Occupational Stress-Related Sleep Anomaly in Frontline COVID-19 Health Workers: The Possible Underlying Mechanisms

Abstract

COVID-19 is a highly contagious viral illness that has claimed millions of lives worldwide. Since its emergence, it has exerted a negative impact on many sectors globally without the exception of frontline COVID-19 healthcare providers. Specifically, in frontline COVID-19 healthcare workers, occupational stress-related sleep disorders such as insomnia and daytime somnolence have been extensively reported and were characterized by neuro-immunological changes. However, the possible mechanisms that underlie the sleep disorders have not been elucidated. The review was designed to highlight possible sleep mechanisms responsible for insomnia and daytime somnolence reported in frontline COVID-19 health workers. Available evidence shows that emotional perturbation, hypertension, chronobiological disruption and prolonged exposure to artificial light are among the events orchestrating occupational-stress-related sleep disorders in frontline COVID-19 healthcare workers. Anxiety-associated sleep anomaly is attributable to stimulation of the reticular activating system which occurs as a result of activation of noradrenergic fiber and sympatho-adrenal axis. Another mechanism includes depletion of hippocampal and brain glycogen by anxiety-induced activation of corticotropin releasing hormone (CRH)-secreting brain neurons and hypothalamic-corticotropic-adrenal cortex axis. Spontaneous discharge of noradrenergic fiber during basal state and changes in normal secretory rhythm of hypnosis-related chemical messengers may be responsible for hypertension- and chronobiological disruption-induced sleep disorders, respectively. Lastly, prolonged light exposure-induced suppression of melatonin secretion may elicit disruption of normal circadian sleep.

1. Introduction

Stress can be defined as any sensation that indicates physical, psychological, or physical-psychological discomforts [1, 2, 3]. Climaxing stress is the sensation of discomfort and the sensations may be described as unimodal when one major sensation of discomfort is involved [2]. Psychological sensations of discomfort may be characterized by emotional and behavioral swings [1]. When there is more than one strain sensation, stress is said to be polymodal. Examples of such are fluctuations in vital signs, body functions, and physical states manifesting as digestive disorders (diarrhea, vomiting, and nausea), headache, hyperthermia, palpitations, muscle fatigue, aches, and reduced libido [2] among others. Gravitational stress can cause dizziness, pedal pain, muscle fatigue, anger, and sleep deprivation. It is important to add that stress occurs when there is a deviation from what the body has perceived as normal or homeostatic. In fact, it is typically characterized by a non-specific response to any deviation from the homeostatic state.

Any strain sensations occurring either physically, psychological, or both in relation to one’s job or profession is referred to as occupational stress [3]. Occupational stress is a type of stress that occurs when employees are overwhelmed by the dictates of their jobs or by institutional, organizational, and personal targets. Usually, the stress ensues when demands, expectations, and projections are incapable of being met at the set time. Switching from one job to another and exposure to long working periods are heavily implicated in occupational stress. Occupational stress also bouts where and when employees feel inadequately rewarded, appraised, and motivated [3]. During occupational stress, hemodynamic changes occur such that blood is diverted more to the central nervous system and some skeletal muscles at the expense of other body systems. This invariably results in cerebral vascular changes, and headache, among others culminating in increased sleep latency and delay in sleep onset. It is not unusual that the hypothalamo-hypophyseal-adrenal axis is activated leading to the release of cortisol. The sympatho-adrenal axis, the rapid response mechanism, is unarguably largely perturbed during occupational stress, manifesting as an increase in epinephrine, norepinephrine, and dopamine levels [4]. Non-hormonal consequences of sympatho-adrenal activation include increases in heart rate, respiratory rate and blood pressure, blood glucose, blood urea nitrogen, urine specific gravity, changes in heart rhythms, skin conductance, and sleep disturbances. Others include changes in brain activities and mood swings. Long-term exposure to occupational stress results in musculoskeletal impairments and cardiovascular adversities. Apart from musculoskeletal and cardiovascular impairments, occupational stress has a connection with posttraumatic stress syndrome, anxiety, depression, drug misuse, and insomnia [5]. Occupational stress is one of the underlying causes of morbidity and mortality [2], responsible for around 10% of job-induced ailments and diseases [6].

Sleep disruption, as one of the features of occupational stress, can be described as an impediment to normal sleep pattern. It has been implicated in occupational stress-induced injuries, accidents, and diseases [5, 6]. COVID-19 (severe acute respiratory syndrome-2) is a transmissible disease of the viral clan that belongs to the Coronaviridae family [7, 8, 9, 10]. It is caused by a new coronavirus strain that was discovered in 2019 in Wuhan, China. COVID-19 has affected millions of people worldwide [7, 8, 9]. It has claimed many lives globally [7, 8, 9, 10]. The disease is contagious and can be contracted through respiratory droplets, contact, and interface with COVID-19 contaminated surfaces [11, 12]. Currently, there is no specific cure but COVID-19 patients benefit from secondary treatments though vaccines are now available to induce an active artificial immune defense [12].

COVID-19 outbreak created huge pressure on frontline health workers owing to many reasons [12, 13]. First, the novelty of the disease elicited an unprecedented increase in the number of healthcare seekers from the usual counts. Since there was no specific forewarning and preparation across the globe in terms of boosting the capacity of healthcare providers, hospital facilities, diagnostic and management sectors, the whole tension mounted on healthcare personnel. In fact, there was a subjective increase in expectation of health seekers and the general public from the healthcare providers. Another important concern was the contagiousness of the disease. All of these culminated significantly in mounting tension on healthcare providers resulting in adverse health consequences including alteration in their normal sleep pattern. Many primary studies have been done to examine the sleep pattern of healthcare providers during COVID-19. The review was designed to highlight the possible mechanisms that underlie occupational stress-related sleep impairment in frontline healthcare workers during COVID-19 outbreak.

2. Methodology

A narrative literature search was done using Web-based databases like Google Scholar, Pubmed, Scopus, and Web of Science. The search was done using several terms and text words such as occupational stress, COVID-19, sleep, sleep disorders relating to occupational stress, sleep mechanisms and stress. Inclusion and exclusion criteria were set to filter relevant articles. Articles that were not directly related with the topic are excluded. Each of the filtered articles was independently examined to ascertain the eligibility to the study.

3. Structure of human stress control

Although stress response is not specific, there are distinct neural and non-neural mechanisms that are in charge. These can be divided into intrinsic and extrinsic stress controls with the latter modulated by the former.

4. Intrinsic stress control

The intrinsic stress control includes brainstem, hypothalamus, noradrenergic neurons, histaminergic neurons, orexinergic neurons, opioid peptide-secreting neurons, serotonergic neurons, corticotropin releasing hormone (CRH)—secreting neurons, cholinergic neurons and dopaminergic neurons of the brain [14, 15].

Dopaminergic pathways including the mesolimbic and tuberoinfundibular dopamine pathway are influenced by stress. Signal from tuberoinfundibular dopamine pathway is widely known to cause inhibition of prolactin secretion. This is mediated through the interaction of dopamine with the D2 receptor on the surface of lactotrophs via decreased cyclic adenosine monophosphate. The absence of dopamine removes inhibition on prolactin secretion.

Conversely, increased prolactin secretion occasioned by stress represents a response to an increase in metabolic demand and hypoglycemia [16]. Although the specific contribution of prolactin during stress is not well understood, the hormone may increase blood glucose. It may also act on the brain and elicits a euphoric state, thereby helping relieve stress [17]. Despite insufficiency of evidence from human studies, a study has shown that prolactin may increase erythrocyte count in mice [18]. An increase in erythrocytes during stress is an important compensatory mechanism as it leads to an improvement in tissue oxygen supply.

Ghrelin level has been reported to increase during stress [19]. Ghrelin acts on the hypothalamus to induce secretion of growth hormone releasing hormone (GHRH) and inhibit growth hormone inhibiting hormone (somatostatin). GHRH in turn binds with its receptors on somatotroph causing growth hormone secretion. Growth hormone mobilizes free fatty acid and reduces peripheral tissue utilization of glucose. These actions help in maintaining blood glucose for ATP production. Another hormone elicited by stress is glucagon. Like growth hormone, glucagon helps in maintaining blood glucose levels.

Other intrinsic stress controls include increased levels of prostaglandins E2 [20], arginine vasopressin, heat shock proteins, interleukins-6, 10, and 19 [21] and adrenal progesterone [22]. Increased level of adrenal progesterone during stress might help in improving blood flow since progesterone is a vasodilator. However, it is unlikely the increased adrenal progesterone affects extracellular progesterone significantly under physiological conditions especially during active reproductive life. Like progesterone, adenosine is another chemical messenger that has been reported to increase during stressful situations [23].

The outcomes of stimulation of intrinsic stress control include modulation of stress which can manifest as increase in mood, stress-alleviating behavioral changes (like swaying or sitting down after prolonged standing), alterations in consciousness and sensory perception, change in blood flow, and maintenance of energy production among others.

5. Extrinsic stress control

The extrinsic component consists of autonomic-adrenal medulla axis, which connects the spinal cord and lower brain areas to peripheral organs through adrenal medulla. Epinephrine and norepinephrine secreted from the medium exert their effect on peripheral organs by binding with adrenergic receptors [4] and the effects are discussed in Table 1.

S/N	Peripheral organ/system	Effect of stimulation of autonomic-adrenal medulla axis	Effect of stimulation of hypothalamic-corticotroph-adrenal cortex axis
(1)	Heart and arteries (cardiovascular system)	Increased heart rate and cardiac output, vasoconstriction of peripheral arteries, Increased blood pressure	Needed for constrictor and calorigenic effects of norepinephrine and epinephrine, Gluconeogenesis, glycogenolysis, lipolysis, increased hepatic glucose output, maintenance of blood glucose level.
(2)	Eyes (Visual system)	Pupillary dilation
(3)	Liver (Hepatobiliary system)	Increased hepatic glucose output; constriction of sphincter of oddi
(4)	Kidney (urinary system)	Decreased glomerular filtration rate
(5)	Skin (integumentary system)	Constriction of cutaneous arterioles causes decreased perspiration. This reverses as more heat is produced.
(6)	Muscles (musculoskeletal system)	Increased blood flow to active muscles
(7)	Lungs (respiratory system)	Increased in blood flow to lung for gas exchange; rise is respiratory rate and pulmonary ventilation
(8)	Brain (nervous system)	Increase in activity of cortical neurons; increased alertness. Inhibition of sleep.
(9)	Gastrointestinal tract (digestive system)	Inhibition of GIT motility and secretion. Increase in salivary alpha amylase
(10)	Blood and immune system	Increase in erythrocyte count, interlukins 6 and 10
(11)	Endocrine glands (endocrine system)	Alpha cells of islet secret glucagon, increase growth hormone secretion, Increased secretions from adrenal gland; increased adrenal progesterone and androgen
(12)	Reproductive organs (reproductive system)	Inhibition of tumescence

Table 1.

Extrinsic stress control in human body.

Another part of the extrinsic neural stress control is the hypothalamic-corticotropin-adrenal cortex axis. The parvocellular neurosecretory cells of the paraventricular nucleus of the anterior hypothalamus communicate via arginine vasopressin with the corticotroph of adenohypophysis to form a central unit [15, 24]. Unlike the autonomic-adrenal medulla axis, the axis connects the control area with the peripheral organs through the adrenal cortex. Glucocorticoid and dehydroepiandrosterone sulfate (DHEAS) released from the adrenal cortex bind with their expressed receptors in the peripheral organs.

6. History of COVID-19

It was on record that animal respiratory infections linked to the coronavirus group had occurred precisely in chickens earlier in the 1920’s, with a mortality rate of 40–90% [25]. The virus, identified as infectious bronchitis virus, was then cultivated in 1937 as Beaudette strain. Two other viruses of the coronavirus group responsible for murine encephalitis and mouse hepatitis virus were detected in the later part of 1940 [26]. However, scientists did not realize that these three viruses had similarities [26, 27]. In the course of research activities on common cold, a group of Scientists namely David Tyrrell, C. Kendall and Malcolm Bynoe, and David Tyrrell in 1961 isolated a distinct virus and was designated as B814 [28, 29]. Unfortunately, the virus could not be cultivated using the same methods which were used for adenoviruses, rhinoviruses, and many more. It was not until 1965 that the new virus was grown courtesy of a technique that involves serial passage through human embryonic trachea organ culture [30]. It was observed that inoculation of the novel virus into volunteers through the intranasal route resulted in cold. However, inactivation of the virus occurs in the presence of ether showing the virus exhibits lipid envelope. Thereafter, the isolate was grown in kidney tissue culture and designated as 229E [31]. 229E was capable of being inactivated just like B814 by ether [32]. In 1967, Scientists were able to compare 229E, B814, and infectious bronchitis virus and with the aid of an electron microscope, they were found to be related [26]. Specifically, they were observed to exhibit a crown-like presentation [33]. Therefore, the word ‘corona’ is a Greek meaning ‘crown or wreath’ in English and was formulated to describe the signatory appearance of a group of viruses [34]. OC43 was another novel respiratory virus with similar morphology as infectious bronchitis virus, 229E, and EB814. Exclusive investigations on these strains dated over 20 years after the discovery and it was shown that while the latter demonstrated a tendency of orchestrating epidemic in the entire United States, the former was more associated with local outbreak. It was later clear that apart from these strains, other respiratory viruses exist.

Over the years, many other strains have been discovered. For instance, in 2003, a human coronavirus named severe acute respiratory syndrome-coronavirus (SARCOV-1) was identified. This virus infects pulmonary epithelial cells [35] in bats, palm civets and humans [36, 37] using angiotensin-converting enzyme 2 (ACE2) [38]. Human Coronavirus NL63, another positive sense single-stranded enveloped RNA which invades the host cell through ACE2 was also detected in 2013. Human coronavirus HKU1 was detected in 2004 in Hongkong using N-acetyl-9-O-acetylneuraminic acid receptor [39]. In 2013, Middle East coronavirus (MERS-COV) was discovered [10]. This virus was found to infect bats, humans, and camels by binding to Dipeptidyl peptidase 4 (DPP4) receptors. In 2019, severe acute respiratory syndrome-coronavirus-2 was discovered in Wuhan, China [40].

Coronaviruses are responsible for 15% of common cold [41]. Other features signifying coronavirus infection are swollen adenoids, pneumonia, sore throat, bronchitis, fever, and many more [42]. Human coronavirus OC43, human coronavirus HKU1, human coronavirus 229E, and human coronavirus NL63 produce mild symptoms while Middle East respiratory syndrome-coronavirus, severe acute respiratory syndrome-1 coronavirus, and severe acute respiratory syndrome-2 coronavirus produce potentially severe problems [11].

7. Effect of occupation stress on sleep pattern IN frontline health workers during COVID-19 outbreak

A number of studies indicated the effects of occupational stress on sleep patterns in frontline healthcare providers during COVID-19. For instance, Hassinger et al. [13] reported that 68% of frontline healthcare workers exhibited aberration in their normal sleep patterns such as insomnia and daytime somnolence during COVID-19 outbreak with physicians being more affected than nurses. A total of 43% had increased daytime somnolence and 37 experienced a reduction in sleep efficiency. An increase in daytime sleepiness occurs when normal circadian nocturnal sleep is insufficient.

Jahrami et al. [43] conducted a systematic review in 13 countries with the aim of evaluating how COVID-19 pandemic had affected the sleep of the general population including frontline healthcare providers in the previous eight-month from July 2020. Although the review showed that the rate of sleep problems such as insomnia was 36%, there was no specific information about the prevalence of the abnormality across frontline healthcare workers. Sanghera et al. [44] concluded that insomnia was one of the negative impacts of SARS-CoV-2, with a prevalence range of 7.4–37.4%. Marvaldi et al. [45] in their systematic review identified sleep disorders as one of the prevalent health problems among frontline health workers accounting for 44.0%. However, the nature of sleep disorder was not too clear. In China, Jing et al. [46] assessed sleep disorders among 801 frontline healthcare workers using the Pittsburgh Sleep Quality Index, Visual Analogue Scale, and Athens Insomnia Scale. Frontline healthcare workers were shown to have a greater Pittsburgh Sleep Quality Index when compared with non-frontline workers.

Conroy et al. [47] utilized internet-based cross-sectional survey data retrieved from frontline healthcare personnel over a period of 1 month in the United States of America. There was a reduction in total sleep time in workers who reported to work continuously when compared with workers who work from home. According to the trend of the study, it was much more possible for the sleeping length of personnel who worked from home as a circadian rhythm to be entrained. In France, Germany, United Kingdom, USA, Italy, and Spain, Kim et al. [48] conducted an internet-based survey among frontline healthcare workers to identify the association between sleep pattern and COVID-19 susceptibility. The study was for 2 months and a total of 2884 frontline healthcare workers drawn from the countries were used. It was reported that the more sleep disorders such as insomnia, the more the risk of COVID-19. In Bahrain, Jahrami et al. [49] investigated the quality of sleep of frontline personnel during COVID-19 outbreak using 280 healthcare personnel through internet-based Pittsburgh Sleep Quality Index. While 75% of frontline health personnel and 76% of non-frontline health personnel claimed that they did not sleep well, respectively. In India, Gupta et al. [50] assessed the impact of COVID-19 pandemic on sleep quality among healthcare personnel and noted that 31.5% of the healthcare workers experienced poor sleep quality. In frontline healthcare workers, Rossi et al. [51] conducted an internet-based cross-sectional investigation through web-based questionnaires and reported that 8.27% of respondents experienced insomnia. Wang et al. [52] investigated the effect of COVID-19 on sleep quality of healthcare personnel in Wuhan Pediatric healthcare center using a self-reported questionnaire. The questionnaire contained the Pittsburgh Sleep Quality Index and the result indicated that 38% of the respondents experienced sleep disturbance. Shaukat et al. [53] noted in their review that frontline healthcare personnel were at risk of COVID-19-induced insomnia. Zeng et al. [54] reported in their review that the prevalence of abnormal sleep patterns was 61% in nursing staff. Among the sleep patterns taken into consideration include daytime dysfunction, sleep latency, and sleep duration. Stewart et al. [55] evaluated the sleep pattern in USA frontline health professionals during COVID-19 outbreak using online platforms such as Instagram, Facebook, and Twitter. The result indicated that 95.5% of respondents reported sleep abnormalities. Thirty percent indicated moderate or severe insomnia and 60.9% experienced sleep disruptions attributable to device utilization. In a systematic review by Salari et al. [56] the prevalence of sleep abnormalities in frontline physicians and nurses during COVID-19 pandemic was found to be 41.6 and 34.8%, respectively. In Western China, Yue et al. [57] in their cross-sectional investigation discovered via self-administered questionnaire that out of 543 respondents who were frontline medical staff, nearly 40% claim to experience insomnia.

8. Neuro-immunologic effects of COVID-19 induced sleep disruption IN frontline health workers

Quality of sleep is an important determinant of a person’s physical and psychological well-being, including the capacity of a person to respond to environmental challenges such as those posed by microbes and toxins [58]. Virtually all the body’s physiological systems are affected by the daily and seasonal changes in the timing, intensity, and spectral frequency composition of environmental light known as circadian rhythm [59]. The suprachiasmatic nucleus (SCN) is the brain’s sensor of light-dark cycles and, therefore, a regulator of circadian rhythm. Light sensed by the SCN modulates sympathetic activity and release of the sleep-promoting hormone melatonin, which, in turn, modulates the production, and release of the hypothalamic-pituitary-adrenal (HPA) axis hormones CRH, ACTH, and cortisol [60]. Some viruses, including the SARS-Cov2 variants, appear to suppress pineal gland production of melatonin which, in turn, disinhibits neutrophil activity thereby contributing to a pro-inflammatory “cytokine storm,” thought to be the main source of inflammation and Covid-related tissue damage in Covid19 [61]. Melatonin suppression, in turn, down-regulates expression of Bmal1, the body’s “molecular timekeeper,” known to generate circadian rhythms. Down-regulation of Bmal1 pyruvate dehydrogenase complex and conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) and ATP production by mitochondrial oxidative phosphorylation shifts the redox balance toward glycolysis as the main source of ATP for immune cells [62]. This inhibition of mitochondrial ATP production and shift toward cytosolic ATP production by glycolysis in granulocytes, dendritic cells, macrophages, and other immune cells is known to maintain a high level of immunological reactivity, thereby contributing to a strong inflammatory response and immune-related tissue damage in a wide variety of body organs [63] and cause sleep disruption. One of the more interesting aspects of Covid19 is the heightened anxiety and emotional responses associated with the changes in psychosocial interactions imposed by the Covid19 pandemic. Such emotional imbalances, therefore, have similar effects on the HPA axis and melatonin as exposure to the virus, thereby creating a potential to augment and exacerbate the effects of Covid19 [64].

Another interesting aspect is that geriatric age appears to be a risk factor for the more serious, lethal manifestations of Covid19 [65]. It has been shown that sleep architecture changes with age. Deep sleep, characterized by the appearance of delta-waves in the electroencephalogram (EEG) decreases in the elderly [66]. Delta-wave sleep is also known as slow-wave sleep. Because the dura mater appears to be the only source of lymphatics for the brain, the brain parenchyma has evolved a lymphatic system of neuroglia referred to as the “glymphatic” clearance system to rid the brain of toxic metabolites. Glymphatic clearance is shown to occur mainly during slow-wave sleep [67]. In addition to metabolite clearance, slow-wave sleep has numerous other functions including learning and memory consolidation [68, 69]. Slow-wave EEG activity is also associated with blood-brain barrier opening which facilitates clearance of macromolecules from the brain parenchyma [70]. During the slow-wave EEG activity associated with sleep, the chemosensory functions of microglia, subserved by purinergic receptors, are directed toward binding the ATP and adenosine released by degenerating neurons [71, 72]. This phagocytic activity of microglia appears to be critical for pruning synapses during cortical maturation and memory formation or preservation [73]. During slow-wave sleep, brain levels of adenosine, the main metabolite of ATP, and TNF-alpha, a primary pro-inflammatory mediator of immunity, appear to increase; whereas the brain’s acetylcholine and monoamines (norepinephrine, dopamine, and serotonin) decrease. Adenosine and TNF receptor signaling are known to disrupt the blood-brain barrier [74, 75]. Taken together, these findings are consistent with the concept that slow-wave sleep serves mainly a metabolic waste-clearance, restorative function for the brain. Still another interesting aspect of Covid19 pathophysiology is the “brain fog” and cognitive decline, often associated with elevation of pro-inflammatory serum markers such as TNF-alpha, which a significant proportion of individuals appear to experience for months to years after recovery from the acute manifestations of Covid infection [76]. These findings concerning neuro-immunological interactions do not bode well for the long-term consequences and health care manpower shortage when frontline health care workers contract Covid19.

9. Occupational stress-related sleep disorders in frontline healthworkers during COVID-19 pandemic: Roles of emotional perturbations

Studies provide evidence that COVID-19 caused emotional perturbation in frontline healthcare workers. Serrano-Ripoll et al. [77] in a systematic review noted that the prevalence of anxiety in frontline healthcare workers during COVID-19 pandemic stood at 30%. Mrklas et al. [78] conducted a six-week cross-sectional investigation to ascertain the prevalence of anxiety and depression in frontline healthcare workers during COVID-19 pandemic. They found that the prevalence of anxiety and depression was 47 and 46%, respectively. Using a structured internet-based questionnaire method, Ghio et al. [79] documented that there was a rise in the quanta of depression and anxiety with values of 62 and 61%, respectively in frontline health workers during COVID-19. Saragih et al. [80] indicated that the prevalence of depression and anxiety in Doctors and Nurses stood at 40 and 37%, respectively during COVID-19 pandemic. In a review by Sofia et al. [81] about 23.2 and 22.8% of healthcare professionals who faced COVID-19 patients experienced anxiety and depression in India, respectively. Ching et al. [82] showed in their review that 37.5 and 39.7% of healthcare workers suffered from depression and anxiety, respectively during COVID-19 pandemic in Asia. Health Professionals managing COVID-19 were studied by Magnavita et al. [83]. The result of the study showed that 27.8% of the respondents experienced anxiety and 51.1% had depression in Italy.

Emotional arousal induced sleep disorders may be mediated through increased sympathetic activation [84]. In the rat model, an increase in sympathetic nervous system index has been documented [85]. Activation of noradrenergic neurons and sympatho-adrenal axis by anxiety leads to increased secretion of epinephrine and norepinephrine, neurotransmitters which stimulate reticular activating system, and result in increased wakefulness. For many years, interruption of upper thoracic sympathetic ganglions has been reported to lead to elevated perspiration occurring in the arms and palms, blushing, and trembling [86]. Activation of the sympathetic nervous system results in increased expression of Cannabinoid type-1 (CB1) receptors [87]. CB1 receptors are expressed in the brain where they modulate GABA release. Wilkinson et al. [88] showed an increase in muscle sympathetic activity and plasma epinephrine in panic patients. Reduction in basal forebrain brain-derived neurotrophic factor (BDNF) and adenosine and a rise in nitric oxide in animal models have been linked with emotional disorder-related alteration in sleep pattern [89].

Apart from the involvement of brain derived neurotrophic factor, nitric oxide, adenosine, and sympathoadrenal axis, occupational stress-related sleep disorders in frontline health workers during COVID-19 pandemic may be due to elevation in glucocorticoid and corticotropin releasing hormone profile. CRH and cortisol are integrated through ACTH. ADH from parvocellular hypothalamic neuro-secretory cells induces the secretion of ACTH by binding V1bR of hypophyseal corticotroph. ACTH acts on its receptors on the adrenal cortex. A study by D’Angelo et al. [90] showed that there was marked disruption of sleep in Cushing Syndrome patients. However, the study found no correlation between urinary free cortisol and sleep impairment. In another development, there is increasing evidence that occupational stress-induced sleep disorders may be characterized by changes in EEG. Holsboer et al. [91] investigated the electroencephalographic effects of exogenous corticotropin-releasing hormone (CRH) and reported a reduction in slow wave sleep and an increase in wakefulness. The possibility that sleep disorders associated with frontline health workers might be due to glucocorticoid-induced changes in hippocampal glycogen is increasing. Gip et al. [92] reported that sleep-deprived rats, characterized by elevated glucocorticoid, exhibited decreased hippocampal glycogen and brain glycogen. Depression in hippocampal glycogen and brain glycogen has been linked with EEG waves [93]. Bradbury et al. [94] demonstrated the possible role of CRH and glucocorticoids on hypnotic EEG. Suppression of adrenal glucocorticoid secretion via adrenal gland removal led to decreased delta waves but alpha waves increased. While reversion occurs with physiological glucocorticoid treatment, the quantity of non-rapid eye movement was depressed with extra-physiological glucocorticoid administration. Furthermore, administration of REM-prolonging peptide secreted by the intermediate lobe of the hypophysis known as corticotropin-like intermediate lobe peptide raised the latency of sleep [95, 96]. Another way through which CRH may disrupt sleep is the inhibition of spontaneous reticular thalamic discharge implicated in synchronizing NREM waves (Figure 1). Injection of CRH has been reported to suppress NREM waves in C57BL/67 and CRH-R1 CL mice [97].

Figure 1.

Connection between occupational stress-induced emotional perturbation (anxiety) and sleep disorders in frontline COVID-19 healthcare providers. Activation of noradrenergic neurons and sympatho-adrenal axis by anxiety leads to increased secretion of epinephrine and norepinephrine, neurotransmitters which stimulate reticular activating system, and result in increased wakefulness. Furthermore, Hypothalamo-hypophyseal-adrenal axis and CRH secreting brain neurons become activated by anxiety resulting into inhibition of spontaneous thalamic reticular discharge and lowered hippocampal and brain glycogen. This then culminate into decreased non rapid eye movement sleep and increased light sleep.

10. Occupational stress-related sleep disorders IN frontline health workers during COVID-19 pandemic: roles of hypertension

Among the frontline healthcare workers recruited by Gupta et al. [98] 28.8% who had no history of hypertension were reported to be hypertensive during COVID outbreak. Gopal et al. [99] measured blood pressure among frontline male healthcare workers especially those whose body fat was 26.06. The study results showed that 52.4% of these people exhibited stage I hypertension with a heart rate of 92.5 BPM.

Evidence abounds on how hypertension may impair normal hypnosis. In animal studies, spontaneous hypertensive rats were shown to exhibit fewer quiet sleeps and paradoxical sleep, very mild accumulated REM and NREM sleep, and more transition from quiet sleep to active waking when compared to Wistar rats [100]. They also have lower R-R interval, higher low frequency/high-frequency ratio, higher low frequency, and lower high frequency during REM sleep when compared with Wistar rats [100]. Norepinephrine and epinephrine are excitatory neurotransmitters in the cerebral cortex and the neurotransmitter mediates wakefulness, consciousness, and alertness. Increased concentration of norepinephrine in body fluid including cerebrospinal fluid [101] could lead to sleep problems. Increased norepinephrine and serotonin in the brainstem and adrenal epinephrine and norepinephrine might be implicated in high blood pressure induced insomnia [102]. In adult spontaneous hypertensive rats, hypertension is mediated by selective stimulation of the intermediolateral area, locus coeruleus and peripheral sympathetic nerves [103]. Once these areas are activated, the ascending reticular activating fibers become active leading to increased awareness and impaired hypnosis. Noradrenergic fibers are one of the examples of ascending reticular activating fibers. Studies by Russell et al. [104] revealed noradrenergic neurons are activated while inhibitory dopaminergic neurons are suppressed in spontaneous hypertensive rats. Therefore, in hypertensive cases, spontaneous discharge of noradrenergic fibers during basal state may explain how hypertension causes insomnia in frontline COVID-19 healthcare workers.

11. Occupational stress-related sleep disorders IN frontline health workers during COVID-19 pandemic: roles of chronobiological disruption

One of the important attributes of physiological processes is rhythmicity. Physiological processes occur in distinct patterns, reaching peak level (acrophase) at a phase of 24 hour day and nadir (bathophase) during the other phase of 24 hour day. The periodic variation in physiological processes is known as chronobiology. Some processes are completed (reaching both acrophase and bathophase) in appropriately 24 hours (circadian rhythms). Others require either less than 24 hours (ultradian rhythms) or greater than 24 hour (infradian rhythms) to be completed [105]. Interestingly, all internal biological rhythms are serviced by external rhythms which can range from environmental factors to physico-mental situations like occupational demand. Studies from shift workers are enormous in support of the deleterious impact of work schedules on sleep pattern and body temperature (circadian), hormone secretions (ultradian and circadian), and reproductive cycle (infradian). Wan and Chung [106] showed that nurses on a rotatory schedule had a greater proportion of irregular ovarian cycle. In Sweden, midwives on irregular duty schedules showed reduced fecundity.

In Night shift workers, there was a change in the timing of LH surge [107, 108, 109]. Ning et al. [110] reported that oil workers on different work schedules exhibited sleep disorders and noted that cortisol level, Per3 gene, and rs680 loci of CLOCK influence sleep quality in these workers. Specifically, they discovered that CLOCK rs1801260 locus bearing TC and CLOCK rs680524 bearing GC and CC exhibited lower sleep disorders. The change in sleep pattern reported by Ning et al. [110] and many other investigators are significant viewing from the perspectives of the human activity cycle. Human beings are diurnal, designed to be active in the daytime and passive at night, working during the daytime and resting in the nighttime. Prolongation of working period to nighttime due to need, incentive, or disease adversely affects sleep quantity and quality.

In people whose work schedules extend into night, the ascending reticular fibers continue to release excitatory neurotransmitters (norepinephrine, epinephrine, serotonin, acetylcholine, histamine, orexin among others). Under the influence of these hormones, it is very difficult for sleep to be induced. In addition, shift workers experience changes in normal secretory pattern and rhythm of hypnotic hormones including melatonin, leptin, Gamma Amino Butyric Acid (GABA) among others [111]. This, in part, explains the importance of sleep hygiene. Sleep hygiene is simply defined as a sleep-promoting lifestyle. One of these lifestyles is voluntary withdrawal from active engagements [107, 109, 112]. Prolongation of activity is not only common in workers. Students exhibit this habit before, during, and after examination or contest [107, 109]. Ghrelin and leptin are chemical messengers that strongly influence feeding patterns and sleep and their secretions follow circadian pattern. Ghrelin peaks in the daytime and falls in the nighttime while leptin rises during nighttime/sleep and falls in daytime (usually in the absence of meal ingestion), respectively [113]. In people whose activities extend into night, nocturnal secretions of ghrelin and leptin rise and fall respectively. This results in hunger perception and nighttime eating which culminate in sleep and health problems. People who travel across latitude and shift workers exhibit a deranged sleep/wakefulness cycle [114, 115]. Other health issues that may co-exist with deranged sleep/wakefulness cycle include mood disorders, cardiovascular diseases, menstrual cycle anomaly, and breast cancer risk [116, 117].

In addition to leptin, disruption of secretory rhythm of Gamma Amino Butyric Acid (GABA) may be implicated in sleep abnormality [118]. A study by Junkermann et al. [119] supports the possibility that night work induced- alteration in progesterone secretory rhythm may participate in sleep abnormality that characterizes frontline COVID-19 health workers.

12. Occupational stress-related sleep disorders IN frontline health workers during COVID-19 pandemic: roles of prolonged exposure to artificial light

Work at night is practically impossible without light exposure. Sequel to the advent of light in 1860, exposure to anthropogenic light has been one of the major challenges in the modern world. Besides being an electromagnetic wave, ambient light is one of the most potent synchronizers of internal rhythms [120]. Shift in light/dark cycle by 6 hours orchestrated desynchronization that spanned for more than 6 days in rodents [116]. This indicates the tendency of light to shift circadian phase. In other studies, exposure to irregular lighting schedules have been claimed to cause prolongation of estrous cycle, lengthening of follicular phase, and an increase in estrous cycle ratio [121, 122, 123, 124].

Furthermore, exposure to light is one of the underlying mechanisms of shift work induced sleep problems. Exposure to anthropogenic nocturnal light causes repression of Arylalkylamine N-acetyltransferase (ANAT), an enzyme that is responsible for melatonin secretion by the pineal gland. The absence of melatonin inhibits normal nocturnal sleep. Studies in both human and animal studies have extensively documented the adversities associated with light-induced suppression of melatonin [124]. Melatonin is known to interact with its MTI and MT2 receptors resulting in a decrease in cyclic adenosine monophosphate (CAMP). MTI is found in hypothalamic nuclei where it decreases neural discharge. Melatonin reduces the firing of ascending reticular fibers which project via hypothalamus to the cerebral cortex and thus inhibit consciousness and alertness while promoting sleep [123, 124]. This results in disruption of normal circadian sleep (Figure 2).

Figure 2.

Prolonged light exposure and sleep disorders in frontline health workers during COVID-19. Pineal melatonin becomes suppressed by prolonged exposure to light resulting into disruption of normal circadian sleep.

The hormonal consequences of light-induced melatonin suppression have been reported. Davis et al. [111] showed that health workers on night shift duty exhibit low levels of urinary sulfatoxymelatonin and since melatonin exerts regulatory influence on gonadotropins. The authors also found high urinary levels of FSH and LH in the same people. Increased prolactin level was recorded in women exposed to lengthened lighting period [125, 126]. In rat studies, exposure to constant light may modulate suprachiasmatic PER2 expression. PER2 is a member of the PERIOD protein. PERIOD is a circadian protein that combines with cryptochrome (CRP) to form a dimer which then acts in a negative loop to inhibit brain and muscle arnt like protein (BMAL) and circadian locomotor oscillator cycles of kaput (CLOCK), which positively promotes the production of PERIOD and Cryptochrome [115]. Blue light has been reported to exert the greatest suppressive effects on melatonin because blue light provides sufficient stimulus for the suppression of ANAT [117]. Light-related suppression in melatonin is due to a reduction in postganglionic noradrenergic neural discharge to the pineal gland.

13. Discussion

Sleep doubles as an important component of activity cycle and a restoration-driven physiological state [107, 109, 127]. Inability to sleep or insufficiency of sleep in frontline health workers managing COVID patients is caused by and has been associated with a number of adverse consequences [83]. Anxiety either due to fear of infection or an increase in job demand, hypertension, chronobiological disruption, prolonged exposure to artificial light, and stress are important contributing factors to insomnia experienced by frontline COVID-19 health workers. Sleep disruption in frontline health workers may present a number of ugly consequences including neurocognitive decline. This is due to a number of reasons. The dura mater appears to be involved in the clearance of brain toxins via a novel lymphatic system of neuroglia referred to as the “glymphatic” clearance system. Glymphatic clearance is shown to occur mainly during slow-wave sleep [67]. During slow-wave sleep, brain levels of adenosine, the main metabolite of ATP, and TNF-alpha, a primary pro-inflammatory mediator of immunity, appear to increase; whereas the brain’s acetylcholine and monoamines (norepinephrine, dopamine, and serotonin) decrease. Disruption of slow wave sleep experienced by frontline COVID-19 health workers makes it difficult to eliminate brain toxins and increases the risk of diseases including sleep disorders.

Anxiety in frontline COVID-19 health workers is another concern. Generally, anxiety is characterized by sympathetic activation. Increased expression of Cannabinoid type-1 (CB1) receptors owing to activation of the sympathetic nervous system has been documented [87]. CB1 receptors are expressed in the brain where they modulate GABA release culminating in sleep deprivation. Moreover, decline in basal forebrain brain derived neurotrophic factor (BDNF) and adenosine and a rise in nitric oxide in animal models have been linked with emotional disorder-related alteration in sleep pattern [89]. Hippocampus, a birthplace of theta waves, plays an important role during sleep. Depletion of hippocampal glycogen and attendant alteration in EEG waves may atone for sleep disruption that characterizes COVID-19 frontline health workers [92]. CRH is released during stress and anxiety and this hormone has been shown to depress NREM waves in C57BL/67 and CRH-R1 CL mice [97]. Spontaneous reticular thalamic discharges, implicated in synchronizing NREM waves, are known to suppress cortical activation by peripheral stimuli. Disruption of sleep occasioned by Inhibition of spontaneous reticular thalamic discharge has been reported following CRH injection [94].

Spontaneous discharge of noradrenergic fibers during basal state may explain how hypertension causes insomnia in frontline COVID-19 healthcare workers [104]. Disruption of normal secretory rhythm of hormones and chemical messengers and presence of circadian genes such as CLOCK rs1801260 locus bearing TC and CLOCK rs680524 bearing GC and CC may contribute in substantive level to sleep disruption in frontline COVID-19 health workers. At least, studies have indicated an alteration in the circadian rhythm of leptin in people with sleep deprivation [113]. Changes in the normal secretory rhythm of Gamma Amino Butyric Acid (GABA) have also been implicated in sleep abnormality [118]. Like circadian disruption, prolonged exposure to ambient light may increase sleep latency. Light is known to suppress nocturnal melatonin synthesis making initiation of sleep difficult. Blue light has been shown to exert the greatest suppressive effect on melatonin secretion [117]. Light-related suppression in melatonin is due to a reduction in postganglionic noradrenergic neural discharge to the pineal gland. The ability of light to suppress melatonin secretion is known as the negative masking effect of light.

In summary, the review highlighted the possible mechanisms that underlie sleep anomaly that characterized frontline COVID-19 workers using existing information from experimental studies. Presence of CLOCK rs1801260 locus bearing TC and CLOCK rs680524 bearing GC and CC and stress-induced elevation of cannabinoid receptors, depletion of adenosine and forebrain derived neurotrophic factor, depletion of hippocampal glycogen and a rise in nitric oxide suppress spontaneous thalamic discharges which are involved in sleep induction are possible underlying mechanisms.

14. Conclusion

COVID-19 emergence and the attendant waves of responses from frontline healthcare officers have been very remarkable. The review has highlighted the possible underlying mechanisms associated with occupational stress-induced sleep disorders in frontline healthcare providers managing COVID-19. It is very glaring from primary studies that COVID-19-induced occupational stress causes sleep disorders most especially insomnia in both male and female frontline healthcare workers which are connectable to a number of underlying factors including anxiety leading to neuro-immunological changes. Anxiety-associated sleep anomaly is attributable to stimulation of the reticular activating system which occurs as a result of activation of noradrenergic fiber and sympatho-adrenal axis. Depletion of hippocampal and brain glycogen by anxiety-induced activation of corticotropin releasing hormone (CRH)-secreting brain neurons and hypothalamic-corticotropic-adrenal cortex axis are important implicating mechanisms. Spontaneous discharge of noradrenergic fiber during basal state and changes in the normal secretory rhythm of hypnosis-related chemical messengers may be responsible for hypertension- and chronobiological disruption-induced sleep disorders respectively. Lastly, prolonged light exposure-induced suppression of melatonin secretion may elicit disruption of normal circadian sleep.

Conflict of interest

The authors declare no conflict of interest.