The Relationship between Nonrestorative Sleep and Persistent Post-Acute Sequelae of COVID-19: A Longitudinal Study of Recovery Trajectories

The Relationship between Nonrestorative Sleep and Persistent Post-Acute Sequelae of COVID-19: A Longitudinal Study of Recovery Trajectories | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Relationship between Nonrestorative Sleep and Persistent Post-Acute Sequelae of COVID-19: A Longitudinal Study of Recovery Trajectories Megumi Hazumi, Mayumi Kataoka, Kentaro Usuda, Michi, Ayako Nakashita, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7271333/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: Nonrestorative sleep (NRS) may contribute to the persistence of post-acute sequelae of COVID-19 (PASC), but no longitudinal studies have investigated this relationship. This study examined the association between NRS and PASC persistence over one year. Study design: This was a one-year prospective cohort study conducted using an online survey. Methods: We conducted a one-year prospective cohort study through an online survey between September 2022 (Time 1, T1) and September 2023 (Time 2, T2). Eligible patients were adults aged18 years or older who had experienced COVID-19 infection after February 2022 and were more than one month post-infection with at least one PASC symptom. NRS, difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awaking (EMA) were evaluated at T1. PASC persistence was evaluated at T2. Relative risk ratio calculations with multiple imputations were performed to examine associations between sleep disturbances and PASC. Results: Among 957 participants with PASC at baseline, 559 (58.4%) completed the follow-up assessment. NRS at T1 was associated with PASC persistence at T2 (Relative Risk = 1.33, 95% confidence interval = 1.08 – 1.64). In contrast, DIS, DMS, and EMA showed no significant associations with PASC persistence. Sensitivity analyses using different NRS thresholds yielded consistent trends. Conclusion: This study suggests that NRS might contribute to PASC persistence through a potentially distinct mechanism from DIS, DMS, and EMA. Psychiatry COVID-19 Post-Acute Sequelae of COVID-19 Nonrestorative sleep Insomnia Difficulty Initiating Sleep Difficulty Maintaining Sleep Early Morning Awaking Figures Figure 1 Introduction Post-acute sequelae of COVID-19 (PASC) refers to symptoms persisting for over a month following COVID-19 infection 1 . These symptoms encompass a wide spectrum, including respiratory, general, and neurologic manifestations 2 , 3 . The underlying mechanism remains under investigation but is thought to involve immune dysregulation and chronic inflammation 4 , 5 . Dysfunctions in the hypothalamic-pituitary axis, such as reduced growth hormone and cortisol levels, have also been implicated 4 , 6 – 8 . These findings suggest that PASC is driven by complex physiological processes that remain or exacerbate symptoms. The public burden of PASC is substantial. Approximately 54% of COVID-19 survivors report at least one lingering symptom six months post-infection 1 . Although it gradually fades with time, individuals with histories of COVID-19 exhibit higher rates of symptoms compared to individuals without it 9 . PASC contributes to a significant reduction in quality of life 10 , 11 and imposes economic costs through increased medical utilization and reduced productivity 12 – 14 . Therefore, it is crucial to identify factors that maintain or exacerbate PASC. Nonrestorative sleep (NRS), a subjective experience of unrefreshing sleep 15 , 16 , is prevalent in 2.4–16.1% of the general population 17 and is associated with a range of sleep disturbances, including sleep apnea, restless legs syndrome, snoring, sleep bruxism, sleep debt, social jet lag, and evening chronotype 18 – 21 , as well as insomnia. The International Classification of Sleep Disorders 2nd Edition (ICSD-2) historically included NRS as a diagnostic criterion for insomnia 22 . However, the ICSD-3 excluded NRS from insomnia criteria because it is also observed in almost all sleep disorders such as sleep apnea, and psychoneurologic disorders as well, as contrasted to the other insomnia symptoms including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awaking (EMA). Currently, NRS is recognized as a nonspecific symptom that arises from various sleep disturbances. Polysomnographic studies suggested that a little amounts of slow-wave sleep 23 , increased alpha activity during non-rapid-eye-movement (non-REM) sleep 16 , and large amounts of wake after sleep onset are associated with NRS 24 , 25 . NRS can influence PASC, because sleep disturbances are prevalent in PASC 26 . A meta-analysis indicated that sleep disturbances, including poor sleep quality, conceptually related to NRS, are more strongly associated with PASC than duration or timing of sleep 27 . Additionally, risk factors for NRS, such as obstructive sleep apnea, have been identified as predictors of PASC 28 . NRS is also associated with symptoms commonly observed in PASC, including fatigue 29 , 30 , respiratory disease 18 , neuralgic pain 31 , and migraine 32 . Previous studies suggested that NRS may exacerbate PASC through inflammatory and symptomatic pathways: elevated levels of C-reactive protein, a marker of systemic inflammation, have been observed in individuals with NRS compared to those with insomnia symptoms, including DIS, DMS, and EMA 18 . It has also been reported that chronic post-SARS syndrome, a condition associated with related coronavirus, showed NRS-like features along with alpha electroencephalogram abnormalities and cyclic alternating patterns 33 . Despite these connections, no cohort studies have directly investigated the relationship between NRS and PASC. Existing research has focused on pre-existing sleep disturbances as predictors of PASC 34 , but many individuals report new-onset sleep problems, including NRS, following COVID-19 infection 26 . Understanding the role of post-infection NRS in PASC persistence is essential for identifying modifiable factors and guiding interventions. Therefore, this study examined the association between NRS and the persistence of PASC symptoms over one year. We hypothesized that individuals with PASC who experience NRS are more likely to exhibit persistent PASC than those without. Methods 1.1 Participants and setting The two-point longitudinal survey for COVID-19 was performed through the Rakuten Insight Corporation, one of Japan’s largest and most established online research companies, with over 2.2 million actively managed panels across Japan 35 . The company maintains high-quality panels through strict screening processes and regularly validates panel members’ information, ensuring reliable data collection. Data collection occurred at two time points: Time 1 (T1) from September 2022 and Time 2 (T2) from September 2023. Potential participants received study recruitment information and accessed an online survey platform. Participation was confirmed through an electronic informed consent process, with respondents receiving shopping reward points upon completion. Study eligibility required participants to be at least 18, with their first Polymerase-Chain-Reaction (PCR)-confirmed COVID-19 infection occurring after February 2022, coinciding with the predominance of the Omicron variant in Japan 36 . To align with established PASC definitions, participants needed at least one month post-infection and to be experiencing at least one post-COVID symptom at T1 1 . We excluded data from participants who failed validation questions, self-reported absence of PCR-confirmed infection, or provided inconsistent responses across the survey. 1.2 Measurements All data were collected through an online questionnaire system. 1.2.1 Outcome The outcome was the presence of PASC symptoms at T2, assessed through a detailed symptom inventory. Participants responded: “Which of the following symptoms do you currently experience related to COVID-19?” The inventory included 24 specific symptoms: fever, cough, fatigue, muscle/body pain, sore throat, headache, diarrhea, conjunctivitis, taste loss/alteration, smell loss/alteration, skin manifestations, respiratory difficulties, chest symptoms, mobility issues, menstrual problems, vision changes, dizziness, gastrointestinal symptoms, convulsions, neuralgia, cardiovascular symptoms, auditory problems, new allergies, and other symptoms (with free-text specification). Cognitive and psychological symptoms were excluded from this analysis. These symptoms were categorized into 10 symptom groups 2 . Categorization is detailed in the previous study 37 . 1.2.2 Exposure NRS was evaluated using a frequency assessment of the feeling of NRS 38 – 40 . Participants indicated their experience over the previous month using five frequency categories: none, rarely (< 1/month), sometimes (2–4 times/month), frequently (5–15 times/month), and very frequently (≥ 16 times/month). We defined NRS as reporting “frequently” or “very frequently”. For robustness, we conducted sensitivity analyses using “sometimes” or more instead of “frequently” or more. DIS, DMS, and EMA were additionally assessed using the items regarding nocturnal sleep in the Insomnia Severity Index (ISI): “Difficulty falling asleep,” “Difficulty staying asleep,” and “Problem waking up too early.” Each item is rated on five frequency categories (None/ Mild/ Moderate/ Severe/ Very), with higher scores indicating greater severity. We defined each symptom as reporting “Severe” or more. For robustness, we conducted sensitivity analyses using “Moderate” or more instead of “Severe” or more. 1.2.3 Covariates Our analyses incorporated a comprehensive set of potential confounders measured at T1. Demographic factors included sex (male/ female or others) 41 , age group (20s/ 30s/ 40s/ 50s/ ≥ 60s) 41 , educational attainment (Higher than high school graduates or not) 41 , household income (< 3,000,000 yen/ < 10,000,000 yen/ ≥ 10,000,000 yen/ Unknown or refuse) 42 , and cohabitant status 43 . Clinical history included psychiatric histories 44 – 46 and physical comorbidities 47 – 49 , which encompassed a broad range of conditions, including cardiovascular, respiratory, metabolic, autoimmune, and neurological disorders. COVID-19-specific factors included hospitalization status at infection 45 , 50 , duration after infection (months) 9 , vaccination status 41 , and psychological distress (K6 ≥ 13) 37 , 51 . 1.3 Statistical analysis All analyses were performed using Stata version 18.0 (StataCorp LLC, College Station, TX, USA), with statistical significance set at p < 0.05. After calculating the number and proportion of variables, univariate absolute risk differences were calculated to assess the associations between nocturnal sleep complaints and PASC persistence. Subsequently, the modified Poisson analyses with robust error were performed to estimate adjusted relative risk ratios (RR) by accounting for covariates. The presence of PASC symptoms at T2 was used as the dependent variable, and NRS, DIS, DMS, and EMA were used as independent variables, as well as covariates. E-values of variables with significant associations observed were calculated. The same analyses using mild and severe cutoffs for exposure were also performed as sensitivity analyses. Loss-to-follow-up was handled using the multiple imputation by chained equation (MICE) for the modified Poisson regression analyses. Exposure variables and covariates were used as auxiliary variables. The number of imputations was set to m = 50. Supplementarily, a complete case analysis (CCA) was also performed. 1.4 Ethics The study was reviewed and approved by the Research Ethics Committee of the National Center of Neurology and Psychiatry (approval number: A2021-034) and performed per the Declaration of Helsinki. All participants provided informed consent electronically before participating in the survey. Results 2.1 Characteristics A total of 957 participants were included in the analysis, with 559 (58.4%) providing follow-up data at T2 (Fig. 1 ). The sample comprised 48.26% males, with the largest age group being those in their 40s (33.03%). Among the participants, 33.84%, 22.49%, 29.14%, and 24.23% experienced NRS, DIS, DMS, and EMA (Table 1 ). Table 1 Characteristics of participants Total n or mean SD or % Sex: male 472 48.26% Age 20s 89 9.10% 30s 240 24.54% 40s 323 33.03% 50s 240 24.54% ≥ 60s 86 8.79% Cohabitant: yes 843 86.20% Educational level: Higher than high school graduates 741 75.77% Household income < 3,000,000 yen 137 14.01% < 10,000,000 yen 579 59.20% ≥ 10,000,000 yen 141 14.42% Unknown/ refuse 121 12.37% Psychological distress 91 9.30% Psychiatric history 111 11.35% Physical comorbidity 274 28.02% Duration after infection (months) 2.4 SD = 2.0 Hospitalized 26 2.66% Vaccination status 835 85.38% NRS 331 33.84% DIS 220 22.49% DMS 285 29.14% EMA 237 24.23% NRS, nonrestorative sleep; DIS, difficulty initiating sleep; DMS, difficulty maintaining sleep; EMA, early morning awaking At T1, respiratory symptoms were the most prevalent PASC manifestation (52.76%), followed by general symptoms (37.83%). At T2, 45.97% of participants reported at least one PASC (Table 2 ). Table 2 Details of PASC Time 1 (n = 978) Time 2 (n = 559) n % n % Presence of PASC - - 257 45.97% Respiratory 516 52.76% 116 20.75% General 370 37.83% 143 25.58% Neurologic 260 26.58% 127 22.72% Musculoskeletal 67 6.85% 54 9.66% Eye 57 5.83% 50 8.94% Cardiac 57 5.83% 25 4.47% Gastrointestinal 55 5.62% 40 7.16% Dermatologic 47 4.81% 14 2.50% Urinary 0 0% 0 0% Other 46 4.70% 23 4.11% PASC, Post Acute Sequelae of COVID- 19 Absolute risk differences of NRS DIS, DMS, and EMA were 0.19 (95% Confidence Interval [CI] = 0.10–0.28), 0.14 (95% CI = 0.04–0.24), 0.16 (95% CI = 0.07–0.25), and 0.17 (95% CI = 0.07–0.26). 2.2 Associations between NRS, Insomnia, and subsequent PASC A significant association between NRS at T1 and the presence of PASC at T2 was observed (RR = 1.25, p = 0.04, 95% CI = 1.01–1.54). No significant associations were observed between DIS, DMS, and EMA at T1 and PASC at T2. The E-value for the RR between NRS and PASC was 1.80. Analysis with CCA confirmed results similar to those of analysis with MICE. The significant association between NRS and PASC, while maintaining the absence of significant associations with DIS, DMS, and EMA (Appendix 1). Sensitivity analyses using different cutoff points for NRS showed similar patterns of association with PASC, but these did not reach statistical significance. There was no significant association between DIS, DMS, EMA, and PASC (Appendix 2). Table 3 Associations between Sleep disturbances and PASC RR SE p 95% CI NRS 1.33 0.14 0.007 1.08 1.64 DIS 1.02 0.16 0.89 0.75 1.39 DMS 1.10 0.18 0.55 0.80 1.53 EMA 0.83 0.13 0.23 0.62 1.12 Covariates: sex, age, cohabitant, educational level, household income, psychological distress, psychiatric history, physical comorbidity, duration after infection, hospitalized, vaccination status NRS, nonrestorative sleep; DIS, difficulty initiating sleep; DMS, difficulty maintaining sleep; EMA, early morning awaking; RR, Relative Risk; SE, Standard Error; 95% CI, 95% Confidence Interval Discussion In this one-year longitudinal study for individuals with PASC, we found that NRS at baseline was significantly associated with the subsequent persistence of PASC at the one-year follow-up. DIS, DMS, and EMA showed no significant relationship with PASC persistence. These findings suggest that NRS may influence PASC persistence more than symptoms specific to insomnia, including DIS, DMS, and EMA. Therefore, focusing on a broader range of sleep disorders that may underlie NRS could be crucial for preventing and improving PASC persistence. This study is the first to examine the influences of sleep on longitudinal PASC recovery trajectories. While previous studies demonstrated that pre-infection sleep problems, including obstructive sleep apnea, short sleep duration, night-shift work, and other sleep disturbances, predict PASC development 27 , 28 , 52 , 53 , our findings extend this knowledge by showing that NRS during PASC also predicts its persistence. The observation that NRS, but not insomnia symptoms like DIS, DMS, and EMA, was associated with PASC persistence aligns with a previous study indicating stronger associations between PASC and non-insomnia sleep problems compared to insomnia 27 . Several mechanisms may explain the association between NRS and PASC persistence. First, increased alpha activity during non-REM sleep, a characteristic of NRS 28 , may exacerbate fatigue, a common PASC symptom 16 . Second, NRS may be further associated with lower growth hormone secretion by disrupting slow-wave sleep 16 , 23 , 54 , potentially compounding the reduced growth hormone levels observed in PASC 4 , 6 – 8 . Given the important role of growth hormone in tissue repair and immune function, this disruption could impair recovery processes and contribute to PASC persistence. The differential contribution of NRS versus insomnia symptoms, including DIS, DMS, and EMA, to PASC persistence may be attributed to several factors. Individuals with NRS show more pronounced inflammatory responses than those with DIS, DMS, and EMA 18 , suggesting NRS may more strongly maintain or exacerbate the inflammatory process underlying PASC 4 , 5 . Additionally, some individuals reporting insomnia symptoms like DIS, DMS, and EMA exhibit normal slow-wave sleep and sleep duration compared to healthy controls 55 and have minimal objective disturbance despite substantial subjective complaints 56 . These characteristics of insomnia symptoms, where objective parameters may be preserved despite subjective sleep complaints, may have attenuated its association with PASC persistence. NRS may be more relevant to PASC persistence than DIS, DMS, and EMA, consistent with previous findings on its stronger associations with to depression and hypertension 57 , 58 . This study has some clinical implications. Screening for NRS in individuals with PASC may help identify those at higher risk for PASC persistence, allowing for early intervention and more targeted treatment approaches. Healthcare providers should specifically inquire about NRS rather than focusing on insomnia symptoms like DIS, DMS, and EMA. Furthermore, addressing NRS in addition to standard PASC treatment might promote earlier PASC recovery in affected individuals. This could involve interventions specifically targeting sleep restoration, such as sleep hygiene education and treatment of underlying sleep disorders. Several limitations warrant consideration. First, all measures relied on self-reporting, limiting the diagnostic precision of PASC and comorbid conditions. While this approach allowed us to capture data from individuals who may not have sought medical attention, future studies using claim data, such as precise diagnoses and vaccination status, could provide more detailed insights. Second, we could not determine whether sleep problems predated COVID-19 infection or emerged as PASC symptoms, although we controlled for pre-infection psychiatric symptoms. Prospective studies beginning before COVID-19 infection would be valuable in clarifying this temporal relationship. Finally, the retention rate was relatively low at 58.4%. We addressed this limitation through multiple imputations to minimize potential bias even with high levels of missing data 59 , but caution in interpretation is warranted. Future studies with higher retention and longer follow-up periods would help confirm and extend our findings. Conclusion This longitudinal study suggests that NRS is associated with PASC persistence over one year, different from insomnia symptoms like DIS, DMS, and EMA. This finding indicates that NRS may influence PASC recovery through mechanisms distinct from those involved in DIS, DMS, and EMA. These results highlight the importance of comprehensive sleep assessment in patients with PASC. Future research should explore the biological mechanism underlying this relationship and evaluate whether interventions targeting NRS can improve PASC outcomes. Declarations 5 Funding This study was supported by an Intramural Research Grant for Neurological and Psychiatric Disorders from the NCNP (4-3). 6 Competing interests DN reports personal fees outside of the submitted work from Startia, Inc., en-Power, Inc., MD.net, and Takeda Pharmaceutical Company, Ltd. MH, MK, KK, KU, MK, EM, ND, EO, TY, KM, NK declare no conflict of interest to disclose regarding this study. 7 Contribution Concept and design: MH, MK, KK, DN, KU, MK, EM, ND, EO, TY, KM, DN, NK Data curation: MH, MK, AN, and MK Analysis: MH Interpretation of analysis: MH, KK, and NK Drafting of the manuscript: MK Critical revision of the manuscript for important intellectual content: MH, MK, ND, KU, MM, AN, MK, EM, EO, KK, TY, KM, NK Supervision: KK, DN, NK All authors have read and agreed to the published version of the manuscript. 8 Acknowledgment While preparing this work, the authors used Claude 3 Opus, by Anthropic, to enhance the readability and proofread the English text. 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Kataoka","email":"","orcid":"https://orcid.org/0000-0001-9611-2119","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Mayumi","middleName":"","lastName":"Kataoka","suffix":""},{"id":494318857,"identity":"8b41ed72-8b50-4496-b50b-7374a4c90453","order_by":2,"name":"Kentaro Usuda","email":"","orcid":"https://orcid.org/0000-0002-6666-8535","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Usuda","suffix":""},{"id":494318858,"identity":"1da3f26e-f521-4a95-8956-446c29ff1f72","order_by":3,"name":"Michi","email":"","orcid":"https://orcid.org/0009-0009-7503-3943","institution":"Miyake","correspondingAuthor":false,"prefix":"","firstName":"","middleName":"","lastName":"Michi","suffix":""},{"id":494318859,"identity":"35357e8e-b488-4417-b069-5a475475f4fd","order_by":4,"name":"Ayako Nakashita","email":"","orcid":"https://orcid.org/0009-0001-0826-7952","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Nakashita","suffix":""},{"id":494318860,"identity":"e4d142e1-521a-4e0d-8661-bfc0bdc6c76a","order_by":5,"name":"Makiko Kitamura","email":"","orcid":"https://orcid.org/0009-0002-8947-9080","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Makiko","middleName":"","lastName":"Kitamura","suffix":""},{"id":494318861,"identity":"cf5ff10e-14ff-4d5b-a3e6-fa272b12d725","order_by":6,"name":"Emi Okazaki","email":"","orcid":"https://orcid.org/0000-0002-1720-4048","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Emi","middleName":"","lastName":"Okazaki","suffix":""},{"id":494318862,"identity":"d422fec0-54e2-40d4-bd9f-5b7640fe6d46","order_by":7,"name":"Takuya Yoshiike","email":"","orcid":"https://orcid.org/0000-0002-6071-8167","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Yoshiike","suffix":""},{"id":494318863,"identity":"d780a750-6f54-4076-a232-d1a2b7bbf67f","order_by":8,"name":"Kentaro Matsui","email":"","orcid":"https://orcid.org/0000-0003-4538-5381","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Matsui","suffix":""},{"id":494318864,"identity":"3d2c97d3-5b4a-4a49-910b-6bc9bf9cee17","order_by":9,"name":"Kenichi Kuriyama","email":"","orcid":"https://orcid.org/0000-0002-0254-4357","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Kenichi","middleName":"","lastName":"Kuriyama","suffix":""},{"id":494318865,"identity":"864ec62e-7b4d-4d97-a54a-a8db8d78b826","order_by":10,"name":"Daisuke Nishi","email":"","orcid":"https://orcid.org/0000-0001-9349-3294","institution":"University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Nishi","suffix":""},{"id":494318866,"identity":"8637972d-75ee-4ed7-a857-4089eb90e833","order_by":11,"name":"Naoaki Kuroda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYDACHhDBxiAHF2BsIFKLMelaEgkqhANznjNmHz6U2aVvZz977AHDLxsG5tkEdFv29hjPnHEuOXdnT166AWNfGgPjnAP4tRic5zFm5m1jzt1wg8dMgrHnMAPjjASitNSnGxCv5WwPSMvhBLAWhh/EaDlzrJhxxrnjhhvO5JgbJDak8RD2y5nkzQwfyqrlDY6fMXvw4Y+NnCGhEEMGwNhpY+AxnEG8DqAWhj8MDPISJGgZBaNgFIyCEQEAcRJAilzKhfcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-0407-0228","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":true,"prefix":"","firstName":"Naoaki","middleName":"","lastName":"Kuroda","suffix":""}],"badges":[],"createdAt":"2025-08-01 12:38:41","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7271333/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7271333/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88350664,"identity":"7a1724cb-7bfb-4f98-b60e-990db6f8625e","added_by":"auto","created_at":"2025-08-05 14:16:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":133194,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7271333/v1/e2933ac5c46eb3e4a3ab0e9e.png"},{"id":88350670,"identity":"7c1e0c9a-0ed0-493e-a9e2-9ba2b239eda2","added_by":"auto","created_at":"2025-08-05 14:16:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":841320,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7271333/v1/21572bbe-bdc1-46a1-99d7-3d79466b59c8.pdf"},{"id":88348509,"identity":"14b07317-e4ef-4dd0-9ebd-af1560d9f94f","added_by":"auto","created_at":"2025-08-05 14:00:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18141,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixs.docx","url":"https://assets-eu.researchsquare.com/files/rs-7271333/v1/0435345d2b7aae33d50a9ece.docx"}],"financialInterests":"The authors declare potential competing interests as follows: DN reports personal fees outside of the submitted work from Startia, Inc., en-Power, Inc., MD.net, and Takeda Pharmaceutical Company, Ltd. MH, MK, KK, KU, MK, EM, ND, EO, TY, KM, NK declare no conflict of interest to disclose regarding this study.","formattedTitle":"\u003cp\u003eThe Relationship between Nonrestorative Sleep and Persistent Post-Acute Sequelae of COVID-19: A Longitudinal Study of Recovery Trajectories\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePost-acute sequelae of COVID-19 (PASC) refers to symptoms persisting for over a month following COVID-19 infection\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. These symptoms encompass a wide spectrum, including respiratory, general, and neurologic manifestations\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The underlying mechanism remains under investigation but is thought to involve immune dysregulation and chronic inflammation\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Dysfunctions in the hypothalamic-pituitary axis, such as reduced growth hormone and cortisol levels, have also been implicated\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. These findings suggest that PASC is driven by complex physiological processes that remain or exacerbate symptoms. The public burden of PASC is substantial. Approximately 54% of COVID-19 survivors report at least one lingering symptom six months post-infection\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although it gradually fades with time, individuals with histories of COVID-19 exhibit higher rates of symptoms compared to individuals without it\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. PASC contributes to a significant reduction in quality of life\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e and imposes economic costs through increased medical utilization and reduced productivity\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Therefore, it is crucial to identify factors that maintain or exacerbate PASC.\u003c/p\u003e\u003cp\u003eNonrestorative sleep (NRS), a subjective experience of unrefreshing sleep\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, is prevalent in 2.4\u0026ndash;16.1% of the general population\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and is associated with a range of sleep disturbances, including sleep apnea, restless legs syndrome, snoring, sleep bruxism, sleep debt, social jet lag, and evening chronotype \u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, as well as insomnia. The International Classification of Sleep Disorders 2nd Edition (ICSD-2) historically included NRS as a diagnostic criterion for insomnia\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, the ICSD-3 excluded NRS from insomnia criteria because it is also observed in almost all sleep disorders such as sleep apnea, and psychoneurologic disorders as well, as contrasted to the other insomnia symptoms including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awaking (EMA). Currently, NRS is recognized as a nonspecific symptom that arises from various sleep disturbances. Polysomnographic studies suggested that a little amounts of slow-wave sleep \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, increased alpha activity during non-rapid-eye-movement (non-REM) sleep\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, and large amounts of wake after sleep onset are associated with NRS\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNRS can influence PASC, because sleep disturbances are prevalent in PASC\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. A meta-analysis indicated that sleep disturbances, including poor sleep quality, conceptually related to NRS, are more strongly associated with PASC than duration or timing of sleep\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Additionally, risk factors for NRS, such as obstructive sleep apnea, have been identified as predictors of PASC\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. NRS is also associated with symptoms commonly observed in PASC, including fatigue\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, respiratory disease\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, neuralgic pain\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e, and migraine\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Previous studies suggested that NRS may exacerbate PASC through inflammatory and symptomatic pathways: elevated levels of C-reactive protein, a marker of systemic inflammation, have been observed in individuals with NRS compared to those with insomnia symptoms, including DIS, DMS, and EMA\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. It has also been reported that chronic post-SARS syndrome, a condition associated with related coronavirus, showed NRS-like features along with alpha electroencephalogram abnormalities and cyclic alternating patterns\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDespite these connections, no cohort studies have directly investigated the relationship between NRS and PASC. Existing research has focused on pre-existing sleep disturbances as predictors of PASC\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, but many individuals report new-onset sleep problems, including NRS, following COVID-19 infection\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Understanding the role of post-infection NRS in PASC persistence is essential for identifying modifiable factors and guiding interventions. Therefore, this study examined the association between NRS and the persistence of PASC symptoms over one year. We hypothesized that individuals with PASC who experience NRS are more likely to exhibit persistent PASC than those without.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Participants and setting\u003c/h2\u003e\u003cp\u003eThe two-point longitudinal survey for COVID-19 was performed through the Rakuten Insight Corporation, one of Japan\u0026rsquo;s largest and most established online research companies, with over 2.2\u0026nbsp;million actively managed panels across Japan\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. The company maintains high-quality panels through strict screening processes and regularly validates panel members\u0026rsquo; information, ensuring reliable data collection. Data collection occurred at two time points: Time 1 (T1) from September 2022 and Time 2 (T2) from September 2023. Potential participants received study recruitment information and accessed an online survey platform. Participation was confirmed through an electronic informed consent process, with respondents receiving shopping reward points upon completion.\u003c/p\u003e\u003cp\u003eStudy eligibility required participants to be at least 18, with their first Polymerase-Chain-Reaction (PCR)-confirmed COVID-19 infection occurring after February 2022, coinciding with the predominance of the Omicron variant in Japan\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. To align with established PASC definitions, participants needed at least one month post-infection and to be experiencing at least one post-COVID symptom at T1\u003csup\u003e1\u003c/sup\u003e. We excluded data from participants who failed validation questions, self-reported absence of PCR-confirmed infection, or provided inconsistent responses across the survey.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2 Measurements\u003c/h2\u003e\u003cp\u003eAll data were collected through an online questionnaire system.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e1.2.1 Outcome\u003c/h2\u003e\u003cp\u003eThe outcome was the presence of PASC symptoms at T2, assessed through a detailed symptom inventory. Participants responded: \u0026ldquo;Which of the following symptoms do you currently experience related to COVID-19?\u0026rdquo; The inventory included 24 specific symptoms: fever, cough, fatigue, muscle/body pain, sore throat, headache, diarrhea, conjunctivitis, taste loss/alteration, smell loss/alteration, skin manifestations, respiratory difficulties, chest symptoms, mobility issues, menstrual problems, vision changes, dizziness, gastrointestinal symptoms, convulsions, neuralgia, cardiovascular symptoms, auditory problems, new allergies, and other symptoms (with free-text specification). Cognitive and psychological symptoms were excluded from this analysis. These symptoms were categorized into 10 symptom groups\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Categorization is detailed in the previous study \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e1.2.2 Exposure\u003c/h2\u003e\u003cp\u003eNRS was evaluated using a frequency assessment of the feeling of NRS\u003csup\u003e\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Participants indicated their experience over the previous month using five frequency categories: none, rarely (\u0026lt;\u0026thinsp;1/month), sometimes (2\u0026ndash;4 times/month), frequently (5\u0026ndash;15 times/month), and very frequently (\u0026ge;\u0026thinsp;16 times/month). We defined NRS as reporting \u0026ldquo;frequently\u0026rdquo; or \u0026ldquo;very frequently\u0026rdquo;. For robustness, we conducted sensitivity analyses using \u0026ldquo;sometimes\u0026rdquo; or more instead of \u0026ldquo;frequently\u0026rdquo; or more.\u003c/p\u003e\u003cp\u003eDIS, DMS, and EMA were additionally assessed using the items regarding nocturnal sleep in the Insomnia Severity Index (ISI): \u0026ldquo;Difficulty falling asleep,\u0026rdquo; \u0026ldquo;Difficulty staying asleep,\u0026rdquo; and \u0026ldquo;Problem waking up too early.\u0026rdquo; Each item is rated on five frequency categories (None/ Mild/ Moderate/ Severe/ Very), with higher scores indicating greater severity. We defined each symptom as reporting \u0026ldquo;Severe\u0026rdquo; or more. For robustness, we conducted sensitivity analyses using \u0026ldquo;Moderate\u0026rdquo; or more instead of \u0026ldquo;Severe\u0026rdquo; or more.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e1.2.3 Covariates\u003c/h2\u003e\u003cp\u003eOur analyses incorporated a comprehensive set of potential confounders measured at T1. Demographic factors included sex (male/ female or others) \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, age group (20s/ 30s/ 40s/ 50s/ \u0026ge; 60s) \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, educational attainment (Higher than high school graduates or not) \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, household income (\u0026lt;\u0026thinsp;3,000,000 yen/ \u0026lt; 10,000,000 yen/ \u0026ge; 10,000,000 yen/ Unknown or refuse) \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, and cohabitant status\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Clinical history included psychiatric histories \u003csup\u003e\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e and physical comorbidities \u003csup\u003e\u003cspan additionalcitationids=\"CR48\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, which encompassed a broad range of conditions, including cardiovascular, respiratory, metabolic, autoimmune, and neurological disorders. COVID-19-specific factors included hospitalization status at infection \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e, duration after infection (months) \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, vaccination status \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, and psychological distress (K6\u0026thinsp;\u0026ge;\u0026thinsp;13) \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e1.3 Statistical analysis\u003c/h2\u003e\u003cp\u003eAll analyses were performed using Stata version 18.0 (StataCorp LLC, College Station, TX, USA), with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003cp\u003eAfter calculating the number and proportion of variables, univariate absolute risk differences were calculated to assess the associations between nocturnal sleep complaints and PASC persistence. Subsequently, the modified Poisson analyses with robust error were performed to estimate adjusted relative risk ratios (RR) by accounting for covariates. The presence of PASC symptoms at T2 was used as the dependent variable, and NRS, DIS, DMS, and EMA were used as independent variables, as well as covariates. E-values of variables with significant associations observed were calculated. The same analyses using mild and severe cutoffs for exposure were also performed as sensitivity analyses.\u003c/p\u003e\u003cp\u003eLoss-to-follow-up was handled using the multiple imputation by chained equation (MICE) for the modified Poisson regression analyses. Exposure variables and covariates were used as auxiliary variables. The number of imputations was set to m\u0026thinsp;=\u0026thinsp;50. Supplementarily, a complete case analysis (CCA) was also performed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e1.4 Ethics\u003c/h2\u003e\u003cp\u003e The study was reviewed and approved by the Research Ethics Committee of the National Center of Neurology and Psychiatry (approval number: A2021-034) and performed per the Declaration of Helsinki. All participants provided informed consent electronically before participating in the survey.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1 Characteristics\u003c/h2\u003e\n\u003cp\u003eA total of 957 participants were included in the analysis, with 559 (58.4%) providing follow-up data at T2 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The sample comprised 48.26% males, with the largest age group being those in their 40s (33.03%). Among the participants, 33.84%, 22.49%, 29.14%, and 24.23% experienced NRS, DIS, DMS, and EMA (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of participants\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en or mean\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSD or %\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex: male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e472\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.26%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.10%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e240\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.54%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e323\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.03%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e240\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.54%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;60s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.79%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCohabitant: yes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e843\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86.20%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEducational level: Higher than high school graduates\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e741\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.77%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHousehold income\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;3,000,000 yen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.01%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;10,000,000 yen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e579\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59.20%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;10,000,000 yen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e141\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.42%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown/ refuse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.37%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePsychological distress\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.30%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePsychiatric history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e111\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.35%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhysical comorbidity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e274\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28.02%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration after infection (months)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSD\u0026thinsp;=\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHospitalized\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.66%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVaccination status\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e835\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85.38%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNRS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e331\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.84%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDIS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e220\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.49%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDMS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e285\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29.14%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEMA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e237\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.23%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003eNRS, nonrestorative sleep; DIS, difficulty initiating sleep; DMS, difficulty maintaining sleep; EMA, early morning awaking\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAt T1, respiratory symptoms were the most prevalent PASC manifestation (52.76%), followed by general symptoms (37.83%). At T2, 45.97% of participants reported at least one PASC (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDetails of PASC\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTime 1 (n\u0026thinsp;=\u0026thinsp;978)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTime 2 (n\u0026thinsp;=\u0026thinsp;559)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePresence of PASC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e257\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45.97%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRespiratory\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e516\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.76%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e116\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.75%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGeneral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e370\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.83%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e143\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.58%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeurologic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e260\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.58%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e127\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.72%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMusculoskeletal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.85%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.66%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEye\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.83%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.94%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCardiac\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.83%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.47%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGastrointestinal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.62%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.16%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDermatologic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.81%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.50%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.70%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.11%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003ePASC, Post Acute Sequelae of COVID- 19\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbsolute risk differences of NRS DIS, DMS, and EMA were 0.19 (95% Confidence Interval [CI]\u0026thinsp;=\u0026thinsp;0.10\u0026ndash;0.28), 0.14 (95% CI\u0026thinsp;=\u0026thinsp;0.04\u0026ndash;0.24), 0.16 (95% CI\u0026thinsp;=\u0026thinsp;0.07\u0026ndash;0.25), and 0.17 (95% CI\u0026thinsp;=\u0026thinsp;0.07\u0026ndash;0.26).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003e2.2 Associations between NRS, Insomnia, and subsequent PASC\u003c/h2\u003e\n\u003cp\u003eA significant association between NRS at T1 and the presence of PASC at T2 was observed (RR\u0026thinsp;=\u0026thinsp;1.25, p\u0026thinsp;=\u0026thinsp;0.04, 95% CI\u0026thinsp;=\u0026thinsp;1.01\u0026ndash;1.54). No significant associations were observed between DIS, DMS, and EMA at T1 and PASC at T2. The E-value for the RR between NRS and PASC was 1.80.\u003c/p\u003e\n\u003cp\u003eAnalysis with CCA confirmed results similar to those of analysis with MICE. The significant association between NRS and PASC, while maintaining the absence of significant associations with DIS, DMS, and EMA (Appendix 1).\u003c/p\u003e\n\u003cp\u003eSensitivity analyses using different cutoff points for NRS showed similar patterns of association with PASC, but these did not reach statistical significance. There was no significant association between DIS, DMS, EMA, and PASC (Appendix 2).\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAssociations between Sleep disturbances and PASC\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNRS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDIS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDMS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEMA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eCovariates: sex, age, cohabitant, educational level, household income, psychological distress, psychiatric history, physical comorbidity, duration after infection, hospitalized, vaccination status\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eNRS, nonrestorative sleep; DIS, difficulty initiating sleep; DMS, difficulty maintaining sleep; EMA, early morning awaking; RR, Relative Risk; SE, Standard Error; 95% CI, 95% Confidence Interval\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this one-year longitudinal study for individuals with PASC, we found that NRS at baseline was significantly associated with the subsequent persistence of PASC at the one-year follow-up. DIS, DMS, and EMA showed no significant relationship with PASC persistence. These findings suggest that NRS may influence PASC persistence more than symptoms specific to insomnia, including DIS, DMS, and EMA. Therefore, focusing on a broader range of sleep disorders that may underlie NRS could be crucial for preventing and improving PASC persistence.\u003c/p\u003e\u003cp\u003eThis study is the first to examine the influences of sleep on longitudinal PASC recovery trajectories. While previous studies demonstrated that pre-infection sleep problems, including obstructive sleep apnea, short sleep duration, night-shift work, and other sleep disturbances, predict PASC development\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e, our findings extend this knowledge by showing that NRS during PASC also predicts its persistence. The observation that NRS, but not insomnia symptoms like DIS, DMS, and EMA, was associated with PASC persistence aligns with a previous study indicating stronger associations between PASC and non-insomnia sleep problems compared to insomnia\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSeveral mechanisms may explain the association between NRS and PASC persistence. First, increased alpha activity during non-REM sleep, a characteristic of NRS\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, may exacerbate fatigue, a common PASC symptom\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Second, NRS may be further associated with lower growth hormone secretion by disrupting slow-wave sleep\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e, potentially compounding the reduced growth hormone levels observed in PASC\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Given the important role of growth hormone in tissue repair and immune function, this disruption could impair recovery processes and contribute to PASC persistence.\u003c/p\u003e\u003cp\u003eThe differential contribution of NRS versus insomnia symptoms, including DIS, DMS, and EMA, to PASC persistence may be attributed to several factors. Individuals with NRS show more pronounced inflammatory responses than those with DIS, DMS, and EMA\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, suggesting NRS may more strongly maintain or exacerbate the inflammatory process underlying PASC\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Additionally, some individuals reporting insomnia symptoms like DIS, DMS, and EMA exhibit normal slow-wave sleep and sleep duration compared to healthy controls\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e and have minimal objective disturbance despite substantial subjective complaints\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. These characteristics of insomnia symptoms, where objective parameters may be preserved despite subjective sleep complaints, may have attenuated its association with PASC persistence. NRS may be more relevant to PASC persistence than DIS, DMS, and EMA, consistent with previous findings on its stronger associations with to depression and hypertension \u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis study has some clinical implications. Screening for NRS in individuals with PASC may help identify those at higher risk for PASC persistence, allowing for early intervention and more targeted treatment approaches. Healthcare providers should specifically inquire about NRS rather than focusing on insomnia symptoms like DIS, DMS, and EMA. Furthermore, addressing NRS in addition to standard PASC treatment might promote earlier PASC recovery in affected individuals. This could involve interventions specifically targeting sleep restoration, such as sleep hygiene education and treatment of underlying sleep disorders.\u003c/p\u003e\u003cp\u003eSeveral limitations warrant consideration. First, all measures relied on self-reporting, limiting the diagnostic precision of PASC and comorbid conditions. While this approach allowed us to capture data from individuals who may not have sought medical attention, future studies using claim data, such as precise diagnoses and vaccination status, could provide more detailed insights. Second, we could not determine whether sleep problems predated COVID-19 infection or emerged as PASC symptoms, although we controlled for pre-infection psychiatric symptoms. Prospective studies beginning before COVID-19 infection would be valuable in clarifying this temporal relationship. Finally, the retention rate was relatively low at 58.4%. We addressed this limitation through multiple imputations to minimize potential bias even with high levels of missing data\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e, but caution in interpretation is warranted. Future studies with higher retention and longer follow-up periods would help confirm and extend our findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis longitudinal study suggests that NRS is associated with PASC persistence over one year, different from insomnia symptoms like DIS, DMS, and EMA. This finding indicates that NRS may influence PASC recovery through mechanisms distinct from those involved in DIS, DMS, and EMA. These results highlight the importance of comprehensive sleep assessment in patients with PASC. Future research should explore the biological mechanism underlying this relationship and evaluate whether interventions targeting NRS can improve PASC outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e5\u0026nbsp; \u0026nbsp;\u0026nbsp;Funding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by an Intramural Research Grant for Neurological and Psychiatric Disorders from\u0026nbsp;the NCNP (4-3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDN reports personal fees outside of the submitted work from Startia, Inc., en-Power, Inc., MD.net, and Takeda Pharmaceutical Company, Ltd.\u0026nbsp;MH, MK, KK, KU, MK, EM, ND, EO, TY, KM, NK\u0026nbsp;declare no conflict of interest to disclose regarding this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7\u0026nbsp; \u0026nbsp;\u0026nbsp;Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design:\u0026nbsp;MH, MK, KK, DN, KU, MK, EM, ND, EO, TY, KM, DN, NK\u003c/p\u003e\n\u003cp\u003eData curation: MH, MK, AN, and MK\u003c/p\u003e\n\u003cp\u003eAnalysis: MH\u003c/p\u003e\n\u003cp\u003eInterpretation of analysis: MH, KK, and NK\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: MK\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectual content:\u0026nbsp;MH, MK, ND, KU, MM, AN, MK, EM, EO, KK, TY, KM, NK\u003c/p\u003e\n\u003cp\u003eSupervision: KK, DN, NK\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8\u0026nbsp; \u0026nbsp;\u0026nbsp;Acknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile preparing this work, the authors used Claude 3 Opus, by Anthropic, to enhance the readability and proofread the English text. After using these services, the authors reviewed and edited the content as needed and took full responsibility for the publication’s content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGroff D et al (2021) Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection. JAMA Netw Open 4:e2128568\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThaweethai T et al (2023) Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA 329:1934\u0026ndash;1946\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXu Z et al (2024) Excess risks of long COVID symptoms compared with identical symptoms in the general population: A systematic review and meta-analysis of studies with control groups. J Glob Health 14\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKlein J et al (2023) Distinguishing features of long COVID identified through immune profiling. 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Iran J Public Health 50:1372\u0026ndash;1380\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"eb61b768-7552-4c1f-888a-9e04d7bf0856","identifier":"10.13039/501100009438","name":"National Center of Neurology and Psychiatry","awardNumber":"4-3","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"National Center of Neurology and psychitry","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Post-Acute Sequelae of COVID-19, Nonrestorative sleep, Insomnia, Difficulty Initiating Sleep, Difficulty Maintaining Sleep, Early Morning Awaking","lastPublishedDoi":"10.21203/rs.3.rs-7271333/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7271333/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNonrestorative sleep (NRS) may contribute to the persistence of post-acute sequelae of COVID-19 (PASC), but no longitudinal studies have investigated this relationship. This study examined the association between NRS and PASC persistence over one year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a one-year prospective cohort study conducted using an online survey.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a one-year prospective cohort study through an online survey between September 2022 (Time 1, T1) and September 2023 (Time 2, T2). Eligible patients were adults aged18 years or older who had experienced COVID-19 infection after February 2022 and were more than one month post-infection with at least one PASC symptom. NRS, difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awaking (EMA) were evaluated at T1. PASC persistence was evaluated at T2. Relative risk ratio calculations with multiple imputations were performed to examine associations between sleep disturbances and PASC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 957 participants with PASC at baseline, 559 (58.4%) completed the follow-up assessment. NRS at T1 was associated with PASC persistence at T2 (Relative Risk = 1.33, 95% confidence interval = 1.08 – 1.64). In contrast, DIS, DMS, and EMA showed no significant associations with PASC persistence. Sensitivity analyses using different NRS thresholds yielded consistent trends.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study suggests that NRS might contribute to PASC persistence through a potentially distinct mechanism from DIS, DMS, and EMA.\u003c/p\u003e","manuscriptTitle":"The Relationship between Nonrestorative Sleep and Persistent Post-Acute Sequelae of COVID-19: A Longitudinal Study of Recovery Trajectories","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-05 14:00:18","doi":"10.21203/rs.3.rs-7271333/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98cf31e2-75e2-4837-a2e4-b2ce9131177f","owner":[],"postedDate":"August 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52502752,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-08-05T14:00:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-05 14:00:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7271333","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7271333","identity":"rs-7271333","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}