Sébastien Bailly

Obstructive Sleep Apnea: A Cluster Analysis at Time of Diagnosis.

Background The classification of obstructive sleep apnea is on the basis of sleep study criteria that may not adequately capture disease heterogeneity. Improved phenotyping may improve prognosis prediction and help select therapeutic strategies. Objectives: This study used cluster analysis to investigate the clinical clusters of obstructive sleep apnea. Methods An ascending hierarchical cluster analysis was performed on baseline symptoms, physical examination, risk factor exposure and co-morbidities from 18,263 participants in the OSFP (French national registry of sleep apnea). The probability for criteria to be associated with a given cluster was assessed using odds ratios, determined by univariate logistic regression. Results: Six clusters were identified, in which patients varied considerably in age, sex, symptoms, obesity, co-morbidities and environmental risk factors. The main significant differences between clusters were minimally symptomatic versus sleepy obstructive sleep apnea patients, lean versus obese, and among obese patients different combinations of co-morbidities and environmental risk factors. Conclusions Our cluster analysis identified six distinct clusters of obstructive sleep apnea. Our findings underscore the high degree of heterogeneity that exists within obstructive sleep apnea patients regarding clinical presentation, risk factors and consequences. This may help in both research and clinical practice for validating new prevention programs, in diagnosis and in decisions regarding therapeutic strategies.

Obstructive Sleep Apnea Syndrome, Objectively Measured Physical Activity and Exercise Training Interventions: A Systematic Review and Meta-Analysis

A systematic review of English and French articles using Pubmed/Medline and Embase included studies assessing objective physical activity levels of obstructive sleep apnea (OSA) patients and exploring the effects of exercise training on OSA severity, body mass index (BMI), sleepiness, and cardiorespiratory fitness [peak oxygen consumption (VO2peak)]. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. For objective physical activity levels, eight studies were included. The mean number of steps per day across studies was 5,388 (95% CI: 3,831–6,945; p < 0.001), which was by far lower than the recommended threshold of 10,000 steps per day. For exercise training, six randomized trials were included. There was a significant decrease in apnea–hypopnea-index following exercise training (mean decrease of 8.9 events/h; 95% CI: −13.4 to −4.3; p < 0.01), which was accompanied by a reduction in subjective sleepiness, an increase in VO2peak and no change in BMI. OSA patients present low levels of physical activity and exercise training is associated with improved outcomes. Future interventions (including exercise training) focusing on increasing physical activity levels may have important clinical impacts on both OSA severity and the burden of associated co-morbidities. Objective measurement of physical activity in routine OSA management and well-designed clinical trials are recommended. Registration # CRD42017057319 (Prospero).

Maximal exercise capacity in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis

Maximal aerobic capacity is a strong health predictor and peak oxygen consumption (V′O2peak) is considered a reflection of total body health. No systematic reviews or meta-analyses to date have synthesised the existing data regarding V′O2peak in patients with obstructive sleep apnoea (OSA). A systematic review of English and French articles using PubMed/MEDLINE and Embase included studies assessing V′O2peak in OSA patients either in mL·kg−1·min−1 compared with controls or in % predicted. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence. Mean V′O2peak expressed in mL·kg−1·min−1 was significantly lower in patients with OSA than in controls (mean difference −2.7 mL·kg−1·min−1; p<0.001; n=850). This reduction in V′O2peak was found to be larger in non-obese patients (body mass index <30 kg·m−2). Mean V′O2peak % pred was 89.9% in OSA patients (n=643). OSA patients have reduced maximal aerobic capacity, which can be associated with increased cardiovascular risks and reduced survival in certain patient subgroups. Maximal exercise testing can be useful to characterise functional limitation and to evaluate health status in OSA patients. Maximal exercise capacity as a reflection of total body health is reduced in patients with obstructive sleep apnoea http://ow.ly/EdaD30jAE7k

Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations

How pharmacogenetics modulates the inhibitory effects of inflammation on voriconazole trough concentration (Cmin) remains unknown. In 29 recipients of allogeneic hematopoietic stem cell transplantation retrospectively studied, both a genetic score (which aggregated CYP2C19 and CYP3A genotypes) and inflammation significantly influenced voriconazole Cmin (n = 260). A trend toward (p = 0.03) a greater impact of inflammation in patients with the highest genetic score (corresponding to ultra-rapid metabolizers) was observed. Further researches are needed to confirm these data.

Added Value of Next-Generation Sequencing for Multilocus Sequence Typing Analysis of a Pneumocystis jirovecii Pneumonia Outbreak1

Pneumocystis jirovecii is a major threat for immunocompromised patients, and clusters of pneumocystis pneumonia (PCP) have been increasingly described in transplant units during the past decade. Exploring an outbreak transmission network requires complementary spatiotemporal and strain-typing approaches. We analyzed a PCP outbreak and demonstrated the added value of next-generation sequencing (NGS) for the multilocus sequence typing (MLST) study of P. jirovecii strains. Thirty-two PCP patients were included. Among the 12 solid organ transplant patients, 5 shared a major and unique genotype that was also found as a minor strain in a sixth patient. A transmission map analysis strengthened the suspicion of nosocomial acquisition of this strain for the 6 patients. NGS-MLST enables accurate determination of subpopulation, which allowed excluding other patients from the transmission network. NGS-MLST genotyping approach was essential to deciphering this outbreak. This innovative approach brings new insights for future epidemiologic studies on this uncultivable opportunistic fungus.

Molecular diagnosis of toxoplasmosis: value of the buffy coat for the detection of circulating Toxoplasma gondii

Early detection of Toxoplasma tachyzoites circulating in blood using PCR is recommended for immunosuppressed patients at high risk for disseminated toxoplasmosis. Using a toxoplasmosis mouse model, we show that the sensitivity of detection is higher using buffy coat isolated from a large blood volume than using whole blood for this molecular monitoring.

Baclofen and sleep apnoea syndrome: analysis of VigiBase, the WHO pharmacovigilance database

Baclofen is a centrally acting gamma aminobutyric acid (GABA)-B agonist, widely used for chronic spasticity in neurological disorders, available in oral and intrathecal formulations. Depending on the severity of spasticity and tolerance, standard treatment includes daily oral administration of 40–80 mg [1]. The main adverse effects reported with baclofen are sedation, sleepiness, weakness, dizziness and psychological disturbances [2]. According to the depressant effects of GABA on the central nervous system, baclofen might also induce or aggravate sleep-disordered breathing by depressing central ventilatory drive and/or increasing upper airway obstruction. A single oral low dose of baclofen did not significantly impair the apnoea–hypopnoea index (AHI) in a population with moderate obstructive sleep apnoea [3], but bolus intrathecal administration of the drug increased central sleep apnoea (CSA) in patients with severe spasticity [4]. Baclofen is associated with sleep apnoea syndrome especially the high oral doses prescribed for alcohol addiction http://ow.ly/J5H730h4znW

Effect of Transfusion on Mortality and Other Adverse Events Among Critically Ill Septic Patients: An Observational Study Using a Marginal Structural Cox Model*

Objectives: RBC transfusion is often required in patients with sepsis. However, adverse events have been associated with RBC transfusion, raising safety concerns. A randomized controlled trial validated the 7 g/dL threshold, but previously transfused patients were excluded. Cohort studies led to conflicting results and did not handle time-dependent covariates and history of treatment. Additional data are thus warranted to guide patient’s management. Design: To estimate the effect of one or more RBC within 1 day on three major outcomes (mortality, ICU-acquired infections, and severe hypoxemia) at day 30, we used marginal structural models. A trajectory modeling, based on hematocrit evolution pattern, allowed identification of subgroups. Secondary analyses were performed into each of them. Setting: A prospective French multicenter database. Patients: Patients with sepsis at admission. Patients with hemorrhagic shock at admission were excluded. Interventions: None. Measurements and Main Results: Overall, in our cohort of 6,016 patients, RBC transfusion was not associated with death (hazard ratio, 1.07; 95% CI, 0.88–1.30; p = 0.52). However, RBC transfusion was associated with increased occurrence of ICU-acquired infections (hazard ratio, 2.77; 95% CI, 2.33–3.28; p < 0.01) and of severe hypoxemia (hazard ratio, 1.29; 95% CI, 1.14–1.47; p < 0.01). A protective effect from death by the transfusion was found in the subgroup with the lowest hematocrit level (26 [interquartile range, 24–28]) (hazard ratio, 0.72; 95% CI, 0.55–0.95; p = 0.02). Conclusions: RBC transfusion did not affect overall mortality in critically ill patients with sepsis. Increased occurrence rate of ICU-acquired infection and severe hypoxemia are expected outcomes from RBC transfusion that need to be weighted with its benefits in selected patients.

Contribution of a Simple Bioassay in Effective Therapeutic Drug Monitoring of Posaconazole and Voriconazole.

Background: With the constantly growing incidence of invasive fungal infections, any failure of antifungal treatment is worrying. Azole antifungals present high variability of their plasma trough concentrations (Cmin), justifying their therapeutic drug monitoring (TDM). The authors aimed to develop a simple bioassay to determine the in vitro growth inhibition diameter (ID) and to correlate this ID with Cmin in patients treated with voriconazole or posaconazole. Methods: The bioassay determined the ID for Candida parapsilosis using a disk diffusion method. Calibration curves were built for posaconazole and voriconazole in water and in 45% plasma. ID was determined in plasma from patients currently undergoing TDM for posaconazole (n = 73) or voriconazole (n = 90). Results: In water or plasma spiked with antifungals and patient samples, cubic regression between ID and Cmin gave coefficient of determination values of 0.997, 0.999, and 0.819, respectively, for posaconazole and 0.996, 0.990 and 0.925, respectively, for voriconazole (P < 0.001 for each curve). Calibration curves with or without plasma did not differ. For voriconazole, Cmin of 1 and 4.7 mg/L corresponded to 54% and 90% of maximal ID, respectively. For posaconazole, Cmin of 0.5, 0.7, and 1 mg/L corresponded to 26%, 40%, and 53% of maximal ID, respectively. Conclusions: Bioassay could be useful to better characterize the antifungal therapeutic range and brings additional information to the interpretation of TDM in patients for whom Cmin alone is insufficient to adjust the antifungal dosage.

Contribution of obstructive sleep apnoea to arterial stiffness: a meta-analysis using individual patient data

Background Arterial stiffness, measured by pulse wave velocity (PWV), is a strong independent predictor of late cardiovascular events and mortality. It is recognised that obstructive sleep apnoea (OSA) is associated with cardiovascular comorbidities and mortality. Although previous meta-analyses concluded that PWV is elevated in OSA, we feel that an individual patient data analysis from nine relatively homogeneous studies could help answer: to what extent does OSA drive arterial stiffness? Methods Individual data from well-characterised patients referred for suspicion of OSA, included in nine studies in which carotid–femoral PWV was measured using a Complior device, were merged for an individual patient data meta-analysis. Results 893 subjects were included (age: 56±11 (mean±SD), 72% men, 84% with confirmed OSA). Body Mass Index varied from 15 to 81 kg/m2 (30±7 kg/m2). PWV ranged from 5.3 to 20.5 m/s (10.4±2.3 m/s). In univariate analysis, log(PWV) was strongly related to age, gender, systolic blood pressure, presence of type 2 diabetes (all p<0.01) as well as to dyslipidaemia (p=0.03) and an Epworth Sleepiness Scale score ≥9 (p=0.04), whereas it was not related to obesity (p=0.54), a severe Apnoea–Hypopnoea Index (p=0.14), mean nocturnal saturation (p=0.33) or sleep time with oxygen saturation below 90% (p=0.47). In multivariable analysis, PWV was independently associated with age, systolic blood pressure and diabetes (all p<0.01), whereas severe OSA was not significantly associated with PWV. Conclusion Our individual patient meta-analysis showed that elevated arterial stiffness in patients with OSA is driven by conventional cardiovascular risk factors rather than apnoea parameters.