Sleep quality and COVID-19 outcomes: the evidence-based lessons in the framework of predictive, preventive and personalised (3P) medicine

Sleep quality and duration play a pivotal role in maintaining physical and mental health. In turn, sleep shortage, deprivation and disorders are per evidence the risk factors and facilitators of a broad spectrum of disorders, amongst others including depression, stroke, chronic inflammation, cancers, immune defence insufficiency and individual predisposition to infection diseases with poor outcomes, for example, related to the COVID-19 pandemic. Keeping in mind that COVID-19-related global infection distribution is neither the first nor the last pandemic severely affecting societies around the globe to the costs of human lives accompanied with enormous economic burden, lessons by predictive, preventive and personalised (3P) medical approach are essential to learn and to follow being better prepared to defend against global pandemics. To this end, under extreme conditions such as the current COVID-19 pandemic, the reciprocal interrelationship between the sleep quality and individual outcomes becomes evident, namely, at the levels of disease predisposition, severe versus mild disease progression, development of disease complications, poor outcomes and related mortality for both - population and healthcare givers. The latter is the prominent example clearly demonstrating the causality of severe outcomes, when the long-lasting work overload and shift work rhythm evidently lead to the sleep shortage and/or deprivation that in turn causes immune response insufficiency and strong predisposition to the acute infection with complications. This article highlights and provides an in-depth analysis of the concerted risk factors related to the sleep disturbances under the COVID-19 pandemic followed by the evidence-based recommendations in the framework of predictive, preventive and personalised medical approach.


Preamble
Keeping in mind that COVID-19-related global infection distribution is neither the first nor the last pandemic severely affecting societies around the globe to the costs of human lives accompanied with enormous economic burden, lessons by predictive, preventive and personalised medical (PPPM/3PM) approach are essential to learn and to follow being better prepared to defend against global pandemics. To this end, 3PM knowledge towards the COVID-19 pandemic is regularly updated in the literature [1,2]. Unique research data towards individual outcomes in COVID-19-affected patient cohorts accompanied by potent predictive and preventive approaches have been presented and acknowledged as a great contribution of 3P medicine to the global challenge by COVID-19 [3][4][5].
This article focused on the comprehensive sleep quality impacts, follows the series of publications presenting valuable 3PM lessons towards the COVID-19 relevant knowledge. Sleep quality plays a pivotal role in maintaining physical and mental health. In turn, sleep shortage, deprivation as well as sleep disorders are per evidence the risk factors and facilitators of a broad spectrum of disorders, among others including depression, stroke, chronic inflammation, cancer, immune defence insufficiency and individual predisposition to infection diseases with poor outcomes. Therefore, sleep deficits are highly relevant for the COVID-19 distribution and outcomes.

Sleep quality and immune defence
Sleep quality and duration have been shown to play a pivotal role in immune health. Accumulated research data clearly indicate that the immune defence is supported by sleep, whereas sleep deprivation, e.g. caused by insomnia and circadian disruption, can severely impair the immune system functionality serving therefore, as a reliable predictor [6,7]. During the sleep, there is an increased activity of two major subtypes of lymphocytes, which are important for the adaptive immune response and general disease prevention, namely, CD4 + "helper" T cells and cytotoxic CD8 + "killer" T cells. Further, a decreased activity of natural killer cells and increased production of pro-inflammatory cytokines are important for the host defence against pathogens including viral infections [7][8][9][10][11][12][13]. During nighttime sleep, pro-inflammatory hormones and cytokines are synchronised to facilitate the onset of an adaptive immune response. In contrast, during the daytime activity, anti-inflammatory signals, hormones and cytokines are supportive for immediate reactions towards biological and other environmental challenges [14]. Additionally, the cytokines TNF-α and IL-12 as well as antigen-presenting dendritic cells (DCs) show their highest activity during the night in those adhering to a normal sleep-wake routine, but also in those kept awake for 24 h, and without change of the period (24 h) of these rhythms. The peak time of the circadian rhythms of cortisol, epinephrine, norepinephrine and the cytokine IL-10 occurs early in the morning, around the time of awakening from night-time sleep according to the individual sleep-wake rhythm. In situations of continuous wakefulness, epinephrine displays an undefined rhythm. The peak time of the rhythm in IL-10 shifts to the night-time. Cortisol and norepinephrine show peak value rhythms similar to sleep values, which Nadir values, for both, are higher under conditions of constant wakefulness [15]. Also reduced activities of natural killer cell activity and T cell cytokine production in sleep-deprived subjects compared to subjects with a full night of sleep have been demonstrated [16,17].
In this context, the relationship between sleep quality and proper immune defence functionality becomes particularly relevant for the COVID-19 pandemic outcomes. Indeed, tiredness occurs as one of the common symptoms in the early stages of COVID-19 infection, and as the diseases progresses, insomnia may emerge as an additional problem, with disturbed sleep persisting beyond the acute stage of the disease. In terms of possible long-term effects of COVID-19 that exceed the typical recovery period, bundled under the term long COVID-19 or post-acute sequelae of SARS-CoV-2 infection, effects on sleep and fatigue are apparent, with sleep problems and fatigue becoming typical symptoms of long COVID-19 6 months after infection. In the context of long COVID-19, Huang et al. reported in a sample of N = 1655 that 437 individuals (26%) showed sleep problems and fatigue or muscle weakness for 1038 individuals (63%) [17].
Among its multi-faceted functions, sleep has been shown to regulate glucose metabolism and weight gain, both of which are acknowledged risk factors of diabetes, obesity and sleep apnoea, which in turn have been associated with a higher predisposition to disease on viral infections [18] and to severe COVID-19 disease progression [19,20].

Sleep quality and vaccination efficacy
Considering the importance of vaccination as the primary strategy to combat viral pandemics, research data provide clear evidence towards an important role of the sleep quality in the level of vaccination efficacy [21]. It has been reported that a sufficient amount of deep and slow-wave sleep could be essential for vaccine effectiveness, as the common flu vaccination seems to be more effective in people who have slept well in the days preceding the vaccination [22]. Another study conducted by Lange et al. examined the role of sleep and wakefulness after receiving hepatitis A vaccination on immune responses. Results have shown that after sleep compared to wakefulness, the relative portion of the virus-specific Th cells were doubled, and the portion of Th1 cytokine-producing cells increased being important for an adaptive immune response [23]. Contextually, research data on the relationship between the sleep quality and the vaccination efficacy as well as the relevance of the impaired sleep are of great importance.

Sleep quality-improving medication and COVID-19 outcomes
While there are no specific antiviral therapeutic agents available for the COVID-19 yet [24,25], sleep-related treatment options improving individual outcomes are available. To this end, Zhou et al. demonstrated that coronavirus infection can lead to insomnia resulting in a disturbed production of melatonin with adverse effects on the immune defence and long-term pathologic alterations in the nervous systems [26]. Based on the collected statistics, this research group hypothesised that the COVID-19 replication could be inhibited by the intake of melatonin [26].
A retrospective analysis performed by Columbia University indicated improved survival rates for the intubated ICU patients, if they were treated with melatonin [27]. To this end, Cheng et al. suggest the melatonin function in the sleep quality. In addition to its key role in regulating circadian rhythms, melatonin also modulates the immune system by inhibiting inflammation and cytokine storm as one of the most dangerous components of the COVID-19 disease [28]. Indeed, melatonin acts as anti-inflammatory and immune-modulating agent effectively boosting human immune system [22]. The review of Mohamed et al. summarises evidence on the utility of melatonin as a potential antioxidant adjuvant in COVID-19-infected individuals with diabetes and obesity, suggesting melatonin as a potent treatment option to improve COVID-19 outcomes by supporting immune health [29]. To date, there is no direct experimental evidence on the virucidal effect of melatonin; however, research data demonstrate indirect activities of melatonin as a potent antiviral helper, due to its complex anti-inflammatory, antioxidant and immunomodulatory properties [30,31].

Poor sleep quality predicts a susceptibility to infections in healthcare gives
Healthcare givers, among the shift workers in general, are particularly susceptible to impaired sleep, due to rotating working hours and night work. Shift work, especially night work, induces a disruption of the circadian rhythm compromising the neuroimmune-endocrine homeostasis including a reduction in natural killer cells activity that has been well documented for nurses [32][33][34][35][36][37]. Sleep rhythm disturbance characteristic for the shift workers is clearly associated with a higher vulnerability to infectious diseases such as a flu [38][39][40], whereas reduced sleep (< 5 h) and poor sleep quality and/or excessive sleep (> 9 h) are linked with a higher risk for pneumonia [41,42]. Further, sleep-deprived shift workers are at higher risk of respiratory infections and their severity grad [43,44] that is highly relevant for the susceptibility to the COVID-19 infection and related complications. The higher risk and severity of respiratory and other infections may thus not only be associated with sleep disorders, but also to a reduced amount of slow-wave NREM sleep, which is responsible for the secretion of the cytokine IL-12 and DCs, the main precursors of Antigen-presenting cells [45,46].
An epidemiological survey conducted in December 2019 in Wuhan revealed the highest prevalence of the poor sleep quality in 18.2% of the sample (N = 7236) specifically for healthcare givers demonstrating compared to all other professional occupations [47]. In particular, healthcare givers working on the frontline with the acutely COVID-19 diseased individuals are directly exposed to the pathogen accompanied with the sleep imbalance and circadian disruption that makes them to a special group of risk which well-designed predictive and preventive medical approach should be applied for to protect against the health damage linked to their professional duties [48].

Working hypothesis in the context of PPPM
Based on the above presented facts, a reciprocal interrelationship has been hypothesised between the sleep quality and individual outcomes for both COVID-19 diseased and medical staff involved in the care. If being valid, this concept opens great prospects for implementing risk assessment, patient stratification, individualised prediction and targeted prevention to persons at high risk among professional and in the population linked to the well-justified educational measures.

Literature search methodology
Systematic literature search has been conducted utilising electronic data available in PubMed and Google Scholar.
Literature search investigated effects of COVID-19 on a sleep quality in hospital populations, separately considering both -the medical staff and affected patient cohorts.
Studies dedicated to the sleep quality of healthcare givers were identified by following combinations of the keywords, "COVID-19", "sleep quality", "medical staff", "sleep disturbances" and "insomnia". The review was limited to published research articles written in English. Only original research articles about or literature reviews of the effects of sleep on medical staff with reported sleep assessments as outcome variables were included.
Studies dedicated to the sleep quality of the affected patients were identified by following combination of the keywords, "COVID-19", "patients", "sleep", "sleep quality" and "ICU". The review was limited to published research articles written in English. Only original research articles or literature reviews on the effects of COVID-19 on patients' sleep were included. Furthermore, only studies measuring sleep status were included.
Both search approaches are summarised in Figs. 1 and 2, respectively. Table 1 presents the collected data with corresponding interpretation towards analysed sleep quality and related aspects in the COVID-19-affected patients. Analysed studies clearly demonstrate that insomnia symptoms persist in 36-88% of all included COVID-19 patients -the level which is significantly higher compared to the prevalence of insomnia in the general population estimated as being 10 to 40% [49,50]. The underlying causes of the poor sleep parameters are considered as being:

Sleep quality in the COVID-19-affected patients
1. Potentially related to early awakening by medical staff and disrupted sleep 2. Due to sedative administration 3. Due to mechanical ventilation of affected COVID-19 patients [51].  Poor sleep quality was consequently associated with the lower levels of lymphocytes in the blood of COVID-19 patients [58]. To this end, deep sleep modulates the T-Help cell response that plays a key role in the immune response towards viral infections suggesting that a focus on improving sleep quality in COVID-19 patients may be decisive for the recovery.
Further, an evident gender difference has been observed: female patients suffered more frequently from poorer psychiatric outcomes, such as depression and anxiety, compared to the male patients [52,53].

Sleep quality in the healthcare givers under the COVID-19 pandemic condition
In agreement with earlier demonstrated sex differences in the sleep quality [81,82], female sex is associated with poorer sleep outcomes. The collected data indicate that female healthcare givers working in shifts during the pandemic are at significantly higher risk for insomnia and other mental health disturbances. In consensus with previous studies dedicated to the sleep quality for the shift workers, female nurses are at increased risk to develop sleep disorders and to a cancer predisposition. In summary, working in shifts with the COVID-19-affected patients significantly increases overall risk of adverse effects to nurses' health.

Being frontline healthcare givers under COVID-19 pandemics
Data collected clearly demonstrate that particularly frontline healthcare givers reported worse sleep outcome variables, such as insomnia symptoms or significantly decreased sleep quality accompanied by increased levels of stress and burnout as well as increased appearance of psychiatric symptoms such as depression and anxiety. Indeed, under the pandemic condition, the frontline healthcare givers are facing sudden outbreak, which given the severity of the pandemic leads to the work overloads and extended working time frame with insufficient time to recover and consequent chronic exposure to stress, psychological distress [47] and increased vulnerability to the stress-related disorders including viral infections. Sleep deprivation in shift workers is associated with a higher incidence and severity of respiratory infections compared to non-shift workers [43,44], suggesting that shift workers are more susceptible to COVID-19 infection and, consequently, to severe disease outcomes. In consensus, being dependent on the individual circadian rhythms, the adaptive and innate immune systems are disrupted by working in shifts. This in turn increases susceptibility of the affected individuals to infections [10,[38][39][40]83]. To this end, the analysed molecular mechanisms argue in favour of a severe impairment of the immune memory in shift workers.
However, stress response and stress-related predisposition to pathologies have been demonstrated as being highly individual. Contextually, for working in shifts, an application of predictive diagnostic and patient stratification approaches followed by the targeted preventive measures is strongly recommended utilising corresponding tools and recommendations developed for a population screening and identification of individuals in sub-optimal health conditions [84,85] and insomnia [86].
Contextually, perceived social and psychological support is considered as the preventive strategy to mild poor sleep quality and psychiatric symptoms in healthcare givers treating the COVID-19-affected patients [74,75,77,78]. Recent studies on insomnia and sleep disorders related to working in shifts further indicate good effects for Internet-based interventions and conclude that hospital authorities are well advised to offer this new approach to their staff as part of workplace health promotion [87].

Being COVID-19-affected
Analysed data clearly demonstrate that insomnia symptoms persist in big portion of the COVID-19 patient cohort with the monitored prevalence which significantly exceeds the level of insomnia in the general population. Several underlying causes have been proposed. Poor sleep quality was further associated with the decreased immune system functionality in the COVID-19 patients [58], suggesting that a focus on improving sleep quality may be decisive for the recovery and significantly better individual outcomes of the disease. Further, an evident gender difference indicates that particularly for the female patients, the focus on psychiatric aspects such as frequent depression and anxiety is strongly recommended as an essential part of individualised anti-COVID-19 treatment algorithms.
To this end, periodontopathic microflora is implicated in systemic inflammation and pneumonia development, in severe cases leading to sepsis and death. Diagnosed periodontitis is associated with high risk of admission to intensive care units and increased COVID-19-related death [88]. To this end, educational measures play a pivotal role, conducting principles of participatory medicine as an essential element of 3PM and promoting an active participation of patients in the treatment procedure and taking great responsibility for their health status [5].
Taking into account multi-faceted anti-inflammatory and anti-mitochondriopathic effects of melatonin, melatonin treatment is strongly recommended as an essential pillar of the anti-COVID-19 protection for the shift workers, COVID-19-affected individuals and patients suffering from chronic non-communicable disorders under the viral pandemic conditions [89][90][91].
Author contributions KR and OG have created concepts of the study. KR has coordinated the project and drafted the paper. SK has performed literature search and drafted the data interpretation. OG has elaborated on the 3PM aspects. OG, KR and TH have elaborated on the final version of the manuscript. All authors have read and approved the final version.
Funding Open Access funding enabled and organized by Projekt DEAL.

Data availability Not applicable.
Code availability Not applicable.

Declarations
Ethics approval Not applicable. Consent to participate Not applicable.

Conflict of interest The authors declare no competing interests.
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