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1.
Artigo em Inglês | MEDLINE | ID: mdl-33548398

RESUMO

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility, due to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of lung function fluctuation allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to the twice-daily FEV1 measurements recorded over a one-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or COPD from the European BIOAIR cohort. RESULTS: Independent of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing lung functional alterations that corresponded with patterns of increasing clinical severity, risk of exacerbation and lower quality of life. Clusters of patients with airway disease were identified with significantly elevated biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation and loss of diffusion capacity. The 4 clusters generated were stable over time and revealed no differences in markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information, complementary to clinical diagnosis, and unrelated to eosinophilic inflammation, that could identify patients who may benefit from specific treatment strategies or closer monitoring.

2.
Eur J Intern Med ; 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33563506

RESUMO

Long-acting muscarinic antagonists (LAMAs) have a recognised role in the management of chronic obstructive pulmonary disease. In asthma, muscarinic antagonists (both short- and long-acting) were historically considered less effective than ß2-agonists; only relatively recently have studies been conducted to evaluate the efficacy of LAMAs, as add-on to either inhaled corticosteroid (ICS) monotherapy or ICS/long-acting ß2-agonist (LABA) combinations. These studies led to the approval of the first LAMA, tiotropium, as an add-on therapy in patients with poorly controlled asthma. Subsequently, a number of single-inhaler ICS/LABA/LAMA triple therapies have been approved or are in clinical development for the management of asthma. There is now substantial evidence of the efficacy and safety of LAMAs in asthma that is uncontrolled despite treatment with an ICS/LABA combination. This regimen is recommended by GINA as an optimisation step for patients with severe asthma before any biologic or systemic corticosteroid treatment is initiated. This narrative review summarises the potential mechanisms of action of LAMAs in asthma, together with the initial clinical evidence supporting this use. We also discuss the studies that led to the approval of tiotropium for asthma and the data evaluating the efficacy and safety of the various triple therapies, before considering other potential uses for triple therapy.

3.
Crit Care ; 25(1): 74, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608030

RESUMO

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33485959

RESUMO

BACKGROUND: Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting ß2-agonist (LABA) formoterol fumarate (FF) and long-acting muscarinic antagonist (LAMA) glycopyrronium (G) is in development for asthma. OBJECTIVE: To evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate-and-severe asthma exacerbations. METHODS: TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 ≥1.5), pre-bronchodilator FEV1 <80% predicted, history of ≥1 asthma exacerbation, who had been receiving ICS/LABA for ≥4 weeks prior to entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post-hoc analyses, the annual moderate-and-severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. RESULTS: In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the LAMA component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [p=0.0008]). Reductions in the other seasons ranged between 8.6 and 12.0%. CONCLUSIONS: These post-hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate-and-severe exacerbations, and confirm the overall utility of adding LAMA to ICS/LABA in the management of asthma.

5.
Eur Respir J ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33419889

RESUMO

BACKGROUND: Asthma exacerbations are major contributors to asthma morbidity and mortality. They are usually managed with bronchodilators and oral corticosteroids (OCS), but clinical trial evidence suggests antibiotics could be beneficial. We aimed to assess whether treatment of asthma exacerbations with antibiotics in addition to OCS improved outcomes in larger more representative routine care populations. METHOD: A retrospective comparative effectiveness study into managing asthma exacerbations with OCS alone versus OCS plus antibiotics was conducted using the Optimum Patient Care Research Database. The dataset included 28 637 patients, following propensity score matching 20 024 adults and 4184 children were analysed. RESULTS: Antibiotics in addition to OCS were prescribed for the treatment of asthma exacerbations in 45% of adults and 32% of children.Compared to OCS alone, OCS plus antibiotics was associated with reduced risk of having an asthma/wheeze consultation in the following 2 weeks (children HR 0.84 (95% CI 0.73-0.96), p=0.012; adults HR 0.86 (95% CI 0.81-0.91), p<0.001), but an increase in risk of a further OCS prescription for a new/ongoing exacerbation within 6 weeks in adults (HR 1.11 (95% CI 1.01-1.21), p=0.030), but not children.Penicillins, but not macrolides, were associated with a reduction in the odds of a subsequent asthma/wheeze consultation compared to OCS alone, in both adults and children. CONCLUSION: Antibiotics were frequently prescribed in relation to asthma exacerbations, contrary to guideline recommendations. Overall, the routine addition of antibiotics to OCS in the management of asthma exacerbations appeared to confer little clinical benefit, especially when considering the risks of antibiotic overuse.

6.
Respir Res ; 22(1): 25, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478491

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. METHOD: Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. RESULTS: A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/µL. CONCLUSIONS: In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).


Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Retirada de Medicamento Baseada em Segurança/tendências , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Resultado do Tratamento , Reino Unido/epidemiologia
7.
Asthma Res Pract ; 7(1): 1, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514439

RESUMO

BACKGROUND: The treatment with short-acting beta-2 agonists (SABA) alone is no longer recommended due to safety issues. Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the rapid/long-acting beta-2 agonist formoterol, although the use in steps 1 and 2 is still off-label in the EU and in many countries. It is important to understand clinicians' knowledge and opinions on the issue with the ultimate goal to encourage the implementation of the new approach in clinical practice. METHODS: We performed an international survey, directed to pulmonologists interested in the management of patients with asthma. RESULTS: Most participants reported that SABA alone should not be used in GINA Step 1 asthma treatment. As-needed low-dose ICS/formoterol combination to patients in step 1, and as-needed low-dose ICS/formoterol as reliever therapy in any step were found to be of current use prescribed in their real-life settings. SABA alone was still prescribed to a proportion of patients, although the pulmonologists' opinion was that it should no longer be used. CONCLUSIONS: Most specialists are up to date and understand the relevance of the changes in GINA reports from 2019. Nevertheless, dissemination and implementation of GINA novel management strategy is still needed.

8.
Eur J Pharmacol ; 893: 173839, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359650

RESUMO

Inhaled corticosteroids (ICS) are recommended treatments for all degrees of asthma severity and in combination with bronchodilators are indicated for COPD patients with a history of frequent exacerbations. However, the long-term side effects of glucocorticoids (GCs) may include increased risk of respiratory infections, including viral triggered exacerbations. Rhinovirus (RV) infection is the main trigger of asthma and COPD exacerbations. Thus, we sought to explore the influence of GCs on viral replication. We demonstrate the ICS fluticasone propionate (FP) and two selective non-steroidal (GRT7) and steroidal (GRT10) glucocorticoid receptor (GR) agonists significantly suppress pro-inflammatory (IL-6 and IL-8) and antiviral (IFN-λ1) cytokine production and the expression of the interferon-stimulated genes (ISGs) OAS and viperin in RV-infected bronchial epithelial cells, with a consequent increase of viral replication. We also show that FP, GRT7 and GRT10 inhibit STAT1 Y701 and/or STAT2 Y690 phosphorylation and ISG mRNA induction following cell stimulation with recombinant IFN-ß. In addition, we investigated the effects of the ICS budesonide (BD) and the long-acting ß2 agonist (LABA) formoterol, alone or as an ICS/LABA combination, on RV-induced ISG expression and viral replication. Combination of BD/formoterol increases the suppression of OAS and viperin mRNA observed with both BD and formoterol alone, but an increase in viral RNA was only observed with BD treatment and not with formoterol. Overall, we provide evidence of an impairment of the innate antiviral immune response by GC therapy and the potential for GCs to enhance viral replication. These findings could have important clinical implications.

9.
Drug Saf ; 44(3): 273-290, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33326056

RESUMO

N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the efficacy of NAC at higher doses. The aim of this review was to evaluate the adverse effects profile of NAC at higher than the standard dose in chronic respiratory diseases to establish a risk-benefit ratio in increasing the daily dose; therefore, studies using NAC at a dose of at least 600 mg/day were selected. Forty-one articles where NAC has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. Most of the studies used oral NAC and were conducted on patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, chronic bronchitis and cystic fibrosis. In general, the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group.

10.
Int J Chron Obstruct Pulmon Dis ; 15: 3093-3103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33273812

RESUMO

Introduction: The Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF). Methods: A matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerbations on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤1.2. Results: This study included 537 and 540 patient pairs in the BDP/FF vs FP/SAL cohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacerbations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67-1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58-1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51-1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43-0.96). Conclusion: Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33264064

RESUMO

The interplay of type-2 inflammation and anti-viral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma, however mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild-to-moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then employed to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface (ALI) differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression: increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6 which was required for CCL17, but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, findings suggest therapeutic targeting of type-2-STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

12.
Platelets ; : 1-8, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33270471

RESUMO

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality. ClinicalTrials.gov number: NCT04343053.

13.
Front Cardiovasc Med ; 7: 585866, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195473

RESUMO

Background: Italy has one of the world's oldest populations, and suffered one the highest death tolls from Coronavirus disease 2019 (COVID-19) worldwide. Older people with cardiovascular diseases (CVDs), and in particular hypertension, are at higher risk of hospitalization and death for COVID-19. Whether hypertension medications may increase the risk for death in older COVID 19 inpatients at the highest risk for the disease is currently unknown. Methods: Data from 5,625 COVID-19 inpatients were manually extracted from medical charts from 61 hospitals across Italy. From the initial 5,625 patients, 3,179 were included in the study as they were either discharged or deceased at the time of the data analysis. Primary outcome was inpatient death or recovery. Mixed effects logistic regression models were adjusted for sex, age, and number of comorbidities, with a random effect for site. Results: A large proportion of participating inpatients were ≥65 years old (58%), male (68%), non-smokers (93%) with comorbidities (66%). Each additional comorbidity increased the risk of death by 35% [adjOR = 1.35 (1.2, 1.5) p < 0.001]. Use of ACE inhibitors, ARBs, beta-blockers or Ca-antagonists was not associated with significantly increased risk of death. There was a marginal negative association between ARB use and death, and a marginal positive association between diuretic use and death. Conclusions: This Italian nationwide observational study of COVID-19 inpatients, the majority of which ≥65 years old, indicates that there is a linear direct relationship between the number of comorbidities and the risk of death. Among CVDs, hypertension and pre-existing cardiomyopathy were significantly associated with risk of death. The use of hypertension medications reported to be safe in younger cohorts, do not contribute significantly to increased COVID-19 related deaths in an older population that suffered one of the highest death tolls worldwide.

14.
Respir Med ; 175: 106190, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33217537

RESUMO

BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

15.
BMJ Open Respir Res ; 7(1)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33208304

RESUMO

INTRODUCTION: Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels. METHODS: The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort. RESULTS: This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008-0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status. DISCUSSION: The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33146552

RESUMO

The SARS-CoV-2 pandemic has raised many questions about the management of COPD patients and whether modifications of their therapy are required. It has raised questions about recognising and differentiating COVID-19 from COPD given the similarity of the symptoms. It is unclear whether COPD patients are at increased risk of becoming infected with SARS-CoV-2. During periods of high prevalence of COVID-19, spirometry should be used when essential for COPD diagnosis and/or to assess lung function status for interventional procedures or surgery. COPD patients should follow basic infection control measures including social distancing, hand washing and wearing a mask or face covering. Although data are limited, inhaled corticosteroids, long-acting bronchodilators, roflumilast, or chronic macrolides should continue to be used as indicated for stable COPD management. Systemic steroids and antibiotics should be used in COPD exacerbations according to the usual indications. Differentiating symptoms of COVID-19 infection from chronic underlying symptoms or those of an COPD exacerbation may be challenging. If there is suspicion for COVID-19, testing for SARS-CoV-2 should be considered. Patients who developed moderate to severe COVID-19, including hospitalization and pneumonia, should be treated with evolving pharmacotherapeutic approaches, as appropriate, including remdesivir, dexamethasone, and anticoagulation. Managing acute respiratory failure should include appropriate oxygen supplementation, prone positioning, noninvasive ventilation, and protective lung ventilation in patients with ARDS. Patients who develop mild COVID-19 should be followed as normal. Patients who developed moderate or worse COVID-19 should be monitored more frequently than normally with particular attention to the need for oxygen therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

17.
Artigo em Inglês | MEDLINE | ID: mdl-33211970

RESUMO

Currently the diagnosis of chronic obstructive pulmonary disease (COPD) requires the demonstration of airflow limitation, defined as a post-bronchodilator FEV1/FVC <0.7, a measurement that remains methodologically robust and widely available. FEV1 is one of the most powerful predictors of clinically relevant outcomes including symptoms, exacerbations and mortality. However, reliable data suggest that respiratory symptoms, in particular chronic bronchitis, airway abnormality and emphysema detected using modern imaging techniques such as computed tomography (CT), and certain physiologic measures including rapid decline in FEV1 and DLCO are present among individuals who do not meet spirometric criteria for COPD. These abnormalities may help to identify individuals at increased risk for developing airflow limitation in the future. Here, we review the evidence that support the use of the term "pre-COPD" in individuals with symptoms (e.g., "Non-Obstructive Chronic Bronchitis" (NOCB)), physiologic (e.g., low DLCO) and/or imaging abnormalities (e.g. CT emphysema) but spirometry in the normal range, who are at risk of developing COPD defined by a reduced FEV1/FVC ratio. We acknowledge, however, that further research on early disease in young individuals will be critical to develop a clinically operable definition of "pre-COPD" that demonstrates good sensitivity and specificity. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

18.
Adv Ther ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146843

RESUMO

INTRODUCTION: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals. METHODS: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study. RESULTS: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants. CONCLUSIONS: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.

19.
Clin Exp Allergy ; 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33247470

RESUMO

Asthma is a chronic respiratory disease in which airway inflammation is a key feature, even in the milder expressions of the disease. The conventional pharmacological approach to mild asthma has long relied on reliever therapy with as-needed short-acting beta-agonists (SABA), while anti-inflammatory maintenance with inhaled corticosteroids (ICS) has been reserved for patients with more persistent asthma. Poor adherence to maintenance treatment is an important issue in asthma management, and can partly explain suboptimal symptom control. Over-reliance on SABA bronchodilators for rapid symptom relief is common in real life and potentially leads to an increased risk of asthma morbidity and mortality. Combined anti-inflammatory and reliever medications in a single inhaler have the potential to overcome these limitations. Recent studies in patients with mild asthma have shown that anti-inflammatory reliever therapy with budesonide-formoterol, given on an as-needed basis, is superior to SABA in ensuring asthma control, and non-inferior to budesonide maintenance therapy in preventing exacerbations. To address the implications of these important findings for the management of patients with asthma, Italian specialists convened at a series of meetings held during the second half of 2018 across Italy. This article presents their position on these topics, and includes a review of the evidence supporting the use of anti-inflammatory reliever therapy in mild asthma and the implementation of this novel approach in clinical practice.

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