Subjects with medical history of SAS have a significantly increased risk for COVID-19 infection; 51 (35.4%) of 144 COVID-19 + subjects had been diagnosed and treated with SAS, compared to only 231 (2.7%) of 8693 COVID-19- subjects (i.e., 13-fold greater risk) (Table 2). While the difference was surprisingly large, our findings are consistent with those from a report by Maas et al. 16 where the authors reported that patients with OSA in the United States experienced an approximately 8-fold higher risk for COVID-19 infection compared to a similar age group receiving care in a large, racially and socioeconomically diverse healthcare system. Since the prevalence of COVID-19 was evaluated in the designated OSA subjects and in the data of the health care system respectively, several authors raised questions about the accuracy of the data comparison 20. They especially questioned the low prevalence of OSA (0.8%) in the control group (vs. 6.3% in the OSA patient’s group), while the prevalence of OSA in the United States has been reported to be 3–7% 21.
The prevalence of SAS was 3.2% (282/8837) in our study, which is well within the range of SAS prevalence in Japan 22. With regards to the COVID-19 + status, none of the participants had received the COVID-19 vaccine during the research period, and a positive polymerase chain reaction result for SARS-CoV-2 was confirmed prior to hospitalization and hotel therapy as per government standards 18. In contrast, COVID-19– statuses were self-reported, and it is possible that some subjects with subclinical infection were included in our COVID-19– group. Therefore we attempted to exclude subjects with any poor physical condition, such as persistent fatigue, or flu symptoms (sore throat, cough, sputum, and fever) from January 2020 to the time subjects answered the questionnaire, from the COVID-19– group. In addition, subjects who had visited clinics and undergone home isolation due to COVID-19 + close contact, as well as subjects whose relatives, friends or coworkers had been diagnosed with COVID-19 + were excluded from the COVID-19- group. Although contamination of subclinical COVID-19 + cases may still occur in the COVID-19– group, we believe this would increase the SAS prevalence in the COVID-19- group rather than overestimate the odds ratio for SAS positivity for the risk for COVID-19+.
A recent cross-sectional population-based web survey of 20,598 adults from 14 countries/regions found that having a high risk for OSA (evaluated with a standardized questionnaire and 9.5% prevalence) was linked to an increased risk of COVID-19 hospitalization or ICU treatment (OR 2.11, 95%CI: 1.10–4.01) 17. Furthermore, male gender (OR: 2.82, 95%CI: 1.55–5.12), diabetes (OR: 3.93, 95%CI: 1.70–9.12), and depression (OR: 2.33, 95% CI: 1.15–4.77) were found to be associated with an increased risk of COVID-19 hospitalization or ICU treatment 17. Several other non-population-based studies have also reported an increased risk of COVID-19 infections in OSA patients, with consistent results, though the risk odds ratio reported varied depending on the study 12,13,16.
As previously reported 18, a large majority of COVID-19 + subjects were in their 20s (67.4%) and a relatively large number of subjects with a medical history of SAS were in their 20s as well (26.6%). Nishijima et al. 23, recently reported that the prevalence of OSA in young adults in Japan, particularly males under 30 years old, is comparable to or even higher than that in older age groups (23). The negative impacts of SAS and other sleep disorders on health and disease have become more widely recognized in Japan in recent years. Consequently, young people frequently visit sleep clinics, and more SAS cases are likely to be diagnosed as a result. Furthermore, some public or commercial transportation companies require an SAS examination as part of the job application process (Dr. Chiba, a personal communication). These circumstances may explain why there are so many young SAS subjects. Nonetheless, in our study we also found that older age is still one of the risk factors for SAS (Table 7). However, because a large majority of COVID-19 + subjects were in their 20s and the mean age of COVID-19 + was significantly younger than that of COVID-19-, we also analyzed the data set of only 20s to avoid potential confounding factors related to aging. We discovered very similar results for this selected population, which corresponded to the findings for all ages (Table 2–7).
We found that COVID-19 + subjects were also more susceptible to FLU. 35.4% of 144 COVID-19 + subjects were infected with FLU, while only 3.0% of 8693 COVID-19- subjects were infected (χ2 = 422.7, p < 0.001) (Table 3). Because COVID-19 + and FLU + were not exclusive to each other, the vulnerability to upper airway viral infections was most likely involved in both infections, with SAS being the risk factor for both infections.
The multivariate logistic analysis for 8837 subjects revealed that high risk for COVID-19 + was associated with going out without a face mask (OR 7.05), FLU+ (OR 6.33), excessive exercise before going to bed (OR 2.10), SAS+ (OR 5.08), younger age (OR 1.05), dozing off [falling asleep while sitting and talking with someone] (OR 3.70), and use of hypnotics (OR 2.28) (Table 5).
We initially hypothesized that impaired sleep decreases the immune function, and that it may result in an increased risk for COVID-19 and FLU infections. This may still be partially true, but having SAS itself appeared to have a much larger influence on COVID-19 infection risk. The sleep indexes (i.e., PSQI) of COVID-19+ (7.2 ± 3.2) were significantly worse than those of COVID-19- (5.4 ± 2.6) (p < 0.001). However, since having SAS contributed significantly to the impaired sleep index of the entire COVID-19 + group (COVID-19+/SAS+: 8.9 ± 2.6, p < 0.001, compared to COVID-19-, Kruskal-Wallis test with Bonferroni test ), contributions of sleep impairments for COVID-19+/SAS- (6.3 ± 3.1) are not significant (p < 0.02, compared to COVID-19-). As a result, the global PSQI sleep index became a non-significant explanatory variable with the multivariate analysis for COVID-19+. Dozing off [falling asleep while sitting and talking with someone] and use of hypnotics remained significant for COVID-19 + in the multivariate analysis. The use of hypnotics could indicate that severe insomnia is a risk factor for COVID-19+. Although it is unclear how excessive exercise before going to bed increases the risk for COVID-19+, a recent study suggests that excessive exercise may reduce immune function 24. These individuals are more likely to go out at night, which may also affect their sleep and biological rhythms.
The mechanisms underlying the increased risk of COVID-19 + in SAS patients remain largely unknown. As discussed by several authors, angiotensin converting enzyme 2 (ACE2)-mediated mechanisms may be involved, since higher ACE2 activity in SAS has been reported 25 and both SARS-CoV-2 and influenza viruses infect through the ACE2 protein 26,27. Although the treatment status of SAS at the time of survey was not recorded in our study, mouth breathing due to SAS may also increase the risk for upper airway infections, as normal nose breathing adds humidity and warmness to the airflow and also increases nitric oxide levels in the airways, which may decrease viral load and enhance antiviral response during sleep 28. Proton pump inhibitor (PPI) use has recently been linked to an increased risk of COVID-19 + 29. Since SAS + patients often exhibit gastroesophageal reflux disease (GERD), and GERD is commonly treated with PPIs 30, suggesting that a PPI mediated mechanism may also be involved. Interestingly, our study also revealed that sleeping immediately after eating a meal is a risk factor for SAS+. Further studies on the mechanisms that increase the risk of COVID-19 infection in SAS patients will be useful in preventing COVID-19 infection for SAS patients and the general public.
Limitations of the study must be addressed. In order to participate in the survey, participants needed access to the internet and the ability to input their answers online, and these factors potentially limit the generalizability of our findings. However, since we focused on office workers and the main results came from the younger population, we believe this does not significantly bias the results. We were also unable to include subjects who died as a result of severe COVID-19 infection but because the ratio for these cases is estimated to be very low 18, the overall outcome of the study would remain unchanged. Due to the limitations of the internet survey, we also were unable to analyze the relationship between severity of SAS, treatment status, and their adherence for the COVID-19 + risk. In addition, we did not examine and compare the COVID-19 + risk among SAS, diabetes, hypertension, and depression, all of which have been linked to an increased risk of COVID-19 infection. Nonetheless, our study is the first population-based study to report on SAS and the increased risk of COVID-19 infection in Japanese business workers, and we believe the findings will have substantial value on COVID-19 and SAS epidemiology.
In conclusion, through an internet-based survey of 10,000 Japanese business workers, we identified SAS+, tendency to doze off, use of hypnotics, and FLU + as risk factors for COVID-19 infection, in addition to the well-known risk factors, such as going out without a mask, and younger age. Given the small contributions for sleep impairment in COVID-19+/SAS- subjects, we believe that SAS itself is a more significant risk factor for COVID-19 infection. The mechanisms for increased susceptibility to COVID-19 and FLU infections in SAS patients is vital to study in order to prevent and better manage COVID-19 infections in the general population.