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Sleep for COVID-19: real-time meta analysis of 7 studies
Covid Analysis, July 5, 2022, DRAFT
https://c19early.com/slmeta.html
0 0.5 1 1.5+ All studies 35% 7 1,636 Improvement, Studies, Patients Relative Risk Mortality 43% 1 0 Hospitalization 36% 1 0 Cases 13% 3 0 Peer-reviewed 29% 6 1,636 Prophylaxis 35% 7 1,636 Sleep for COVID-19 c19early.com/sl Jul 2022 Favorsgood sleep Favorscontrol
Statistically significant improvements are seen for mortality, hospitalization, recovery, and cases. 7 studies from 7 independent teams in 4 different countries show statistically significant improvements in isolation (6 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 35% [20‑48%] improvement. Results are similar for peer-reviewed studies.
0 0.5 1 1.5+ All studies 35% 7 1,636 Improvement, Studies, Patients Relative Risk Mortality 43% 1 0 Hospitalization 36% 1 0 Cases 13% 3 0 Peer-reviewed 29% 6 1,636 Prophylaxis 35% 7 1,636 Sleep for COVID-19 c19early.com/sl Jul 2022 Favorsgood sleep Favorscontrol
Studies analyze sleep quality before infection.
No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix.
Highlights
Good quality sleep reduces risk for COVID-19 with very high confidence for hospitalization, recovery, cases, and in pooled analysis, and high confidence for mortality.
We show traditional outcome specific analyses and combined evidence from all studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 42 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% 0.88 [0.61-1.27] cases n/a n/a Improvement, RR [CI] Treatment Control Marcus 16% 0.84 [0.76-0.93] symp. case n/a n/a Li 43% 0.57 [0.35-0.90] death n/a n/a Mohsin 38% 0.62 [0.49-0.77] severe case 327/948 273/552 Huang 81% 0.19 [0.05-0.66] severe case 12/127 4/9 Kim 17% 0.83 [0.70-0.99] m/s case n/a n/a Paul 67% 0.33 [0.19-0.55] no recov. n/a n/a Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Prophylaxis 35% 0.65 [0.52-0.80] 339/1,075 277/561 35% improvement All studies 35% 0.65 [0.52-0.80] 339/1,075 277/561 35% improvement 7 sleep COVID-19 studies c19early.com/sl Jul 2022 Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) Favors good sleep Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% case Improvement Relative Risk [CI] Marcus 16% symp. case Li 43% death Mohsin 38% severe case Huang 81% severe case Kim 17% mod./sev. case Paul 67% recovery Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Prophylaxis 35% 35% improvement All studies 35% 35% improvement 7 sleep COVID-19 studies c19early.com/sl Jul 2022 Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors good sleep Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies reporting COVID-19 outcomes as a function of sleep quality and providing adjusted results. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Results
Figure 2 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 3, 4, 5, 6, 7, and 8 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, hospitalization, recovery, cases, and peer reviewed studies.
0 0.5 1 1.5+ ALL STUDIES MORTALITY HOSPITALIZATION CASES PEER-REVIEWED All Prophylaxis Sleep for COVID-19 C19EARLY.COM/SL JUL 2022
Figure 2. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Prophylaxis 7 7 100% 35% improvement
RR 0.65 [0.52‑0.80]
p < 0.0001
All studies 7 7 100% 35% improvement
RR 0.65 [0.52‑0.80]
p < 0.0001
Table 1. Results by treatment stage.
Studies Prophylaxis PatientsAuthors
All studies 735% [20‑48%] 1,636 79
Peer-reviewed 629% [14‑42%] 1,636 77
Table 2. Results by treatment stage for all studies and with different exclusions.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% 0.88 [0.61-1.27] cases n/a n/a Improvement, RR [CI] Treatment Control Marcus 16% 0.84 [0.76-0.93] symp. case n/a n/a Li 43% 0.57 [0.35-0.90] death n/a n/a Mohsin 38% 0.62 [0.49-0.77] severe case 327/948 273/552 Huang 81% 0.19 [0.05-0.66] severe case 12/127 4/9 Kim 17% 0.83 [0.70-0.99] m/s case n/a n/a Paul 67% 0.33 [0.19-0.55] no recov. n/a n/a Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Prophylaxis 35% 0.65 [0.52-0.80] 339/1,075 277/561 35% improvement All studies 35% 0.65 [0.52-0.80] 339/1,075 277/561 35% improvement 7 sleep COVID-19 studies c19early.com/sl Jul 2022 Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) Favors good sleep Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% case Improvement Relative Risk [CI] Marcus 16% symp. case Li 43% death Mohsin 38% severe case Huang 81% severe case Kim 17% mod./sev. case Paul 67% recovery Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Prophylaxis 35% 35% improvement All studies 35% 35% improvement 7 sleep COVID-19 studies c19early.com/sl Jul 2022 Tau​2 = 0.05, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors good sleep Favors control
Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Li 43% 0.57 [0.35-0.90] n/a n/a Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.017 Prophylaxis 43% 0.57 [0.35-0.90] 43% improvement All studies 43% 0.57 [0.36-0.90] 43% improvement 1 sleep COVID-19 mortality result c19early.com/sl Jul 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.017 Favors good sleep Favors control
Figure 4. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Li 36% 0.64 [0.46-0.89] hosp. n/a n/a Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.008 Prophylaxis 36% 0.64 [0.46-0.89] 36% improvement All studies 36% 0.64 [0.46-0.89] 36% improvement 1 sleep COVID-19 hospitalization result c19early.com/sl Jul 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.008 Favors good sleep Favors control
Figure 5. Random effects meta-analysis for hospitalization.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Paul 67% 0.33 [0.19-0.55] no recov. n/a n/a Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 67% 0.33 [0.19-0.55] 67% improvement All studies 67% 0.33 [0.19-0.55] 67% improvement 1 sleep COVID-19 recovery result c19early.com/sl Jul 2022 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Favors good sleep Favors control
Figure 6. Random effects meta-analysis for recovery.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% 0.88 [0.61-1.27] cases n/a n/a Improvement, RR [CI] Treatment Control Marcus 16% 0.84 [0.76-0.93] symp. case n/a n/a Kim 11% 0.89 [0.81-0.97] cases n/a n/a Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 13% 0.87 [0.82-0.93] 13% improvement All studies 13% 0.87 [0.82-0.93] 13% improvement 3 sleep COVID-19 case results c19early.com/sl Jul 2022 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Favors good sleep Favors control
Figure 7. Random effects meta-analysis for cases.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Holt 12% 0.88 [0.61-1.27] cases n/a n/a Improvement, RR [CI] Treatment Control Marcus 16% 0.84 [0.76-0.93] symp. case n/a n/a Li 43% 0.57 [0.35-0.90] death n/a n/a Mohsin 38% 0.62 [0.49-0.77] severe case 327/948 273/552 Huang 81% 0.19 [0.05-0.66] severe case 12/127 4/9 Kim 17% 0.83 [0.70-0.99] m/s case n/a n/a Tau​2 = 0.04, I​2 = 80.9%, p = 0.00072 Prophylaxis 29% 0.71 [0.58-0.86] 339/1,075 277/561 29% improvement All studies 29% 0.71 [0.58-0.86] 339/1,075 277/561 29% improvement 6 sleep COVID-19 peer reviewed trials c19early.com/sl Jul 2022 Tau​2 = 0.04, I​2 = 80.9%, p = 0.00072 Effect extraction pre-specified(most serious outcome, see appendix) Favors good sleep Favors control
Figure 8. Random effects meta-analysis for peer reviewed studies. [Zeraatkar] analyze 356 COVID-19 trials, finding no significant evidence that peer-reviewed studies are more trustworthy. They also show extremely slow review times during a pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Conclusion
Better sleep reduces risk for COVID-19. Statistically significant improvements are seen for mortality, hospitalization, recovery, and cases. 7 studies from 7 independent teams in 4 different countries show statistically significant improvements in isolation (6 for the most serious outcome). Meta analysis using the most serious outcome reported shows 35% [20‑48%] improvement. Results are similar for peer-reviewed studies.
Studies analyze sleep quality before infection.
Study Notes
0 0.5 1 1.5 2+ Case 12% Improvement Relative Risk Case (b) 12% Case (c) 22% c19early.com/sl Holt et al. NCT04330599 Sleep Prophylaxis Favors good sleep Favors control
[Holt] Prospective survey-based study with 15,227 people in the UK, showing reduced risk of COVID-19 cases with 8 hours sleep, with statistical significance when compared with ≥9 hours. NCT04330599. COVIDENCE UK.
0 0.5 1 1.5 2+ Severe case 81% Improvement Relative Risk c19early.com/sl Huang et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Huang] Retrospective 164 COVID-19 patients and 188 controls in China, showing the risk of severe cases associated with lack of sleep.
0 0.5 1 1.5 2+ Moderate/severe case 17% Improvement Relative Risk Case 11% c19early.com/sl Kim et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Kim] Retrospective 2,884 high-risk healthcare workers in France, Germany, Italy, Spain, UK, and the USA, showing shorter sleep duration associated with increased risk of COVID-19 cases and severity.
0 0.5 1 1.5 2+ Mortality 43% Improvement Relative Risk Hospitalization 36% Hospitalization (b) 21% c19early.com/sl Li et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Li] UK Biobank retrospective, 46,535 participants with sleep behavior assessed between 2006 and 2010, showing higher risk of hospitalization and mortality with poor sleep.
0 0.5 1 1.5 2+ Symptomatic case 16% Improvement Relative Risk c19early.com/sl Marcus et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Marcus] Prospective survey based study with 14,335 participants, showing risk of viral symptoms associated with shorter sleep duration.
0 0.5 1 1.5 2+ Severe case 38% Improvement Relative Risk c19early.com/sl Mohsin et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Mohsin] Retrospective 1,500 COVID+ patients in Bangladesh, showing lower risk of severe cases with good sleep.
0 0.5 1 1.5 2+ Long COVID 67% Improvement Relative Risk Long COVID (b) 54% c19early.com/sl Paul et al. Sleep for COVID-19 Prophylaxis Favors good sleep Favors control
[Paul] Retrospective 1,811 COVID-19 patients in the UK, showing lower risk of self-reported long COVID with good sleep quality in the month before infection.
We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.com. Search terms were sleep AND COVID-19. Automated searches are performed every few hours with notification of new matches. All studies regarding the use of sleep for COVID-19 that report a comparison with a control group are included in the main analysis. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to [Zhang]. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. Adjusted primary outcome results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed [Altman, Altman (B)], and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 [Sweeting]. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.9.13) with scipy (1.8.0), pythonmeta (1.26), numpy (1.22.2), statsmodels (0.14.0), and plotly (5.6.0).
Forest plots are computed using PythonMeta [Deng] with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective [McLean, Treanor].
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19early.com/slmeta.html.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
[Holt], 3/30/2021, prospective, United Kingdom, Europe, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599. risk of case, 12.3% lower, OR 0.88, p = 0.50, adjusted per study, fully adjusted, 8 hours vs. ≤6 hours, RR approximated with OR.
risk of case, 12.3% lower, OR 0.88, p = 0.33, adjusted per study, fully adjusted, 8 hours vs. 7 hours, RR approximated with OR.
risk of case, 22.5% lower, OR 0.78, p = 0.04, adjusted per study, fully adjusted, 8 hours vs. ≥9 hours, RR approximated with OR.
[Huang], 11/30/2021, retrospective, China, Asia, peer-reviewed, survey, 5 authors, study period 10 February, 2020 - 28 March, 2020. risk of severe case, 80.9% lower, RR 0.19, p = 0.02, higher quality sleep 12 of 127 (9.4%), lower quality sleep 4 of 9 (44.4%), NNT 2.9, adjusted per study, odds ratio converted to relative risk, recommended vs. lack of sleep, multivariable.
[Kim], 3/22/2022, retrospective, multiple countries, multiple regions, peer-reviewed, survey, mean age 48.0, 8 authors, study period 17 July, 2020 - 25 September, 2020. risk of moderate/severe case, 17.0% lower, OR 0.83, p = 0.03, per extra hour of sleep, RR approximated with OR.
risk of case, 11.0% lower, OR 0.89, p = 0.003, per extra hour of sleep, model 3, RR approximated with OR.
[Li], 6/18/2021, retrospective, USA, North America, peer-reviewed, mean age 69.4, 8 authors, study period March 2020 - December 2020. risk of death, 43.2% lower, OR 0.57, p = 0.02, fully adjusted model C, significant poor sleep burden, RR approximated with OR.
risk of hospitalization, 35.9% lower, OR 0.64, p = 0.008, fully adjusted model C, significant poor sleep burden, RR approximated with OR.
risk of hospitalization, 21.3% lower, OR 0.79, p = 0.02, fully adjusted model C, moderate poor sleep burden, RR approximated with OR.
[Marcus], 6/17/2021, prospective, multiple countries, multiple regions, peer-reviewed, survey, 12 authors, study period 26 March, 2020 - 3 May, 2020. risk of symptomatic case, 16.0% lower, OR 0.84, p < 0.001, adjusted per study, per extra hour sleep, multivariable, RR approximated with OR.
[Mohsin], 9/30/2021, retrospective, Bangladesh, South Asia, peer-reviewed, survey, 10 authors, study period November 2020 - April 2021. risk of severe case, 37.9% lower, RR 0.62, p < 0.001, higher quality sleep 327 of 948 (34.5%), lower quality sleep 273 of 552 (49.5%), NNT 6.7, adjusted per study, odds ratio converted to relative risk, sleep disturbance, multivariable.
[Paul], 4/13/2022, retrospective, United Kingdom, Europe, preprint, survey, 2 authors. risk of long COVID, 67.3% lower, RR 0.33, p < 0.001, adjusted per study, odds ratio converted to relative risk, very good/good vs. not good/very poor, multivariable, model 4, control prevalance approximated with overall prevalence.
risk of long COVID, 54.0% lower, RR 0.46, p = 0.002, adjusted per study, odds ratio converted to relative risk, very good/good vs. average, multivariable, model 4, control prevalance approximated with overall prevalence.
Supplementary Data
References
Please send us corrections, updates, or comments. Vaccines and treatments are both valuable and complementary. All practical, effective, and safe means should be used. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. Denying the efficacy of any method increases mortality, morbidity, collateral damage, and the risk of endemic status. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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