key: cord-1045846-ahrxe370
authors: Alimoradi, Zainab; Broström, Anders; Tsang, Hector W.H.; Griffiths, Mark D.; Haghayegh, Shahab; Ohayon, Maurice M.; Lin, Chung-Ying; Pakpour, Amir H.
title: Sleep problems during COVID-19 pandemic and its’ association to psychological distress: A systematic review and meta-analysis
date: 2021-06-10
journal: EClinicalMedicine
DOI: 10.1016/j.eclinm.2021.100916
sha: 486e2f22a888a0625180957c021823e1817d6d5c
doc_id: 1045846
cord_uid: ahrxe370

BACKGROUND: The emerging novel coronavirus disease 2019 (COVID-19) has become one of the leading cause of deaths worldwide in 2020. The present systematic review and meta-analysis estimated the magnitude of sleep problems during the COVID-19 pandemic and its relationship with psychological distress. METHODS: Five academic databases (Scopus, PubMed Central, ProQuest, ISI Web of Knowledge, and Embase) were searched. Observational studies including case-control studies and cross-sectional studies were included if relevant data relationships were reported (i.e., sleep assessed utilizing the Pittsburgh Sleep Quality Index or Insomnia Severity Index). All the studies were English, peer-reviewed papers published between December 2019 and February 2021. PROSPERO registration number: CRD42020181644. FINDINGS: 168 cross-sectional, four case-control, and five longitudinal design papers comprising 345,270 participants from 39 countries were identified. The corrected pooled estimated prevalence of sleep problems were 31% among healthcare professionals, 18% among the general population, and 57% among COVID-19 patients (all p-values < 0.05). Sleep problems were associated with depression among healthcare professionals, the general population, and COVID-19 patients, with Fisher's Z scores of -0.28, -0.30, and -0.36, respectively. Sleep problems were positively (and moderately) associated with anxiety among healthcare professionals, the general population, and COVID-19 patients, with Fisher's z scores of 0.55, 0.48, and 0.49, respectively. INTERPRETATION: Sleep problems appear to have been common during the ongoing COVID-19 pandemic. Moreover, sleep problems were found to be associated with higher levels of psychological distress. With the use of effective programs treating sleep problems, psychological distress may be reduced. Vice versa, the use of effective programs treating psychological distress, sleep problems may be reduced. FUNDING: The present study received no funding.

Prior to 2020, respiratory diseases were the fourth leading cause of death [1] . However, with the outbreak of the novel coronavirus disease 2019 in December 2019, respiratory infections caused more deaths due to COVID-19 [2] . According to the World Health Organization (WHO) as of April 16, 2021 , there were over 137,866,000 known cases of COVID-19 and over 2,965,000 cases of COVID-19 death worldwide [3] .

Prior research has found that the prevalence of COVID-19 is associated with major psychological distress and significant symptoms of mental health illness [4] [5] [6] [7] [8] . The sudden onset of a threatening illness puts great pressure on healthcare workers [9] . Consequently, healthcare workers may have impaired sleep because they need to deal with the illness, suffer from the high risk of death, and adapt to irregular work schedules and frequent shifts [10] [11] [12] [13] [14] [15] . They may experience sleep problems, anxiety, depression, and stress when faced with this major public health threat [16] [17] [18] . Due to their job demands, they are in frequent contact with patients and therefore suffer from extremely high-level stress. Therefore, they may develop acute sleep problems, including poor sleep quality and experience too little sleep [19] . Given that healthcare professionals are the frontline workers who take care of patients, their health is extremely important. More specifically, if healthcare providers have any health issues that prevent them from taking care of patients, their local communities more specifically, and their country more generally, will encounter a huge challenge of healthcare burden and consequently impact on all residents' health.

In addition to healthcare workers, the general population is likely to develop mental health and sleep problems due to the impacts of COVID-19 [20] because a substantial change in lifestyle is a huge stressor [21, 22] . For example, individuals may need to self-isolate and quarantine at home, avoid social activities for leisure and recreation that they had participated in previously, and strictly obey the new policies to minimize spread of the virus (e.g., wearing a mask in public areas) [23, 24] . The general population may also receive threatening information such as daily statistics concerning COVID-19 infection and deaths reported from the news or social media [25, 26] . With the lifestyle changes and threatening information, the general population may avoid contact with other individuals due to great fear of infection, developing feelings of helplessness or suffering from panic [27] . In other words, the general population might experience psychological problems directly due to the COVID-19 pandemic [28] .

Different factors contributing to insomnia and psychological problems have been reported. The most important risk factors for insomnia and mental health problems during the COVID-19 pandemic are being a healthcare worker, having an underlying illness, living in rural areas, being a woman, and being at risk of contact with COVID-19 infected patients. Among non-medical healthcare workers, having an underlying disease is a risk factor for insomnia and mental health problems [29] . Indeed, among the natural and non-natural disasters that can occur to humans, the COVID-19 pandemic has caused severe psychological distress due to the large number of individuals affected globally and the contagious and deadly nature of the virus [30] . The COVID-19 pandemic as a worldwide public health issue is a traumatic event that has affected both the sleep and mental health of the general public and healthcare providers [31] [32] [33] [34] [35] . Moreover, several policies implemented to reduce the spread of COVID-19 (e.g., quarantine) have been found to have some negative effects on an individuals' psychological health [34] .

Because sleep is important for human beings to maintain daily functions [36] , several studies have focused on sleep problems all with the use of self-report data during the COVID-19 pandemic. Different findings regarding the sleep and psychological problems during COVID-19 in different populations have been reported among these studies. For example, Zhang et al. reported that the prevalence of insomnia was higher among non-medical healthcare workers (e.g., students, community workers, and volunteers) than among medical healthcare workers (prevalence rate of 38.4 vs. 30 .5%, p<.01). Wang et al. reported higher prevalence of sleep problem among medical staff compared to non-medical staff comprising students, community workers, and volunteers (66.1% vs. 47.8, p<.01) and frontline healthcare providers compared to non-frontline medical workers (68.1 vs. 64.5, p=0.14) [37] .

The quality of sleep during the COVID-19 pandemic and its related factors have been reported in an increasing number of studies. A recent study conducted a meta-analysis to understand the sleep problems during the COVID-19 pandemic [38] . The study found that the pooled prevalence rate of sleep problems globally was 35.7%, with the most affected group being patients with COVID-19 (74.8%), followed by healthcare providers (36.0%), and the general population (32.3%). In addition, sleep difficulties and psychological distress due to COVID-19 on those patients with COVID-19 were reported in a cohort study [39] . Patients with COVID-19 had sleep difficulties, depression, and anxiety at six months after acute infection. Another systematic review found the associations between COVID-19 and psychiatric symptoms among patients with mental illness, healthcare workers, and non-healthcare workers [40] . However, only the information on sleep difficulties has been well analyzed using robust meta-analysis method. Therefore, psychological distress and the associations between sleep problems and psychological distress have yet to be synthesized. Given the significant number of published studies on sleep quality, psychological distress, and related factors, and the importance of systematic reviews and meta-analyses in summarizing and analyzing the results of existing studies, the present study was designed and conducted with the aim of estimating sleep problems during the COVID-19 period (January to October, 2020) and its relationship with psychological distress.

The present systematic review was conducted utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [41] . A systematic literature search was carried out utilizing five academic databases, and relevant studies were extracted and their methodological quality was assessed using the Newcastle Ottawa Scale (NOS) checklist. Findings were synthesized using a meta-analysis approach. The protocol was registered in the PROSPERO International prospective register of systematic reviews (ID code: CRD42020181644 [42] ).

Five academic databases including Scopus, PubMed Central, Pro-Quest, ISI Web of Knowledge, and Embase were searched

Evidence before this study The novel coronavirus disease 2019 (COVID-19) pandemic has  caused psychological problems and sleep problems in different  populations, including healthcare professionals, COVID-19 infected individuals, and the general population.

Patients with COVID-19 infection had the highest prevalence of sleep problems, and healthcare professions had the second highest prevalence of sleep problems. Moderate associations between sleep problems and psychological distress (including depression and anxiety) were found.

Patients with COVID-19 infection and health professions are at risk of having sleep problems, and that there are moderate associations between sleep problems and psychological distress.

These data emphasize the need of programs and treatments to assist different populations in overcoming sleep problems and psychological distress, especially patients with COVID-19 infection and health professions. systematically between February 17 to 19, 2021. The search terms were extracted from published reviews and primary studies in addition to PubMed Medical Subject Headings (MeSH). The main search terms were 'sleep' and 'COVID-19'. The Boolean search method (AND/ OR/NOT) was used to develop the search. Search syntax was customized based on the advanced search attributes of each database. The full search strategy for each database is provided in Supplementary  Table 1 . Additionally, further sources (i.e., reference lists of included studies and systematic reviews of published papers) were searched to increase the likelihood of retrieving relevant empirical studies.

Observational studies including case-control studies and crosssectional studies were included if relevant data relationships were reported (i.e., sleep assessed using the Pittsburgh Sleep Quality Index or Insomnia Severity Index). More specifically, if the studies were included if they estimated the prevalence of sleep disorders and/or examined the relationship between sleep and psychological distress using Pearson's correlation coefficient (e.g., if the odds ratio [OR] information reported by the studies could be converted into Pearson's correlation coefficient; detailed information in 2.6 Data synthesis). English, peer-reviewed papers published between December 2019 and August 2020 were included. There were no limitations regarding participants' characteristics.

Estimation of sleep problems frequency was the primary outcome. Sleep problems were defined in a broad category of sleep disorders characterized by either hypersomnolence or insomnia. The three major subcategories of sleep problems were intrinsic (i.e., arising from within the body), extrinsic (secondary to environmental or pathological conditions), and disturbances of circadian rhythm. Sleep problems had to have been assessed using valid and reliable psychometric scales or confirmed with defined cut-off points for characterizing as sleep problems. More specifically, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were used to assess the primary outcomes because PSQI and ISI have items assessing the three major subcategories of the aforementioned sleep problems. For instance, a global score of 5 or more indicates poor sleep quality on the Pittsburgh Sleep Quality Index [43] , or total score of 8 or more on the Insomnia Severity Index [44] 2.2.2. Secondary outcomes There were three secondary outcomes: (i) association of sleep problems with psychological distress in the context of the COVID-19 pandemic; (ii) heterogeneity and its possible sources; and (iii) moderator variables in association of sleep problems and psychological distress related to COVID-19 pandemic. Ridner defined psychological distress (PD) as: "a state in response to stressors marked by perceived discomfort and inability to cope" [45] . In the present study, psychological distress was considered as either depression (defined as having depressed mood) and/or anxiety (defined as having excessive worry and being nervous). These had to have been assessed using valid and reliable psychometric scales. That is, studies were excluded if psychological distress was assessed using a non-psychometrically validated self-designed questionnaire. Moreover, in the present systematic review and meta-analysis, depression, and anxiety were treated as continuous variables.

In the first step, title and abstract of all retrieved papers were screened independently by two researchers based on the inclusion criteria. The full texts of potentially relevant studies were further (continued on next page) (continued on next page) (continued on next page) examined based on the aforementioned criteria. In this process, relevant studies were selected.

The Newcastle Ottawa Scale (NOS) was used to evaluate the methodological quality of the studies in observational studies. Three characteristics (i.e., selection, comparability, and outcome) were examined with the NOS checklist. The checklist has three versions for evaluating cross-sectional studies (seven items), case-control studies (eight items), and cohort studies (eight items). Despite a slight difference in number and content of items, each item is rated with a star, except comparability which can have two stars. This results in a maximum quality score of 9 for each study. Studies with less than 5 points are classified as having a high risk of bias [46] . No studies were excluded based on the quality rating. However, subgroup analysis was conducted to assess the impact of quality on pooled effect size

A pre-designed form was prepared to extract data from included studies. Data including first author's name, collection date, study design, country, number of participants, gender, mean age, scales used to assess psychological distress and sleep problems, numerical results regarding the frequency of sleep problems, and relationship between sleep problems and psychological distress. It should also be noted that study selection, quality assessment, and data extraction were processes performed independently by two reviewers. Disagreements were resolved through discussion.

A quantitative synthesis using STATA software version 14 was conducted. Meta-analysis was run using random effect model because included studies were taken from different populations, and both within-study and between-study variances should be accounted for [47] . The Q Cochrane statistic was used to assess heterogeneity. Also, the severity of heterogeneity was estimated using the I 2 index. Heterogeneity is interpreted as (i) mild when I 2 is less than 25%, (ii) moderate when I 2 is 25 to 50%, (iii) severe when I 2 is 50 to 75%, and (iv) highly severe when I 2 is greater than 75% [48] .

Two key measures were selected for present study: (i) prevalence of sleep problems and (ii) correlation of sleep problem with psychological distress. The numerical findings regarding prevalence of sleep problems were reported consistently in 177 included studies. This key measure and its 95% confidence interval (CI) are reported. However, the association between sleep problems and psychological distress was reported differently in the included studies. Pearson's correlation coefficient was the selected effect size for meta-analysis. Due to the inconsistency in reporting numerical findings of this association, the other effect sizes of standardized mean difference and crude odds ratio were transformed into Pearson's correlation coefficients [49, 50] using the Psychometrica website [51] . Also, Pearson's r correlation coefficient was converted to Fisher's z, due to the potential instability of variance. Consequently, all analyses were performed using Fisher's z values as effect size (ES) [52, 53] . Fisher's ztransformation was applied using the following formula: z = 0.5 £ ln (1+r-1-r). The standard error of z was calculated based on the following formula: SEz = 1/x (n-3) [54] . Therefore, the selected measure of effect, selected for current meta-analysis, is expressed as Fisher's z score and its 95% CI.

For assessing moderator analysis and finding the possible sources of heterogeneity, subgroup analysis or meta-regression was carried out based on the number of studies in each group. Moreover, the three subgroups for synthesized analyses (i.e., general population, healthcare professionals, and patients) did not have any overlapping participants. More specifically, the general population did not include healthcare professionals or patients. If the number of studies in any group was less than four studies, meta-regression was used. Funnel plot and the Begg's Test were used to assess publication bias [55] . The Jackknife method was used for sensitivity analysis [56] .

The present systematic review and meta-analysis did not receive any specific funding. However, one of the authors (Dr. C-Y Lin) received a grant on COVID-19 research to support his works on COVID-19. The grant that Dr. Lin received had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The initial search in five databases resulted in 7263 studies: Scopus (n=2518), ISI Web of Knowledge (n=474), PubMed (n=338), Embase (n=1426), and ProQuest (n=2507). After removing duplicate papers, a further 5647 papers were screened based on title and abstract. Finally, 555 papers appeared to be potentially eligible and their fulltexts were reviewed. In this process, 177 studies met the eligibility criteria and were pooled in the meta-analysis. Figure 1 shows the search process based on the PRISMA flowchart.

All the included studies (N=177) collected the data online and comprised 345,270 participants from 39 different countries (, Algeria, Argentine, Australia, Austria, Bahrain, Bangladesh, Belgium, Brazil, Canada, China, Colombia, Egypt, Ethiopia, Finland, France, Greece, India, Iran, Iraq, Israel, Italy, Lebanon, Malaysia, Morocco, Nepal, Netherlands, Nigeria, Oman, Pakistan, Palestine, Poland, Qatar, Saudi Arabia, Serbia, Spain, Sweden, Syria, Turkey, Tunisia, United Arab Emirates, UK, USA, and Vietnam). Of these, 28 studies collected data during the national lockdown period in the respective countries. The two countries with the highest number of eligible studies were China (N=76) and Italy (n=17). The smallest sample size was 20, and the largest sample size was 56,932. The mean age of participants varied from 15.26 years to 69.85 years. Approximately two-thirds of overall participants were females (63.5%) and one-third were married (35.33%). The most frequently used study design was cross-sectional (n=168). Four studies had a case-control design and five studies had a longitudinal design. In longitudinal studies, collected data during the COVID-19 pandemic were extracted. Various measures were used to assess sleep problems, with the Insomnia Severity Scale (ISI; n=93) and Pittsburgh Sleep Quality Index (PSQI; n=60) being the most frequently used scales in the studies. Psychological distress was also assessed with different measures, with the Patient Health Questionnaire (PHQ; n=73) and Generalized Anxiety Disorder Scale (GAD; n=75) being the most frequently used scales in the studies. Table 1 provides the summary characteristics of all included studies.

As aforementioned, the maximum score on the NOS is 9 and a score less than 5 is classified as having a high risk of bias [46] . Based on this criterion, 130 studies were categorized as being high quality studies. The impacts of study quality were further assessed and reported in subgroup analysis. The most common problems were in selection of participants. Online sampling leads to non-representativeness of the sample, sample size being not estimated or justified, and number of non-respondents being not reported. The results of the quality assessment are provided in Figure 2 .

Three target groups of participants were studied: healthcare professionals (n=62), general population (n= 105), and COVID-19 patients (n=10). Outcome measures are reported based on these target groups. Table 2 ) and uni-variable meta-regression (Table 3) , and multivariable meta-regression (Table 4 ) showed that none of the examined variables influenced the prevalence of sleep problems or heterogeneity. The probability of publication bias was assessed using Begg's test and funnel plot. Based on Begg's test (p=0.12) and funnel plot (Figure 4) , the probability of Figure 2 . Results of quality assessment publication bias was confirmed. Due to probability of publication bias in estimation of pooled prevalence of sleep problems in healthcare professions, the fill-and-trim method was used to correct the results. In this method, 20 studies were imputed and the corrected results based on this method showed that pooled prevalence of sleep problems among healthcare professions was 0.31 (95% CI: 0.27 to 0.36; p<.001). Funnel plot after trimming is provided in Figure 5 . Also, sensitivity analysis showed that pooled effect size was not affected by a single study effect. Table 2) showed that during lockdown, participants in longitudinal studies showed a significantly higher prevalence of sleep problems. Based on uni-variable metaregression (Table 3) , the country of residence was the other significant variable in prediction of prevalence of sleep problems among the general population. Also, multivariable meta-regression (Table 4) confirmed that country and lockdown period were significant influential factors on prevalence of sleep problems, explaining 26.32% of variance.

The probability of publication bias was assessed using Begg's test and funnel plot. Based on Begg's test (p=0.01) and funnel plot (Figure 7) , the probability of publication bias was confirmed. Due to probability of publication bias in estimation of pooled prevalence of sleep problems among the general population, the fill-and-trim method was used to correct the results. In this method, 50 studies were imputed and the corrected results based on this method showed that pooled prevalence of sleep problems was 18% (95% CI: 15-21%; p<.001). Funnel plot after trimming is provided in Figure 8 . Also, sensitivity analysis showed that pooled effect size was not affected by a single study effect.

The pooled estimated prevalence of sleep problems was 57% among COVID-19 patients [95% CI: 42 to 72%, I 2 :98.5%, Tau 2 :0.06]. Figure 9 provides the forest plot showing the pooled prevalence. Subgroup analysis ( Table 2) showed studies with female-only participants had a higher prevalence of sleep problems significantly (82% vs. 54% respectively). Other variables did not influence heterogeneity or estimated pooled prevalence in this participants group. The probability of publication bias was assessed using Begg's test and funnel plot. Based on Begg's test (p=0.53) and funnel plot (Figure 10 ), the probability of publication bias was rejected. Also, sensitivity analysis showed that pooled effect size was not affected by a single study effect. Overall, the prevalence of sleep problems was significantly different in target participants considering 95% confidence interval of sleep prevalence. The corrected pooled estimated prevalence of sleep problems was 31% (95% CI: 27-36%), 18% (95% CI: 15-21%) and 57% (95% CI: 42-72%), among healthcare professional, general population and COVID-19 patients respectively. The highest prevalence of sleep problems was seen among COVID-19 patients. Based on subgroup analysis ( Table 5) , quality of studies (low vs. high), gender group of participants (female vs. both gender), and measure of sleep problems (PSQI vs. others) influenced heterogeneity of association of sleep problems and depression among health professionals. Meta-regression (Table 7) showed that age and marital status (married vs. others) significantly decreased the heterogeneity and explained substantial proportion of variance (72.8% and 43.85% respectively). Examined variables in subgroup analysis and metaregression were not identified as possible source of heterogeneity or influential in the estimated pooled effect size in the association of sleep problems and anxiety (Table 6) . Publication bias and small study effect was not found in association of sleep problems and depression/anxiety based on Begg's test (p=0.87 and p=0.81 respectively). (Table 5 and 6), lockdown status (no vs. yes) reduced the heterogeneity in association of sleep problems and depression. Based on metaregression (Table 7) , age was a significant moderator in association between sleep problems and anxiety, which explained 50.37% of variance. However, the other examined variables were not identified as possible sources of heterogeneity or influential on the estimated pooled effect size in the association between sleep problems and depression/anxiety.

Based on Begg's test, publication bias and small study effect were not found in the association between sleep problems and depression (p=0.52). Although publication bias was not significant in association between sleep problems and anxiety (p=0.41), based on funnel plot, publication bias was probable. Consequently, fill and trim method was used to correct probable publication bias. After imputation of three studies, the association between sleep problems and anxiety was estimated as Fisher's z score of 0.48 (95% CI: 0.41 to 0.54).

The association of sleep problems with depression and anxiety among general population was reported in only two studies. The pooled estimated effect size showed moderate correlation between sleep problems and depression with Fisher's z score of -0.36 [95% CI: -0.49 to -0.24, p=0.0007, I 2 =7.4%; Tau 2 = 0.001]. Also, a moderate correlation was found between sleep problems and anxiety with Fisher's z score 0.49 [95% CI: -0.12 to 1.1, p<0.001, I 2 =95.2%; Tau 2 = 0.01]. The forest plots are shown in Figures 15 and 16 . The number of studies was too few to conduct further secondary analysis including subgroup/meta-regression analysis, controlling publication bias, and small study effect.

The present systematic review and meta-analysis synthesized data from 177 recently published studies on this topic to more rigorously investigate the prevalence of sleep problems and how sleep associated with psychological distress. The synthesized results showed that the pooled estimated prevalence of sleep problems regardless of gender and population was 37% during the COVID-19 outbreak. Additionally, a much higher prevalence rate of sleep problems was identified among patients with COVID-19 infection (55%) and healthcare professionals (43%). These findings concur with Jahrami et al. [38] who reported in their meta-analysis that the highest prevalence rate of sleep problems was found among COVID-19 patients. Meta-regression in the present review further indicated that country, age, gender, and marital status did not contribute to the estimated prevalence in sleep problems.

The nonsignificant finding for gender contradicts prior evidence showing that being female is a risk factor for insomnia and mental health problems [27, 56] . This may be explained by the samples recruited because the analyzed studies in the present review comprised a large proportion of females. The imbalanced gender distribution may have led to a reduced gender effect, which in turn, resulted in a nonsignificant finding. Regarding the association between sleep problems and psychological distress, sleep problems were found to be moderately correlated with depression (ES=0.54) and anxiety (ES=0.55). Subgroup analysis and meta-regression additionally showed that being a COVID-19 patient and being of older age were significant predictors of a higher association between sleep problems and psychological distress.

The high prevalence of sleep problems found in the present review can be explained by fear of COVID-19 and sleep-related factors (e.g., the changes in sleep-wake habits with delayed bedtime, lights off time, and sleep onset time due to quarantine and lockdown) [57] . The national and global COVID-19 death statistics are commonly and routinely reported by the social media and news [57] . Therefore, prior research has found the higher levels of psychological distress and significant symptoms of mental illness in various populations since the start of the pandemic [4] [5] [6] . Indeed, evidence prior to the pandemic has demonstrated that individuals may experience sleep problems when they experience major public health threats [16] [17] [18] . The higher prevalence of sleep problems found among healthcare professionals can be further explained by their job nature. Health professionals, especially those who are frontline workers dealing with COVID-19 infected patients on a daily basis, encounter much higher high risk of infection and irregular work schedules than those working in other occupations [10] [11] [12] [13] [14] [15] .

Lockdown was found to be a significant factor in explaining sleep problems. However, this finding may be confounded by the different policies implemented to inhibit the spread of COVID-19 across the 39 countries analyzed in the present review. For example, mainland China launched a strict lockdown policy to prohibit almost all outdoor activities, while the lockdown policy in other countries was not as strict. Nevertheless, the present findings support prior evidence that lockdown negatively impacted individuals' psychological health and sleep [57] .

There are several clinical implications from the present study's findings. First, government and healthcare providers worldwide need to design and implement appropriate programs and treatments to assist different populations, including healthcare professionals, patients, and the general population, in overcoming sleep problems. For example, effective programs (e.g., cognitive behavioral therapy for insomnia and meditation) [58] reported in prior research can be embedded in smartphone apps and healthcare professional training to prevent or deal with the sleep problems for different populations. Second, the associations between sleep problems and psychological distress provide the empirical evidence that healthcare providers should simultaneously tackle sleep problems and psychological distress. Consequently, psychological distress can be reduced when an individual's sleep is improved (and vice versa). Third, special attention may need to be paid to COVID-19 patients and older individuals because the present review showed a higher association between their sleep problems and psychological distress. Moreover, specific populations such as children and their caregivers should not be ignored regarding their psychological needs and sleep issues. Although the present review did not provide evidence on pediatric populations, the present findings concerning the specific group of older individuals may generalize to other specific populations. It is recommended that programs comprising psychological support for family having children to overcome the difficulties during COVID-19 pandemic are implemented [60] .

The present review has some strengths. First, the prevalence of sleep problems has been estimated across different populations and this information provides healthcare providers with a greater and more contextualized picture regarding the impacts of COVID-19 on sleep problems. Second, methodological quality of each analyzed study was assessed using the NOS checklist. Within the meta-analysis findings, subgroup analysis and meta-regression were used to provide thorough information and therefore the meta-analysis findings are robust. Third, generalizability of the present review's findings is good because the synthesized sample size was large (N=345,270) and the participants were recruited from 39 countries.

The present review has some limitations. First, most of the studies adopted a cross-sectional design (n=56) and only seven studies (three which used a case-control design and four which used a longitudinal design) considered the time effect in the causal relationship. Therefore, the relationships between sleep problems and psychological distress found in the present review do not have strong causality evidence. Diverse evidence in the causality has been proposed. Using longitudinal designs, Vaghela and Sutin [59] found that psychological distress might lead to poor sleep, while Mazzer and Linton [60] found that shorter sleep duration might lead to higher levels of psychological distress. Moreover, the lack of pre-COVID-19 pandemic information on sleep problems hinders the understanding of changes of sleep problems caused by COVID-19. Second, different measures were used in the studies that were evaluated (e.g., PSQI, ISI, and ASI for sleep problems). Given that different measures may have different features in capturing the severity of sleep problems, there may have some biases in estimating prevalence for sleep problems and effect sizes for the associations between sleep problem and psychological Figure 11 . Forest plot displaying the estimated pooled Fishers' Z score in association of sleep problems and depression among health professionals distress. All the studies evaluated here used self-report methods in assessing sleep problems and psychological distress. Therefore, findings in the present review cannot rule out social desirability and memory recall biases. Third, the impacts of COVID-19 on sleep and mental health problems are dynamic. That is, individuals may have different levels of sleep and mental health problems according to the severity of COVID-19 outbreak in their localities or countries. Moreover, the policies in controlling the COVID-19 outbreak are different across countries [57, [61] [62] [63] [64] [65] [66] . Therefore, the estimated findings in the present review cannot represent the impacts of COVID-19 during a specific period. Fourth, the analyzed studies in the present review had a large proportion of Chinese and Italian populations. Similarly, the synthesized samples were mostly young adults. Therefore, the generalizability of the present review's findings to different ethnic populations and age groups (i.e., older people and children) is restricted. Given that China and Italy were the first two countries to be severely impacted by the COVID-19 pandemic, there is understandably more research carried out in these two countries. However, the contributions of other countries, especially the American and African populations, should not be ignored. Further research should be carried out in other ethnic populations and different countries to balance the findings and maximize the generalizability. Fifth, the present meta-analysis had very large heterogeneity (as shown in Fig. 3 ) and evidence of publication bias (as shown in Fig. 4) . Therefore, the findings without removing the heterogeneity in the meta-regression and subgroup analysis might be biased. Finally, most of the studies included in the meta-analysis were not of high quality (as shown in Fig. 2) . Therefore, future studies require higher quality designs to investigate sleep problems during COVID-19 pandemic.

In conclusion, sleep problems appear to have been common during the COVID-19 pandemic. One in every three individuals reported the sleep problems. Nearly half of the healthcare professionals (43%) encountered sleep problems during the pandemic period. Healthcare providers may want to design appropriate programs to help individuals overcome their sleep problems. Moreover, sleep problems were found to be associated with higher levels of psychological distress (including depression and anxiety). Therefore, with the use of effective programs treating sleep problems, psychological distress may be reduced. Vice versa, the use of effective programs treating psychological distress, sleep problems may be reduced. However, it is possible that the association between sleep problems and psychological distress found in the present review is contributed by confounders. In other words, causality may not be happened between sleep problems and psychological distress. Therefore, more longitudinal studies and randomized controlled trials are needed to investigate the causality between sleep problems and psychological distress.

Chung-Ying Lin was supported in part by a research grant from the Ministry of Science and Technology, Taiwan (MOST109-2327-B-006-005). All other authors have nothing to declare.

No additional unpublished data are available.

No funding was received. 

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Mental health and psychosocial problems of medical health workers during the COVID-19 epidemic in China

The nature and treatment of pandemic-related psychological distress

The immediate impact of the 2019 novel coronavirus (COVID-19) outbreak on subjective sleep status

The evaluation of sleep disturbances for Chinese frontline medical workers under the outbreak of COVID-19

Prevalence of sleep disturbances in Chinese healthcare professionals: a systematic review and meta-analysis

Prevalence of and risk factors for poor sleep quality among residents in training in KSA

Prevalence of poor sleep quality in nursing staff: a meta-analysis of observational studies

The Role of Factors in Psychosocial Health

Sleep disturbance and psychological profiles of medical staff and non-medical staff during the early outbreak of COVID-19 in Hubei Province

Sleep problems during the COVID-19 pandemic by population: a systematic review and meta-analysis

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

COVID-19 pandemic and mental health consequences: Systematic review of the current evidence

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Sleep and Covid-19 related psychological distress

The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research

The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response

Psychological distress: concept analysis

Assessing the quality of studies in meta-analyses: advantages and limitations of the Newcastle Ottawa Scale

Multilevel models for meta-analysis

Assessing heterogeneity in meta-analysis: Q statistic or I2 index?

Statistical power analysis for the behavioral sciences

Parametric measures of effect size. The handbook of research synthesis

Calculation of Effect Sizes

Practical meta-analysis

Weightrelated stigma and psychological distress: A systematic review and meta-analysis

Complex data structures. Introduction to Meta-Analysis

Publication bias in meta-analysis. Publication bias in meta-analysis: Prevention, assessment and adjustments

Statistical methods for meta-analysis

Investigating mediated effects of fear of COVID-19 and COVID-19 misunderstanding in the association between problematic social media use, psychological distress, and insomnia

Efficacy of a Theory-Based Cognitive Behavioral Technique App-Based Intervention for Patients With Insomnia: Randomized Controlled Trial

Discrimination and sleep quality among older US adults: the mediating role of psychological distress

A longitudinal view of rumination, poor sleep and psychological distress in adolescents

Anxiety and suicidal thoughts during COVID-19 pandemic: A cross-country comparison among Indonesian, Taiwanese, and Thai university students

Psychological distress and internet-related behaviors between schoolchildren with and without overweight during the COVID-19 outbreak

The COVID-19 pandemic and serious psychological consequences in Bangladesh: a population-based nationwide study

Factors related to preventive COVID-19 infection behaviors among people with mental illness

Using an integrated social cognition model to predict COVID-19 preventive behaviours

Internet-related behaviors and psychological distress among schoolchildren during COVID-19 school suspension

Stress and sleep: a survey based on wearable sleep trackers among medical and nursing staff in Wuhan during the COVID-19 pandemic

Survey of insomnia and related social psychological factors among medical staff involved in the 2019 novel coronavirus disease outbreak

Generalized anxiety disorder, depressive symptoms and sleep quality during COVID-19 outbreak in China: a web-based cross-sectional survey

Social capital and sleep quality in individuals who self-isolated for 14 days during the coronavirus disease 2019 (COVID-19) outbreak in January 2020 in China

Is returning to work during the COVID-19 pandemic stressful? A study on immediate mental health status and psychoneuroimmunity prevention measures of Chinese workforce

COVID-19 pandemic and lockdown measures impact on mental health among the general population in Italy. An N= 18147 web-based survey

Sleep quality and mood symptoms in conscripted frontline nurse in Wuhan, China during COVID-19 outbreak: a cross-sectional study

The examination of sleep quality for frontline healthcare workers during the outbreak of COVID-19

Symptoms in health care workers during the COVID-19 epidemic. A cross-sectional survey

Hern andez-Martínez A. Sleep Pattern Changes in Nursing Students during the COVID-19 Lockdown

Psychological health, sleep quality, and coping styles to stress facing the COVID-19 in Wuhan

Coping with COVID-19: Exposure to COVID-19 and Negative Impact on Livelihood Predict Elevated Mental Health Problems in Chinese Adults

Mental health problems during the COVID-19 pandemics and the mitigation effects of exercise: a longitudinal study of college students in China

The prevalence of psychiatric symptoms of pregnant and non-pregnant women during the COVID-19 epidemic

Sleep disturbances among medical workers during the outbreak of COVID-2019

The endless quarantine: The impact of the COVID-19 outbreak on healthcare workers after three months of mandatory social isolation in Argentina

The effects of social support on sleep quality of medical staff treating patients with coronavirus disease 2019 (COVID-19

Impact of COVID-19 lockdown on sleep quality in university students and administration staff

Analysis of Psychological and Sleep Status and Exercise Rehabilitation of Front-Line Clinical Staff in the Fight Against COVID-19 in China

Effects of Covid-19 lockdown on mental health and sleep disturbances in Italy

Prevalence, risk factors and clinical correlates of depression in quarantined population during the COVID-19 outbreak

The effect of age, gender, income, work, and physical activity on mental health during coronavirus disease (COVID-19) lockdown in Austria

Sleep problems among Chinese adolescents and young adults during the coronavirus-2019 pandemic

Chinese mental health burden during the COVID-19 pandemic

Epilepsy care in the time of COVID-19 pandemic in Italy: risk factors for seizure worsening

Psychological impact of the COVID-19 pandemic on healthcare workers: a cross-sectional study in China

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

Mental health and work attitudes among people resuming work during the Covid-19 pandemic: A cross-sectional study in China

Public mental health under the long-term influence of COVID-19 in China: Geographical and temporal distribution

Prevalence of and risk factors associated with mental health symptoms among the general population in China during the coronavirus disease 2019 pandemic

Do psychiatric patients experience more psychiatric symptoms during COVID-19 pandemic and lockdown? A case-control study with service and research implications for immunopsychiatry

Suicide risk during the lockdown due to coronavirus disease (COVID-19) in Colombia

Evidence for elevated psychiatric distress, poor sleep, and quality of life concerns during the COVID-19 pandemic among US young adults with suspected and reported psychiatric diagnoses

Quality of sleep and health-related quality of life among health care professionals treating patients with coronavirus disease-19. The International journal of social psy

Anxiety in Chinese pediatric medical staff during the outbreak of Coronavirus Disease 2019: a cross-sectional study

Changes in sleep pattern, sense of time and digital media use during COVIDÀ19 lockdown in Italy

Covid-19 pandemic impact on mental health: a web-based cross-sectional survey on a sample of Italian general practitioners

The mental health of frontline and non-frontline medical workers during the coronavirus disease 2019 (COVID-19) outbreak in China: A case-control study

Sleep quality and mental health in the context of COVID-19 pandemic and lockdown in Morocco

The prevalence and risk factors of psychological disturbances of frontline medical staff in china under the COVID-19 epidemic: Workload should be concerned

Patient reported outcomes of breast cancer patients during the COVID-19 outbreak in the epicenter of China: A cross sectional survey study

The psychological impact of COVID-19 pandemic on medical staff in Guangdong, China: a cross-sectional study

Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019

Impact on mental health and perceptions of psychological care among medical and nursing staff in Wuhan during the 2019 novel coronavirus disease outbreak: A cross-sectional study

Factors associated with insomnia among Chinese frontÀline nurses fighting against COVIDÀ19 in Wuhan: A cross-Àsectional survey

Bidirectional influence of the COVID-19 pandemic lockdowns on health behaviors and quality of life among chinese adults

Prevalence and Demographic Correlates of Poor Sleep Quality Among Frontline Health Professionals in Liaoning Province, China During the COVID-19 Outbreak

Poor-sleep is associated with slow recovery from lymphopenia and an increased need for ICU care in hospitalized patients with COVID-19: A retrospective cohort study

Effect of COVID-19 pandemic on mental wellbeing of healthcare workers in tertiary care hospital

Moving More and Sitting Less as Healthy Lifestyle Behaviors are Protective Factors for Insomnia, Depression, and Anxiety Among Adolescents During the COVID-19 Pandemic

Mental health of healthcare professionals during the early stage of the COVID-19 pandemic in Ethiopia

Perceived Stress, and Family Support among Nursing Staff during the Pandemic Crisis. Healthcare; 2020: Multidisciplinary Digital Publishing Institute

Psychological impact in noninfectious disease specialists who had direct contact with patients with COVID-19

Mental Health Outcomes Among Healthcare Workers and the General Population During the COVID-19 in Italy

COVID-19 and Obstetrical Care: Coping With New Stress

Effects of home confinement on mental health and lifestyle behaviours during the COVID-19 outbreak: Insight from the "ECLB-COVID19" multi countries survey

Mental health outcomes in healthcare workers in COVID-19 and non-COVID-19 care units: a cross-sectional survey in Belgium

Poor sleep quality and its consequences on mental health during the COVID-19 lockdown in Italy

Nurses' Sleep Quality of "Fangcang" Hospital in China during the COVID-19 Pandemic

Mental health of frontline healthcare workers exposed to COVID-19 in Egypt: A call for action

Relationship between eHealth literacy andpsychological status during COVIDÀ19 pandemic A survey of Chinese residents

The effect and mechanism of adverse childhood experience on suicide ideation in young cancer patients during coronavirus disease 2019 (COVID-19) pandemic. Risk management and healthcare policy 2020

Social capital and psychological distress during Colombian coronavirus disease lockdown

The Mental Health of Female Physicians and Nurses in Oman during the COVID-19 Pandemic

Objectively-assessed physical activity, sedentary behavior, smartphone use, and sleep patterns pre-and during-COVID-19 quarantine in young adults from spain

COVID-19 pandemic: Psychological impact on anaesthesiologists

Interactions between socioeconomic status and mental health outcomes in the nigerian context amid covid-19 pandemic: a comparative study

Depressive and anxiety symptoms, quality of sleep, and coping during the 2019 coronavirus disease pandemic in general population in Kashmir. Middle East

The role of psychological flexibility in the context of COVID-19: Associations with depression, anxiety, and insomnia

Globally altered sleep patterns and physical activity levels by confinement in 5056 individuals: ECLB COVID-19 international online survey

Mental health problems among Chinese adolescents during the COVID-19: The importance of nutrition and physical activity

The Combined Impact of Gender and Age on Post-traumatic Stress Symptoms, Depression, and Insomnia During COVID-19 Outbreak in China

Psychiatric morbidity and dietary habits during COVID-19 pandemic: a cross-sectional study among Egyptian Youth (14À24 years). Middle East

Personnel Well-Being in the Helsinki University Hospital during the COVID-19 Pandemic-A Prospective Cohort Study

Prevalence and associated factors of DSM-5 insomnia disorder in the general population of Qatar

Correlation Between Atopic Dermatitis and Sleep Quality Among Adults in Saudi Arabia

Relationship between sleep quality and the psychological status of patients hospitalised with COVID-19

Psychological burden of the COVID-19 pandemic and its associated factors among frontline doctors of Bangladesh: a cross-sectional study 2020

Psychological distress and sleep problems when people are under interpersonal isolation during an epidemic: a nationwide multicenter cross-sectional study

An analysis on sleep quality of the healthcare professionals during the covid-19 pandemic

The importance of sleep and physical activity on well-being during COVID-19 lockdown: Reunion island as a case study

Maladaptive coping with the infodemic and sleep disturbance in the COVIDÀ19 pandemic

Depression, perceived stress related to COVID, post-traumatic stress, and insomnia among asthma and COPD patients during the COVID-19 pandemic

Decrease in sleep quality during COVID-19 outbreak

Mental Health and Health-Related Quality-of-Life Outcomes Among Frontline Health Workers During the Peak of COVID-19 Outbreak in Vietnam: A Cross-Sectional Study

Mental health status of health-care professionals working in quarantine and non-quarantine Egyptian hospitals during the COVID-19 pandemic

Predicting Psychological State Among Chinese Undergraduate Students in the COVID-19 Epidemic: A Longitudinal Study Using a Machine Learning

Effect of 2019 coronavirus pandemic on ophthalmologists practicing in Saudi Arabia: A psychological health assessment. Middle East African

Changes in sleep pattern and sleep quality during COVID-19 lockdown

Younger people are more vulnerable to stress, anxiety and depression during COVID-19 pandemic: A global crosssectional survey

The prevalence of depressive and anxiety symptoms and their associations with quality of life among clinically stable older patients with psychiatric disorders during the COVID-19 pandemic

Psychologic distress and sleep quality among adults in Turkey during the COVID-19 pandemic

Prevalence of and risk factors associated with sleep disturbances among HPCD exposed to COVID-19 in China

Physical activity, dietary habits and sleep quality before and during COVID-19 lockdown: A longitudinal study

COVID-19 and Mental Health During Pregnancy: The Importance of Cognitive Appraisal and Social Support

Prevalence of psychological disorders in the COVID-19 epidemic in China: A real world cross-sectional study

Maternal perceptions of sleep problems among children and mothers during the coronavirus disease 2019 (COVIDÀ19) pandemic in Israel

Perceived Stress, Hope, and Health Outcomes Among Medical Staff in China During the COVID-19 Pandemic

Mental Health Outcomes Amongst Health Care Workers During COVID 19 Pandemic in Saudi Arabia

Predictive Factors for Impaired Mental Health among Medical Students during the Early Stage of the COVID-19 Pandemic in Morocco

Psychological impact of COVID-19 outbreak among Jimma University Medical Centere visitors in Southwestern Ethiopia: a cross-sectional study

Alteration in the psychologic status and family environment of pregnant women before and during the CovidÀ19 pandemic

YinSocial Media Use J. Unhealthy Lifestyles, and the Risk of Miscarriage Among Pregnant Women During the COVID-19 Pandemic: Prospective Observational Study

COVID-19 Pandemic Stressors and Psychological Symptoms in Breast Cancer Patients

Psychiatric morbidity and protracted symptoms after COVID-19

Factors associated with psychological distress among patients with breast cancer during the COVID-19 pandemic: a cross-sectional study in Wuhan, China

Correlates of insomnia among the adults during COVID19 pandemic: evidence from an online survey in India

Changes in sleep timing and subjective sleep quality during the COVID-19 lockdown in Italy and Belgium: age, gender and working status as modulating factors

Weathering the Storm: Psychological Impact of COVID-19 Pandemic on Clinical and Nonclinical Healthcare Workers in India

Assessment of Depression, Anxiety, and Sleep Disturbance in COVID-19 Patients at Tertiary Care Centre of North India

Insomnia is associated with worry, cognitive avoidance and low academic engagement in Argentinian university students during the COVID-19 social isolation

Mental health conditions among the general population, healthcare workers and quarantined population during the coronavirus disease 2019 (COVID-19) pandemic

Occupational Stress and Mental Health: A Comparison Between Frontline Medical Staff and Non-frontline Medical Staff During the 2019 Novel Coronavirus Disease Outbreak. Frontiers in

Early psychiatric impact of COVID-19 pandemic on the general population and healthcare workers in Italy: a preliminary study

The Psychological Pressures of Breast Cancer Patients During the COVID-19 Outbreak in China-A Comparison With Frontline Female Nurses

Insomnia in the Italian population during Covid-19 Outbreak: A snapshot on one major risk factor for Depression and Anxiety

Factors associated with mental health outcomes among health care workers in the Fangcang shelter hospital in China

Prevalence and related factors of insomnia among Chinese medical staff in the middle and late stage of COVID-19

Mental health and psychological responses during the coronavirus disease 2019 (COVID-19) epidemic: A comparison between Wuhan and other areas in China

Insomnia and stress of physicians during COVID-19 outbreak

Nurses endured high risks of psychological problems under the epidemic of COVID-19 in a longitudinal study in Wuhan China

Sleep quality during the COVID-19 pandemic: not one size fits all

A psychological investigation of coronavirus disease 2019 (COVID-19) patients in mobile cabin hospitals in Wuhan

Depression, anxiety, and stress mediate the associations between internet gaming disorder, insomnia, and quality of life during the COVID-19 outbreak

Worry and insomnia as risk factors for depression during initial stages of COVID-19 pandemic in India

Healthy lifestyle behaviors are major predictors of mental wellbeing during COVID-19 pandemic confinement: A study on adult Arabs in higher educational institutions

Depression, anxiety symptoms, Insomnia, and coping during the COVID-19 pandemic period among individuals living with disabilities in Ethiopia

Prevalence of depression, anxiety, distress and insomnia and related factors in healthcare workers during COVID-19 pandemic in Turkey

Short-term insomnia disorder in health care workers in an academic medical center before and during COVID-19: rates and predictive factors

Mental health impacts of the COVID-19 pandemic on international university students, related stressors, and coping strategies

Anxiety and sleep problems of college students during the outbreak of COVID-19

fatigue and psychosocial wellÀbeing during COVIDÀ19 pandemic: A crossÀsectional survey of hospital nursing staff in the United States

Occupational Stress and Mental Health among Anesthetists during the COVID-19 Pandemic

The enemy who sealed the world: Effects quarantine due to the COVID-19 on sleep quality, anxiety, and psychological distress in the Italian population

Mental health during the COVID-19 pandemic: Effects of stay-at-home policies, social distancing behavior, and social resources

Association of insomnia disorder with sociodemographic factors and poor mental health in COVID-19 inpatients in China

Sleep characteristics in health workers exposed to the COVID-19 pandemic

Socioeconomic and psychological impact of the COVID-19 outbreak on private practice and public hospital radiologists

Status and influential factors of anxiety depression and insomnia symptoms in the work resumption period of COVID-19 epidemic: A multicenter cross-sectional study

Investigation on sleep and mental health of patients with Parkinson's disease during the Coronavirus disease 2019 pandemic

Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: A monocentric experience

The psychological impact of Covid-19 disease is more severe on Intensive Care Unit healthcare providers: a cross-sectional study

Sleep disturbances among physicians during COVID-19 pandemic

Impact of COVID-19 outbreak on the mental health status of undergraduate medical students in a COVID-19 treating medical college: a prospective longitudinal study

Early indicators and risk factors associated with mental health problems during COVID-19 quarantine: Is there a relationship with the number of confirmed cases and deaths?

Sex differences in self-report anxiety and sleep quality during COVID-19 stay-at-home orders

Factors associated with mental health outcomes across healthcare settings in Oman during COVID-19: frontline versus non-frontline healthcare workers

Patient-reported outcomes of patients with breast cancer during the COVID-19 outbreak in the epicenter of China: a cross-sectional survey study

Prevalence of sleep disturbances during covid-19 outbreak in an urban Chinese population: a cross-sectional study

Sleep disturbances among Chinese residents during the Coronavirus Disease 2019 outbreak and associated factors

COVID-19: PTSD symptoms in Greek health care professionals

Mental health impacts among health workers during COVID-19 in a low resource setting: a cross-sectional survey from Nepal

Mental health in frontline medical workers during the 2019 novel coronavirus disease epidemic in China: a comparison with the general population

Assessment of mental health factors among health professionals depending on their contact with COVID-19 patients

Relationship quality and mental health during COVID-19 lockdown

Mental health in the era of COVID-19: prevalence of psychiatric disorders in a cohort of patients with type 1 and type 2 diabetes during the social distancing

Prevalence and correlation of anxiety, insomnia and somatic symptoms in a Chinese population during the COVID-19 epidemic

Psychological impact of COVID-19 in the Swedish population: Depression, anxiety, and insomnia and their associations to risk and vulnerability factors

Intolerance of uncertainty and loneliness in older adults during the COVID-19 pandemic

Does Sars-Cov-2 threaten our dreams? Effect of quarantine on sleep quality and body mass index

Evaluation of mental health factors among people with systemic lupus erythematosus during the SARS-CoV-2 pandemic

Anxiety and depressive symptoms among COVID-19 patients in Jianghan Fangcang Shelter Hospital in Wuhan

The Association Between Health Status and Insomnia, Mental Health, and Preventive Behaviors: The Mediating Role of Fear of COVID-19