Oral appliance therapy and hypoglossal nerve stimulation as non-positive airway pressure treatment alternatives for obstructive sleep apnea: a narrative expert review.

This perspective on alternatives to positive airway pressure (PAP) therapy for the treatment of obstructive sleep apnea (OSA) summarizes the proceedings of a focus group that was conducted by the Sleep Research Society Foundation. This perspective is from a multidisciplinary panel of experts from sleep medicine, dental sleep medicine, and otolaryngology that aims to identify the current role of oral appliance therapy and hypoglossal nerve stimulation for the treatment of OSA with emphasis on the US practice arena. A secondary aim is to identify-from an implementation science standpoint-the various barriers and facilitators for adoption of non-PAP treatment that includes access to care, multidisciplinary expertise, reimbursement, regulatory aspects, current treatment guidelines, health policies, and other factors related to the delivery of care. The panel has contextualized the review with recent events-such as a large-scale PAP device recall compounded by supply chain woes of the pandemic-and emerging science in the field of OSA and offers solutions for multidisciplinary approaches while identifying knowledge gaps and future research opportunities.

Circadian disruption dysregulates lung gene expression associated with inflammatory lung injury.

Rationale: Circadian systems drive the expression of multiple genes in nearly all cells and coordinate cellular-, tissue-, and system-level processes that are critical to innate immunity regulation. Objective: We examined the effects of circadian rhythm disorganization, produced by light shift exposure, on innate immunity-mediated inflammatory lung responses including vascular permeability and gene expression in a C57BL/6J murine model of inflammatory lung injury. Methods: A total of 32 C57BL/6J mice were assigned to circadian phase shifting (CPS) with intratracheal phosphate-buffered saline (PBS), CPS with intratracheal lipopolysaccharide (LPS), control (normal lighting) condition with intratracheal PBS, and control condition with intratracheal LPS. Bronchoalveolar lavage (BAL) protein, cell counts, tissue immunostaining, and differentially expressed genes (DEGs) were measured in lung tissues at 2 and 10 weeks. Measurements and results: In mice exposed to both CPS and intratracheal LPS, both BAL protein and cell counts were increased at both 2 and 10 weeks compared to mice exposed to LPS alone. Multiple DEGs were identified in CPS-LPS-exposed lung tissues compared to LPS alone and were involved in transcriptional pathways associated with circadian rhythm disruption, regulation of lung permeability, inflammation with Rap1 signaling, and regulation of actin cytoskeleton. The most dysregulated pathways included myosin light chain kinase, MAP kinase, profilin 2, fibroblast growth factor receptor, integrin b4, and p21-activated kinase. Conclusion: Circadian rhythm disruption results in exacerbated immune response and dysregulated expression of cytoskeletal genes involved in the regulation of epithelial and vascular barrier integrity-the mechanistic underpinnings of acute lung injury. Further studies need to explore circadian disorganization as a druggable target.

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals.

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown. Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC. Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular. Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

The lived experience of positive airway pressure therapy in patients with obstructive sleep apnea across the lifespan: a qualitative study.

STUDY OBJECTIVES: Although treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy is effective, adherence is often poor. Understanding the patient perspective is needed to inform adherence-promoting interventions. This qualitative study assessed the experiences, preferences, facilitators, and barriers surrounding PAP therapy for the management of OSA in patients from adolescence to older adulthood. METHODS: Eligible participants ages 19 and older were identified from administrative health care claims; adolescent participants ages 12-18 and their parents/caregivers were identified via electronic health records of a tertiary sleep specialty clinic at a large children's hospital. Forty English-speaking patients and 10 parents of adolescents diagnosed with OSA and prescribed PAP therapy completed semistructured 60-minute telephone interviews conducted by a trained facilitator. Common themes and illustrative quotes were identified. RESULTS: Themes around OSA diagnosis, initiating OSA treatment, learning about OSA/PAP, decision to start PAP, PAP benefits and challenges, and reasons for nonadherence were identified. Participants suggested design and delivery changes to improve PAP devices. Issues unique to adolescents and their parents were discussed. CONCLUSIONS: The unique perspectives of patients regarding PAP therapy should be taken into consideration when developing interventions to increase PAP adherence and improve clinical care. Based on identified themes, opportunities for intervention may exist at all stages of care, from diagnosis to treatment initiation. Involving partners, parents, and other caregivers in PAP therapy may be beneficial for optimizing adherence. CITATION: Simon SL, Stephenson JJ, Haynes K, et al. The lived experience of positive airway pressure therapy in patients with obstructive sleep apnea across the lifespan: a qualitative study. J Clin Sleep Med. 2024;20(3):407-416.

A real-world observational study assessing relationships between excessive daytime sleepiness and patient satisfaction in obstructive sleep apnea.

OBJECTIVES/BACKGROUND: To estimate prevalence and severity of excessive daytime sleepiness among patients with obstructive sleep apnea (OSA) who were prescribed treatment; assess perception and satisfaction of OSA-related care; describe relationships between excessive daytime sleepiness, treatment adherence, and patient satisfaction. PATIENTS/METHODS: A national population-based cross-sectional sample of US adults with clinician-diagnosed OSA was surveyed in January 2021 via Evidation Health's Achievement App. Patients completed the Epworth Sleepiness Scale, rated satisfaction with healthcare provider and overall OSA care, and reported treatment adherence. Covariates affecting excessive daytime sleepiness (average weekly sleep duration, treatment adherence, sleepiness-inducing medications, age, sex, body mass index, nasal congestion, smoking status, and comorbidities) were adjusted in multivariate regression models. RESULTS: In 2289 participants (50.3 % women; 44.8 ± 11.1 years), EDS was highly prevalent (42 %), and was experienced by 36 % of patients with high positive airway pressure (PAP) therapy adherence. Each additional hour of nightly PAP use was associated with improved sleepiness (a 0.28-point lower Epworth score; p < 0.001). Excessive daytime sleepiness was associated with lower patient satisfaction with healthcare providers and overall care (OR [95 % CI] 0.62 [0.48-0.80] and 0.50 [0.39-0.64], respectively; p < 0.0001), whereas PAP adherence was associated with higher patient satisfaction (OR [95 % CI] 2.37 [1.64-3.43] and 2.91 [2.03-4.17]; p < 0.0001), after adjusting for confounders. CONCLUSIONS: In a real-world population-based study of patients with OSA, excessive daytime sleepiness was highly prevalent and associated with poor patient satisfaction ratings. Better patient-centered care among patients with OSA may require interventions aimed at addressing excessive daytime sleepiness and treatment adherence.

Vibro-Acoustic Platelet Activation: An Additive Mechanism of Prothrombosis with Applicability to Snoring and Obstructive Sleep Apnea.

Introduction: Obstructive sleep apnea (OSA) and loud snoring are conditions with increased cardiovascular risk and notably an association with stroke. Central in stroke are thrombosis and thromboembolism, all related to and initiaing with platelet activation. Platelet activation in OSA has been felt to be driven by biochemical and inflammatory means, including intermittent catecholamine exposure and transient hypoxia. We hypothesized that snore-associated acoustic vibration (SAAV) is an activator of platelets that synergizes with catecholamines and hypoxia to further amplify platelet activation. Methods: Gel-filtered human platelets were exposed to snoring utilizing a designed vibro-acoustic exposure device, varying the time and intensity of exposure and frequency content. Platelet activation was assessed via thrombin generation using the Platelet Activity State assay and scanning electron microscopy. Comparative activation induced by epinephrine and hypoxia were assessed individually as well as additively with SAAV, as well as the inhibitory effect of aspirin. Results: We demonstrate that snore-associated acoustic vibration is an independent activator of platelets, which is dependent upon the dose of exposure, i.e., intensity x time. In snoring, acoustic vibrations associated with low-frequency sound content (200 Hz) are more activating than those associated with high frequencies (900 Hz) (53.05% vs. 22.08%, p = 0.001). Furthermore, SAAV is additive to both catecholamines and hypoxia-mediated activation, inducing synergistic activation. Finally, aspirin, a known inhibitor of platelet activation, has no significant effect in limiting SAAV platelet activation. Conclusion: Snore-associated acoustic vibration is a mechanical means of platelet activation, which may drive prothrombosis and thrombotic risk clinically observed in loud snoring and OSA.

Association of Birthplace for Sleep Duration, Sleep Quality, and Sleep Disorder Symptoms, at the US-Mexico Border.

OBJECTIVES: The present study investigated the roles birthplace and acculturation play in sleep estimates among Hispanic/Latino population at the US-Mexico border. MEASURES: Data were collected in 2016, from N = 100 adults of Mexican descent from the city of Nogales, AZ, at the US-Mexico border. Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index categorized as none, mild, moderate, and severe, and Multivariable Apnea Prediction Index (MAP) categorized as never, infrequently, and frequently. Acculturation was measured with the Acculturation Rating Scale for Mexican-Americans II (ARSMA-II). RESULTS: The sample consisted of majority Mexican-born (66%, vs. born in the USA 38.2%). Being born in the USA was associated with 55 fewer minutes of nighttime sleep (p = .011), and 1.65 greater PSQI score (p = .031). Compared to no symptoms, being born in the USA was associated with greater likelihood of severe difficulty falling asleep (OR = 8.3, p = .030) and severe difficulty staying asleep (OR = 11.2, p = .050), as well as decreased likelihood of breathing pauses during sleep (OR = 0.18, P = .020). These relationships remained significant after Mexican acculturation was entered in these models. However, greater Anglo acculturation appears to mediate one fewer hour of sleep per night, poorer sleep quality, and reporting of severe difficulty falling asleep and staying asleep. CONCLUSIONS: Among individuals of Mexican descent, being born in the USA (vs Mexico) is associated with about 1 hour less sleep per night, worse sleep quality, more insomnia symptoms, and less mild sleep apnea symptoms. These relationships are influenced by acculturation, primarily the degree of Anglo rather than the degree of Mexican acculturation.

Distinct temporal trajectories and risk factors for Post-acute sequelae of SARS-CoV-2 infection.

Background: The understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period. Methods: We conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection. Results: We identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: -4; -17, 3), persistent (-2; -14, 7), or incident (4.5; -5, 17) (p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)]. Conclusion: An incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC.

Genetic QT Score and Sleep Apnea as Predictors of Sudden Cardiac Death in the UK Biobank.

Introduction: The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and mortality in patients enrolled in the UK Biobank with and without sleep apnea. Methods: The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism SNP. Competing-risk regression models adjusting for age, sex, BMI, QT prolonging medication, race, and comorbid cardiovascular conditions were used for sudden cardiac death (SCD) analyses. Results: 500,584 participants were evaluated (56.5 ±8 years, 54% women, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (p<0.0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (p<0.001). Sleep apnea was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted HR per 5-unit change in QTc-PRS for SCD was 1.64 (95% CI 1.16 - 2.31, p=0.005) among those with sleep apnea and 1.04 (95% CI 0.95 - 1.14, p=0.44) among those without sleep apnea (p for interaction =0.01). Black participants with sleep apnea had significantly elevated adjusted risk of SCD compared to White participants (HR=9.6, 95% CI 1.24 - 74, p=0.03). Conclusion: In the UK Biobank population, the QTc-PRS was associated with SCD among participants with sleep apnea but not among those without sleep apnea, indicating that sleep apnea is a significant modifier of the genetic risk. Black participants with sleep apnea had a particularly high risk of SCD.

Healthcare Utilization in Patients with Chronic Obstructive Pulmonary Disease Discharged from Coronavirus 2019 Hospitalization.

Rationale: There is concern that patients with chronic obstructive pulmonary disease (COPD) are at greater risk of increased healthcare utilization (HCU) following Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-COV-2) infection. Objective: To assess whether COPD is an independent risk factor for increased post-discharge HCU. Methods: We conducted a retrospective cohort study of patients with COPD discharged home from a hospitalization due to Coronavirus Disease 2019 (COVID-19) between April 1, 2020, and March 31, 2021, using Optum's de-identified Clinformatics® Data Mart Database (CDM). COVID-19 was identified by an International Classification of Diseases, tenth revision, clinical modification (ICD-10-CM) diagnosis code of U07.1. The primary outcome was HCU (ie, emergency department (ED) visits, readmissions, rehabilitation/skilled nursing facility (SNF) visits, outpatient office visits, and telemedicine visits) nine months post-discharge after COVID-19 hospitalization (from here on "post-discharge") in patients with COPD compared to HCU of patients without COPD. Poisson regression modeling was used to calculate relative risk (RR) and confidence interval (CI) for COPD, adjusted for the other covariates. Results: We identified a cohort of 160,913 patients hospitalized with COVID-19, with 57,756 discharged home and 14,622 (25.3%) diagnosed with COPD. Patients with COPD had a mean age of 75.48 years (±9.49); 55.5% were female and 70.9% were White. Patients with COPD had an increased risk of HCU in the nine months post-discharge after adjusting for the other covariates. Risk of ED visits, readmissions, length of stay during readmission, rehabilitation/SNF visits, outpatient office visits, and telemedicine visits were increased by 57% (RR 1.57; 95% CI 1.53-1.60), 50% (RR 1.50; 95% CI 1.46-1.54), 55% (RR 1.55; 95% CI 1.53-1.56), 18% (RR 1.18; 95% CI 1.14-1.22), 16% (RR 1.16; 95% CI 1.16-1.17), and 28% (RR 1.28; 95% CI 1.24-1.31), respectively. Younger patients (ages 18 to 65 years), women, and Hispanic patients with COPD showed an increased risk for post-discharge HCU. Conclusion: Patients with COPD hospitalized with COVID-19 experienced increased HCU post-discharge compared to patients without COPD.

Disparities in outcomes of COVID-19 hospitalizations in native American individuals.

Objectives: This study aimed to investigate COVID-19-related disparities in clinical presentation and patient outcomes in hospitalized Native American individuals. Methods: The study was performed within 30 hospitals of the Banner Health system in the Southwest United States and included 8,083 adult patients who tested positive for SARS-CoV-2 infection and were hospitalized between 1 March 2020 and 4 September 2020. Bivariate and multivariate analyses were used to assess racial and ethnic differences in clinical presentation and patient outcomes. Results: COVID-19-related hospitalizations in Native American individuals were over-represented compared with non-Hispanic white individuals. Native American individuals had fewer symptoms at admission; greater prevalence of chronic lung disease in the older adult; two times greater risk for ICU admission despite being younger; and 20 times more rapid clinical deterioration warranting ICU admission. Compared with non-Hispanic white individuals, Native American individuals had a greater prevalence of sepsis, were more likely to require invasive mechanical ventilation, had a longer length of stay, and had higher in-hospital mortality. Conclusion: Native American individuals manifested greater case-fatality rates following hospitalization than other races/ethnicities. Atypical symptom presentation of COVID-19 included a greater prevalence of chronic lung disease and a more rapid clinical deterioration, which may be responsible for the observed higher hospital mortality, thereby underscoring the role of pulmonologists in addressing such disparities.

The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome.

STUDY OBJECTIVES: Children with Down syndrome (DS) are at very high risk for obstructive sleep apnea (OSA). Current OSA treatments have limited effectiveness in this population. We evaluated the effectiveness of atomoxetine and oxybutynin (ato-oxy) to treat OSA in children with Down syndrome. METHODS: Children ages 6-7 years old with Down syndrome and OSA participated in a double-blind crossover clinical trial evaluating two dose regimens of ato-oxy. Participants received low-dose ato-oxy (0.5 mg/kg atomoxetine and 5 mg oxybutynin) and high-dose ato-oxy (1.2 mg/kg atomoxetine and 5 mg oxybutynin) for 1 month in random order. The primary study outcome was change in obstructive apnea-hypopnea index. Health-related quality of life as measured by the OSA-18 as well as changes in sleep architecture were secondary outcomes. RESULTS: Fifteen participants qualified for randomization and 11 participants had complete data at all points. Baseline obstructive apnea-hypopnea index was 7.4 ± 3.7 (mean ± standard deviation), obstructive apnea-hypopnea index with low-dose ato-oxy was 3.6 ± 3.3 (P = .001 vs baseline), and obstructive apnea-hypopnea index with high-dose ato-oxy was 3.9 ± 2.8 (P = .003 vs baseline). No significant sleep architecture differences were present with ato-oxy. No significant difference in OSA-18 score was present. OSA-18 total score was 51 ± 19 at baseline, 45 ± 17 (P = .09) at the end of 4 weeks of low-dose ato-oxy, and 45 ± 16 (P = .37) at the end of high-dose ato-oxy therapy. The most common adverse effects were irritability and fatigue, and these were generally mild. CONCLUSIONS: Ato-oxy is a promising treatment for OSA in children with Down syndrome. CLINICAL TRIAL REGISTRATION: Registry: Clinicaltrials.gov; Name: Medications for Obstructive Sleep Apnea In Children With Down Syndrome (MOSAIC); URL: https://clinicaltrials.gov/ct2/show/NCT04115878; Identifier: NCT04115878. CITATION: Combs D, Edgin J, Hsu C-H, et al. The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. J Clin Sleep Med. 2023;19(12):2065-2073.

Comparisons of Sleep, Demographics, and Health-Related Variables in Older Long and Average Duration Sleepers.

Introduction Long sleep duration is associated with many health risks, particularly in older adults, but little is known about other characteristics associated with long sleep duration. Methods Across 5 sites, adults aged 60-80 years who reported sleeping 8-9 h ("long sleepers", n = 95) or 6-7.25 h ("average sleepers", n = 103) were assessed for two weeks using actigraphy and sleep diary. Demographic and clinical characteristics, objective sleep apnea screening, self-reported sleep outcomes, and markers of inflammation and glucose regulation were measured. Results Compared to average sleepers, long sleepers had a greater likelihood of being White and unemployed and/or retired. Long sleepers also reported longer time in bed, total sleep time and wake after sleep onset by sleep diary and by actigraphy. Other measures including medical co-morbidity, apnea/hypopnea index, sleep related outcomes such as sleepiness, fatigue, depressed mood, or markers of inflammation and glucose metabolism did not differ between long and average sleepers. Conclusion Older adults with long sleep duration were more likely to be White, report unemployment and retirement suggesting the social factors or related sleep opportunity contributed to long sleep duration in the sample. Despite known health risks of long sleep duration, neither co-morbidity nor markers of inflammation or metabolism differed in older adults with long sleep duration compared with those with average sleep duration.

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Long COVID: a review and proposed visualization of the complexity of long COVID.

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

Biomarkers of gut barrier dysfunction in obstructive sleep apnea: A systematic review and meta-analysis.

We conducted this systematic review and meta-analysis to evaluate the impact of obstructive sleep apnea (OSA) on gut barrier dysfunction as represented by the following biomarkers: zonulin, lipopolysaccharide, lipopolysaccharide binding protein, intestinal fatty acid binding protein, and lactic acid. A comprehensive search of the literature was conducted in Ovid MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov without language restrictions from inception to October 2022. The analysis of all outcomes was performed using a random-effects model. We included eight studies (seven cross sectional and one case control) in the final quantitative synthesis with a total of 897 patients. We concluded that OSA was associated with higher levels of gut barrier dysfunction biomarkers [Hedges' g = 0.73 (95%CI 0.37-1.09, p < 0.01). Biomarker levels were positively correlated with the apnea-hypopnea index [r = 0.48 (95%CI 0.35-0.6, p < 0.01)] and oxygen desaturation index [r = 0.30 (95%CI 0.17-0.42, p < 0.01)], and negatively correlated with the nadir oxygen desaturation values [r = -0.45 (95%CI - 0.55 - - 0.32, p < 0.01). Our systematic review and meta-analysis suggests that OSA is associated with gut barrier dysfunction. Furthermore, OSA severity appears to be correlated with higher biomarkers of gut barrier dysfunction. PROSPERO REGISTRATION NUMBER: CRD42022333078.