Short-acting inhaled bronchodilators for cystic fibrosis.

BACKGROUND: Respiratory disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and many different therapies are used by people with CF in the management of respiratory problems. Bronchodilator therapy is used to relieve symptoms of shortness of breath and to open the airways to allow clearance of mucus. Despite the widespread use of inhaled bronchodilators in CF, there is little objective evidence of their efficacy. A Cochrane Review looking at both short- and long-acting inhaled bronchodilators for CF was withdrawn from the Cochrane Library in 2016. That review has been replaced by two separate Cochrane Reviews: one on long-acting inhaled bronchodilators for CF, and this review on short-acting inhaled bronchodilators for CF. For this review 'inhaled' includes the use of pressurised metered dose inhalers (MDIs), with or without a spacer, dry powder devices and nebulisers. OBJECTIVES: To evaluate short-acting inhaled bronchodilators in children and adults with CF in terms of clinical outcomes and safety. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books on 28 March 2022 and searched trial registries for any new or ongoing trials on 12 April 2022. We also searched the reference lists of relevant articles and reviews. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) or quasi-RCTs that looked at the effect of any short-acting inhaled bronchodilator delivered by any device, at any dose, at any frequency and for any duration compared to either placebo or another short-acting inhaled bronchodilator in people with CF. We screened references as per standard Cochrane methodology. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias using the Cochrane RoB 1 tool. Where we were not able to enter data into our analyses we reported results directly from the papers. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 11 trials from our systematic search, with 191 participants meeting our inclusion criteria; three of these trials had three treatment arms. Eight trials compared short-acting inhaled beta-2 agonists to placebo and four trials compared short-acting inhaled muscarinic antagonists to placebo. Three trials compared short-acting inhaled beta-2 agonists to short-acting inhaled muscarinic antagonists. All were cross-over trials with only small numbers of participants. We were only able to enter data into the analysis from three trials comparing short-acting inhaled beta-2 agonists to placebo. Short-acting inhaled beta-2 agonists versus placebo All eight trials (six single-dose trials and two longer-term trials) reporting on this comparison reported on forced expiratory volume in 1 second (FEV1), either as per cent predicted (% predicted) or L. We were able to combine the data from two trials in a meta-analysis which showed a greater per cent change from baseline in FEV1 L after beta-2 agonists compared to placebo (mean difference (MD) 6.95%, 95% confidence interval (CI) 1.88 to 12.02; 2 trials, 82 participants). Only one of the longer-term trials reported on exacerbations, as measured by hospitalisations and courses of antibiotics. Only the second longer-term trial presented results for participant-reported outcomes. Three trials narratively reported adverse events, and these were all mild. Three single-dose trials and the two longer trials reported on forced vital capacity (FVC), and five trials reported on peak expiratory flow, i.e. forced expiratory flow between 25% and 75% (FEF25-75). One trial reported on airway clearance in terms of sputum weight. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short-acting inhaled beta-2 agonists on any of the outcomes we assessed. Short-acting inhaled muscarinic antagonists versus placebo All four trials reporting on this comparison looked at the effects of ipratropium bromide, but in different doses and via different delivery methods. One trial reported FEV1 % predicted; three trials measured this in L. Two trials reported adverse events, but these were few and mild. One trial reported FVC and three trials reported FEF25-75. None of the trials reported on quality of life, exacerbations or airway clearance. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short-acting inhaled muscarinic antagonists on any of the outcomes we assessed. Short-acting inhaled beta-2 agonists versus short-acting inhaled muscarinic antagonists  None of the three single-dose trials reporting on this comparison provided data we could analyse. The original papers from three trials report that both treatments lead to an improvement in FEV1 L. Only one trial reported on adverse events; but none were experienced by any participant. No trial reported on any of our other outcomes. We judged the certainty of evidence to be very low, meaning we are very uncertain about the effect of short-acting inhaled beta-2 agonists compared to short-acting inhaled muscarinic antagonists on any of the outcomes we assessed. AUTHORS' CONCLUSIONS: All included trials in this review are small and of a cross-over design. Most trials looked at very short-term effects of inhaled bronchodilators, and therefore did not measure longer-term outcomes. The certainty of evidence across all outcomes was very low, and therefore we have been unable to describe any effects with certainty.

A nationwide survey on the use of heated humidified high flow oxygen therapy on the paediatric wards in the UK: current practice and research priorities.

BACKGROUND: Heated Humidified High Flow Nasal Cannula Oxygen Therapy (HHFNC) is increasingly used on the paediatric wards and High Dependency Units (HDU) for different types of pathologies and different age groups. We aimed to describe current practice related to the use of HHFNC on the paediatric wards and HDUs, weaning practices and preferred outcome measures for future research. METHODS: We carried out a cross-sectional online survey of UK paediatric consultants or their delegates working on the paediatric wards. Descriptive analysis of their geographical, and organizational characteristics, their specialties, and their level of experience was investigated. Reasons for HHFNC initiation, weaning criteria, patients' characteristics and their primary pathologies were also analysed. RESULTS: Participation of 218 paediatricians from 81 hospitals (Median: 2.7, Range: 1-11) was registered. HHFNC was provided in most of the surveyed hospitals (93%, 75/81). A High Dependency Unit (HDU) was available in 47 hospitals (58%); less than a third of those have a dedicated paediatrician. Decisions around HHFNC were made solely by paediatricians in (75%) of the cases, mostly at hospitals with no HDU compared to those with dedicated HDUs (70.3% VS 36.6, 95%CI:22.6-50.4%, P < .001). HHFNC was reported by nearly two-thirds (68%) of the practitioners who used it on the wards to be as effective or superior to CPAP (Continuous Positive Airway Pressure) with fewer complications. Failure rate while on HHFNC was identified as the most important outcome measure in any future research followed by the length of need for HHFNC support (37.1, and 28% respectively). CONCLUSION: This survey showed support for developing paediatric-specific national guidance on the use of HHFNC on the wards. Our list of defined research priorities may help guide further collaborative research efforts in this field.

Long-acting inhaled bronchodilators for cystic fibrosis.

BACKGROUND: Cystic fibrosis is a life-limiting inherited condition which affects one in 2500 newborns in the UK and 70,000 children and adults worldwide. The condition is multifaceted and affects many systems in the body. The respiratory system is particularly affected due to a build up of thickened secretions and a predisposition to infection. Inhaled bronchodilators are prescribed for 80% of people with cystic fibrosis in order to widen the airways and alleviate symptoms. Both short- and long-acting inhaled bronchodilators are used to improve respiratory symptoms. Short-acting inhaled bronchodilators take effect in minutes and typically last for four to eight hours (muscarinic antagonists). Long-acting inhaled bronchodilators also take effect within minutes but typically last for around 12 hours and sometimes longer. This review is one of two which are replacing a previously published review of both long- and short-acting inhaled bronchodilators. OBJECTIVES: This review aims to evaluate long-acting inhaled bronchodilators in children and adults with cystic fibrosis in terms of clinical outcomes and safety. If possible, we aimed to assess the optimal drug and dosage regimen. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search: 10 October 2017.We also carried out a separate search of Embase and the reference lists of included trials. We searched clinical trials registries for any ongoing trials and made contact with pharmaceutical companies for any further trials.Date of Embase search: 11 October 2017. SELECTION CRITERIA: Randomised or quasi-randomised parallel trials comparing long-acting inhaled bronchodilators (beta-2 agonists and muscarinic antagonists) with placebo, no treatment or a different long-acting inhaled bronchodilator in adults and children with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trials for inclusion (based on title, abstract and full text). The authors independently assessed the included trials for quality and risk of bias and extracted data. Discrepancies were resolved by a third party. MAIN RESULTS: The searches identified 195 unique references, of which 155 were excluded on title and abstract. We assessed the full texts of the remaining references, excluded 16 trials (28 references) and included four trials (12 references) in the review with 1082 participants.One trial (n = 16) measuring the effect of beta-2 agonists reported an improvement in forced expiratory volume at one second (FEV1) after treatment (at one month), but the trial was small with an unclear risk of bias so we judged the evidence to be very low quality. The trial did not report on participant-reported outcomes, quality of life or adverse events.Three trials (n = 1066) looked at the effects of the muscarinic antagonist tiotropium at doses of 2.5 µg and 5.0 µg in both the short term (up to 28 days) and the longer term (up to three months). Only one of the trials reported the change in FEV1 (L) after 28 days treatment and showed no significant difference between groups; with 2.5 µg tiotropium, mean difference (MD) -0.02 (95% confidence interval (CI) -0.13 to 0.09), or 5.0 µg tiotropium, MD 0.00 (95% CI -0.10 to 0.10) (moderate-quality evidence). All three trials of muscarinic antagonists provided data on adverse events which were found to differ little from placebo at doses of 2.5 µg, risk ratio (RR) 1.01 (95% CI 0.92 to 1.11) or 5.0 µg, RR 0.98 (95% CI 0.90 to 1.06). Very little participant-reported outcome data or quality of life data were available for analysis. Two of the trials were at low risk of bias overall whilst the remaining trial was at an unclear risk overall. AUTHORS' CONCLUSIONS: Neither long-acting beta-2 agonists nor long-acting muscarinic antagonist bronchodilators demonstrate improvement in our primary outcome of FEV1. No difference was observed between intervention and placebo in terms of quality of life or adverse events. The quality of evidence for the use of beta-2 agonists was very low. The use of a long-acting inhaled bronchodilator may help to reduce the burden of treatment for people with cystic fibrosis as it is taken less often than a short-acting inhaled bronchodilator, but future trials would benefit from looking at the effects on our primary outcomes (spirometric changes from baseline, quality of life and adverse effects) in the longer term.

TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques.

The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.