Endothelial dysfunction and persistent inflammation in severe post-COVID-19 patients: implications for gas exchange.

BACKGROUND: Understanding the enduring respiratory consequences of severe COVID-19 is crucial for comprehensive patient care. This study aims to evaluate the impact of post-COVID conditions on respiratory sequelae of severe acute respiratory distress syndrome (ARDS). METHODS: We examined 88 survivors of COVID-19-associated severe ARDS six months post-intensive care unit (ICU) discharge. Assessments included clinical and functional evaluation as well as plasma biomarkers of endothelial dysfunction, inflammation, and viral response. Additionally, an in vitro model using human umbilical vein endothelial cells (HUVECs) explored the direct impact of post-COVID plasma on endothelial function. RESULTS: Post-COVID patients with impaired gas exchange demonstrated persistent endothelial inflammation marked by elevated ICAM-1, IL-8, CCL-2, and ET-1 plasma levels. Concurrently, systemic inflammation, evidenced by NLRP3 overexpression and elevated levels of IL-6, sCD40-L, and C-reactive protein, was associated with endothelial dysfunction biomarkers and increased in post-COVID patients with impaired gas exchange. T-cell activation, reflected in CD69 expression, and persistently elevated levels of interferon-ß (IFN-ß) further contributed to sustained inflammation. The in vitro model confirmed that patient plasma, with altered levels of sCD40-L and IFN-ß proteins, has the capacity to alter endothelial function. CONCLUSIONS: Six months post-ICU discharge, survivors of COVID-19-associated ARDS exhibited sustained elevation in endothelial dysfunction biomarkers, correlating with the severity of impaired gas exchange. NLRP3 inflammasome activity and persistent T-cell activation indicate on going inflammation contributing to persistent endothelial dysfunction, potentially intensified by sustained viral immune response.

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Characteristics of obstructive sleep apnea related to insulin resistance.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with multiple comorbidities, including diabetes. Its development is preceded by alterations in the initial phase of carbohydrate metabolism characterized by insulin resistance. This study aims to evaluate the role of intermittent hypoxia and sleep fragmentation characteristic of OSA on the risk of insulin resistance among apneic patients without diabetes. METHODOLOGY: 92 consecutive patients with OSA without evidence of diabetes were recruited. Overnight video polysomnography was performed and, the following morning, fasting blood glucose, insulin and glycosylated hemoglobin were determined. Insulin resistance was measured using the HOMA-IR index. RESULTS: Insulin resistance was present in 52.2% of OSA patients. In these subjects, insulin resistance was independently associated to the apnea index during REM sleep (adjusted odds ratio [aOR] 1.09; 95% CI, 1.03 to 1.16; p = 0.004), desaturation index (aOR 1.08; 95% CI: 1.04 to 1.13; p = 0.027), and sleep time with oxygen saturation below 90% (aOR 1.04; 95% CI 1.00 to 1.08; p = 0.049). Furthermore, the HOMA-IR level was also directly related to the desaturation index (standardized regression coefficient [B] = 0.514, p < 0.001) and to the apnea index during REM sleep (B = 0.344, p = 0.002). CONCLUSIONS: Intermittent hypoxia and disturbances in REM sleep emerge as main contributors to insulin resistance in OSA patients yet to experience diabetes onset.

Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea.

Rationale: As the mechanism that links obstructive sleep apnea (OSA) with the regulation of inflammatory response is not well known, it is important to understand the inflammasome activation, mainly of NLRP3 (nucleotide-binding oligomerization domain-like receptor 3). Objectives: To assess the NLRP3 activity in patients with severe OSA and to identify its role in the systemic inflammatory response of patients with OSA. Methods: We analyzed the NLRP3 activity as well as key components of the inflammasome cascade, such as adaptor molecule apoptosis-associated speck-like protein, caspase-1, Gasdermin D, IL-1ß, IL-18, and tissue factor, in monocytes and plasma from patients with severe OSA and control subjects without sleep apnea. We explored the association of the different key markers with inflammatory comorbidities. Measurements and Main Results: Monocytes from patients with severe OSA presented higher NLRP3 activity than those from control subjects, which directly correlated with the apnea-hypopnea index and hypoxemic indices. NLRP3 overactivity triggered inflammatory cytokines (IL-1ß and IL-18) via caspase-1 and increased Gasdermin D, allowing for tissue factor to be released. In vitro models confirmed that monocytes increase NLRP3 signaling under intermittent hypoxia in a hypoxia-inducible factor-1α-dependent manner, and/or in combination with plasma from patients with OSA. Plasma concentrations of tissue factor were higher in patients with OSA with systemic inflammatory comorbidities than in those without them. Conclusions: In patients with severe OSA, NLRP3 activation might be a linking mechanism between intermittent hypoxia and other OSA-induced immediate changes with the development of systemic inflammatory response.

SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-ß) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-ß pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.

[Palliative Sedation at the End of Life: A Comparative Study of Chronic Obstructive Pulmonary Disease and Lung Cancer Patients].

BACKGROUND: Although patients with chronic obstructive pulmonary disease (COPD) receive poor-quality palliative care, information about the use of palliative sedation (PS) in the last days of life is very scarce. OBJECTIVES: To compare the use of PS in hospitalized patients who died from COPD or lung cancer and identify factors correlating with PS application. METHODS: In a retrospective observational cohort study, from 1,675 patients died at a teaching hospital between 2013 and 2015, 109 patients who died from COPD and 85 from lung cancer were compared. Sociodemographic data, clinical characteristics, health care resource utilization, application of PS and prescribed drugs were recorded. RESULTS: In the last 6 months of life, patients who died from COPD had more hospital admissions due to respiratory causes and less frequent support by a palliative home care team (PHCT). Meanwhile, during their last hospitalization, patients who died from COPD had fewer do-not-resuscitate orders and were subjected to more intensive care unit admissions and cardiopulmonary resuscitation maneuvers. PS was applied less frequently in patients who died from COPD than in those who died from lung cancer (31 vs. 53%, p = 0.002). Overall, previous use of opioid drugs, support by a PHCT, and a diagnosis of COPD (adjusted odds ratio 0.48, 95% CI: 0.26-0.89, p = 0.020) were retained as factors independently related to PS. In COPD patients, only previous use of opioid drugs was identified as a PS-related factor. CONCLUSION: During their last days of life, hospitalized COPD patients receive PS less frequently than patients with lung cancer.

Age-dependent hypoxia-induced PD-L1 upregulation in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model. METHODS: PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice. RESULTS: In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA. CONCLUSION: PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.

Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Global Lung Function Initiative recommends reporting lung function measures as z-score, and a classification of airflow limitation (AL) based on this parameter has recently been proposed. OBJECTIVES: To evaluate the prognostic capacity of the AL classifications based on z-score or percentage predicted of FEV1 in patients with chronic obstructive pulmonary disease (COPD). METHODS: A cohort of 2,614 patients with COPD recruited outside the hospital setting was examined after a mean (± SD) of 57 ± 13 months of follow-up, totaling 10,322 person-years. All-cause mortality was analyzed, evaluating the predictive capacity of several AL staging systems. MEASUREMENTS AND MAIN RESULTS: Based on Global Initiative for Chronic Obstructive Lung Disease guidelines, 461 patients (17.6%) had mild, 1,452 (55.5%) moderate, 590 (22.6%) severe, and 111 (4.2%) very severe AL. According to z-score classification, 66.3% of patients remained with the same severity, whereas 23.7% worsened and 10.0% improved. Unlike other staging systems, patients with severe AL according to z-score had higher mortality than those with very severe AL (increase of risk by 5.2 and 3.9 times compared with mild AL, respectively). The predictive capacity for 5-year survival was slightly higher for FEV1 expressed as percentage of predicted than as z-score (area under the curve: 0.714-0.760 vs. 0.649-0.708, respectively). A severity-dependent relationship between AL grades by z-score and mortality was only detected in patients younger than age 60 years. CONCLUSIONS: In patients with COPD, the AL classification based on z-score predicts worse mortality than those based on percentage of predicted. It is possible that the z-score underestimates AL severity in patients older than 60 years of age with severe functional impairment.

Identification of non-coding genetic variants in samples from hypoxemic respiratory disease patients that affect the transcriptional response to hypoxia.

A wide range of diseases course with an unbalance between the consumption of oxygen by tissues and its supply. This situation triggers a transcriptional response, mediated by the hypoxia inducible factors (HIFs), that aims to restore oxygen homeostasis. Little is known about the inter-individual variation in this response and its role in the progression of disease. Herein, we sought to identify common genetic variants mapping to hypoxia response elements (HREs) and characterize their effect on transcription. To this end, we constructed a list of genome-wide HIF-binding regions from publicly available experimental datasets and studied the genetic variability in these regions by targeted re-sequencing of genomic samples from 96 chronic obstructive pulmonary disease and 144 obstructive sleep apnea patients. This study identified 14 frequent variants disrupting potential HREs. The analysis of the genomic regions containing these variants by means of reporter assays revealed that variants rs1009329, rs6593210 and rs150921338 impaired the transcriptional response to hypoxia. Finally, using genome editing we confirmed the functional role of rs6593210 in the transcriptional regulation of EGFR. In summary, we found that inter-individual variability in non-coding regions affect the response to hypoxia and could potentially impact on the progression of pulmonary diseases.

Obstructive Sleep Apnea Monocytes Exhibit High Levels of Vascular Endothelial Growth Factor Secretion, Augmenting Tumor Progression.

Obstructive sleep apnea (OSA) is a syndrome characterized by repeated pauses in breathing induced by a partial or complete collapse of the upper airways during sleep. Intermittent hypoxia (IH), a hallmark characteristic of OSA, has been proposed to be a major determinant of cancer development, and patients with OSA are at a higher risk of tumors. Both OSA and healthy monocytes have been found to show enhanced HIF1α expression under IH. Moreover, these cells under IH polarize toward a tumor-promoting phenotype in a HIF1α-dependent manner and influence tumor growth via vascular endothelial growth factor (VEGF). Monocytes from patients with OSA increased the tumor-induced microenvironment and exhibited an impaired cytotoxicity in a 3D tumor in vitro model as a result of the increased HIF1α secretion. Adequate oxygen restoration both in vivo (under continuous positive airway pressure treatment, CPAP) and in vitro leads the monocytes to revert the tumor-promoting phenotype, demonstrating the plasticity of the innate immune system and the oxygen recovery relevance in this context.

The effect of treatment for sleep apnoea on determinants of blood pressure control.

Our aim was to assess the effect of continuous positive airway pressure (CPAP) on the nocturnal evolution of peripheral chemosensitivity, renin-angiotensin-aldosterone system activity, sympathetic tone and endothelial biomarkers in obstructive sleep apnoea (OSA) patients with isolated nocturnal hypertension (INH) or day-night sustained hypertension (D-NSH).In a crossover randomised trial, 32 OSA patients newly diagnosed with hypertension and without antihypertensive treatment were randomly assigned to 12 weeks of CPAP or sham CPAP. Peripheral chemosensitivity was evaluated before and after sleep using the hypoxic withdrawal test (%ΔVI).At baseline, D-NSH patients showed higher %ΔVI before sleep and higher levels of aldosterone and diurnal catecholamines. CPAP only reduced the nocturnal increase of %ΔVI in INH patients (6.9%, 95% CI 1.0-12.8%; p=0.026). CPAP-induced change from baseline in %ΔVI after sleep was 7.5% (95% CI 2.6-12.2%, p=0.005) in the INH group and 5.7% (95% CI 2.2-9.3%, p=0.004) in the D-NSH group. In contrast, %ΔVI before sleep only decreased with CPAP in the D-NSH patients (3.0%, 95% CI 0.5-5.6%; p=0.023).In conclusion, CPAP reduces the nocturnal increase of peripheral chemosensitivity experienced by INH patients and corrects the high daytime sensitivity of patients with D-NSH. Differences in response to CPAP between these patients can help better understand the mechanisms of perpetuation of hypertension in sleep apnoea.

Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

Monocytes inhibit NK activity via TGF-ß in patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry and in vitro assays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-ß (TGF-ß), in contrast to those from the HV and CPAP groups. High levels of TGF-ß were detected in OSA sera. TGF-ß release by GARP+ monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+ monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-ß. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.

Dynamic hyperinflation in patients with asthma and exercise-induced bronchoconstriction.

BACKGROUND: Little is known about the behavior of operative lung volumes during exercise in patients with asthma and exercise-induced bronchoconstriction (EIB). OBJECTIVE: To compare the presence of dynamic hyperinflation (DH) in patients with mild asthma with and without EIB and in healthy individuals and to relate the changes in end-expiratory lung volume (EELV) with postexercise airflow reduction. METHODS: A total of 122 consecutive stable patients (>12 years of age) with mild asthma and 38 controls were studied. Baseline lung volumes were measured, and all patients performed an exercise bronchial challenge. At each minute of exercise, EELV and end-inspiratory lung volume (EILV) were estimated from inspiratory capacity measurements to align the tidal breathing flow-volume loops to within the maximal expiratory curve. RESULTS: DH was more frequent in patients with asthma and EIB (76%) than in patients with asthma but without EIB (11%) or controls (18%). The EELV increased in patients with asthma and EIB and decreased in patients with asthma without EIB and controls during exercise. In the patients with asthma, the decrease in forced expiratory volume in 1 second after the exercise challenge correlated with age (r = -0.179, P = .05), baseline forced vital capacity (r = 0.255, P = .005), EELV increase (r = 0.447, P < .001), and EILV increase (r = 0.246, P = .007). Age, baseline forced vital capacity, and magnitude of DH were retained as independent predictors of EIB intensity. CONCLUSION: In patients with asthma and EIB, the development of DH is very frequent and related to the intensity of postexercise bronchoconstriction. This finding could implicate DH in the development of EIB.

Effect of Continuous Positive Airway Pressure on Glycemic Control in Patients with Obstructive Sleep Apnea and Type 2 Diabetes. A Randomized Clinical Trial.

RATIONALE: Obstructive sleep apnea (OSA) is a risk factor for type 2 diabetes that adversely impacts glycemic control. However, there is little evidence about the effect of continuous positive airway pressure (CPAP) on glycemic control in patients with diabetes. OBJECTIVES: To assess the effect of CPAP on glycated hemoglobin (HbA1c) levels in patients with suboptimally controlled type 2 diabetes and OSA, and to identify its determinants. METHODS: In a 6-month, open-label, parallel, and randomized clinical trial, 50 patients with OSA and type 2 diabetes and two HbA1c levels equal to or exceeding 6.5% were randomized to CPAP (n = 26) or no CPAP (control; n = 24), while their usual medication for diabetes remained unchanged. MEASUREMENTS AND MAIN RESULTS: HbA1c levels, Homeostasis Model Assessment and Qualitative Insulin Sensitivity Check Index scores, systemic biomarkers, and health-related quality of life were measured at 3 and 6 months. After 6 months, the CPAP group achieved a greater decrease in HbA1c levels compared with the control group. Insulin resistance and sensitivity measurements (in noninsulin users) and serum levels of IL-1ß, IL-6, and adiponectin also improved in the CPAP group compared with the control group after 6 months. In patients treated with CPAP, mean nocturnal oxygen saturation and baseline IL-1ß were independently related to the 6-month change in HbA1c levels (r(2) = 0.510, P = 0.002). CONCLUSIONS: Among patients with suboptimally controlled type 2 diabetes and OSA, CPAP treatment for 6 months resulted in improved glycemic control and insulin resistance compared with results for a control group. Clinical trial registered with www.clinicaltrials.gov (NCT01801150).

Dynamic hyperinflation is a risk factor for mortality and severe exacerbations in COPD patients.

OBJECTIVE: To assess if dynamic hyperinflation is an independent risk factor for mortality and severe exacerbations in COPD patients. METHODS: A cohort of 141 patients with stable COPD and moderate to very severe airflow limitation, treated according to conventional guidelines, was followed for a median of 9 years. Clinical characteristics were recorded and arterial blood gases, pulmonary function tests, 6-min walk and incremental exercise test with measurement of respiratory pattern and operative lung volumes were performed. Endpoints were all-cause mortality and hospitalization for COPD exacerbation. RESULTS: 58 patients died during the follow-up period (1228 patients x year). The mortality rate was higher in patients with dynamic hyperinflation (n = 106) than in those without it (n = 35) (14.6; 95% CI, 14.5-14.8 vs. 7.2; 95% CI, 7.1-7.4 per 1000 patients-year). After adjusting for sex, age, body mass index, pack-years and treatment with inhaled corticosteroids, dynamic hyperinflation was associated with a higher mortality risk (adjusted hazard ratio [aHR], 2.725; 95% CI, 1.010-8.161), and in a multivariate model, comorbidity, peak oxygen uptake and dynamic hyperinflation were retained as independent predictors of mortality. The time until first severe exacerbation was shorter for patients with dynamic hyperinflation (aHR, 3.961; 95% CI, 1.385-11.328), and dynamic hyperinflation, FEV1 and diffusing capacity were retained as independent risk factors for severe exacerbation. Moreover, patients with dynamic hyperinflation had a higher hospitalization risk than those without it (adjusted incidence rate ratio, 1.574; 95% CI, 1.087-2.581). CONCLUSION: In stable COPD patients, dynamic hyperinflation is an independent prognostic factor for mortality and severe exacerbations.

Continuous Positive Airway Pressure Effect on Progression of Retinal Disease in Patients with Sleep Apnea and Nonproliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic retinopathy. However, the effect of apnea-hypopnea suppression on retinal disease progression is unclear. Objectives: To evaluate the efficacy and safety of continuous positive airway pressure (CPAP) for the reduction of retinal lesions in patients with non-proliferative diabetic retinopathy (NPDR) and OSA. Methods: This open-label, parallel-group, randomized controlled trial was conducted between October 2016 and February 2020 at a university hospital in Spain. The date of final follow-up was March 2, 2021. Eighty-three patients with OSA and mild to moderate NPDR receiving stable treatment were randomized to receive CPAP and usual care (43 patients with 79 available eyes) or usual care alone (40 patients with 67 available eyes) for 52 weeks. The primary outcomes were the change in the percentage of eyes with retinal exudates and the number of retinal microhemorrhages from baseline to week 52. We also assessed the effects of both interventions on retinal thickness by means of optical coherence tomography, serum concentrations of glycated hemoglobin, blood pressure, lipid concentrations, sleepiness, and quality of life. Results: Fifty-two weeks of CPAP treatment was associated with reductions from baseline in the percentage of eyes with hard exudates (overall difference, -21.7%; P = 0.035) and in optical coherence tomography indices of retinal edema, including central subfield thickness and cube volume. However, in patients who met prespecified criteria for CPAP adherence, treatment was also associated with a higher number of retinal microhemorrhages at 52 weeks (intergroup adjusted difference, 6.0 [95% confidence interval, 0.6-11.5]; P = 0.029), which was directly related to prescribed pressure levels. CPAP treatment also improved glycemic control, sleepiness, and general health-related quality of life. Conclusions: In patients with OSA and NPDR, long-term CPAP treatment in addition to usual care may result in slower progression of retinal disease, although it could also induce an increase in retinal microhemorrhages. Clinical trial registered with www.clinicaltrials.gov (NCT02874313).

Dysregulation in CD39/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients.

INTRODUCTION: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression. METHODS: Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models. RESULTS: Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells' membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients. CONCLUSION: Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients.

Medium-Term Disability and Long-Term Functional Impairment Persistence in Survivors of Severe COVID-19 ARDS: Clinical and Physiological Insights.

BACKGROUND: Although the medium- and long-term sequelae of survivor of acute respiratory distress syndrome (ARDS) of any cause have been documented, little is known about the way in which COVID-19-induced ARDS affects functional disability and exercise components. Our aims were to examine the medium-term disability in severe COVID-19-associated ARDS survivors, delineate pathophysiological changes contributing to their exercise intolerance, and explore its utility in predicting long-term functional impairment persistence. METHODS: We studied 108 consecutive subjects with severe COVID-19 ARDS who remained alive 6 months after intensive care unit (ICU) discharge. Lung morphology was assessed with chest non-contrast CT scans and CT angiography. Functional evaluation included spirometry, plethysmography, muscle strength, and diffusion capacity, with assessment of gas exchange components through diffusing capacity of nitric oxide. Disability was assessed through an incremental exercise test, and measurements were repeated 12 and 24 months later in patients with functional impairments. RESULTS: At 6 months after ICU discharge, a notable dissociation between morphological and clinical-functional sequelae was identified. Moderate-severe disability was present in 47% of patients and these subjects had greater limitation of ventilatory mechanics and gas exchange, as well as greater symptomatic perception during exercise and a probable associated cardiac limitation. Female sex, hypothyroidism, reduced membrane diffusion component, lower functional residual capacity, and high-attenuation lung volume were independently associated with the presence of moderate-severe functional disability, which in turn was related to higher frequency and greater intensity of dyspnea and worse quality of life. Out of the 71 patients with reduced lung volumes or diffusion capacity at 6 months post-ICU discharge, only 19 maintained a restrictive disorder associated with gas exchange impairment at 24 months post-discharge. In these patients, 6-month values for diffusion membrane component, maximal oxygen uptake, ventilatory equivalent for CO2, and dead space to tidal volume ratio were identified as independent risk factors for persistence of long-term functional sequelae. CONCLUSIONS: Less than half of survivors of COVID-19 ARDS have moderate-severe disability in the medium term, identifying several risk factors. In turn, diffusion membrane component and exercise tolerance at 6-month ICU discharge are independently associated with the persistence of long-term functional sequelae.

Procoagulant State of Sleep Apnea Depends on Systemic Inflammation and Endothelial Damage.

INTRODUCTION: Growing evidence shows a hypercoagulable state in obstructive sleep apnea (OSA) that could be a risk factor for thromboembolic disease. OBJECTIVES: We aimed to elucidate mechanisms involved in the procoagulant profile observed in patients with OSA and to investigate the potential utility of global tests in its characterization. METHODS: Thirty-eight patients with severe OSA without previous history of thrombosis and nineteen healthy age- and sex-matched controls were included. Kinetic of clot formation was determined using rotational thromboelastometry. Haemostatic capacity of plasma and microparticles was determined by Calibrated Automated Thrombinography. Platelet surface receptors, activation markers and formation of platelet/leukocytes aggregates were analyzed by flow cytometry. RESULTS: Thromboelastometry showed a procoagulant state in patients with OSA that did not seem to be related to a basal activation of platelets but by the increased existence of platelet/leukocyte aggregates. Patients with OSA presented many signs of endothelial damage such as increased plasma levels of E-selectin and cfDNA and enhanced thrombin generation due to the presence of microparticles rich in tissue-factor, which is related to OSA severity. CONCLUSIONS: OSA induces an enhancement in the dynamics of clot formation which appears to be caused by at least two pathological mechanisms. First, a greater formation of platelet-leukocyte aggregates; secondly, endothelial damage which provokes a greater procoagulant potential due to the increase in tissue factor-rich microparticles. Moreover, this study has identified thromboelastometry and thrombin generation assay as useful tools to evaluate the prothrombotic state in these patients.