key: cord-0821788-v3hm7siz
authors: Hariyanto, Timotius Ivan; Kurniawan, Andree
title: Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A Systematic Review and Meta-Analysis
date: 2021-04-01
journal: Sleep Med
DOI: 10.1016/j.sleep.2021.03.029
sha: e456c7f0f6202c9832494aa824bd1117c46311a9
doc_id: 821788
cord_uid: v3hm7siz

BACKGROUND: Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder which could impair someone's quality of life and is also associated with poor outcomes from many diseases. Currently, the evidence regarding the link between OSA and coronavirus disease 2019 (COVID-19) is still conflicting. This study aims to analyze the relationship between OSA and poor outcomes of COVID-19. MATERIALS AND METHODS: We systematically searched the PubMed and Europe PMC database using specific keywords related to our aims until December 10(th), 2020. All articles published on COVID-19 and OSA were retrieved. The quality of the study was assessed using the Newcastle Ottawa Scale (NOS) tool for observational studies. Statistical analysis was done using Review Manager 5.4 software. RESULTS: A total of 21 studies with 54,276 COVID-19 patients were included in this meta-analysis. This meta-analysis showed that OSA was associated with composite poor outcome [OR 1.72 (95% CI 1.55 – 1.91), p < 0.00001, I(2) = 36%, random-effect modelling] and its subgroup which comprised of severe COVID-19 [OR 1.70 (95% CI 1.18 – 2.45), p = 0.005], ICU admissions [OR 1.76 (95% CI 1.51 – 2.05), p < 0.00001], the need for mechanical ventilation [OR 1.67 (95% CI 1.48 – 1.88), p < 0.00001], and mortality [OR 1.74 (95% CI 1.39 – 2.19), p < 0.00001]. CONCLUSIONS: Extra care and close monitoring should be provided to patients with OSA to minimize the risk of infections. Simple questionnaires such as STOP-Bang questionnaire can be used for screening patients who may be at risk for severe adverse outcomes.

Coronavirus disease 2019 (COVID- 19) can have a wide variety of clinical manifestations, from mild respiratory symptoms such as fever, cough, and anosmia to severe-life threatening conditions such as respiratory distress, arrhythmia, sepsis, shock, and loss of consciousness. [1, 2] Previously published meta-analysis studies have identified several comorbidities that were associated with severe outcomes from COVID-19, such as obesity, hypertension, diabetes, thyroid disease, dyslipidemia, cardiovascular disease, and pulmonary disease. [3] [4] [5] [6] [7] [8] [9] [10] Among patients with obesity, one of the most prevalent co-existing comorbid conditions was obstructive sleep apnea (OSA). OSA is the most common sleep-related breathing disorder and is highly prevalent, possibly affecting up to 1 billion people around the world. [11] It is characterized by transient increases in upper airway resistance, causing reductions or interruption of the airflow accompanied by increased respiratory effort. [12] This condition can disrupt breathing during sleeping and make someone becomes awake during night time. As a result, people with OSA often experience severe daytime drowsiness, fatigue, irritability, having difficulty concentrating, and may have a higher risk of work-related accidents. [13] During the COVID-19 pandemic, many people experience difficulty in sleeping where their sleep quality has been significantly impaired because of high mental burden, changes in their daily routines, and feelings of helplessness, abandonment, loneliness, and fear. [14] The presence of OSA can make these matters even worse. Unfortunately, until now, the evidence regarding the link between OSA and COVID-19 is still conflicting. Several observational studies showed that the presence of OSA was associated with poor COVID-19 outcomes [15] [16] [17] , but several others showed that OSA did not alter the outcomes of COVID-19 [18, 19] . This article aims to explore and give J o u r n a l P r e -p r o o f clear evidence regarding the potential association between OSA and poor outcomes of COVID-19.

Studies were included in this review if met the following inclusion criteria: representation [20, 21] , type of study was a randomized control trial, cohort, clinical trial, case-cohort, and cross-over design, and if the full-text article was available. The following types of articles were excluded: articles other than original research (e.g., review articles, letters, or commentaries); case reports; articles not in the English language; articles on research in pediatric populations (17 years of age or younger); and articles on research in pregnant women.

A systematic search of the literature was conducted on PubMed and Europe PMC using the keywords "sleep apnea syndrome" OR "obstructive sleep apnea" OR "OSA" AND 

Data extraction was performed independently by two authors, we used standardized forms that include author, year, study design, number of participants, age, gender, hypertension, Two investigators independently evaluated the quality of the included cohort and casecontrol studies using the Newcastle-Ottawa Scale (NOS). [23, 24] The selection, comparability, and exposure of each study were broadly assessed and studies were assigned a score from zero to nine. Studies with scores ≥7 were considered of good quality.

A meta-analysis was performed using Review Manager 5.4 (Cochrane Collaboration) software. We used the Generic Inverse Variance formula with random-effects models to calculate each outcome's risk. The heterogeneity was assessed by using the I 2 statistic with a value of < 25%, 26-50%, and > 50% were considered as low, moderate, and high degrees of heterogeneity, respectively. The effect estimate was reported as odds ratio (OR) along with its 95% confidence intervals (CIs) for dichotomous variables, respectively. P-value was two-tailed, and the statistical significance was set at ≤0.05. Subgroup analysis was performed for each component of composite poor outcomes. We performed Begg's funnel-plot analysis to qualitatively assess the risk of publication bias.

A total of 255 records were obtained through systematic electronic searches. After the removal of duplicates, 234 records remained. A total of 204 records were excluded after screening the titles/abstracts because they did not match our inclusion and exclusion criteria.

After evaluating 30 full-texts for eligibility, 5 full-text articles were excluded because they do not have the outcome of interest (severe COVID-19, ICU admission, the need for mechanical ventilation, and mortality), 3 full-text articles were excluded because they do not have the control/comparison group, 1 full-text article were excluded because the articles were not in English, and finally, 21 studies [15] [16] [17] [18] [19] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] Table 1 .

Studies with various study designs including cohort and case-control were included in this review and assessed accordingly with the appropriate scale or tool. Newcastle Ottawa Scales (NOS) were used to assess the cohort and case-control studies ( Table 2 ). All included studies were rated 'good'. In conclusion, all studies were seemed fit to be included in the meta-analysis.

Our pooled analysis showed that OSA was associated with composite poor outcome [OR 

The funnel-plot analysis showed a qualitatively symmetrical inverted funnel-plot for the association between OSA and composite poor outcome (Figure 3 were overweight or obese and OSA itself is strongly associated with other comorbid conditions such as hypertension, cardiovascular disease, and diabetes. [41] As we know, obesity, hypertension, cardiovascular disease, and diabetes is also associated with severe COVID-19 and mortality outcomes from COVID-19. [3, 6, 10] Second, repetitive episodes of complete/partial cessation of airflow or breathing during sleep which is frequently observed in patients with OSA, is associated with dysregulation of the renin-angiotensin system (RAS) pathway. [42] A published meta-analysis study has shown that higher levels of angiotensin II and aldosterone were observed in patients with OSA, especially in patients with pre-existing hypertension. [43] Another study has also shown that patients with untreated OSA, regardless of the presence of hypertension, was associated with an increased angiotensin-converting enzyme (ACE) activity. [44] In addition, obesity, significant comorbidity in OSA patients, also influences the RAS. [41] On the other side, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, uses the angiotensin-converting enzyme 2 (ACE2) as their entry receptor into host cells.

ACE2 is the nonclassical pathway of RAS, thus, RAS itself is involved in the pathogenesis of J o u r n a l P r e -p r o o f COVID-19. [42] The dysregulation of RAS which is happened in patients with OSA can promote SARS-CoV-2 entry into host cells, increasing its viral load and infectivity, and finally resulting in the severe outcome and mortality of the disease. The dysregulation of RAS may also contribute to the increased prevalence of cardiovascular and cerebrovascular disease reported in OSA patients where all of those are associated with severity and mortality outcomes from COVID-19. [42, 44] Third, patients with OSA often have sleep deprivation because of frequent awakening during sleeping time. Sleep deprivation itself will increase the interleukin-6 (IL-6),

interleukin-17 (IL-17), and tumor necrosis factor- (TNF-) which promote the inflammatory activity in neutrophils. [45, 46] Elevation in the IL-6 and TNF- levels have been implicated in severe COVID-19 cases, thus sleep deprivation in OSA could exacerbate the cytokine storm in COVID-19 which can cause acute respiratory distress syndrome (ARDS) and multiorgan failure. [47] Finally, repetitive airway collapse which happened in OSA not only causes dysregulation in RAS but also causes hypoxia during sleep. This resulting hypoxia from OSA could potentially contribute to worsening of the hypoxia in COVID-19 pneumonia and increase the likelihood of developing poor outcomes from COVID-19. [41] This study has several limitations. First, data on the definition, duration, grading, and type of treatment for OSA patients were lacking in the included studies, hence, cannot be analyzed. Second, we include some pre-print studies to minimize the risk of publication bias, however, the authors have made exhaustive efforts to ensure that only sound studies were included and we expect that most of those studies currently available in pre-print form will eventually be published and that we will identify them through ongoing electronic literature surveillances. We hope that this study can give further insight into OSA in COVID-19 patients. outcomes. [48, 49] Finally, OSA should be considered as an important factor in future risk stratification models for COVID-19.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Argenziano MG et al. [25] 2020 Cohort *** ** *** 8 Good

Cade BE et al. [15] 2020 Cohort ** ** *** 7 Good

Cariou B et al. [26] 2020 Cohort **** ** *** 9 Good

Dashti HT et al. [27] 2020 Cohort ** ** *** 7 Good

Dreher M et al. [28] 2020 Cohort *** ** *** 8 Good

Feuth T et al. [18] 2020 Cohort *** ** *** 8 Good

Goodall JW et al. [29] 2020 Cohort *** ** *** 8 Good

Gottlieb M et al. [30] 2020 Case-control *** ** *** 8 Good

Ioannou GN et al. [31] 2020 Cohort *** ** **** 9 Good

Izquierdo JL et al. [32] 2020 Cohort *** ** *** Good

Maas MB et al. [17] 2020 Cohort *** ** ** 7 Good

Mazzoleni L et al. [34] 2020 Cohort *** ** *** 8 Good

McCarthy CP et al. [35] 2020 Cohort **** ** *** 9 Good

Memtsoudis SG et al. [19] 2020 Cohort ** ** *** 7 Good

Palaiodimos L et al. [36] 2020 Cohort *** ** *** 8 Good

Pellaud C et al. [37] 2020 Cohort *** ** *** 8 Good

Suleyman G et al. [38] 2020 Cohort *** ** *** 8 Good

Vu C et al. [39] 2020 Cohort *** ** *** 8 Good

Xie J et al. [40] 2020 Cohort *** ** *** 

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