Sleep is an important factor for human wellbeing in order to maintain daily functions [12], while lack of sleep may lead to an increase in accidents, mood changes, impaired psychological functioning and concentration, and decreased immune response rendering individuals more susceptible to contracting the virus [13]. Thus, several studies have focused on sleep problems during the COVID-19 pandemic mostly using self-reported data in different populations. In fact, the prevalence of COVID-19 related sleep disorders has been reported to be high, affecting approximately 30–35% of the general public and HCPs [14,15]. Patients suffering from active COVID-19 display an even higher prevalence of sleep problems [14,15]. In a recent systematic review and meta-analysis, the corrected pooled estimated prevalence of sleep problems was 57% among COVID-19 patients compared to 31% in HCPs and 18% in the general population [14].

In all groups studied, sleep problems were positively associated with psychological distress, such as depression and anxiety. Country of residence and lockdown period significantly influenced the development of sleep difficulties. However, the meta-regression analysis in this study indicated that factors such as age, gender, country, and marital status did not contribute to the prevalence of sleep problems. Furthermore, COVID-19 patients displayed the highest prevalence of sleep problems with HCPs having the second place [14], especially front-line clinical staff [15,16,17,18]. HCPs due to their job demands may suffer from a high level of sleep difficulties and stress as they need to be in frequent contact with infected patients and need to adapt to irregular and sometimes prolonged work schedules and shifts [18,19,20]. More specifically, the prevalence of insomnia has been found to be higher among non-medical HCPs (e.g., students, community workers, and volunteers) than among medical HCPs and among frontline HCPs compared to non-frontline HCPs [21,22].

Another recently conducted meta-analysis on this subject [15] also confirmed that the most affected group for sleep problems during the pandemic was patients with COVID-19 with a pooled prevalence rate of 74.8%, followed by HCPs (36.0%), and then by the general population (32.3%). The prevalence of sleep problems including all the populations from the available different studies (general population, HCPs, patients) was estimated at almost 36% [15]. The subgroup analysis by population showed that most of the studies evaluated the sleep problems of the general population, followed by those of HCPs, and the minority evaluated sleep problems of patients with SARS-COV-2. In the subgroup of COVID 19 patients, older age and male sex were associated with higher sleep problems prevalence [15]. However, a subgroup analysis in the study of Jahrami et al. showed that studies that included only female participants reported a higher prevalence of sleep problems [15], which is in accordance to prior evidence that female gender is related to higher risk for insomnia and mental health problems [23]. On the other hand, in a study assessing the mental health status and sleep quality of COVID-19 patients hospitalized during different pandemic stages in a single center in Wuhan [24], about half of the patients reportedly exhibited a mild level of depressive mood, especially female and elderly patients, indicating that gender might be an independent predictor for anxiety and depression status. Elderly patients and those with co-morbid chronic diseases were more likely to report sleep problems. Additionally, those patients who reported moderate or severe symptoms were more likely to suffer from sleep problems compared to those who only reported mild symptoms. The factor that was significantly associated with mental distress and disturbed sleep quality was patients’ subjective perception of disease severity rather than the objective clinical classification [24].

The definition of insomnia varied among the published studies during the pandemic; most referred to insomnia in its broader presentation, as insomnia disorder or insomnia symptoms, with limited information about its onset and maintenance (acute/transient, short term, chronic) [25]. Being an HCP or at risk of contact with COVID- 19 patients, being a woman, having co-morbidities, and living in rural areas were found to be the most important risk factors for insomnia [26]. Insomnia symptoms and fatigue were more frequently reported from COVID-19 patients during the recovery from acute infection, compared with shortness of breath [27] and depression [28]. In any case, effective management with the appropriate interventions of this disorder is crucial, as it may lead to severe consequences such as an increased risk of suicide and substance abuse [29,30].

The instrument used to estimate sleep problems in most of the studies (50%) was the Pittsburgh Sleep Quality Index (PSQI) [31]. The mean PSQI for all different populations examined in the meta-analysis of Jahrami et al. [15] was estimated to be 7.1 (95% CI, 6.3–8.0) with scores for the general population around 6.0 (95% CI, 5.3–6.8) and higher for HCPs with a score of 7.7. Sleep latency, sleep disturbances, and sleep duration estimated with the PSQI were affected the most, presenting with the highest scores [15]. Apart from PSQI, a range of other validated scales were used for the assessment of sleep disturbances such as Athens Insomnia Scale, Insomnia Severity Index (ISI) [32], alongside researcher-developed measures or subsections of an established questionnaire [15]. This range of different measures used in the studies to assess symptoms across different time frames has contributed to the large heterogeneity of results in the meta-analysis of the studies. For example, PSQI and Athens Insomnia Scale [33] evaluate sleep symptoms during the past month, whereas ISI evaluates sleep symptoms during the past 2 weeks. On the other hand, PSQI evaluates a very broad range of sleep disorders such as nightmares and snoring, which could explain the higher prevalence rates in the studies using this instrument compared with others such as ISI, which evaluate insomnia symptoms but do not evaluate other sleep disturbances.

However, the pandemic is ongoing, and the results of different studies cannot be generalized. Nevertheless, it remains important to evaluate the impact of COVID-19 on sleep in different ethnicities, different age groups, and different strata of society, including those with limited access to health care services as well as the longer-term consequences [34]. Furthermore, most of the current studies did not investigate lifestyle factors such as smoking, substance use, physical activity, marital status, or employment; thus, their results should be interpreted taking these limitations into consideration.

SARS-CoV2′s most frequent severe clinical finding is pneumonia, leading to acute respiratory distress syndrome (ARDS). However, mounting evidence has shown that it can affect the nervous system, causing neurological symptoms from the early phases of the disease [35]. Sleep impairment was found to be the most frequent neurological symptom, followed by headache, dysgeusia, hyposmia, and depression. Daytime sleepiness was more frequent in the first two days after admission, and sleep problems were observed more commonly in patients after 7 days of hospitalization. These patients also demonstrated higher white blood cells and lower C-reactive protein (CRP) levels. A gender-based difference was reported with women experiencing daytime sleepiness more frequently; this was attributed to the different immune responses to viral infections, which were more marked in women compared to men [36].

In a prospective study evaluating the neurologic disorders in hospitalized COVID-19 patients in New York, patients with new neurological complications during hospitalization were matched to COVID-19 patients without neurological complications and were followed up for 6 months [37]. Almost two-thirds of all patients reported fatigue, sleep disorders, depression, and anxiety. Moreover, poorer sleep quality was associated with acute respiratory failure requiring invasive mechanical ventilation. Over 90% of COVID-19 patients reported at least one abnormal outcome at 6 months follow up, with 62% experiencing worse than average anxiety, depression, fatigue, or sleep. Additionally, patients with neurological complications presented with significantly worse functional outcomes.

In fact, there is evidence to support a link between coronavirus infections and various nervous system manifestations. Neuroinflammation has been also noted with COVID-19 but appears to play a role in other neuropsychiatric diseases, several of which are characterized by immune-inflammatory states, and their treatments may have anti-inflammatory properties and effects. The underlying mechanism of the psychiatric, neuropsychiatric, and sleep consequences of COVID-19 are multifactorial and may include the social isolation, the severity of viral infection, immunological reactions, different treatments applied as corticosteroids, the Intensive Care Unit (ICU) stay, and the social stigma [38].

Sleep strongly affects the immune system, and there is evidence that sleep deprivation negatively impacts immune responses [39,40], possibly leading to immunosuppression [41]. However, the effects of sleep quality during hospitalization for COVID-19 remain unclear. Almost 15% of COVID-19 hospitalized patients reported somnolence [42]; however, it is not certain whether this was a consequence of factors such as pain, anxiety, constipation, physical discomfort from illness, or prolonged hospitalization or directly linked to COVID-19 [43,44]. A study [44] that objectively assessed with wrist actigraphy the consequence of severe symptoms of COVID-19 on sleep quality found that the patients with the most severe respiratory symptoms and those who required prolonged intensive care unit (ICU) stay presented lower Sleep Efficiency and Immobility Time and higher Fragmentation Index compared to those with mild respiratory symptoms not requiring ICU. In addition, a retrospective, single-center cohort study [45] conducted to investigate the effects of sleep, assessed by Campbell sleep questionnaire and PSQI, on recovery from lymphopenia and clinical outcomes of hospitalized COVID-19 patients found that patients with poor sleep recorded lower absolute lymphocyte count (ALC) and increased neutrophil-to-lymphocyte ratio (NLR). In COVID-19 patients with lymphopenia, poor sleep quality during hospitalization was associated with a slow lymphopenia recovery and an increased need for ICU admission. The reported slow recovery from lymphopenia and increased deterioration of NLR were associated with poor sleep quality during hospitalization for at least 2 weeks.

These findings are suggestive of a potential close relationship between poor sleep quality during hospitalization and worse clinical outcomes in COVID-19 patients. This is further supported by evidence indicating that sleep deprivation has a substantial effect on immune cell number, function, and cytokine production. Lack of sleep may promote inflammatory factors release and impair human immunity [46], and both reduced and prolonged sleep time have been associated with a higher risk of respiratory infections [47,48]. Furthermore, insufficient sleep has been linked to illness severity with a study reporting that reduced sleep during the week prior to COVID-19 diagnosis was associated with more severe presentations and an inverse relationship between average daily sleep time before illness and severity of disease. In fact, the presence of co-morbidities and reduced sleep were the two most significant risk factors affecting the disease severity [49].

4. Sleep Impairment and Psychological Distress in COVID-19 Patients