014SGR424, SEPAR 2015, and SEPAR Becario 2015

Hospital admissions and mortality in patients with COPD exacerbations and vertebral body compression fractures

BACKGROUND: Vertebral compression fractures (VCF) are common in COPD patients, with osteoporosis being the main cause. The clinical impact of VCF derives mostly from both pain and chest deformity, which may lead to ventilatory and physical activity limitations. Surprisingly, the consequences of VCF on the quality outcomes of hospital care are poorly known. OBJECTIVE: To assess these indicators in patients hospitalized due to a COPD exacerbation (ECOPD) who also have VCF. METHODS: Clinical characteristics and quality care indicators were assessed in two one-year periods, one retrospective (exploratory) and one prospective (validation), in all consecutive patients hospitalized for ECOPD. Diagnosis of VCF was based on the reduction of >20% height of the vertebral body evaluated in standard lateral chest X-ray (three independent observers). RESULTS: From the 248 patients admitted during the exploratory phase, a third had at least one VCF. Underdiagnosis rate was 97.6%, and patients with VCF had more admissions (normalized for survival), longer hospital stays, and higher mortality than patients without (4 [25th-75th percentiles, 2-8] vs 3 [1-6] admissions, P<0.01; 12 [6-30] vs 9 [6-18] days, P<0.05; and 50 vs 32.1% deaths, P<0.01, respectively). The risk of dying in the two following years was also higher in VCF patients (odds ratio: 2.11 [1.2-3.6], P<0.01). The validation cohort consisted of 250 patients who showed very similar results. The logistic regression analysis indicated that both VCF and age were factors independently associated with mortality. CONCLUSION: Although VCF is frequently underdiagnosed in patients hospitalized for ECOPD, it is strongly associated with a worse prognosis and quality care outcomes.This study has been partially funded by SEPAR (264/2012), CIBERES, FIS (12/02534), Plan Nacional I+D+i (SAF-2014 – 54371), Generalitat de Catalunya (2009-SGR-393), and FUCAP (2012)

Hospital admissions and mortality in patients with COPD exacerbations and vertebral body compression fractures

BACKGROUND: Vertebral compression fractures (VCF) are common in COPD patients, with osteoporosis being the main cause. The clinical impact of VCF derives mostly from both pain and chest deformity, which may lead to ventilatory and physical activity limitations. Surprisingly, the consequences of VCF on the quality outcomes of hospital care are poorly known. OBJECTIVE: To assess these indicators in patients hospitalized due to a COPD exacerbation (ECOPD) who also have VCF. METHODS: Clinical characteristics and quality care indicators were assessed in two one-year periods, one retrospective (exploratory) and one prospective (validation), in all consecutive patients hospitalized for ECOPD. Diagnosis of VCF was based on the reduction of >20% height of the vertebral body evaluated in standard lateral chest X-ray (three independent observers). RESULTS: From the 248 patients admitted during the exploratory phase, a third had at least one VCF. Underdiagnosis rate was 97.6%, and patients with VCF had more admissions (normalized for survival), longer hospital stays, and higher mortality than patients without (4 [25th-75th percentiles, 2-8] vs 3 [1-6] admissions, P<0.01; 12 [6-30] vs 9 [6-18] days, P<0.05; and 50 vs 32.1% deaths, P<0.01, respectively). The risk of dying in the two following years was also higher in VCF patients (odds ratio: 2.11 [1.2-3.6], P<0.01). The validation cohort consisted of 250 patients who showed very similar results. The logistic regression analysis indicated that both VCF and age were factors independently associated with mortality. CONCLUSION: Although VCF is frequently underdiagnosed in patients hospitalized for ECOPD, it is strongly associated with a worse prognosis and quality care outcomes.This study has been partially funded by SEPAR (264/2012), CIBERES, FIS (12/02534), Plan Nacional I+D+i (SAF-2014 – 54371), Generalitat de Catalunya (2009-SGR-393), and FUCAP (2012)

Differences in micro-RNA expression profile between vastus lateralis samples and myotubes in COPD cachexia

Quadriceps muscle weakness and wasting are common comorbidities in chronic obstructive pulmonary disease (COPD). Micro-RNA expression upregulation may favor muscle mass growth and differentiation. We hypothesized that the profile of muscle-enriched micro-RNAs in cultured myotubes differs between patients with COPD of a wide range of body composition and healthy controls and that expression levels of those micro-RNAs from patients with COPD and controls differ between in vivo and in vitro conditions. Twenty-nine patients with COPD [ n = 15 with muscle wasting and fat-free mass index (FFMI) 15 kg/m2 and n = 14 with normal body composition and FFMI 18 kg/m2] and 10 healthy controls (FFMI 19 kg/m2) were consecutively recruited. Biopsies from the vastus lateralis muscle were obtained in all study subjects. A fragment of each biopsy was used to obtain primary cultures, in which muscle cells were first proliferated to be then differentiated into actual myotubes. In both sets of experiments (in vivo biopsies and in vitro myotubes) the following muscle-enriched micro-RNAs from all the study subjects were analyzed using quantitative real-time PCR amplification: micro-RNA (miR)-1, miR-133a, miR-206, miR-486, miR-29b, miR-27a, and miR-181a. Whereas the expression of miR-1, miR-206, miR-486, and miR-29b was upregulated in the muscle biopsies of patients with COPD compared with those of healthy controls, levels of none of the studied micro-RNAs in the myotubes (primary cultured cells) significantly differed between patients with COPD and the controls. We conclude from these findings that environmental factors (blood flow, muscle metabolism, and inflammation) taking place in vivo (biopsies) in muscles may account for the differences observed in micro-RNA expression between patients with COPD and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting as the profile of micro-RNA expression in myotubes was similar in patients to that observed in the healthy controls. NEW & NOTEWORTHY Environmental factors taking place in vivo (biopsies) in the muscles may explain differences observed in micro-RNA expression between patients with chronic obstructive pulmonary disease (COPD) and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting and cachexia as micro-RNA expression profile in myotubes was similar between patients and controls.This study was supported by Centro de Investigación en Red de Enfermedades Respiratorias, Fondo de Investigación Sanitaria (FIS) 14/00713 [Fondo Europeo de Desarrollo Regional (FEDER)], FIS 18/00075 (FEDER), Grant SAF2014-54371, Sociedad Española de Neumología y Cirugía Torácica (SEPAR) 2016, SEPAR 2018, Fundació Catalana de Pneumologia 2016, and an unrestricted grant from Menarini SA 2018 (Spain). E. Barreiro was a recipient of the European Respiratory Society COPD Research Award 2008