key: cord-0762731-x654r8jm
authors: Cardoso, Emanuel; Herrmann, Matthias J; Grize, Leticia; Hostettler, Katrin E; Bassetti, Stefano; Siegemund, Martin; Khanna, Nina; Sava, Mihaela; Sommer, Gregor; Tamm, Michael; Stolz, Daiana
title: Is sleep-disordered breathing a risk factor for COVID-19 or vice versa?
date: 2022-02-24
journal: ERJ Open Res
DOI: 10.1183/23120541.00034-2022
sha: 58b86a7c12f7904827ae4a46e01557a1f2aa4629
doc_id: 762731
cord_uid: x654r8jm

Sleep is a physiologically invigorating, mostly nocturnal state, that plays an important role in the empowerment of the immune system [1]. Obstructive sleep apnoea (OSA) is the most frequent form of sleep-disordered breathing (SDB) [2], which may represent a relevant risk factor for the clinical course and prognosis of COVID-19 [3, 4]. Common characteristics and comorbidities of OSA and COVID-19 (male gender, age>60 years, metabolic syndrome, cardiovascular- and, chronic pulmonary disease) were recently described as prognostic factors in COVID-19 [5]. However, the prevalence of SDB after COVID-19 remains insufficiently explored.

Sleep is a physiologically invigorating, mostly nocturnal state, that plays an important role in the empowerment of the immune system [1] . Obstructive sleep apnoea (OSA) is the most frequent form of sleep-disordered breathing (SDB) [2] , which may represent a relevant risk factor for the clinical course and prognosis of COVID-19 [3, 4] . Common characteristics and comorbidities of OSA and COVID-19 (male gender, age >60 years, metabolic syndrome, cardiovascular-and, chronic pulmonary disease)

were recently described as prognostic factors in COVID-19 [5] . However, the prevalence of SDB after COVID-19 remains insufficiently explored.

This study included 58 patients who fulfilled the following criteria: age > 18 years, a positive PCR test for SARS-CoV-2, pulmonary infiltrates on chest-CT-scan and a need for hospitalization due to COVID-19 during the period of 8 th March to 1 st May 2020 [6] . The absence of a written informed consent and/or the presence of a positive airway pressure (PAP) therapy were exclusion criteria. At the time of hospitalisation, all patients received treatment according to the local guidelines and were classified according to the WHO Ordinal Scale for Clinical Improvement. For the analysis, we classified the patients into a mild/moderate-(n = 27) and a severe-COVID-19 group (n = 31, Table 1 ).

Severe COVID-19 was defined by oxygen saturation <93%, respiratory rate >30/min, C-reactive protein levels >75 mg/l, extensive area of ground-glass opacities or progression on computed tomography during hospitalization [6] .

Demographic, clinical and outcome data were collected prospectively. Pulmonary function testing including whole-body plethysmography and carbon monoxide diffusion capacity (Vyntus® BODY, Vyaire Medical Germany), as well as home sleep apnoea testing (HSAT) with the WatchPAT200 (Itamar Medical Ltd., Caesarea, Israel) were conducted three to twelve months (mean 5.26 ± 3.08 months) after discharge. WatchPAT200 measurements and analyses are standardized, validated and recommended as a diagnostic tool for OSA according to the American Academy of Sleep Medicine (AASM) clinical practice guidelines [7] . Sleep apnoea severity was graded: mild (apnoea hypopnoea index AHI = 5 -14 /h), moderate (AHI = 15 -30/h) and severe (AHI > 30 /h). Daytime sleepiness was evaluated with the Epworth Sleepiness Scale (ESS).

The patient cohort consisting mainly of males (74%) of Caucasian ethnicity (90%) presented at admission with a mean age of 59.84 ± 13.79 years (mean ± SD) and mean C-reactive protein (CRP) level of 72.80 ± 65.87 mg/l. The initial quantification of radiological lung involvement with pulmonary infiltrates at admission was 15.47 ± 11.06 % of total lung volume. Next to the WHO scale, the following parameters were significantly different between the mild/moderate and severe COVID-19 groups: CRP levels (p=0.005), lymphocyte count (p=0.043), the percentage of radiological lung involvement (p=0.034) as well as the length of hospital stay (p<0.0001).

At the follow-up, six patients (10.3%) presented with obstruction (FEV 1 /FVC < 70%), three patients Patients in the severe COVID-19 group had more moderate (45% vs 30%) and severe sleep apnoea (32% vs 7.4%) compared to the patients in the mild/moderate COVID-19 group, and nocturnal hypoxaemia was higher in severe group (median (IQR) 0.30 (0.00 -1.40) and 0.00 (0.00 -0.50), p=0.008). The associations between CRP at admission, PFT parameters (FEV1, % pred, DLCO, % pred and TLC, % pred) and AHI were not statistically significant.

OSA is the most prevalent sleep-related breathing disorder. Heinzer et al. reported a prevalence of moderate-to-severe sleep apnoea (≥ 15 events/h) in 49.7% men and 23.4% women [2] . The prevalence of sleep apnoea in COVID-19 ranged from 11% to 29% [8] . In our study, moderate-to-severe sleep apnoea was detected in the majority of patients (58.6%) after COVID-19 and was numerically higher in men than in women (63% versus 47%, p=0.364). Interestingly, there was a significant difference in the prevalence of moderate-to-severe OSA between the two COVID-19 groups: 37.0% in the mild/moderate COVID-19 group compared to 77.4% in the severe COVID-19 group.

Our findings give room for an association between the severity of the SARS-CoV-2 infection and a higher prevalence and severity of SDB in disease convalescence. To date, there are little data about the prevalence of sleep apnoea after COVID-19. In a previous study, the prevalence of moderate-to-severe sleep apnoea in a nested cohort of patients with ARDS (n =34, mean age 51, male 67.6%) was significantly higher than in a group with mild/moderate COVID-19 (n=26, mean age 40.4 years, male 34.6) 3-6 months after discharge (38% versus 8%, p < 0.01) [9] . The lower prevalence of moderatesevere sleep apnoea (8%) in this mild/moderate COVID-19 group as compared to our study might be explained by the imbalance in gender (fewer men) and the lower age.

On the other side, a higher prevalence of sleep apnoea in almost 2/3 of participants (n=44) was observed during acute SARS-CoV-2 infection in 52 % patients requiring oxygen support and in 48% patients requiring NIV or invasive ventilation, predicting OSA severity in a previous study [10] .

Moreover, a high prevalence of cognitive dysfunction after 6 months (58.4%, 56.5% to 60.2%) was reported in a symptomatic-oriented follow-up study of 3762 participants over 7 months [11] , presuming an undiagnosed OSA, once neurological impairment have been associated with sleep apnoea [12] [13] [14] [15] .

OSA with sleep deprivation is associated with a higher susceptibility to viral infections. The dysregulation of the renin-angiotensin system and T-cell production of interleukin-2 promotes increased pro-inflammatory activity, which may play a role in the course of viral pneumonias [16] .

Similarly, it is tempting to hypothesize that OSA could lead to a pathophysiological synergic higher level of hypoxemia, complement activation and a severe cytokine storm during COVID-19 [17] .

On the other hand, a possible central nervous system involvement of COVID-19 [18] with impact on chemoreceptors in the lung and lower respiratory airways might represent a risk of developing central sleep apnoea. Rapid eye movement (REM) sleep without atonia has been described after acute COVID-19, which might be an early marker of neurodegenerative disease [19] . Furthermore, it would be similarly plausible to consider that underlying pro-inflammatory processes with elevated CRP and Interleukin-6 in COVID-19 might lead to a higher incidence of OSA [20] . Additionally, a postintubation granulation tissue formation leading to upper airway narrowing could be a hypothetical explanation favoring OSA [21] .

So far, we can neither infer nor refute causality between OSA and COVID-19, as only three individuals of our cohort underwent a sleep study (one of which with no OSA) before the viral disease.

Our analysis suggests a relevant association between the severity of SARS-CoV-2 infection and a higher prevalence and severity of sleep apnoea in disease convalescence. Although this is a small, hypothesis generating study, theoretically, the long-COVID-19 syndrome characterised by excessive sleepiness, fatigue, deterioration of cognitive function, or even depression could also be associated with an undiagnosed novel "covid-induced sleep apnoea" syndrome with clinical consequences and implications on quality-of-life. If these findings are to be confirmed, it might be advisable to encourage the screening for sleep apnoea in the work-up of long-COVID-19. 

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