Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome.

The impact of outpatient versus inpatient management on health-related quality of life outcomes for patients with malignant pleural effusion: the OPTIMUM randomised clinical trial.

BACKGROUND: The principal aim of malignant pleural effusion (MPE) management is to improve health-related quality of life (HRQoL) and symptoms. METHODS: In this open-label randomised controlled trial, patients with symptomatic MPE were randomly assigned to either indwelling pleural catheter (IPC) insertion with the option of talc pleurodesis or chest drain and talc pleurodesis. The primary end-point was global health status, measured with the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) at 30 days post-intervention. 142 participants were enrolled from July 2015 to December 2019. RESULTS: Of participants randomly assigned to the IPC (n=70) and chest drain (n=72) groups, primary outcome data were available in 58 and 56 patients, respectively. Global health status improved in both groups at day 30 compared with baseline: IPC (mean difference 13.11; p=0.001) and chest drain (mean difference 10.11; p=0.001). However, there was no significant between-group difference at day 30 (mean intergroup difference in baseline-adjusted global health status 2.06, 95% CI -5.86-9.99; p=0.61), day 60 or day 90. No significant differences were identified between groups in breathlessness and chest pain scores. All chest drain arm patients were admitted (median length of stay 4 days); seven patients in the IPC arm required intervention-related hospitalisation. CONCLUSIONS: While HRQoL significantly improved in both groups, there were no differences in patient-reported global health status at 30 days. The outpatient pathway using an IPC was not superior to inpatient treatment with a chest drain.

Randomised trial of indwelling pleural catheters for refractory transudative pleural effusions.

OBJECTIVE: Refractory symptomatic transudative pleural effusions are an indication for pleural drainage. There has been supportive observational evidence for the use of indwelling pleural catheters (IPCs) for transudative effusions, but no randomised trials. We aimed to investigate the effect of IPCs on breathlessness in patients with transudative pleural effusions when compared with standard care. METHODS: A multicentre randomised controlled trial, in which patients with transudative pleural effusions were randomly assigned to either an IPC (intervention) or therapeutic thoracentesis (TT; standard care). The primary outcome was mean daily breathlessness score over 12 weeks from randomisation. RESULTS: 220 patients were screened from April 2015 to August 2019 across 13 centres, with 33 randomised to intervention (IPC) and 35 to standard care (TT). Underlying aetiology was heart failure in 46 patients, liver failure in 16 and renal failure in six. In primary outcome analysis, the mean±sd breathlessness score over the 12-week study period was 39.7±29.4 mm in the IPC group and 45.0±26.1 mm in the TT group (p=0.67). Secondary outcomes analysis demonstrated that mean±sd drainage was 17 412±17 936 mL and 2901±2416 mL in the IPC and TT groups, respectively. A greater proportion of patients had at least one adverse event in the IPC group (p=0.04). CONCLUSION: We found no significant difference in breathlessness over 12 weeks between IPCs or TT. TT is associated with fewer complications and IPCs reduced the number of invasive pleural procedures required. Patient preference and circumstances should be considered in selecting the intervention in this cohort.

Dexamethasone in Hospitalized Patients with Covid-19.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration: ISRCTN Identifier: ISRCTN47845793.

Continuous positive airway pressure effect on visual acuity in patients with type 2 diabetes and obstructive sleep apnoea: a multicentre randomised controlled trial.

We sought to establish whether continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA) in people with type 2 diabetes and diabetic macular oedema (DMO) improved visual acuity.We randomly assigned 131 eligible patients aged 30-85 years from 23 UK centres with significant DMO causing visual impairment (LogMAR letters identified ≥39 and ≤78, score 0.92-0.14) plus severe OSA on screening to either usual ophthalmology care (n=67) or usual ophthalmology care plus CPAP (n=64) for 12 months.Mean age of participants was 64 years, 73% male, mean body mass index 35.0 kg·m- 2 Mean 4% oxygen desaturation index was 36 events·h-1 There was no significant difference in the visual acuity at 12 months between the CPAP group and the control group (mean LogMAR 0.33 (95% CI 0.29-0.37) versus 0.31 (95% CI 0.27-0.35); p=0.39), and no significant correlation between change in LogMAR and average CPAP use. The median±sd (range) daily CPAP use was 3.33±2.25 (0-7.93) h at 3 months, 3.19±2.54 (0-8.07) h at 6 months and 3.21±2.70 (0-7.98) h at 12 months.CPAP therapy for OSA did not improve visual acuity in people with type 2 diabetes and DMO compared with usual care alone over 12 months.

A novel postal-based approach to diagnosing obstructive sleep apnoea in a high-risk population.

OBJECTIVE: More than 50% of patients with diabetic macular oedema (DMO) have obstructive sleep apnoea (OSA), but the majority remain undiagnosed. We used a four-channel device (ApneaLink [AL], ResMed, UK) to establish a remote postal-based diagnostic service for patients with DMO. Here we describe our experience. METHODS: Patients with DMO were invited to participate. Interested patients returned a free-post reply slip to the study team, who posted an AL with pictorial and written instructions to them. Following a single night study, the AL was returned by a freepost service. RESULTS: Responses from 733 patients meeting the inclusion criteria were received, comprising 469 males and 264 females, mean age 64 years (standard deviation 10.4 years). ALs were issued to 718 patients, of whom 606 completed a diagnostic study. A total of 71 patients (12%) required a repeat study due to inadequacy of the first attempt. Completed sleep studies showed that 75% of respondents had sleep disordered breathing: 4% ODI 0-4/h, 24%; 5-9/h, 19%; 10-19/h, 23%; ≥20/h, 34%; and AHI 0-4/h, 25%; 5-14/h, 38%; 15-29/h, 20%; ≥30/h, 17%. Among 1592 postal events through the national post service, 20 ALs were lost. CONCLUSIONS: We have demonstrated that a remote postal-based diagnostic service for populations with a high risk of OSA can be successfully performed. This novel approach, which avoids clinic attendance, may be useful in clinical practice.

Primary sleep disorder prevalence in patients with newly diagnosed Parkinson's disease.

BACKGROUND: Sleep disturbance occurs in up to 96% of patients with established Parkinson's disease (PD). We aimed to assess the prevalence of sleep disturbance in newly diagnosed PD. METHODS: Newly diagnosed PD patients and controls were recruited. Patients had motor, non-motor, and sleep assessments, including sleep questionnaires, respiratory home monitoring, actigraphy, and sleep diaries. Controls completed cognitive assessments, sleep questionnaires, and diaries. RESULTS: A total of 106 patients and 99 controls participated. Sleep questionnaire scores were no different between patients and controls. Daytime naps were increased in PD patients on sleep diaries (P > 0.003). Sleepiness was not associated with any motor or non-motor symptom. Periodic limb movements were increased but not associated with restless legs. CONCLUSIONS: Newly diagnosed PD patients had minimal differences in subjective or objective sleep disturbance compared to controls apart from increased daytime naps and symptoms such as dream-enacting behaviors of punching or grabbing. This contrasts with the literature assessing sleep in those with established PD.

Serum urate levels are unchanged with continuous positive airway pressure therapy for obstructive sleep apnea: a randomized controlled trial.

OBJECTIVE: Hyperuricemia is associated with the presence and severity of obstructive sleep apnea (OSA). Previous work has shown that treatment of OSA with continuous positive airway pressure (CPAP) therapy reduces urinary uric acid excretion and serum urate, but there has been no previous randomized controlled investigation on the effects of CPAP therapy on serum urate; we aimed to assess this association. METHODS: Serum urate was measured in samples from participants of a previously published randomized controlled trial. Samples were taken at baseline and after 3months from men with known type 2 diabetes mellitus (T2DM) and newly diagnosed OSA, randomized to receive either therapeutic (n=19) or placebo (n=19) CPAP for 3months. RESULTS: Both groups were well matched at baseline, with no significant difference in age, body mass index (BMI), glycosylated hemoglobin (HbA1c), or oxygen desaturation index (ODI). There was no significant difference in therapeutic or placebo CPAP usage. There was no significant difference in urate levels between groups at baseline (362µmol/L [standard deviation {SD}, 96] vs 413µmol/L [SD, 91] [reference range, 110-428µmol/L]) or at 3months. Baseline urate did not correlate with ODI, BMI, or HbA1c. The mean change in urate at 3months did not significantly differ between treatment groups (-7.6µmol/L [SD, 35.9] vs -6.2µmol/L [SD, 46.2]) (P=.9; [95% confidence interval, -28.7 to +25.9]). CONCLUSION: Our randomized controlled trial has shown no significant reduction in serum urate following 3months treatment with therapeutic or placebo CPAP.

Cough frequency, cough sensitivity and health status in patients with chronic cough.

BACKGROUND: Little is known about the frequency of cough in health and in patients with chronic cough. METHODS: We measured cough frequency and its relationship with other markers of cough severity in 20 patients with chronic cough and 9 healthy subjects using the Leicester Cough Monitor (LCM), which is an automated ambulatory digital cough monitor that records sound only. All subjects had a 6-h recording and recordings were manually counted. A subgroup of 6 normals and 6 patients with a stable chronic cough had repeat measurements up to 6 months apart. RESULTS: Mean (sem) cough counts/hour were 43(8) in patients with chronic cough and 2(1) in normals (mean difference 41; 95% confidence interval 24-59; P<0.001). The cough counts were repeatable (within subject standard deviation: 23 coughs/hour; intraclass correlation coefficient 0.8). Cough counts correlated significantly with physical (r=-0.6, P=0.03), social (r=-0.7, P=0.01) and total Leicester Cough Questionnaire (LCQ) health status scores (r=-0.6, P=0.03) and cough sensitivity (concentration of capsaicin causing 5 coughs: r=0.9, P=0.008). CONCLUSION: We have shown that there are marked differences in cough frequency between patients with chronic cough and healthy subjects, that these measurements are repeatable, and that they correlate with cough-specific health status.

Carbon loading of alveolar macrophages in adults and children exposed to biomass smoke particles.

Exposure to carbonaceous particles from biomass burning is associated with increased respiratory morbidity in both women and children in the developing world. However, the amount of carbon reaching lower airway cells has not been determined in these populations. Alveolar macrophages (AM) remove inhaled particulate matter (PM), and are implicated in the pathogenesis of PM-induced lung disease. In this study, we aimed to compare AM carbon loading in women and children exposed to biomass PM in Gondar, Ethiopia, with individuals exposed to fossil-fuel PM in the developed world (Leicester, UK). To achieve these aims, we sampled AM from Ethiopian mothers and children, and from UK adults and children using induced sputum (IS). AM were imaged under light microscopy, and the total two-dimensional surface area of carbon within each AM determined by image analysis. AM containing carbon were detected in all subjects. The total surface area of carbon per AM was higher in Ethiopian women (n=10) compared with UK adults (n=10, median 9.19 vs. 0.71 microm2/AM, p=0.0002). Similarly, the total surface area of carbon per AM was higher in Ethiopian children (n=10) compared with UK children (n=10, 3.32 vs. 0.44 microm2/AM, p=0.0002). However, loading in Ethiopian children was lower than paired maternal levels (3.32 vs. 9.19 microm2/AM, p=0.011). We conclude that analysis of AM obtained by induced sputum is a practical way of quantifying natural exposure of the lower airway to carbonaceous particles from the burning of biomass fuels.

Cough and glottic-stop reflex sensitivity in health and disease.

STUDY OBJECTIVES: Little is known about the normal ranges and repeatability of cough reflex sensitivity measurements, or the relationship of cough reflex sensitivity to other upper airway reflexes in subjects with chronic dry cough. We set out to define the normal range of cough reflex sensitivity and its repeatability in health and disease, and to assess its relationship to the glottic-stop reflex. DESIGN: Prospective, cross-sectional study. SUBJECTS AND METHODS: We measured capsaicin cough reflex sensitivity in 134 healthy subjects and 88 patients with respiratory disease, and assessed the repeatability over 2 weeks in a subgroup of individuals (healthy subjects, 15; chronic cough patients, 15). In another subgroup (healthy patients, 16; chronic cough patients, 14), we measured the sensitivity of the glottic-stop reflex (using inhaled ammonia). RESULTS: Capsaicin cough sensitivity varied widely in the population of healthy subjects, and there was considerable overlap of cough reflex sensitivity between healthy control subjects and patients with cough. The intraclass correlation coefficients for repeatability of cough sensitivity (concentration of capsaicin that causes two coughs, and concentration of capsaicin that causes five coughs) were 0.89 and 0.88, respectively. Patients with chronic cough had a significantly more sensitive glottic-stop reflex than healthy subjects (glottic-stop sensitivity threshold, 483 ppm vs 1,029 ppm, respectively; p = 0.01), and there was a significant positive correlation between glottic-stop and cough reflex sensitivity (r = 0.5; p < 0.01). CONCLUSIONS: We have shown a wide variation of cough reflex sensitivity in healthy subjects, although the measurement does have good 2-week repeatability. There was a reasonably close relationship between cough sensitivity and glottic-stop reflex sensitivity, indicating either that the cough reflex and the glottic-stop reflex share a common pathway or that subjects who have a chronic cough have a global abnormality of upper airway reflexes.