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

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 dose of acyclovir needed to prevent HSV-2 infection during the active phase was four times more compared to the resting phase in mice. • Corticosteroids are anti-inflammatory drugs that suppress the activation of the immune system, thus prevents cytokine storm.
• Meta-analysis of clinical trials showed that corticosteroids reduced the risk of mortality and the duration of mechanical ventilation in patients suffering from ARDS and COVID-19.

Evidence for chronotherapy
• Elevated levels of pro-inflammatory cytokines throughout the nighttime.
• Full dose anticoagulants when given to moderately ill hospitalized COVID-19 patients, the requirement for vital organ support such as ventilation and ICU was significantly reduced.
• Prophylactic anticoagulation administration did not increase the risk of serious bleeding in COVID-19 patients.

Evidence for chronotherapy
• Hypercoagulatory and hypofibrinolytic conditions are more frequent in the morning because of increased platelet activity and concentration of coagulation factors like Factor V, VII, and prothrombin fragment F1 + 2, and D-dimer.
• Rivaroxaban and Aspirin both have been shown to exert better effects when taken in the evening compared to the morning. • The anti-arrhythmic drug, amiodarone prevents the fusion of the viral envelop with the endosomal membrane and accumulates in late endosomes/ lysosomes, and disrupts the viral endocytic pathway.
• Amiodarone prevents entry of the Filovirus and methyldiethanolamine (metabolite) was able to inhibit Ebola virus entry.
• Amiodarone increased the survival of mice infected with the Ebola virus. • Amiodarone also inhibits other viruses like the Arenavirus, the SARS-CoV-1, and Hepatitis C virus.
• Arrhythmias are common among COVID-19 patients, and it is associated with higher morbidity and mortality.
• Chlorpromazine blocks the formation of clathrin-coated pits and thus prevents viral entry into the cells • Clomiphene blocks the Ebola virus entry by inhibiting the NPC1-dependent pathway, which has been hypothesized to increase cholesterol accumulation in the late endosomes and impair viral entry for SARS-CoV-2

Evidence for chronotherapy
• Prior studies suggest that cardiac arrhythmia peaks mostly between 6:00 am and 12:00 noon. Arrhythmogenesis appeared to be less frequent or suppressed during the nighttime. • A relatively lower dose of chlorpromazine administered at 1:30 was able to show the same sedative effect than when administered at 7:30 (on a 24-hour clock). (Nagayama et al., 1978) Janus-associated Kinase Inhibitor (Baricitinib) • JAK inhibitors can prevent the phosphorylation of proteins that are involved in the signal transduction cascade of the Jak-Stat pathway and thereby reduce cytokine-mediated inflammation and collateral damage in the vital organs.
• Baricitinib significantly reduced the median number of days to recovery, from 18 to 10 days, in hospitalized COVID-19 patients requiring high-flow oxygen or non-invasive ventilation, when used together with remdesivir.
• The need for ventilation support or death was reduced by > 50% (34.9% to 16.9%) using Baricitinib compared to the placebo/control group.
• Baricitinib can successfully inhibit type-1 interferon response (exaggerated in COVID-19 patients) that increases ACE2 expression (in liver cells), the receptor that plays an essential role in the entry of SARS-CoV-2 in host cells to increase the viral load.
• Baricitinib is a potent inhibitor of the Numb-associated kinase (NAK) family of proteins, particularly AAK1, that plays a pivotal role in clathrin-mediated endocytosis, which further prevents viral entry into the cells.

Evidence for chronotherapy
• Studies have shown a peak in IL-6 levels during nighttime and early morning hours. • A better outcome was observed when Baricitinib was administered during the time (evening) when the cytokine production was at the highest. (Yaekura et al., 2020) Drugs that manage comorbidities and pleiotropic effects against SARS-CoV-2 Hyperlipidemia drug (Statins) • Anti-inflammatory effects can block the infectious potential of enveloped viruses (in vitro) and considerably reduce the mortality risk among COVID-19 patients.
• Independently associated with lower ICU admission among COVID-19 patients.
• Reduce hyperlipidemia and decrease cytokine levels with its pleiotropic effects under different non-infectious conditions.

Antihypertensive drugs (ACE inhibitors and ARBs)
• Acute lung damage can be reduced by renin-angiotensinaldosterone system inhibitors.
• Case fatalities are much higher in COVID-19 patients due to pulmonary hypertension. Hypertensive drugs are associated with decreased mortality.

Evidence for chronotherapy
• Blood pressure (BP) is higher during early mornings. Increased nighttime ambulatory BP is related to fatal and non-fatal cardiovascular events.