COVID-19: Sleep, Circadian Rhythms and Immunity – Repurposing Drugs and Chronotherapeutics for SARS-CoV-2

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected nearly 28 million people in the United States and has caused more than five hundred thousand deaths as of February 21, 2021. As the novel coronavirus continues to take its toll in the United States and all across the globe, particularly among the elderly (>65 years), clinicians and translational researchers are taking a closer look at the nexus of sleep, circadian rhythms and immunity that may contribute toward a more severe coronavirus disease-19 (COVID-19). SARS-CoV-2-induced multi-organ failure affects both central and peripheral organs, causing increased mortality in the elderly. However, whether differences in sleep, circadian rhythms, and immunity between older and younger individuals contribute to the age-related differences in systemic dysregulation of target organs observed in SARS-CoV-2 infection remain largely unknown. Current literature demonstrates the emerging role of sleep, circadian rhythms, and immunity in the development of chronic pulmonary diseases and respiratory infections in human and mouse models. The exact mechanism underlying acute respiratory distress syndrome (ARDS) and other cardiopulmonary complications in elderly patients in combination with associated comorbidities remain unclear. Nevertheless, understanding the critical role of sleep, circadian clock dysfunction in target organs, and immune status of patients with SARS-CoV-2 may provide novel insights into possible therapies. Chronotherapy is an emerging concept that is gaining attention in sleep medicine. Accumulating evidence suggests that nearly half of all physiological functions follow a strict daily rhythm. However, healthcare professionals rarely take implementing timed-administration of drugs into consideration. In this review, we summarize recent findings directly relating to the contributing roles of sleep, circadian rhythms and immune response in modulating infectious disease processes, and integrate chronotherapy in the discussion of the potential drugs that can be repurposed to improve the treatment and management of COVID-19.

The Influence of Time of Day of Vaccination with BNT162b2 on the Adverse Drug Reactions and Efficacy of Humoral Response against SARS-CoV-2 in an Observational Study of Young Adults

“…Since circadian rhythms observed in the immune system might not only affect the immune response as presented by the titers of antibodies [ 45 ], but also the strength and occurrence of immediate and late ADR [ 46 ], we asked whether number and characteristics of the reported ADR correlate with time-of-day of vaccination. So far, Langlois et al [ 26 ] and Pollmann and Pollmann [ 24 ] have presented that local ADR tend to be more frequent in individuals revaccinated late during the daytime.…”

The Association of Time of Day of ChAdOx1 nCoV-19 Vaccine Administration With SARS-CoV-2 Anti-Spike IgG Antibody Levels: An Exploratory Observational Study

“…In our study, the shape of the association changed (from reverse J-shape to linear) with age, but morning vaccination was the most potent in mounting antibody titers across all age groups. The age-specific results might be explained by a cross-talk of aging of the circadian system and sleep homeostasis (Giri et al, 2021) with age-related declines in immunity such as impaired immune cell function, diminished chemokine production, that may lead to reduced antibody response following vaccination or infection (Bartleson et al, 2021; Blomberg and Frasca, 2013). We also found suggestive evidence of effect modification by sex, with morning vaccination (vs early afternoon) stimulating a stronger vaccine response among male participants, although our stratified analyses were of limited power.…”

“…Circadian rhythms regulate the immune system by a temporal modulation of the immune function (Giri et al, 2021; Sengupta et al, 2021), with human immune cell counts and inflammatory markers showing daytime variation (Wyse et al, 2021). Circadian parameters such as the time of day of vaccine administration may influence vaccine-induced immune response.…”

Melatonin and REGN-CoV2 combination as a vaccine adjuvant for Omicron variant of SARS-CoV-2

“…It is known that cholesterol production in the body peaks at night [ 30 ]. A recent study reported that statin drugs that decrease cholesterol biosynthesis by inhibiting HMGCoA reductase minimize the severe side effects of COVID-19 [ 31 ]. As a result of this study, it was observed that nighttime administration of the same dose of statins significantly reduced cholesterol levels in COVID-19 patients compared to the morning test group.…”