Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

Sleep medicine and coronavirus disease 2019.

PURPOSE OF REVIEW: To evaluate the impact of the COVID-19 pandemic on the care of people with sleep disorders, to explore relationships between OSA and COVID-19, and to describe current knowledge of the effect of the pandemic on sleep globally. RECENT FINDINGS: COVID-19 has led to significant changes in the practice of sleep medicine, including the care of patients with OSA. An OSA diagnosis may portend a worse prognosis with COVID-19, whilst prior COVID-19 may have an impact on sleep breathing. SUMMARY: The pandemic has caused marked difficulties with access to diagnostic sleep studies and reduced capacity for CPAP initiation. Conversely, adherence to CPAP therapy may have improved, and use of remote consultations and telemonitoring has increased. An OSA diagnosis may be associated with increased risk of severe COVID-19, although any apparent relationship may be attributable to confounding factors, such as obesity and metabolic disease. Small studies have reported some increase in CPAP requirements in OSA patients following COVID-19 infection. More generally, the pandemic has been associated with a deterioration in subjective sleep quality across the population; much of this appears because of increased anxiety and stress. Finally, studies assessing putative links between COVID-19 and REM sleep issues are ongoing.

Adherence to corticosteroids and clinical outcomes in mepolizumab therapy for severe asthma.

INTRODUCTION: Inhaled corticosteroids (ICS) achieve disease control in the majority of asthmatic patients, although adherence to prescribed ICS is often poor. Patients with severe eosinophilic asthma may require treatment with oral corticosteroids (OCS) and/or biologic agents such as mepolizumab. It is unknown if ICS adherence changes on, or alters clinical response to, biologic therapy. METHODS: We examined ICS adherence and clinical outcomes in OCS-dependent severe eosinophilic asthma patients who completed 1 year of mepolizumab therapy. The ICS medicines possession ratio (MPR) was calculated (the number of doses of ICS issued on prescription/expected number) for the year before and the year after biologic initiation. Good adherence was defined as MPR >0.75, intermediate 0.74-0.51 and poor <0.5. We examined outcomes after 12 months of biologic therapy, including OCS reduction and annualised exacerbation rate (AER), stratified by adherence to ICS on mepolizumab. RESULTS: Out of 109 patients commencing mepolizumab, 91 who had completed 12 months of treatment were included in the final analysis. While receiving mepolizumab, 68% had good ICS adherence, with 16 (18%) having poor ICS adherence. ICS use within the cohort remained similar before (MPR 0.81±0.32) and during mepolizumab treatment (0.82±0.32; p=0.78). Patients with good adherence had greater reductions in OCS dose (median (interquartile range) OCS reduction 100 (74-100)% versus 60 (27-100)%; p=0.031) and exacerbations (AER change -2.1±3.1 versus 0.3±2.5; p=0.011) than those with poor adherence. Good ICS adherence predicted the likelihood of stopping maintenance OCS (adjusted OR 3.19, 95% CI 1.02-9.94; p=0.045). CONCLUSION: ICS nonadherence is common in severe eosinophilic asthma patients receiving mepolizumab, and is associated with a lesser reduction in OCS requirements and AER.

Ambulatory detection of sleep apnea using a non-contact biomotion sensor.

The high prevalence of obstructive sleep apnea has led to increasing interest in ambulatory diagnosis. The SleepMinder™ (SM) is a novel non-contact device that employs radiofrequency wave technology to assess the breathing pattern, and thereby estimate obstructive sleep apnea severity. We assessed the performance of SleepMinder™ in the home diagnosis of obstructive sleep apnea. One-hundred and twenty-two subjects were prospectively recruited in two protocols, one from an unselected sleep clinic cohort (n = 67, mean age 51 years) and a second from a hypertension clinic cohort (n = 55, mean age 58 years). All underwent 7 consecutive nights of home monitoring (SMHOME ) with the SleepMinder™ as well as inpatient-attended polysomnography in the sleep clinic cohort or cardiorespiratory polygraphy in the hypertension clinic cohort with simultaneous SleepMinder™ recordings (SMLAB ). In the sleep clinic cohort, median SMHOME apnea-hypopnea index correlated significantly with polysomnography apnea-hypopnea index (r = .68; p < .001), and in the hypertension clinic cohort with polygraphy apnea-hypopnea index (r = .7; p < .001). The median SMHOME performance against polysomnography in the sleep clinic cohort showed a sensitivity and specificity of 72% and 94% for apnea-hypopnea index ≥ 15. Device performance was inferior in females. In the hypertension clinic cohort, SMHOME showed a 50% sensitivity and 72% specificity for apnea-hypopnea index ≥ 15. SleepMinder™ classified 92% of cases correctly or within one severity class of the polygraphy classification. Night-to-night variability in home testing was relatively high, especially at lower apnea-hypopnea index levels. We conclude that the SleepMinder™ device provides a useful ambulatory screening tool, especially in a population suspected of obstructive sleep apnea, and is most accurate in moderate-severe obstructive sleep apnea.

Video polysomnographic findings in non-rapid eye movement parasomnia.

Although video polysomnography (vPSG) is not routinely recommended for the evaluation of typical cases of non-rapid eye movement (NREM) parasomnias, it can aid diagnosis of unusual cases, other sleep disorders and complicated cases with REM behaviour disorder (RBD), and in differentiating parasomnias from epilepsy. In this study, we aimed to assess vPSG findings in consecutive patients with a clinical diagnosis of NREM-parasomnia covering the whole phenotypic spectrum. Five hundred and twelve patients with a final diagnosis of NREM parasomnia who had undergone vPSG were retrospectively identified. vPSGs were analysed for features of NREM parasomnia and for the presence of other sleep disorders. Two hundred and six (40.0%) patients were clinically diagnosed with sleepwalking, 72 (14.1%) with sleep terrors, 39 (7.6%) with confusional arousals, 15 (2.9%) with sexsomnia, seven (1.4%) with sleep-related eating disorder, 122 (23.8%) with mixed phenotype, and 51 (10.0%) with parasomnia overlap disorder (POD). The vPSG supported the diagnosis of NREM parasomnia in 64.4% of the patients and of POD in 98%. In 28.9% of the patients, obstructive sleep apnea (OSA) or/and periodic limb movements during sleep (PLMS) were identified, most commonly in older, male, sleepy and obese patients. vPSG has a high diagnostic yield in patients with NREM parasomnia and should be routinely performed when there is diagnostic doubt, or in patients where there is a suspicion of OSA and PLMS.

Sleep and interstitial lung disease.

PURPOSE OF REVIEW: There is an increasing recognition of the impact of sleep and sleep disorders on respiratory disease. Recent years have seen a new focus on the relationship between sleep and outcomes in patients interstitial lung disease (ILD). RECENT FINDINGS: Recent studies suggest a high prevalence of sleep issues in ILD cohorts, which seem to have a meaningful negative impact on quality of life, disease progression, and survival. SUMMARY: Sleep disordered breathing is common in ILD patients: obstructive sleep apnoea (OSA) is found in 44-72% of ILD patients, and nocturnal hypoxemia is relatively common even in the absence of OSA. Sleep disorders are associated with worse quality of life in ILD, and may also predict more rapid disease progression and increased mortality. It remains unknown if nocturnal hypoxemia may itself cause progression of ILD. Uncontrolled and retrospective studies have suggested that treating OSA may improve ILD-related outcomes, but prospective studies are lacking in this field.

Effectiveness and side-effect profile of stimulant therapy as monotherapy and in combination in the central hypersomnias in clinical practice.

Effectiveness and side-effect profile data on pharmacotherapy for daytime sleepiness in central hypersomnias are based largely upon randomized controlled trials. Evidence regarding the use of combination therapy is scant. The aim of this study was to examine the effectiveness and occurrence of drug-related side effects of these drugs in routine clinical practice. Adult patients diagnosed with a central hypersomnia during a 54-month period at a tertiary sleep disorders centre were identified retrospectively. Side effects were recorded at every follow-up visit. A total of 126 patients, with 3275 patient-months of drug exposure, were categorized into narcolepsy type 1 (n = 70), narcolepsy type 2 (n = 47) and idiopathic hypersomnia (n = 9). Modafinil was the most common drug used as a first-line treatment (93%) and in combination therapy (70%). Thirty-nine per cent of the patients demonstrated a complete, 25% partial and 36% a poor response to treatment. Combination treatment improved daytime sleepiness in 55% of the patients with residual symptoms despite monotherapy. Sixty per cent of patients reported side effects, and 30% reported treatment-limiting side effects. Drugs had similar side-effect incidence (P = 0.363) and their side-effect profile met those reported in the literature. Twenty-seven per cent of the patients received combination treatment and had fewer side effects compared to monotherapy (29.4% versus 60%, respectively, P = 0.001). Monotherapy appears to achieve satisfactory symptom control in most patients with central hypersomnia, but significant side effects are common. Combination therapy appears to be a useful and safe option in patients with refractory symptoms.

Sleep and asthma.

PURPOSE OF REVIEW: There is a longstanding recognition of the detrimental effect of poorly controlled asthma on sleep, but recent years have seen a growing interest in how asthma and sleep may interact. This review examines the current evidence of relationships between asthma, sleep and sleep disorders. RECENT FINDINGS: Poor quality sleep and sleep disturbance is highly prevalent in asthmatic patients, and particularly in those with severe asthma. Impaired sleep quality correlates with worse asthma control and quality of life. Sleep disturbance in asthma may be related to due circadian variation in airway inflammation, but may also be related to specific sleep disorders. Obstructive sleep apnoea (OSA) appears to be significantly more common in asthmatic patients than nonasthmatic patients, and treatment of OSA with continuous positive airway pressure (CPAP) may lead to improved asthma-specific quality of life. Nocturnal CPAP may also be of benefit to asthmatic patients without OSA, potentially because of stretching of airway smooth muscle. Insomnia is also highly prevalent in severe asthma patients, and is associated with a history of poor asthma control and increased healthcare utilization. SUMMARY: Asthma, sleep and sleep disorders appear to have complex, but significant relationships. Prospective observational and controlled interventional studies are needed to quantify how addressing sleep difficulties may benefit asthma patients.

Obstructive sleep apnoea independently predicts lipid levels: Data from the European Sleep Apnea Database.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) and dyslipidaemia are independent risk factors for cardiovascular disease. This study investigates the association between OSA and plasma lipid concentrations in patients enrolled in the European Sleep Apnea Database (ESADA) cohort. METHODS: The cross-sectional analysis included 8592 patients without physician-diagnosed hyperlipidaemia or reported intake of a lipid-lowering drug (age 50.1 ± 12.7 years, 69.1% male, BMI: 30.8 ± 6.6 kg/m2 , mean apnoea-hypopnoea index (AHI): 25.7 ± 25.9 events/h). The independent relationship between measures of OSA (AHI, oxygen desaturation index (ODI), mean and lowest oxygen saturation) and lipid profile (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and fasting triglycerides (TG)) was determined by means of general linear model analysis. RESULTS: There was a dose response relationship between TC and ODI (mean ± SE (mg/dL): 180.33 ± 2.46, 184.59 ± 2.42, 185.44 ± 2.42 and 185.73 ± 2.44; P < 0.001 across ODI quartiles I-IV). TG and LDL concentrations were better predicted by AHI than by ODI. HDL-C was significantly reduced in the highest AHI quartile (mean ± SE (mg/dL): 48.8 ± 1.49 vs 46.50 ± 1.48; P = 0.002, AHI quartile I vs IV). Morbid obesity was associated with lower TC and higher HDL-C values. Lipid status was influenced by geographical location with the highest TC concentration recorded in Northern Europe. CONCLUSION: OSA severity was independently associated with cholesterol and TG concentrations.

Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation.

Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA. Providing mechanistic insight, IH induced a pro-inflammatory phenotype of visceral adipose tissue in mice with pro-inflammatory M1 macrophage polarisation correlating with the severity of insulin resistance. Complimentary in vitro analysis demonstrated that IH led to M1 polarisation of THP1-derived macrophages. In subjects without comorbidities (n=186), OSA was independently associated with insulin resistance. Furthermore, we found an independent correlation of OSA severity with the M1 macrophage inflammatory marker sCD163.This study provides evidence that IH induces a pro-inflammatory phenotype of the adipose tissue, which may be a crucial link between OSA and the development of insulin resistance.

Sleep-stage sequencing of sleep-onset REM periods in MSLT predicts treatment response in patients with narcolepsy.

Current treatment recommendations for narcolepsy suggest that modafinil should be used as a first-line treatment ahead of conventional stimulants or sodium oxybate. In this study, performed in a tertiary sleep disorders centre, treatment responses were examined following these recommendations, and the ability of sleep-stage sequencing of sleep-onset rapid eye movement periods in the multiple sleep latency test to predict treatment response. Over a 3.5-year period, 255 patients were retrospectively identified in the authors' database as patients diagnosed with narcolepsy, type 1 (with cataplexy) or type 2 (without) using clinical and polysomnographic criteria. Eligible patients were examined in detail, sleep study data were abstracted and sleep-stage sequencing of sleep-onset rapid eye movement periods were analysed. Response to treatment was graded utilizing an internally developed scale. Seventy-five patients were included (39% males). Forty (53%) were diagnosed with type 1 narcolepsy with a mean follow-up of 2.37 ± 1.35 years. Ninety-seven percent of the patients were initially started on modafinil, and overall 59% reported complete response on the last follow-up. Twenty-nine patients (39%) had the sequence of sleep stage 1 or wake to rapid eye movement in all of their sleep-onset rapid eye movement periods, with most of these diagnosed as narcolepsy type 1 (72%). The presence of this specific sleep-stage sequence in all sleep-onset rapid eye movement periods was associated with worse treatment response (P = 0.0023). Sleep-stage sequence analysis of sleep-onset rapid eye movement periods in the multiple sleep latency test may aid the prediction of treatment response in narcoleptics and provide a useful prognostic tool in clinical practice, above and beyond their classification as narcolepsy type 1 or 2.

Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression.

INTRODUCTION: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. METHODS AND RESULTS: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. CONCLUSION: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.

Sleep apnoea severity independently predicts glycaemic health in nondiabetic subjects: the ESADA study.

Obstructive sleep apnoea (OSA) is associated with increased risk of dysglycaemia but the intimate link of these conditions with obesity makes discerning an independent relationship between them challenging. Glycosylated haemoglobin (HbA1c) levels predict adverse cardiovascular outcomes in nondiabetics but there is a lack of population-level data exploring the relationship of HbA1c with OSA. A cross-sectional analysis of 5294 participants in the multinational European Sleep Apnoea Cohort (European Sleep Apnoea Database) study was performed, assessing the relationship of OSA severity with HbA1c levels in nondiabetic subjects, with adjustment for confounding factors. HbA1c levels correlated significantly with OSA severity in univariate analysis. Following adjustment for confounding factors, apnoea-hypopnoea index (AHI) (standardised ß 0.158; p<0.001), along with nocturnal hypoxaemia, predicted HbA1c. Adjusted mean HbA1c levels were lower in the lowest AHI quartile (5.24%, 95% CI 5.21-5.27%) than in the second (5.37%, 95% CI 5.34-5.40%), third (5.44%, 95% CI 5.41-5.47%) or highest (5.50%, 95% CI 5.46-5.53%) quartiles. Subjects in the higher quartiles had significantly greater adjusted odds ratios of HbA1c level ≥6.0% than those in the first quartile. In stratified analyses, OSA severity predicted glycaemic health irrespective of sleep study modality, sex, obesity or daytime sleepiness. OSA severity independently predicts glycaemic health in nondiabetic subjects. Further studies should assess the impact of OSA treatment on glycaemic health and elucidate underlying mechanisms.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study.

Obstructive sleep apnoea (OSA) is associated with significantly increased risk of cardiovascular disease. Carotid ultrasonography and retrospective, uncontrolled, coronary imaging studies have suggested an association of OSA with subclinical atherosclerosis, but there is a lack of prospective, controlled studies directly evaluating the relationship of OSA with occult coronary artery disease. We performed coronary computed tomographic angiography and inpatient-attended sleep studies on a cohort of otherwise healthy males attending our sleep laboratory, and compared coronary artery plaque volume between subjects with low and high apnoea/hypopnoea index (AHI) scores. 29 subjects participated. The median AHI was 15.5 events · h(-1), with subjects who scored above this classified as high AHI. No significant differences were observed in demographic, anthropometric and clinical variables between the high- and low-AHI groups. Coronary plaque volume was significantly greater in the high-AHI group (mean plaque volume 2.6 ± 0.7 mm(2) versus 0.8 ± 0.2 mm(2); p=0.017) and, furthermore, correlated significantly with AHI (Spearman's r=0.433; p=0.019). Following adjustment for dyslipidaemia and fasting plasma glucose levels, AHI remained a significant predictor of plaque volume (standardised ß=0.424; p=0.027). In this prospective case-control study, we found that severity of OSA may predict occult coronary atherosclerosis in otherwise healthy overweight or obese male subjects.