Covid Analysis, August 14, 2022, DRAFT
•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.
•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.
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.
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.
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.
|Treatment time||Number of studies reporting positive effects||Total number of studies||Percentage of studies reporting positive effects||Random effects meta-analysis results|
RR 0.65 [0.52‑0.80]
p < 0.0001
RR 0.65 [0.52‑0.80]
p < 0.0001
|All studies||7||35% [20‑48%]||1,636||79|
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.
[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.
[Huang] Retrospective 164 COVID-19 patients and 188 controls in China, showing the risk of severe cases associated with lack of sleep.
[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.
[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.
[Marcus] Prospective survey based study with 14,335 participants, showing risk of viral symptoms associated with shorter sleep duration.
[Mohsin] Retrospective 1,500 COVID+ patients in Bangladesh, showing lower risk of severe cases with good sleep.
[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 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, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599 (history) (COVIDENCE UK).||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, 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, 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, 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, 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, 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, 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.|
Altman, D., BMJ, doi:10.1136/bmj.d2304, How to obtain the P value from a confidence interval, https://www.bmj.com/content/343/bmj.d2304.
Altman (B) et al., BMJ, doi:10.1136/bmj.d2090, How to obtain the confidence interval from a P value, https://www.bmj.com/content/343/bmj.d2090.
Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487, Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK), https://thorax.bmj.com/content/early/2021/11/02/thoraxjnl-2021-217487.
Huang et al., Nature and Science of Sleep, doi:10.2147/NSS.S263488, Reduced Sleep in the Week Prior to Diagnosis of COVID-19 is Associated with the Severity of COVID-19, https://www.dovepress.com/reduced-..sociated-peer-reviewed-article-NSS.
Kim et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000228, COVID-19 illness in relation to sleep and burnout, https://nutrition.bmj.com/content/4/1/132.info.
Li et al., Sleep, doi:10.1093/sleep/zsab138, Poor sleep behavior burden and risk of COVID-19 mortality and hospitalization, https://academic.oup.com/sleep/art../doi/10.1093/sleep/zsab138/6304657.
Marcus et al., PLOS ONE, doi:10.1371/journal.pone.0253120, Predictors of incident viral symptoms ascertained in the era of COVID-19, https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0253120.
McLean et al., Open Forum Infect. Dis. September 2015, 2:3, doi:10.1093/ofid/ofv100, Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525010/.
Mohsin et al., Infection and Drug Resistance, doi:10.2147/IDR.S331470, Lifestyle and Comorbidity-Related Risk Factors of Severe and Critical COVID-19 Infection: A Comparative Study Among Survived COVID-19 Patients in Bangladesh, https://www.dovepress.com/lifestyl..peer-reviewed-fulltext-article-IDR.
Paul et al., medRxiv, doi:10.1101/2022.04.12.22273792, Health behaviours the month prior to COVID-19 infection and the development of self-reported long COVID and specific long COVID symptoms: A longitudinal analysis of 1,811 UK adults, https://www.medrxiv.org/content/10.1101/2022.04.12.22273792.
Sweeting et al., Statistics in Medicine, doi:10.1002/sim.1761, What to add to nothing? Use and avoidance of continuity corrections in meta‐analysis of sparse data, https://onlinelibrary.wiley.com/doi/10.1002/sim.1761.
Treanor et al., JAMA, 2000, 283:8, 1016-1024, doi:10.1001/jama.283.8.1016, Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial, https://jamanetwork.com/journals/jama/fullarticle/192425.
Zeraatkar et al., medRxiv, doi:10.1101/2022.04.04.22273372, The trustworthiness and impact of trial preprints for COVID-19 decision-making: A methodological study, https://www.medrxiv.org/content/10.1101/2022.04.04.22273372.
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.