Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused by the novel coronavirus of the year 2019 (COVID-19) has had a major impact on global health and economy. United States reported a total caseload of 28,998,834 patients and total mortality of 525,031 as of March 2021 (NPR.org; worldometer. Accessed March 8, 2021). The beginning of 2021 ushered positivity with the development of multiple highly effective SARS-CoV-2 vaccines. Although the medical world has gained much knowledge about this deadly disease, there are many unknowns and still much to be learned.
Dr. Ashima S. Sahni
Two early landmark studies from Italy (Lombardy) and United States (New York City area) provided initial insight on comorbid conditions associated with increased risk of severe COVID-19 infection (Richardson S, et al. JAMA. 2020;323[20]:2052; Grasselli G, et al. JAMA Intern Med. 2020;180[10]:1345). In the United States cohort, hypertension (HTN), obesity, and diabetes (DM) were independent risk factors for severe disease, while in the Italy cohort, older age, male, COPD, hypercholesterolemia, and diabetes were independent risk factors for increased mortality. Obstructive sleep apnea (OSA) was not mentioned as a comorbid risk factor.
Dr. Michelle Cao
There is much speculation regarding OSA as an independent risk factor for severe COVID-19 infection. OSA is a common sleep-related breathing disorder with increased prevalence in men, older age, and higher body mass index (BMI); and OSA is associated with hypertension, obesity, and diabetes, all of which are risk factors for severe COVID-19. Because of the shared similarities in pathophysiology between OSA and COVID-19 (Tufik S, et al. J Clin Sleep Med. 2020;16[8]:1425), and shared comorbid conditions associated with increased risk of severe COVID-19 disease, OSA has been suggested as an independent risk factor for unfavorable COVID-19-related outcomes.
SARS-CoV-2 triggers a severe inflammatory response involving type-II pneumocytes and angiotensin-converting enzyme 2 pathway. OSA is characterized by intermittent hypoxia and sleep fragmentation, leading to a cascade of systemic inflammatory response involving oxidative stress, pro-inflammatory cytokines, endothelial dysfunction, and consequent cardiovascular injury (Jose RJ, et al. Lancet Respir Med. 2020;8[6]:e46; Saxena K, et al. Sleep Medicine. 2021;79:223). In this regard, OSA may contribute to COVID-19 “cytokine storm” by causing or exacerbating endothelial dysfunction, inflammation, and oxidative stress.
Multiple studies have recently been published on the impact of OSA on COVID-19 outcomes. The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) study was one of the initial studies that analyzed the relationship between OSA and COVID-19-related outcomes. This was a multicenter observational study involving diabetic patients hospitalized with COVID-19. The primary outcome was mechanical ventilation and/or death within 7 days of admission. Multivariate adjustment showed that age, BMI, and OSA, among other factors, were independently associated with risk of death on day 7 (Cariou B, et al. Diabetologia. 2020;63[8]:1500). Strausz and colleagues also evaluated OSA as an independent risk factor for severe COVID-19 in a large registry of hospital discharge patients (FinnGen study). The authors reported that although the risk of contracting COVID-19 was the same for patients with or without OSA, after adjusting for age, sex, and BMI, OSA was associated with higher risk of hospitalization (Strausz S, et al. BMJ Open Resp Res. 2021;8:e000845). Similar findings were confirmed by the Maas et al. study, which utilized a large socioeconomically diverse database composed of 10 hospital systems. Diagnoses and outcomes were identified by ICD-10 coding and medical record data. After adjustments for diabetes, HTN, and BMI, OSA conferred an eight-fold risk for COVID-19 infection, was associated with increased risk of hospitalization, and doubled the risk of developing respiratory failure (Maas MB, et al. Sleep Breath. 2020 Sep; 29:1-3. doi: 10.1007/s11325-020-02203-0).
Peker and colleagues conducted a prospective multicenter observational study comparing clinical outcomes of severe COVID-19 infection in patients with low vs high pretest probability of having OSA based on the Berlin questionnaire. The authors reported a clinically significant risk of poorer clinical outcomes in the high pretest probability OSA group after adjustments for age, sex, and comorbidities (Peker Y, et al. Ann Am Thorac Soc. 2021. Feb 17. doi: 10.1513/AnnalsATS.202011-1409OC). A timely meta-analysis including 21 studies (19 with retrospective design) with 54,276 COVID-19 patients and 4,640 OSA patients concluded poor composite outcomes including severe COVID-19, intensive care unit admission, mechanical ventilatory support, and death in association with OSA (OR – 1.72 95% CI 1.55-1.91, P< .00001). In patients with obesity, OSA is a highly prevalent co-morbid condition. BMI, however, was not adjusted in this model (Hariyanto TI, et al. Sleep Med. 2021. doi: 10.1016/j.sleep.2021.03.029).
Other studies have concluded the opposite with OSA not being an independent risk factor for severe COVID-19 infection. Cade and colleagues conducted a retrospective analysis from a comprehensive electronic health dataset using ICD codes to identify OSA patients with severe COVID-19 infection. A significant association between OSA and COVID-19 death was noted after adjustment for demographics (ethnicity, age, sex). However, when fully adjusted for demographics, BMI, asthma, COPD, HTN, or DM, OSA was not an independent risk factor for COVID-19-related mortality and hospitalization (Cade BE, et al. Am J Respir Crit Care Med. 2020;202[10]:1462). The FinnGen study (Strausz et al.) was part of a meta-analysis examining the association between OSA and severe COVID-19 with and without adjustments for BMI. This meta-analysis consisted of 15,835 COVID-19 patients including 1,294 with OSA. The authors found that OSA was a risk factor with a two-fold increased risk of severe COVID-19 infection (OR = 2.37, P = .021). However, after adjustments were made for BMI, this finding lost statistical significance (OR=1.55, P=.13) (Strausz S, et al. BMJ Open Resp Res. 2021;8:e000845).
It is worth noting that a majority of studies identified OSA by indirect and imperfect methods through chart review, ICD codes, and databases. Confirmed OSA based on formal testing with a sleep study in COVID-19 patients remains a challenge. Perhaps well performed screening questionnaires, such as STOP-Bang, Berlin, or NoSAS, can be utilized as was the case in one study. It is also unclear if outcomes of COVID-19 infection differ in patients with treated or untreated OSA, as raised by the CORONADO study. A recent cross-sectional telephone interview survey of patients with confirmed OSA in Iran alluded to higher prevalence of COVID-19 in patients with severe OSA with suggestion of lower prevalence in patients who were currently receiving OSA treatment with positive airway pressure (PAP) therapy (Najafi A, et al. Sleep Health. 2021 Feb;7[1]:14). This is a crucial question as PAP therapy is considered an aerosol-generating procedure (Lance CG. Cleve Clin J Med. 2020 May 5. doi: 10.3949/ccjm.87a.ccc003). Studies have suggested continued use of PAP therapy with additional measures to mitigate the spread of virus, since failure to use PAP could be deleterious to the patient’s quality of life. Interestingly, PAP adherence seemed to have improved during the pandemic as evidenced by a telephonic survey done in New York City that showed 88% of patients with OSA used a PAP device consistently (Attias D, et al. Eur Respir J. 2020 Jul 30;56[1]:2001607. doi: 10.1183/13993003.01607-2020).
In summary, the jury is still out on whether OSA is a facilitator for viral replication, or an independent risk factor for poor prognosis related to COVID-19 infection, or has no clinical relevance to COVID-19. COVID-19 and OSA share comorbidities and pathways leading to a systemic inflammatory cascade. Theoretically, it would make sense that OSA is a risk factor for severe COVID-19 infection; however, it remains to be proven. The recent studies are limited by retrospective and observational nature, imprecise OSA classification/diagnostic criteria, and confounded by difficult to control variables. Further research is needed to expand our understanding of OSA -induced intermittent hypoxemia, inflammation, and endothelial dysfunction that may play a role in COVID-19 morbidity and mortality. Until we have more clarity, close monitoring of OSA patients infected with COVID-19 is recommended along with implementation of safe protocols for continuation of PAP usage during the infectious phase. Identifying underlying comorbid conditions that contribute to worsening of a COVID-19 infectious course is a crucial step in improving clinical outcomes.
Dr. Sahni is Assistant Professor of Clinical Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago. Dr. Cao is Clinical Associate Professor, Division of Sleep Medicine and Division of Neuromuscular Medicine, Department of Psychiatry and Department of Neurology, Stanford (Calif.) University.