Currently, and based on the development of relevant biologic therapies, T2-high is the most well-defined endotype of asthma. Although much progress has been made in elucidating T2-high inflammation ...pathways, no specific clinically applicable biomarkers for T2-low asthma have been identified. The therapeutic approach of T2-low asthma is a problem urgently needing resolution, firstly because these patients have poor response to steroids, and secondly because they are not candidates for the newer targeted biologic agents. Thus, there is an unmet need for the identification of biomarkers that can help the diagnosis and endotyping of T2-low asthma.
Ongoing investigation is focusing on neutrophilic airway inflammation mediators as therapeutic targets, including interleukin (IL)-8, IL-17, IL-1, IL-6, IL-23 and tumour necrosis factor-α; molecules that target restoration of corticosteroid sensitivity, mainly mitogen-activated protein kinase inhibitors, tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibitors; phosphodiesterase (PDE)3 inhibitors that act as bronchodilators and PDE4 inhibitors that have an anti-inflammatory effect; and airway smooth muscle mass attenuation therapies, mainly for patients with paucigranulocytic inflammation.
This article aims to review the evidence for noneosinophilic inflammation being a target for therapy in asthma; discuss current and potential future therapeutic approaches, such as novel molecules and biologic agents; and assess clinical trials of licensed drugs in the treatment of T2-low asthma.
Background: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg has proved to be efficacious in patients with ...chronic obstructive pulmonary disease (COPD) in randomized control trials. Objective: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece. Design: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks. Methods: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment. Results: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 ( p < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period ( p < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 ( p < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively ( p < 0.001 comparing Visits 1/2 and Visits 1/3; p = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period ( p < 0.001). Pulmonary function parameters also improved. Conclusion: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.
Uric acid (UA) is the final product of purine metabolism and a marker of oxidative stress that may be involved in the pathophysiology of cardiovascular and thromboembolic disease. The aim of the ...current study is to investigate the potential value of UA to creatinine ratio (UA/Cr) as a diagnostic tool for the outcome of patients admitted with acute pulmonary embolism (PE) and the correlations with other parameters.
We evaluated 116 patients who were admitted for PE in a respiratory medicine department. PE was confirmed with computed tomography pulmonary angiography. Outcomes evaluated were hospitalization duration, mortality or thrombolysis and a composite endpoint (defined as mortality or thrombolysis). Patients were assessed for PE severity with the PE Severity Index (PESI) and the European Society of Cardiology (ESC) 2019 risk stratification.
The median (interquartile range) UA/Cr level was 7.59 (6.3-9.3). UA/Cr was significantly associated with PESI (
0.001), simplified PESI (
0.019), and ESC 2019 risk stratification (
0.001). The area under the curve (AUC) for prediction of 30-day mortality by UA/Cr was 0.793 (95% CI: 0.667-0.918). UA/Cr levels ≥7.64 showed 87% specificity and 94% negative predictive value for mortality. In multivariable analysis UA/Cr was an independent predictor of mortality (HR (95% CI): 1.620 (1.245-2.108),
0.001) and composite outcome (HR (95% CI): 1.521 (1.211-1.908),
0.001). Patients with elevated UA/Cr levels (≥7.64) had longer hospitalization (median (IQR) 7 (5-11) vs. 6 (5-8) days,
0.006)), higher mortality (27.3% vs. 3.2%,
0.001) and worse composite endpoint (32.7% vs. 3.4%,
0.001).
Serum UA/Cr ratio levels at the time of PE diagnosis are associated with disease severity and risk stratification, and may be a useful biomarker for the identification of patients at risk of adverse outcomes.
Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease characterized by airflow limitation that is not completely reversible. The fixed-dose combination of ...salmeterol and fluticasone propionate (SFC) has been approved as a treatment for COPD patients with a history of recurrent exacerbations and significant symptoms despite regular bronchodilator therapy. In the present study, we evaluated the change in FEV1, mMRC dyspnea score and satisfaction in COPD patients with at least one comorbidity versus those without comorbidities treated with a fixed-dose SFC via the Elpenhaler® device for 12 months. Methods: A 12-month multicenter prospective, observational study (NCT02978703) was designed. Data were collected during the enrollment visit (V0) and six (V1) and twelve months (V2) after the initiation of treatment with Elpenhaler® SFC. The evaluation of the efficacy of the fixed-dose SFC was performed by assessing the change in lung function and dyspnea as expressed by FEV1 and the mMRC dyspnea scale score in COPD patients with and without comorbidities. Results: In total 1016 patients were enrolled, following usual daily clinical practice. A statistically significant improvement was observed in FEV1 in the total study population between visits V0, V1 and V2, with a change from the baseline at V1 0.15 ± 0.22 L and at V2 0.21 ± 0.25 L (p < 0.0001 for both comparisons). This improvement was exhibited regardless of the COPD severity at the baseline, being more noticeable in GOLD 2020 groups B and C. Similarly, a significant improvement was observed in mMRC dyspnea scale values between successive visits (p < 0.0001). In patients without comorbidities, there was a significant improvement in FEV1 of 0.19 ± 0.24 L at V1 and 0.28 ± 0.27 L at V2 (p < 0.0001 for both comparisons), as well as in the mMRC dyspnea score (p < 0.0001). In patients with at least one comorbidity, a corresponding but smaller improvement in FEV1 was observed (0.11 ± 0.34 L at V1 and 0.20 ± 0.42 L at V2; p < 0.0001 for both comparisons and in the mMRC score (p < 0.0001). In the multiple linear regression analysis BMI, GOLD 2020 groups, mMRC and the presence of comorbidities at the baseline were significant factors for the change of FEV1 between V0 and V2. Conclusions: COPD patients treated for twelve months with SFC via the Elpenhaler® device showed significant improvement in lung function and dyspnea at 6 and 12 months, irrespective of the presence of comorbidities.
Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common ...risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients.
Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing ...evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.
Inflammation plays a central role in chronic obstructive pulmonary disease (COPD). COPD related inflammation is less responsive to inhaled steroids compared to asthma. There are three major novel ...anti-inflammatory approaches to the management of COPD. The first approach is phosphodiesterase inhibitors, such as roflumilast which provides additional clinical benefit either as a single agent or as an additive treatment to long-acting bronchodilators. The second approach involves novel strategies using drugs licensed for other indications, such as statins and macrolides; limited prospective studies on these strategies exist at the moment. A third potential approach involves novel agents whose mechanism of action is closely related to COPD mechanisms and pathophysiology. Such novel treatments are of great interest since they may treat both COPD and co-morbidities. Several novel agents are currently under development and may be of importance in the future.
•Serum periostin is a surrogate biomarker of Th2 response in asthma.•Periostin levels on COPD hospitalization were elevated compared to discharge.•Periostin was not a good predictor of future risk ...for hospitalization or mortality.
Serum periostin has been proposed as a surrogate biomarker of Th2 inflammatory response in patients with asthma, but its predictive role in hospitalized patients with COPD has not been evaluated.
The aim of the present observational prospective cohort study was to evaluate the possible role of serum periostin as predictor of outcome in COPD patients hospitalized for AECOPD.
Serum periostin was measured on admission and at discharge in patients admitted to the hospital for a COPD exacerbation. Patients were followed-up for 1year for future exacerbations, hospitalizations and mortality.
155 consecutive patients admitted to the hospital for AECOPD were included to the study. Periostin levels on admission were elevated compared to discharge 34.7 (25.2–52.2) vs. 25.9 (17.4–41.0) ng/mL, p=0.003, but serum periostin levels did not differ between patients with or without prolonged hospitalization, or those who required non-invasive ventilation, intubation, or died during hospitalization. Frequent exacerbators had higher serum periostin levels at the time of discharge compared to non-frequent exacerbators 37.9 (26.6, 64.5) vs. 23.9 (16.2, 37.9), p<0.001. Periostin levels above the median value (25ng/mL) were not related to the time of next exacerbation, time of next COPD hospitalization, (p=0.858) or time to death.
The role of serum periostin levels as a predictive biomarker of future risk in hospitalized patients with COPD is of limited value.
IL-26 is a cytokine expressed by infiltrating pro-inflammatory IL-17-producing T cells in the tissues of patients with chronic lung inflammation. IL-26 induces the chemotactic response of human ...neutrophils to bacteria and other inflammatory stimuli. In recent years, the innovative properties of IL-26 have been described. Studies have shown that, as DNA is released from damaged cells, it binds to IL-26, which plays the role of a carrier molecule for extracellular DNA, further contributing to its binding to the site of inflammation. This mechanism of action indicates that IL-26 may serve both as a driver as well as a stimulus of the inflammatory process, leading to the installation of a noxious amplification loop and, eventually, persistent inflammation. IL-26 also demonstrates direct antimicrobial effects derived from its capability to create pores and disrupt bacterial membranes, as indicated by the presence of membrane blebs on the surface of the bacteria and cytosolic leakage pores in bacterial walls, produced in response to microbial stimuli in human airways by several different immune and structural cells. Surprisingly, while this particular cytokine induces the gathering of neutrophils in areas of infection, it also exhibits inhibitory and pro-inflammatory effects on airway epithelial and immune cells. These remarkable effects underline the necessity of a better understating of its biological behavior and its role in the pathophysiology and disease burden in several smoking-related airway inflammatory disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis. In this review, we aim to discuss the current role of IL-26 in the lung, with an emphasis on systemic inflammation in patients suffering from COPD and chronic bronchitis.
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