**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 deltawaves 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

*Occupational Stress-Related Sleep Anomaly in Frontline COVID-19 Health Workers… DOI: http://dx.doi.org/10.5772/intechopen.109148*

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.
