The effect of longitudinal sleep monitoring on clinician agreement in obstructive sleep apnea diagnosis: The ELSA study.

There is strong evidence for clinically relevant night-to-night variability of respiratory events in patients with suspected obstructive sleep apnea. Sleep experts retrospectively evaluated diagnostic data in 56 patients with suspected obstructive sleep apnea. Experts were blinded to the fact that they were diagnosing the same case twice, once based on a short report of a single in-laboratory respiratory polygraphy and once with the additional information of 14 nights of pulse oximetry at home. All experts (n = 22) were highly qualified, 13 experts (59.1%) treated > 100 patients with suspected obstructive sleep apnea per year. In 12 patients, the apnea-hypopnea index in the respiratory polygraphy was < 5 per hr, but the mean oxygen desaturation index of 14 nights of pulse oximetry was ≥ 5 per hr. The additional information of 14 nights of pulse oximetry helped to diagnose obstructive sleep apnea with a 70% consensus in two of those patients (16.7% [95% confidence interval: 4.7/44.8]). In eight patients, experts could not agree to a 70% consensus regarding continuous positive airway pressure therapy recommendation after respiratory polygraphy. The additional information of multiple-night testing led to a consensus in three of those cases (37.5% [95% confidence interval: 14/69]). Change of obstructive sleep apnea diagnosis and continuous positive airway pressure recommendation was significantly negatively associated with the number of treated obstructive sleep apnea patients > 100 per year compared with 0-29 patients per year (Coef. [95% confidence interval] -0.63 [-1.22/-0.04] and -0.61 [-1.07/-0.15], respectively). Experts found already a high level of consensus regarding obstructive sleep apnea diagnosis, severity and continuous positive airway pressure recommendation after a single respiratory polygraphy. However, longitudinal sleep monitoring could help increase consensus in selected patients with diagnostic uncertainty.

Adaptive Immunosuppression in Lung Transplant Recipients Applying Complementary Biomarkers: The Zurich Protocol.

Achieving adequate immunosuppression for lung transplant recipients in the first year after lung transplantation is a key challenge. Prophylaxis of allograft rejection must be balanced with the adverse events associated with immunosuppressive drugs, for example infection, renal failure, and diabetes. A triple immunosuppressive combination is standard, including a steroid, a calcineurin inhibitor, and an antiproliferative compound beginning with the highest levels of immunosuppression and a subsequent tapering of the dose, usually guided by therapeutic drug monitoring and considering clinical results, bronchoscopy sampling results, and additional biomarkers such as serum viral replication or donor-specific antibodies. Balancing the net immunosuppression level required to prevent rejection without overly increasing the risk of infection and other complications during the tapering phase is not well standardized and requires repeated assessments for dose-adjustments. In our adaptive immunosuppression approach, we additionally consider results from the white blood cell counts, in particular lymphocytes and eosinophils, as biomarkers for monitoring the level of immunosuppression and additionally use them as therapeutic targets to fine-tune the immunosuppressive strategy over time. The concept and its rationale are outlined, and areas of future research mentioned.

Multimodal Remote Home Monitoring of Lung Transplant Recipients during COVID-19 Vaccinations: Usability Pilot Study of the COVIDA Desk Incorporating Wearable Devices.

Background and Objectives: Remote patient monitoring (RPM) of vital signs and symptoms for lung transplant recipients (LTRs) has become increasingly relevant in many situations. Nevertheless, RPM research integrating multisensory home monitoring in LTRs is scarce. We developed a novel multisensory home monitoring device and tested it in the context of COVID-19 vaccinations. We hypothesize that multisensory RPM and smartphone-based questionnaire feedback on signs and symptoms will be well accepted among LTRs. To assess the usability and acceptability of a remote monitoring system consisting of wearable devices, including home spirometry and a smartphone-based questionnaire application for symptom and vital sign monitoring using wearable devices, during the first and second SARS-CoV-2 vaccination. Materials and Methods: Observational usability pilot study for six weeks of home monitoring with the COVIDA Desk for LTRs. During the first week after the vaccination, intensive monitoring was performed by recording data on physical activity, spirometry, temperature, pulse oximetry and self-reported symptoms, signs and additional measurements. During the subsequent days, the number of monitoring assessments was reduced. LTRs reported on their perceptions of the usability of the monitoring device through a purpose-designed questionnaire. Results: Ten LTRs planning to receive the first COVID-19 vaccinations were recruited. For the intensive monitoring study phase, LTRs recorded symptoms, signs and additional measurements. The most frequent adverse events reported were local pain, fatigue, sleep disturbance and headache. The duration of these symptoms was 5-8 days post-vaccination. Adherence to the main monitoring devices was high. LTRs rated usability as high. The majority were willing to continue monitoring. Conclusions: The COVIDA Desk showed favorable technical performance and was well accepted by the LTRs during the vaccination phase of the pandemic. The feasibility of the RPM system deployment was proven by the rapid recruitment uptake, technical performance (i.e., low number of errors), favorable user experience questionnaires and detailed individual user feedback.

Obstructive sleep apnoea and the progression of thoracic aortic aneurysm: a prospective cohort study.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with an increased prevalence of aortic aneurysms and it has also been suggested that severe OSA furthers aneurysm expansion in the abdomen. We evaluated whether OSA is a risk factor for the progression of ascending thoracic aortic aneurysm (TAA). METHODS: Patients with TAA underwent yearly standardised echocardiographic measurements of the ascending aorta over 3 years and two level III sleep studies. The primary outcome was the expansion rate of TAA in relation to the apnoea-hypopnoea index (AHI). Secondary outcomes included surveillance for aortic events (composite end-points of rupture/dissection, elective surgery or death). RESULTS: Between July 2014 and March 2020, 230 patients (median age 70 years, 83.5% male) participated in the cohort. At baseline, 34.8% of patients had AHI ≥15 events·h-1. There was no association between TAA diameter and AHI at baseline. After 3 years, mean±sd expansion rates were 0.55±1.25 mm at the aortic sinus and 0.60±1.12 mm at the ascending aorta. In the regression analysis, after controlling for baseline diameter and cardiovascular risk factors, there was strong evidence for a positive association of TAA expansion with AHI (aortic sinus estimate 0.025 mm, 95% CI 0.009-0.040 mm; p<0.001 and ascending aorta estimate 0.026 mm, 95% CI 0.011-0.041 mm; p=0.001). 20 participants (8%) experienced an aortic event; however, there was no association with OSA severity. CONCLUSION: OSA may be a modest but independent risk factor for faster TAA expansion and thus potentially contributes to life-threatening complications in aortic disease.

Predictors of changes in subjective daytime sleepiness in response to CPAP therapy withdrawal in OSA: A post-hoc analysis.

Subjective sleepiness is the hallmark symptom of untreated obstructive sleep apnea (OSA) and leads to an increased risk of motor vehicle accidents and impaired quality of life. Continuous positive airway pressure (CPAP) is the standard therapy for OSA and improves sleepiness. The aim was to identify factors that might predict recurrence of sleepiness in times off CPAP and to define OSA patient types with a likely effect of CPAP on sleepiness. A post-hoc analysis of six clinical trials, including 132 patients with OSA effectively treated with CPAP prior to study inclusion, who were allocated to 2 weeks of CPAP withdrawal, was conducted to assess predictors of a change in subjective sleepiness. A multivariate regression model was used to assess predictors of a change in the Epworth Sleepiness Scale (ESS) score. In response to CPAP withdrawal, the median apnea-hypopnea index (AHI) and the ESS score significantly increased compared to baseline on CPAP by 32.6/hr (95% CI, 28.8, 36.4)/hr and 2.5 (95% CI, 1.8,3.2), respectively (p < .001), in the included 132 patients. There was an independent positive association of AHI (Coef. [95% CI] 0.04 [0.01, 0.08]) with an increase in ESS score upon CPAP withdrawal, and an independent negative association of age (coef. [95% CI], -0.10 [-0.18, -0.2]), ESS on CPAP (coef. [95% CI], -0.21 [-0.40, -0.015]) and active smoking status (coef. [95% CI], -1.22 [-2.26, -0.17]). These findings suggest that younger patients with a low residual sleepiness on CPAP and a recurrence of more severe OSA during CPAP withdrawal are at highest risk of suffering from a clinically relevant return of daytime sleepiness in times off CPAP.

Night-to-night variability of respiratory events in obstructive sleep apnoea: a systematic review and meta-analysis.

BACKGROUND: It is current practice to use a single diagnostic sleep study in the diagnostic workup of obstructive sleep apnoea (OSA). However, a relevant night-to-night variability (NtNV) of respiratory events has been reported. METHODS: We evaluated the NtNV of respiratory events in adults with suspected or already diagnosed OSA who underwent more than one diagnostic sleep study. Data sources were PubMed, Cochrane and Embase up to 23 January 2019. Random-effects models were used for evidence synthesis. For moderator analysis, mixed-effects regression analysis was performed. The study was registered with PROSPERO (CRD42019135277). RESULTS: Of 2143 identified papers, 24 studies, comprising 3250 participants, were included. The mean Apnoea-Hypopnoea Index (AHI) difference between the first and second night was -1.70/hour (95% CI -3.61 to 0.02). REM time differences (first to second night) were significantly positive associated with differences in mean AHI (ß coefficient 0.262 (95% CI 0.096 to 0.428). On average, 41% (95% CI 27% to 57%) of all participants showed changes of respiratory events >10/hour from night to night. Furthermore, 49% (95% CI 32% to 65%) of participants changed OSA severity class (severity thresholds at 5/hour, 15/hour and 30/hour) at least once in sequential sleep studies. Depending on the diagnostic threshold (5/hour, 10/hour or 15/hour), on average 12% (95% CI 9% to 15%), 12% (95% CI 8% to 19%) and 10% (95% CI 8% to 13%) of patients would have been missed during the first night due to single night testing. CONCLUSION: While there was no significant difference between mean AHI in two sequential study nights on a group level, there was a remarkable intraindividual NtNV of respiratory events, leading to misdiagnosis and misclassification of patients with suspected OSA.

Increased augmentation index in patients with Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascular disease progression (e.g. arterial aneurysms, dissections, and ruptures) in EDS patients are still missing. Recently, applanation tonometry derived augmentation index (AIx), an indirect marker of arterial stiffness, has shown to be positively associated with progression of aortic disease in Marfan syndrome. In this study, we assessed aortic AIx in patients with EDS and matched healthy controls. METHODS: We performed noninvasive applanation tonometry in 61 adults with EDS (43 women and 18 men aged 39.3 ± 14.6 years) and 61 age-, gender-, height-, and weight-matched healthy controls. Radial artery pulse waveforms were recorded and analyzed using the SphygmoCor System (AtCor Medical, Sydney, NSW, Australia). Calculated AIx was adjusted to a heart rate of 75/min. Groups were compared and association between AIx and EDS was determined by univariate and multivariate regression analysis. RESULTS: EDS patients were categorized in classical type EDS (34%), hypermobile type EDS (43%), vascular type EDS (5%), or remained unassignable (18%) due to overlapping features. EDS patients showed a significantly increased aortic AIx compared to healthy controls (22.8% ± 10.1 vs 14.8% ± 14.0, p < 0.001). EDS showed a positive association with AIx; independent of age, sex, height, blood pressure, medication, and pack years of smoking. CONCLUSIONS: Patients with EDS showed elevated AIx, indicating increased arterial stiffness when compared to healthy controls. Further investigations are needed in order to assess the prognostic value of increased AIx for cardiovascular outcomes in patients with EDS.

Prevalence of Obstructive Sleep Apnea in Patients with Thoracic Aortic Aneurysm: A Prospective, Parallel Cohort Study.

BACKGROUND: The pathogenesis and etiology of thoracic aortic aneurysms (TAA) are largely unknown. Preliminary data from patients with aortic dissection and abdominal aneurysms suggest a causal link of obstructive sleep apnea (OSA) on aortic disease. OBJECTIVES: The aim of the study was to assess the prevalence of OSA in patients with TAA compared to a matched control group. METHOD: In this prospective parallel-cohort study, we 2-to-1 matched 208 patients with verified TAA (at the aortic sinus and/or ascending aorta) to 104 controls without TAA according to sex, age, height, weight, and left ventricular ejection fraction. All participants underwent an ultrasound of the thoracic aorta and a level III respiratory polygraphy. OSA was defined as apnea-hypopnea index ≥5/h. The prevalence of OSA was compared with conditional logistic regression and controlling for the matching variables. RESULTS: A total of 312 patients (mean age 65 ± 11 years, 82% male, mean body mass index 27 ± 4 kg/m2) were successfully 2-to-1 matched in the final model. Prevalence of OSA was significantly higher in the TAA-group when compared to the matched control group (63 vs. 47%; odds ratio 1.87 [95% CI 1.05-3.34]; p = 0.03). When applying a higher apnea-hypopnea index threshold (≥15/h), the odds ratio increased to 3.25 (95% CI 1.65-6.42; p < 0.001). The median apnea-hypopnea index was higher in patients with TAA (9.2/h [3.3-20.0] vs. 4.5/h [2.2-11.1], p < 0.001). CONCLUSIONS: Patients with TAA have a higher prevalence of OSA when compared to the general population. Since OSA is effectively treatable and might contribute to the pathogenesis of TAA, further longitudinal trials are needed to assess the association between OSA and TAA.

Handgrip Strength Seems Not to Be Affected by COPD Disease Progression: A Longitudinal Cohort Study.

Skeletal muscle dysfunction, functional exercise capacity impairment and reduced physical activity are characteristic features in patients with chronic obstructive pulmonary disease (COPD). Assessments addressing muscle strength of the upper limb, such as measurement of handgrip strength (HGS), are rarely performed and reported. We aimed to analyze the course of HGS and possible predictors of changes in HGS over time in COPD. Yearly assessments of various disease markers were performed for a follow-up of up to seven years in a cohort of COPD patients to assess the longitudinal disease process. Data of 194 patients with at least one follow-up measurement were analyzed. HGS decreased significantly by B = -0.86 (95% CI -1.09/-0.62, p < 0.001) over time. The multivariate mixed effects model showed an independent association between greater annual declines in HGS and lower numbers of steps per day by B = 0.11 (95% CI 0.03/0.18, p = 0.006) and an enhanced change in COPD Assessment Test scores by B = -0.01 (95% CI -0.01/-0.00, p = 0.034). No evidence for an independent association between annual decline in HGS and FEV1% pred. by B = -0.01 (95% CI -0.03/0.01, p = 0.297) was shown. Patients who died during follow-up did not exhibit greater declines in HGS compared to survivors (p = 0.884). Although HGS significantly decreased over time, no pathophysiological link with COPD disease progression could be demonstrated. Previous cross-sectional associations between HGS and mortality could not be confirmed in this longitudinal setting. Our data suggests that repeated monitoring of HGS in clinical settings seems not to be helpful to predict COPD specific disease progression.

Pulmonary manifestation of VEXAS syndrome.

This case report presents the diagnostic journey of a man in his mid-70s who experienced shortness of breath, cough, recurrent episodes of fever, weight loss, pruritic erythroderma, uveitis and macrocytic anaemia. The initial diagnosis of cryptogenic organising pneumonia was made based on antibiotic refractory infiltrates seen in the lung CT scan. The patient initially responded favourably to immunosuppression but experienced a recurrence of symptoms when the corticosteroid dose was tapered. Despite ongoing systemic inflammation and refractory symptoms, it took nearly a year to establish the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) syndrome. This case highlights the challenges in diagnosing and managing VEXAS syndrome due to its recent discovery and limited awareness in the medical community, as well as the need to consider this syndrome as a rare differential diagnosis of therapy-refractory pulmonary infiltrates.

Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis.

BACKGROUND: The novel triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) improves lung function, body mass index (BMI), sinus clearance, and quality of life in patients with cystic fibrosis. Whether treatment with ELX/TEZ/IVA is associated with improved glucose tolerance is unknown. METHODS: This cohort study included adults with CF and at least one copy of F508del.. Study assessments before treatment and at least 3 months after ELX/TEZ/IVA initiation included an oral glucose tolerance test (OGTT) with glucose and insulin measurements, BMI, lung function test, and sweat chloride levels. We used an analysis of response profiles to calculate changes in outcomes. RESULTS: 33 patients (27.8 ± 6.3 years; 73% male; 64% F508del homozygous) were included. After a median of 184 [IQR, 107 - 278] days following treatment initiation 16 (48.5%) patients improved their glucose tolerance category, while 13 (39.4%) remained unchanged and 4 (12.1%) deteriorated. Overall, 60, 90 and 120 min OGTT glycemia decreased significantly from 11.9 ± 2.7 mmol/l to 10.6 ± 2.8 mmol/l (p = 0.012), 10.4 ± 3.0 mmol/l to 8.4 ± 3.6 mmol/l (p = 0.002) and 7.3 ± 3.1 mmol/l to 5.7 ± 3.0 mmol/l (p = 0.012). HbA1c levels also improved significantly, from 5.50±0.24% to 5.39±0.25% (p = 0.039). CONCLUSION: In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with possible improvement of glucose tolerance without increases of insulin secretion. Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible.

Are Predictors for Overall Mortality in COPD Patients Robust over Time?

(1) Background: Mortality is a major outcome in research on chronic obstructive pulmonary disease (COPD) with various predictors described. However, the dynamic courses of important predictors over time are disregarded. This study evaluates if longitudinal assessment of predictors provides additional information on the mortality risk in COPD when compared with a cross-sectional analysis.; (2) In a longitudinal, prospective, non-interventional cohort study including mild to very severe COPD patients, mortality and its various possible predictors were annually assessed up to seven years.; (3) Results: 297 patients were analysed. Mean (SD) age was 62.5 (7.6) years and 66% males. Mean (SD) FEV1 was 48.8 (21.4)%. A total of 105 events (35.4%) happened with a median (95% CI) survival time of 8.2 (7.2/NA) years. No evidence for a difference between the raw variable and the variable history on the predictive value for all tested variables over each visit was found. There was no evidence for changing effect estimates (coefficients) across the study visits due to the longitudinal assessment; (4) Conclusions: We found no evidence that predictors of mortality in COPD are time dependent. This implies that cross-sectional measured predictors show robust effect estimates over time and multiple assessments seem not to change the predictive value of the measure.

The prevalence of obstructive sleep apnea in sarcoidosis and its impact on sleepiness, fatigue, and sleep-associated quality of life: a cross-sectional study with matched controls (the OSASA study).

STUDY OBJECTIVES: Patients with sarcoidosis experience fatigue and excessive daytime sleepiness (EDS). However, the underlying pathomechanism is unclear. Studies suggested undiagnosed obstructive sleep apnea (OSA) to be an important contributor, but reliable data on prevalence and impact of OSA in sarcoidosis are scarce. METHODS: 71 adult patients with sarcoidosis, 1-to-1 matched to 71 adult controls according to sex, age, and body mass index were included. Participants underwent structured interviews (including Epworth Sleepiness Scale [ESS], Fatigue Assessment Scale [FAS], and Functional Outcome of Sleep Questionnaire [FOSQ-30]) and level-3 respiratory polygraphy. OSA was defined as apnea-hypopnea index ≥ 5 events/h. Prevalence of OSA was assessed and possible risk factors for OSA in sarcoidosis were investigated. RESULTS: Mild OSA (AHI ≥ 5 events/h) was prevalent in 32 (45%) sarcoidosis patients vs 22 (31%) controls (P = .040). Sarcoidosis patients presented higher ESS compared with matched controls (P = .037). FAS scores (median [quartile] of 21.5 [16, 27.5]) indicated fatigue in sarcoidosis patients. Patients with EDS (ESS ≥ 11) presented reduced FOSQ-30 results (median [quartile] of 16.7 [15.2, 17.8]). ESS, FAS, and FOSQ were not associated with AHI in sarcoidosis patients. Body mass index, sex, neck circumference, and NoSAS score were predictors for OSA in sarcoidosis. CONCLUSIONS: The risk for mild OSA is 2.5-fold higher in sarcoidosis patients compared with matched controls. OSA seems not to be the reason for increased sleepiness or fatigue in sarcoidosis. Risk factors such as body mass index, sex, neck circumference, and NoSAS score can be used to screen for OSA in sarcoidosis patients. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Obstructive Sleep Apnoea in Sarcoidosis (OSASA); URL: https://clinicaltrials.gov/ct2/history/NCT04156789?V_2=View; Identifier: NCT04156789. CITATION: Roeder M, Sievi NA, Schneider A, et al. The prevalence of obstructive sleep apnea in sarcoidosis and its impact on sleepiness, fatigue, and sleep-associated quality of life: a cross-sectional study with matched controls (the OSASA study). J Clin Sleep Med. 2022;18(10):2415-2422.

Augmentation Index in Patients with Thoracic Aortic Aneurysm: A Matched Case-Control Study.

Thoracic aortic aneurysms (TAA) may be associated with complications such as rupture and dissection, which can lead to a fatal outcome. Increased central arterial stiffness has been proposed to be present in patients with TAA compared to unmatched controls. We aimed to assess whether wall properties in patients with TAA are also altered when compared to a matched control group. Applanation tonometry was performed in 74 adults with TAA and 74 sex, age, weight, height, and left ventricular ejection fraction matched controls. Subsequently analysis of the pulse wave was done using the SphygmoCor System. For comparing the two groups, AIx was adjusted to a heart rate of 75/min (AIx@75). 148 1-to-1 matched participants were included in the final model. There was no significant difference in the Alx@75 between the TAA group and the matched control group [mean (SD) of 24.7 (11.2) % and 22.8 (11.2) %, p = 0.240]. Adjusted for known cardiovascular risk factors, there was no association between TAA and AIx@75. Patients with TAA showed comparable arterial wall properties to cardiovascular risk factor matched controls. Since higher arterial stiffness is associated with TAA progression, it remains to be investigated if increased central arterial stiffness is a relevant factor of TAA emergence.

[CME/Antworten: Nacht-zu-Nacht-Variabilität der obstruktiven Schlafapnoe]. / CME/Answers: Obstructive Sleep Apnea: How to Deal with Night- To-Night Variability of Respiratory Events?

According to current recommendations, the diagnosis of obstructive sleep apnea (OSA) is established by a single-night sleep study. However, recent reports suggest a remarkable night-to-night variability of OSA severity. We report on a 76-year-old man with suspected OSA who underwent six sleep studies within 13 months. Sleep studies demonstrated a remarkable variability of respiratory events based on an apnea-hypopnea index (AHI) varying between 1.1 and 43.1/h. There were no changes in body weight, alcohol intake, medication or comorbidities during the evaluation period. Due to diagnostic uncertainty and missing subjective benefit, the initially implemented CPAP therapy was stopped after one year of therapy. Considering night-to-night variability of OSA severity, single-night sleep studies might not be accurate enough in order to reliably diagnose or exclude OSA.

The cytotoxic effect of Clostridioides difficile pore-forming toxin CDTb.

Clostridioides (C.) difficile is clinically highly relevant and produces several AB-type protein toxins, which are the causative agents for C. difficile-associated diarrhea and pseudomembranous colitis. Treatment with antibiotics can lead to C. difficile overgrowth in the gut of patients due to the disturbed microbiota. C. difficile releases large Rho/Ras-GTPase glucosylating toxins TcdA and TcdB, which are considered as the major virulence factors for C. difficile-associated diseases. In addition to TcdA and TcdB, C. difficile strains isolated from severe cases of colitis produce a third toxin called CDT. CDT is a member of the family of clostridial binary actin ADP-ribosylating toxins and consists of two separate protein components. The B-component, CDTb, binds to the receptor and forms a complex with and facilitates transport and translocation of the enzymatically active A-component, CDTa, into the cytosol of target cells by forming trans-membrane pores through which CDTa translocates. In the cytosol, CDTa ADP-ribosylates G-actin causing depolymerization of the actin cytoskeleton and, eventually, cell death. In the present study, we report that CDTb exhibits a cytotoxic effect in the absence of CDTa. We show that CDTb causes cell rounding and impairs cell viability and the epithelial integrity of CaCo-2 monolayers in the absence of CDTa. CDTb-induced cell rounding depended on the presence of LSR, the specific cellular receptor of CDT. The isolated receptor-binding domain of CDTb was not sufficient to cause cell rounding. CDTb-induced cell rounding was inhibited by enzymatically inactive CDTa or a pore-blocker, implying that CDTb pores in cytoplasmic membranes contribute to cytotoxicity.

A few more steps lead to improvements in endothelial function in severe and very severe COPD.

INTRODUCTION: Cardiovascular disease is among the most prevalent concomitant chronic diseases in COPD. Physical activity (PA) modifies endothelial function and is commonly impaired in COPD. However, studies directly investigating the effects of increased PA on endothelial function in COPD are lacking. We investigated the effect of changes in PA on endothelial function in patients with severe to very severe COPD. Furthermore, we determined which variables modify this effect. MATERIALS AND METHODS: This is a secondary outcome analysis from a randomised controlled trial investigating the effects of combined PA counselling and pedometer-based feedback in COPD. We analysed the change in PA based on three visits during one year. We measured PA using a validated triaxial accelerometer, and endothelial function using flow-mediated dilation. RESULTS: Data was analysed from 54 patients, which provided 101 change scores. Multiple regression modelling, including adjustment for baseline step count, showed strong evidence for an association between changes in flow-mediated dilation and changes in PA (p < 0.001). The analysis of several effect modificators showed no evidence of any influence on the interaction between PA and endothelial function: smoking status (p = 0.766), severity of airflow obstruction (p = 0.838), exacerbation frequency (p = 0.227), lung diffusion capacity of carbon monoxide % pred. (p = 0.735). CONCLUSION: We found strong evidence that increasing steps per day ameliorates the heavily impaired endothelial function in patients with severe and very severe COPD. Further studies should examine which factors influence this relationship in a positive or negative manner.

The Accuracy of Repeated Sleep Studies in OSA: A Longitudinal Observational Study With 14 Nights of Oxygen Saturation Monitoring.

BACKGROUND: Strong evidence exists for clinically relevant night-to-night variability of respiratory events in patients with suspected OSA. RESEARCH QUESTION: How many sleep study nights are required to diagnose OSA accurately? STUDY DESIGN AND METHODS: Patients with suspected OSA underwent up to 14 nights of pulse oximetry (PO) at home and one night of in-hospital respiratory polygraphy (RP). The accuracy of each of the 13 sleep study nights was analyzed using the mean oxygen desaturation index 3% (ODI3%) of all 14 nights as a reference. Multiple regression analyses assessed possible predictors for night-to-night variability. RESULTS: One hundred three patients underwent in-hospital RP. Using only the results of the RP, 19.7% were misdiagnosed using an ODI3% cutoff of 15/h. One hundred eight patients underwent properly performed PO studies at home with a coefficient of variation (CV) of 31.5% (SD, 14.7%) across all nights. The first PO night demonstrated a sensitivity of 71.4% (95% CI, 55.4%-84.3%) and a specificity of 89.4% (95% CI, 79.4%-95.6%) to diagnose moderate OSA. Using only the first PO night, the negative predictive value was 83.1%. Adding a second recording night increased sensitivity up to 88.1% (95% CI, 74.4%-96.0%) with a slightly lower specificity of 85.9% (95% CI, 74.9%-93.4%). The ODI3% of the in-hospital RP showed an independent negative association to the log-transformed CV (exponentiated coefficient, 0.989; 95% CI, 0.984-0.995). INTERPRETATION: One single night of in-hospital RP may miss relevant OSA. Multiple study nights, for example, using ambulatory oxygen saturation monitoring, increase accuracy for diagnosing moderate OSA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03819361; URL: www.clinicaltrials.gov.

[CME: Nacht-zu-Nacht-Variabilität der obstruktiven Schlafapnoe]. / CME: Obstructive Sleep Apnea: How to Deal with Night-To-Night Variability of Respiratory Events?

Die aktuellen Leitlinien empfehlen, unkomplizierte Patientinnen und Patienten mit Verdacht auf obstruktive Schlafapnoe (OSA) mittels einer einzigen Schlafuntersuchung zu diagnostizieren. Eine kürzlich veröffentlichte Meta-Analyse konnte hingegen eine ausgeprägte intra-individuelle Variabilität respiratorischer Parameter von Nacht zu Nacht zeigen. Wir präsentieren den Fall eines 76-jährigen Patienten mit Verdacht auf OSA, der innerhalb von 13 Wochen sechs Schlafuntersuchungen unterzogen wurde. Hierbei präsentierte sich eine relevante Variabilität des AHI zwischen 1,1 und 43,1/h. Es konnten keine relevanten Unterschiede betreffend Gewicht, Alkoholkonsum, Medikation und Begleiterkrankungen zwischen den Schlafuntersuchungen festgestellt werden. Aufgrund fehlender subjektiver Wirksamkeit wurde die CPAP-Therapie nach einem Jahr gestoppt. Die ausgeprägte Nacht-zu-Nacht-Variabilität respiratorischer Parameter stellt eine akkurate OSA-Diagnostik mittels einer einzelnen Schlafuntersuchung in Frage.

Arterial Stiffness Increases Over Time in Relation to Lung Diffusion Capacity: A Longitudinal Observation Study in COPD.

Background: Cardiovascular events are, after cancer, the most common cause of death in COPD patients. Arterial stiffness is an independent predictor of all-cause mortality and cardiovascular events. Several cross-sectional studies have confirmed increased arterial stiffness in patients with COPD. Various mechanisms in the development of arterial stiffness in COPD such as reduced lung function or systemic inflammation have been proposed. However, clinical predictors of arterial stiffness that had been reported in cross-sectional studies have not yet been confirmed in a longitudinal setting. We have assessed the course of augmentation index (AIx) - a measure of systemic arterial stiffness - and possible predictors in a cohort of COPD patients over a period of up to 7 years. Methods: COPD patients underwent annual AIx measurement by applanation tonometry for a maximum duration of 7 years. Additionally, we performed annual assessments of lung function, blood gases, systemic inflammation, serum lipids and blood pressure. Associations between the course of AIx and potential predictors were investigated through a mixed effect model. Results: Seventy-six patients (mean (SD) age 62.4 (7.1), male 67%) were included. The AIx showed a significant annual increase of 0.91% (95% CI 0.21/1.60) adjusted for baseline. The change in diffusion capacity (DLco), low-density lipoprotein (LDL), and high-sensitivity c-reactive protein (hsCRP) was independently associated with the increasing evolution of AIx (Coef. - 0.10, p<0.001, Coef. 1.37, p=0.003, and Coef. 0.07, p=0.033, respectively). Conclusion: This study demonstrated a meaningful increase in arterial stiffness in COPD over time. A greater annual increase in arterial stiffness was associated with the severity of emphysema (measured by DLco), systemic inflammation, and dyslipidaemia. Clinical Trial Registration: www.ClinicalTrials.gov, NCT01527773.