key: cord-0877882-hkc43s6w
authors: Breville, Gautier; Adler, Dan; Uginet, Marjolaine; Assal, Frederic; Tamisier, Renaud; Lalive, Patrice H.; Pepin, Jean-Louis; Allali, Gilles
title: Does endothelial vulnerability in obstructive sleep apnea syndrome promote COVID-19 encephalopathy?
date: 2021-04-27
journal: Chest
DOI: 10.1016/j.chest.2021.04.043
sha: ef9c388fc6ff6d7e56b06c042bec83f88b15ca2a
doc_id: 877882
cord_uid: hkc43s6w

nan

Coronavirus disease 2019 (COVID-19) causes extrapulmonary manifestations, including severe neurological complications, such as acute encephalopathy. 1 COVID-19 encephalopathy has various clinical expressions ranging from subtle cognitive disturbances to coma, but its physiopathology is not fully understood.

Previous reports have put forward the hypothesis of both systemic and cerebral endotheliitis that may be responsive to high-dose glucocorticoids. 2 We observed in a cohort of patients suffering from COVID-19 encephalopathy and hospitalized at Geneva University Hospitals (Switzerland) an increased prevalence of gadolinium enhancement in large arteries on brain MRI (90.6%) suggestive of underlying endotheliitis, and an increased cerebrospinal fluid/plasma albumin ratio, suggestive of blood-brain barrier dysfunction. Pathological findings among COVID-19 patients also found multi-systemic endotheliitis including cerebral arteries. 2 In COVID-19 patients, older age, cardiovascular disease including hypertension, and obesity are known risk factors for poor clinical outcomes and a need of advanced respiratory support. 1 Obstructive sleep apnea syndrome (OSAS) shares the same landscape of comorbidities. Interestingly, the presence of OSAS has been associated with COVID-19 infection and severity, with a higher risk of developing respiratory failure, although a clear causal relationship has not been established. 3 Despite a high prevalence in the specific multimorbid population with severe forms of COVID-19, OSAS remains widely underdiagnosed. 3 In a meta-analysis, OSAS was independently associated with an increased risk of endothelial dysfunction with a dose-response relationship between the severity of intermittent hypoxia (IH) and endothelial dysfunction (endothelial dysfunction was assessed by peripheral arterial tonometry in this meta-analysis, however, endothelial J o u r n a l P r e -p r o o f integrity was not directly evaluated in the cerebral circulation). 4 OSAS-induced IH leads to a pro-inflammatory and a pro-thrombotic immunological state, which causes endothelial dysfunction. 4, 5 As OSAS and severe COVID-19 share at-risk clinical presentations and synergistic intermediary mechanisms triggering endothelial injury, we hypothesized that OSAS patients infected by SARS-CoV-2 may be at higher risk of COVID-19

encephalopathy. An untreated OSAS with pre-existing neurovascular inflammation might favor encephalopathy development.

In the lung, rapid SARS-CoV-2 replication is associated with reduced and delayed interferon-gamma (IFNγ) signaling, leading to an inflammatory monocytemacrophage accumulation and an impaired T cell response. These perturbations of the immune system response lead to a massive production of pro-inflammatory cytokines. In severe COVID-19, the so-called "cytokine storm" (or hypercytokinaemia) in correlation with a sustained innate and adaptive immune system dysregulation provoke diffuse vascular damage with molecular and cellular leakage and prevent the necessary immunological balance for an optimal SARS-CoV-2 neutralization (Fig.1 ).

All these inflammatory mechanisms result in diffuse endothelial injury starting in the lungs and then spreading to multiple organs, thus causing a severe COVID-19. The "cytokine storm" with high levels of circulating pro-inflammatory molecules maintains a global hyper-inflammatory state that might cause an acute encephalopathy. Both direct and indirect mechanisms may explain the endotheliitis found in patients with COVID-19 encephalopathy. Patients with COVID-19 encephalopathy present a similar phenotype to patients with OSAS, such as male gender, obesity, and a prevalence increasing with age. 1, 4, 5 J o u r n a l P r e -p r o o f Untreated OSAS provokes a pro-inflammatory and pro-thrombotic state, which may facilitate endothelial injury and dysfunction, atherosclerosis, and thrombosis. 5 The leukocyte phenotype changes involve both innate and adaptive immunity.

Monocyte-derived cells and neutrophils display a pro-inflammatory phenotype with a prolonged lifespan (decreased pro-apoptotic/anti-apoptotic protein balance) that contribute to increased avidity for endothelial cells. Lymphocytes also acquire an The combination of oxidative stress, metabolic changes and pro-inflammatory phenotype probably leads to endothelial dysfunction and injury in both OSAS and COVID-19 ( Fig. 1 and 2) . The challenge is how to demonstrate the association between OSAS and COVID-19 encephalopathy. Based on the above-mentioned arguments, OSAS is responsible for blood vessel wall disturbances leading to increased permeability due to endothelial cell disruption and impaired recycling. We 

Based on observations of COVID-19 patients at our institution, we hypothesize that OSAS creates a pro-inflammatory condition weakening blood vessel endothelium, including in the brain. Chronic OSAS-related inflammation may contribute to disrupt the blood-brain barrier balance, thus exposing the brain to systemic inflammation that may pave the route for CNS injuries. Thus, OSAS, a frequent and underdiagnosed 

Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients

COVID-19-related encephalopathy responsive to highdose glucocorticoids

Sleep Apnea and COVID-19 Mortality and Hospitalization

Sleep apnoea and endothelial dysfunction: An individual patient data meta-analysis

Obstructive sleep apnoea syndrome

J o u r n a l P r e -p r o o f