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Association of Sleep-Related Hypoxia With Risk of COVID-19 Hospitalizations and Mortality in a Large Integrated Health System

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Key Points

Question  Are sleep-disordered breathing and sleep-related hypoxia associated with SARS-CoV-2 infection and COVID-19 outcomes?

Findings  In this case-control study of 5402 patients in a large integrated health system, sleep-disordered breathing and sleep-related hypoxia were not associated with an increased likelihood of contracting SARS-CoV-2. After accounting for confounding factors including cardiopulmonary disease, cancer, and smoking exposure, sleep-related hypoxia indices were associated with more severe COVID-19 clinical outcomes, including hospitalization and mortality, in time-to-event analyses.

Meaning  These results suggest that baseline sleep-related hypoxia may portend worse clinical prognosis in COVID-19.


Importance  The influence of sleep-disordered breathing (SDB) and sleep-related hypoxemia in SARS-CoV-2 viral infection and COVID-19 outcomes remains unknown. Controversy exists regarding whether to continue treatment for SDB with positive airway pressure given concern for aerosolization with limited data to inform professional society recommendations.

Objective  To investigate the association of SDB (identified via polysomnogram) and sleep-related hypoxia with (1) SARS-CoV-2 positivity and (2) World Health Organization (WHO)-designated COVID-19 clinical outcomes while accounting for confounding including obesity, underlying cardiopulmonary disease, cancer, and smoking history.

Design, Setting, and Participants  This case-control study was conducted within the Cleveland Clinic Health System (Ohio and Florida) and included all patients who were tested for COVID-19 between March 8 and November 30, 2020, and who had an available sleep study record. Sleep indices and SARS-CoV-2 positivity were assessed with overlap propensity score weighting, and COVID-19 clinical outcomes were assessed using the institutional registry.

Exposures  Sleep study–identified SDB (defined by frequency of apneas and hypopneas using the Apnea-Hypopnea Index [AHI]) and sleep-related hypoxemia (percentage of total sleep time at <90% oxygen saturation [TST <90]).

Main Outcomes and Measures  Outcomes were SARS-CoV-2 infection and WHO-designated COVID-19 clinical outcomes (hospitalization, use of supplemental oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, and death).

Results  Of 350 710 individuals tested for SARS-CoV-2, 5402 (mean [SD] age, 56.4 [14.5] years; 3005 women [55.6%]) had a prior sleep study, of whom 1935 (35.8%) tested positive for SARS-CoV-2. Of the 5402 participants, 1696 were Black (31.4%), 3259 were White (60.3%), and 822 were of other race or ethnicity (15.2%). Patients who were positive vs negative for SARS-CoV-2 had a higher AHI score (median, 16.2 events/h [IQR, 6.1-39.5 events/h] vs 13.6 events/h [IQR, 5.5-33.6 events/h]; P < .001) and increased TST <90 (median, 1.8% sleep time [IQR, 0.10%-12.8% sleep time] vs 1.4% sleep time [IQR, 0.10%-10.8% sleep time]; P = .02). After overlap propensity score–weighted logistic regression, no SDB measures were associated with SARS-CoV-2 positivity. Median TST <90 was associated with the WHO-designated COVID-19 ordinal clinical outcome scale (adjusted odds ratio, 1.39; 95% CI, 1.10-1.74; P = .005). Time-to-event analyses showed sleep-related hypoxia associated with a 31% higher rate of hospitalization and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.08-1.57; P = .005).

Conclusions and Relevance  In this case-control study, SDB and sleep-related hypoxia were not associated with increased SARS-CoV-2 positivity; however, once patients were infected with SARS-CoV-2, sleep-related hypoxia was an associated risk factor for detrimental COVID-19 outcomes.

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Article Information

Accepted for Publication: September 16, 2021.

Published: November 10, 2021. doi:10.1001/jamanetworkopen.2021.34241

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Pena Orbea C et al. JAMA Network Open.

Corresponding Author: Reena Mehra, MD, MS, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave, Cleveland, OH 44195 (mehrar@ccf.org).

Author Contributions: Drs Pena Orbea and Mehra had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pena Orbea, Shah, Jehi, Mashaqi, Mehra.

Acquisition, analysis, or interpretation of data: Pena Orbea, Wang, Jehi, Milinovich, Foldvary-Schaefer, Chung, Aboussouan, Seidel, Mehra.

Drafting of the manuscript: Pena Orbea, Wang, Milinovich, Mashaqi, Aboussouan, Mehra.

Critical revision of the manuscript for important intellectual content: Pena Orbea, Shah, Jehi, Milinovich, Foldvary-Schaefer, Chung, Mashaqi, Aboussouan, Seidel, Mehra.

Statistical analysis: Pena Orbea, Wang, Shah.

Administrative, technical, or material support: Jehi, Milinovich, Aboussouan, Mehra.

Supervision: Pena Orbea, Foldvary-Schaefer, Chung, Mehra.

Other–Interpretation and preparation of results and discussion: Shah.

Conflict of Interest Disclosures: Dr Milinovich reported receiving grants from Merck, NovoNordisk, Novartis, Boehringer Ingelheim, Bayer, and the National Institutes of Health outside the submitted work. Dr Chung reported receiving research grant support from the American Heart Association and the National Institutes of Health. Dr Aboussouan reported receiving personal fees from Wolter Kluwer and honoraria for UpToDate topics outside the submitted work. Dr Jehi reported receiving funds from the National Institutes of Health outside the submitted work. Dr Mehra reported receiving funding from the National Institutes of Health and American Heart Association, royalties from UptoDate, and fees for service to the American Board of Internal Medicine outside the submitted work. Dr Pena Orbea reported receiving grant funds from the American Academy of Sleep Medicine outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the Neuroscience Transformative Research Resource Development Award (Dr Mehra), which funded the collection and management of the sleep study registry.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Jian Jin, MS, the data scientist who contributed to the data extraction; Greg Strnad, MS, the creator of the REDCap database; Amy Yamakoski, MA, the COVID-19 registry manager; Peter Imrey, PhD, who read and provided helpful comments on the late version of the manuscript from a study design and statistical perspective; and James Bena, MS, who read and provided helpful feedback for this project from a study design and statistical perspective. Mr Jin, Mr Strnad, and Ms Yamakoski were financially compensated for their contributions.

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