Abstract:
COVID-19, the disease resulting from infection by a novel coronavirus:
SARS-Cov2 that has rapidly spread since November 2019 leading to a
global pandemic. SARS-Cov2 has infected over 2.8 million people and
caused over 180,000 deaths worldwide. Although most cases are mild, a
subset of patients develop a severe and atypical presentation of Acute
Respiratory Distress Syndrome (ARDS) that is characterised by a cytokine
release storm (CRS). Paradoxically, treatment with anti-inflammatory
agents and immune regulators has been associated with worsening of ARDS.
We hypothesize that the intrinsic circadian clock of the lung and the
immune system may regulate individual components of CRS and thus
chronotherapy may be used to effectively manage ARDS in COVID-19
patients.
Since December 2019, SARS-Cov2 has spread rapidly leading to a global
pandemic of COVID-19 (Guo et al., 2020). Although COVID-19 is mild in
the majority of cases, a subset of patients quickly develop acute
respiratory distress syndrome (ARDS), a clinical presentation of acute
lung injury (ALI), that leads to respiratory failure requiring
mechanical ventilation (Fung, Yuen, Ye, Chan & Jin, 2020). This
unprecedented crisis is equal only in magnitude to the 1918 influenza
pandemic (Taubenberger & Morens, 2006). Regrettably, despite important
medical and technological advancements since then, our approach to
treating patients with acute lung injury following influenza or
SARS-Cov2 infection remain palliative at best, with no proven
pharmacological therapies (Mehta, McAuley, Brown, Sanchez, Tattersall &
Manson, 2020).
A central challenge for the development of therapies that target ARDS is
the myriad of pro-inflammatory mediators that are released during ARDS
(Conti et al., 2020). This response in COVID-19-induced ARDS has been
termed as a cytokine release storm (CRS) (Mehta, McAuley, Brown,
Sanchez, Tattersall & Manson, 2020; Ruan, Yang, Wang, Jiang & Song,
2020). The CRS seen in severe cases of COVID-19 include high numbers
neutrophils and low levels of lymphocytes, as well as elevated serum
levels of IL-1β, IL-2, IL-6, IL-8, IL-9, IL-10, IL-17, G-CSF, GM-CSF,
IFNγ, TNFα, IP10, and MCP1 (Huang et al., 2020; Ruan, Yang, Wang, Jiang
& Song, 2020). Thus, understanding the mechanisms that modulate the
release of these pro-inflammatory mediators in ALI is paramount to
developing effective strategies to treat ARDS.
There is an outstanding paradox that COVID-19 causes a CRS that is
associated with increased lethality. Yet, reports suggest that
anti-inflammatory drugs such as ibuprofen could aggravate the
progression of disease. Further, recent studies in respiratory
infections have shown that while anti-inflammatory agents could
alleviate symptoms, they can also promote increased viral shedding
(Walsh et al., 2016). Even though this possibility has not been
confirmed with COVID-19, it is very plausible that this is the reason
why NSAIDS could be detrimental. In this sense, ideal management of
COVID-19 would entail a reduction of harmful inflammatory mediators that
damage the host but maintain expression of key mediators that target the
virus.
An emerging venue of therapeutic development impinges on the circadian
clock, the biological timer that has been shown to control the rhythmic
expression and release of many cytokines in inflammatory settings
(Labrecque & Cermakian, 2015; Thompson, Walmsley & Whyte, 2014).
However, despite the known effects of the circadian clock in lung
diseases such as asthma (Clark, 1987), how the circadian clock
influences the progression of ALI remains largely unknown.
Studying the circadian rhythm of lung injury secondary to ventilation
therapy (Ventilator induced lung injury, VILI) is a current concern for
COVID-19. Circadian rhythm disruption was seen in a rat model of VILI
with high and low tidal volumes by studying the expression of Bmal1,
clock, Per2 and REV-ERBα mRNA expression. REV-ERBα was found to have an
important role in VILI and inflammation. That is, circadian rhythm
disorder in inflammation response may be a novel pathogenesis of
VILI.(Li, Wang, Hu & Tan, 2013) Club cells have been also found to have
a role in lungs circadian rhythm. Selective ablation of these cells
resulted in the loss of circadian rhythm in lung slices, further
demonstrating the importance of this cell type in maintaining pulmonary
circadian rhythm in one murine and human lung tissue study (Gibbs et
al., 2009) .
The immune system displays circadian rhythms, for instance at the
beginning of daily activity there is increased expression of
pro-inflammatory mediators such as interleukin(IL)-1β, IL-6, IL-12,TLR9
and TLR4, CCL2, CXCL1, CCL5, as well as macrophage and leukocyte
activity, which leads to potential damage in injured tissues. By
contrast, anti-inflammatory mediators and other growth or angiogenesis
factors, such as the vascular endothelial growth factor (VEGF), peak
during the resting phase (Curtis, Bellet, Sassone-Corsi & O’Neill,
2014; Koyanagi et al., 2003; Liu et al., 2006; Nakamura et al., 2016;
Scheiermann, Gibbs, Ince & Loudon, 2018; Vgontzas, Bixler, Lin, Prolo,
Trakada & Chrousos, 2005). Moreover, both CD8 and CD4 T cells cytotoxic
activity against viral antigens reach the highest levels during the
resting phase (Bollinger et al., 2011; Nobis, Laramée, Kervezee, De
Sousa, Labrecque & Cermakian, 2019) while the cytotoxic activity of
natural killer (NK) cells was most severe at the beginning of the active
part of the day (Logan et al., 2012).
The lungs also have an intrinsic circadian clock which plays a key role
in inflammation and leukocyte migration in the lungs, as well as in many
lung diseases including viral pneumonia (Nosal, Ehlers & Haspel, 2019;
Sundar, Yao, Sellix & Rahman, 2015).
Circadian rhythms in viral respiratory illness have been so far examined
in mice for parainfluenza and influenza A viruses (IAV), which cause
bronchiolitis, and pneumonia in humans respectively. With either virus,
acute inflammatory responses, but not the peak viral load, vary with the
time of inoculation in wild-type mice (Ehlers et al., 2018; Sengupta et
al., 2019). Similarly, deletion of the clock gene Bmal1 worsens
acute lung injury and lung inflammation in response to parainfluenza or
IAV, suggesting that circadian clocks may play a role (immunologic or
otherwise) in the resolution of viral pneumonia. Additionally, there is
strong evidence from animal models that the circadian regulation within
the lung is important in the likelihood of developing chronic lung
disease such as pulmonary fibrosis in the aftermath of the infections.
The time of the day in which a viral infection occurs affects the
survival. For instance infections at the beginning of the activity phase
are more fatal than infections that occur at the beginning of the
resting phase (Sengupta et al., 2019). Evidence indicates an important
role of the circadian rhythm of NK cells underlying this temporal
pattern.
Due to circadian variations of the immune system and the lungs, the
effect of immune modulators and anti-inflammatory agents on the activity
of cells and cytokines in injured tissues also depend on the time of the
day in which these medications are taken (Al-Waeli et al., 2020). It is
plausible that a proper circadian timing of anti-inflammatory drugs
(chronotherapy) can target the detrimental inflammatory cascade in
COVID- 19 patients without interfering with the fight of the immune
system against the virus. For instance, the circadian time of drug
administration will differentially affect various cytokines involved in
viral immunity and COVID-19, including among others IP10, IL-1b, IL-4 ,
IL-8, IL-10, TCR, INF-α, CIITA, TNF-α, and TLR as well as the activity
of T cells (CD8), NK cells, and B cells (Al-Waeli et al., 2020; Canan et
al., 2014).
Based on the known circadian peak (point of culmination of an
oscillatory function) and circadian through (lowest value of an
oscillatory function) for known detrimental (Table 1 ) or
beneficial (Table 2 ) inflammatory mediators identified in
COVID-19 patients, treatment could be optimized for chronotherapy.
Hereby, adjusting the timing of the day in which the medications are
given to result in highest drug levels at the time point when
detrimental inflammatory mediators reach their Peak (Figure 1 ).
This would mean that afternoon is the preferred time window for drug
administration whereas nighttime intake should be avoided.
Table 1. Detrimental inflammatory mediators in the cytokine release
storm (CRS) in COVID19 (RED).