"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve ...outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.
Background
Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in ...the airways. This is an update of a previously published review.
Objectives
To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance.
Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and books of conference proceedings. We also searched ongoing trials databases.
Date of most recent searches: 08 August 2018.
Selection criteria
Randomised and quasi‐randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
Data collection and analysis
Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE.
Main results
A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.
Hypertonic saline 3% to 7% versus placebo
At four weeks, we found very low‐quality evidence from three placebo‐controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice‐daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV1) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI ‐2.72 to 7.34) (low‐quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low‐quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low‐quality evidence). Four trials (n = 80) found very low‐quality evidence that sputum clearance was better with hypertonic saline.
A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short‐term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post‐discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low‐quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low‐quality evidence).
Hypertonic saline versus mucus mobilising treatments
Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three‐week trial (14 participants) to determine the effects of hypertonic saline on FEV1 % predicted, mean difference (MD) 1.60% (95% CI ‐7.96 to 11.16) (very low‐quality evidence). In the second trial, rhDNase led to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low‐quality evidence). One cross‐over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low‐quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross‐over trial of 47 people (low‐quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.
One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium‐2‐mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium‐2‐mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low‐quality evidence).
One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low‐quality evidence).
Authors' conclusions
Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low‐quality evidence from three trials), but this was not sustained at 48 weeks (low‐quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.
Evidence from one small cross‐over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.
Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.
This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence ...relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL
to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL
) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4-5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
Asthma treatment goals currently focus on symptom and exacerbation control rather than remission. Remission is not identical to cure but is a step closer. This review considers the current ...definitions of remission in asthma, the prevalence and predictors, the pathophysiology of remission, the possibility of achieving it using the available treatment options and the future research directions. Asthma remission is characterised by a high level of disease control, including the absence of symptoms and exacerbations, and normalisation or optimisation of lung function with or without ongoing treatment. Even in those who develop a symptomatic remission of asthma, persistent pathological abnormalities are common, leading to a risk of subsequent relapse at any time. Complete remission requires normalisation or stabilisation of any underlying pathology in addition to symptomatic remission. Remission is possible as part of the natural history of asthma, and the prevalence of remission in the adult asthma population varies between 2% and 52%. The factors associated with remission include mild asthma, better lung function, better asthma control, younger age, early-onset asthma, shorter duration of asthma, milder bronchial hyper-responsiveness, fewer comorbidities and smoking cessation or never smoking. Although previous studies have not targeted treatment-induced remission, there is some evidence to show that the current long-term add on therapies such as biologics and azithromycin can achieve some criteria for asthma remission on treatment, at least in a subgroup of patients. However, more research is required. Long-term remission could be included as a therapeutic goal in studies of asthma treatments.
Nebulised hypertonic saline for cystic fibrosis Wark, Peter; Wark, Peter; McDonald, Vanessa M ...
Cochrane database of systematic reviews,
06/2023, Letnik:
2023, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background
Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
Objectives
To ...investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance.
Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and books of conference proceedings. We also searched ongoing trials databases.
Most recent search: 25 April 2022.
Selection criteria
We included randomised and quasi‐randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
Data collection and analysis
Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross‐over trials we stipulated a one‐week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross‐over trials, we chose to treat the trials as if they were parallel.
Main results
We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions.
Hypertonic saline 3% to 7% versus placebo (stable disease)
We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low‐certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD ‐0.60, 95% CI ‐1.00 to ‐0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo.
Hypertonic saline versus control (acute exacerbation)
Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI ‐14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events.
Hypertonic saline versus rhDNase
Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI ‐7.96 to 11.16; 1 trial, 14 participants; very low‐certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low‐certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported.
Hypertonic saline versus amiloride
One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low‐certainty evidence).
Hypertonic saline compared with sodium‐2‐mercaptoethane sulphonate (Mistabron®)
One trial (29 participants) compared hypertonic saline to sodium‐2‐mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low‐certainty evidence).
Hypertonic saline versus mannitol
One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low‐certainty evidence).
Hypertonic saline versus xylitol
Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low‐certainty evidence). No other outcomes were reported in the review.
Hypertonic saline 7% versus hypertonic saline 3%
We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low‐certainty evidence).
Authors' conclusions
We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low‐certainty evidence); there was no difference seen at 48 weeks (one trial; low‐certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years.
Evidence from one small cross‐over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes.
Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria.
The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.
Anxiety and depression are comorbidities of severe asthma. However, clinical characteristics associated with coexisting severe asthma and anxiety/depression are poorly understood. The study objective ...is to determine clinical characteristics associated with anxiety and depressive symptoms in severe asthma.
Severe asthma participants (N = 140) underwent a multidimensional assessment. Categorization of symptoms of anxiety and depression were based on HADS scale sub-scores and divided into four groups (< 8 on both subscales; ≥ 8 on one subscale; ≥ 8 on both subscales). Clinical characteristics were compared between subgroups. Multivariate logistic regression determined associations of clinical characteristics and anxiety and/or depressive symptoms in people with severe asthma.
Participants were (mean ± SD) 59.3 ± 14.7 years old, and 62% female. There were 74 (53%) severe asthma participants without symptoms of anxiety/depression, 11 (7%) with symptoms of anxiety, 37 (26%) with symptoms of depression and 18 (13%) with symptoms of anxiety and depression. Quality of life impairment was greater in participants with symptoms of depression (4.4 ± 1.2) and combined symptoms of anxiety and depression (4.4 ± 1.1). Asthma control was worse in those with symptoms of depression (2.9 ± 1.1) and combined anxiety and depression (2.6 ± 1.0). In multivariate models, dysfunctional breathing was associated with symptoms of anxiety (OR = 1.24 1.01, 1.53). Dyspnoea was associated with symptoms of depression (OR = 1.90 1.10, 3.25). Dysfunctional breathing (OR 1.16 1.04, 1.23) and obesity (OR 1.17 1.00, 1.35) were associated with combined symptoms of anxiety and depression.
People with severe asthma and anxiety and/or depressive symptoms have poorer QoL and asthma control. Dyspnoea, dysfunctional breathing and obesity are associated with these symptoms. These key clinical characteristics should be targeted in severe asthma management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Treatable traits have been proposed as a new paradigm for airway disease management.
To characterise treatable traits in a severe asthma population and to determine the efficacy of targeting ...treatments to these treatable traits in severe asthma.
Participants (n=140) with severe asthma were recruited to a cross-sectional study and underwent a multidimensional assessment to characterise treatable traits. Eligible participants with severe asthma (n=55) participated in a 16-week parallel-group randomised controlled trial to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patient-reported outcome of health-related quality of life was the trial's primary end-point.
Participants with severe asthma had a mean±sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary and 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors. Individualised treatment that targeted the traits was feasible and led to significantly improved health-related quality of life (0.86 units, p<0.001) and asthma control (0.73, p=0.01).
Multidimensional assessment enables detection of treatable traits and identifies a significant trait burden in severe asthma. Targeting these treatable traits using a personalised-medicine approach in severe asthma leads to improvements in health-related quality of life, asthma control and reduced primary care acute visits. Treatable traits may be an effective way to address the complexity of severe asthma.
The overlap between asthma and COPD is increasingly recognised. This review examines the new insights, treatment and remaining knowledge gaps for asthma-COPD overlap.
A systematic literature review ...of cluster analyses of asthma and COPD was performed. Articles from 2009 to the present dealing with prevalence, morbidity and treatment of asthma-COPD overlap were identified and reviewed.
Asthma-COPD overlap was consistently recognised in studies using a variety of different study designs and sampling. The prevalence was approximately 20% in patients with obstructive airways diseases. Asthma-COPD overlap was associated with increased morbidity and possibly an increased mortality and comorbidity. There was evidence of a heterogeneous pattern of airway inflammation that included eosinophilic (in adult asthma), neutrophilic or mixed patterns (in severe asthma and COPD). Systemic inflammation was present in asthma-COPD overlap and resembled that of COPD. Within asthma-COPD overlap, there is evidence of different subgroups, and recognition using bronchodilator responsiveness has not been successful. Guidelines generally recommend a serial approach to assessment, with treatment recommendations dominated by an asthma paradigm. Research is needed into key clinical features that impact outcome, mechanisms and treatment approaches in asthma-COPD overlap. Identifying and treating disease components by multidimensional assessment shows promise.
Asthma-COPD overlap has drawn attention to the significant heterogeneity that exists within obstructive airway diseases. It should be replaced by novel approaches that identify and manage the components of this heterogeneity, such as multidimensional assessment and treatment. Future research is needed to test these novel and personalised approaches.
Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and chronic airflow limitation, and is associated with exacerbations and comorbidities. ...Advances in the management of COPD are updated quarterly in the national COPD guidelines, the COPD‐X plan, published by Lung Foundation Australia in conjunction with the Thoracic Society of Australia and New Zealand and available at http://copdx.org.au.
Main recommendations:
Spirometry detects persistent airflow limitation (post‐bronchodilator FEV1/FVC < 0.7) and must be used to confirm the diagnosis.
Non‐pharmacological and pharmacological therapies should be considered as they optimise function (ie, improve symptoms and quality of life) and prevent deterioration (ie, prevent exacerbations and reduce decline).
Pulmonary rehabilitation and regular exercise are highly beneficial and should be provided to all symptomatic COPD patients.
Short‐ and long‐acting inhaled bronchodilators and, in more severe disease, anti‐inflammatory agents (inhaled corticosteroids) should be considered in a stepwise approach.
Given the wide range of inhaler devices available, inhaler technique and adherence should be checked regularly.
Smoking cessation is essential, and influenza and pneumococcal vaccinations reduce the risk of exacerbations.
A plan of care should be developed with the multidisciplinary team. COPD action plans reduce hospitalisations and are recommended as part of COPD self‐management.
Exacerbations should be managed promptly with bronchodilators, corticosteroids and antibiotics as appropriate to prevent hospital admission and delay COPD progression.
Comorbidities of COPD require identification and appropriate management.
Supportive, palliative and end‐of‐life care are beneficial for patients with advanced disease.
Education of patients, carers and clinicians, and a strong partnership between primary and tertiary care, facilitate evidence‐based management of COPD.
Changes in management as result of the guideline: Spirometry remains the gold standard for diagnosing airflow obstruction and COPD. Non‐pharmacological and pharmacological treatment should be used in a stepwise fashion to control symptoms and reduce exacerbation risk.
It is largely unrecognised that the impacts of asthma are different in patients with severe disease compared with patients with mild to moderate disease. Severe asthma is associated with a ...significant health-related quality of life (HRQoL) burden due to excessive symptoms, frequent and life-threatening attacks, increased comorbidity burden, and high pharmacological treatment requirements. Interventions aimed at improving HRQoL need to be specifically tested in populations with severe asthma, including multicomponent interventions targeting the many clinical characteristics associated with the disease. It is necessary to have patient-reported outcome measures developed specifically for severe asthma. Public health messages recognising the significant burden of severe asthma on quality of life are needed.
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