Immunosuppression in
COVID-19
Hyperactivation of immune system is a hallmark of COVID-19 severity.
Ample evidences have reported higher number of leukocytes, increased
levels of procalcitonin, C-reactive protein (CRP), and other
proinflammatory cytokines (e.g., IL-1 and IL-6) / chemokines (e.g.,
CXCL10 and CCL2) in COVID-19 patients requiring intensive care. Such
hyperactive inflammatory response initiates cytokine storm and may
contribute to the uncontrolled apoptosis, vascular leakage,
thromboembolism, multiorgan damage and death (Tang, Liu, Zhang, Xu, Ji
& Wen, 2020). Therefore, immunosuppression has been proposed as a
potential therapeutic strategy in COVID-19.
Corticosteroids have a potent anti-inflammatory effect
and are currently used to treat dysregulated inflammatory response in
autoimmune diseases. In COVID-19, inhaled corticosteroid ciclesonide
inhibited SARS-CoV-2 RNA replication by targeting viral
replication-transcription complex (Matsuyama et al., 2020). Despite the
failure of corticosteroids to show significant benefits and their
association with delayed viral clearance in previous coronavirus
(SARS-CoV-1 and MERS-CoV) diseases, studies investigating the effects of
corticosteroids in COVID-19 showed several promising results
(Chatterjee, Wu, Bhardwaj & Siuba, 2020). For example,
methylprednisolone lowered COVID-19-associated mortality in patients
with acute respiratory distress syndrome and reduced the duration of
supplemental oxygen in COVID-19 patients (Chatterjee, Wu, Bhardwaj &
Siuba, 2020). More recently, Randomised Evaluation of COVID-19 Therapy
(RECOVERY) trial, a randomised controlled, open-label trial involving
2104 patients with oral or intravenous dexamethasone reported that
dexamethasone lowered the 28-day mortality among patients receiving
invasive mechanical ventilation and among those receiving oxygen without
invasive mechanical ventilation, but not among those who were receiving
no respiratory support at randomisation (Group et al., 2021). In adult
patients with non-severe COVID-19, corticosteroids therapy was
associated with worse clinical outcomes (Li et al., 2020) and a higher
risk of progression of severity and prolonged hospital stay (Chatterjee,
Wu, Bhardwaj & Siuba, 2020). Additionally, a recent retrospective study
reported that delayed SARS-CoV-2 clearance in moderate/severe COVID-19
was not associated with an early use of corticosteroids (Spagnuolo et
al., 2020), highlighting the potential benefits of corticosteroids in
the treatment of moderate/severe COVID-19 patients.
Interleukin inhibitors are commonly prescribed in
autoimmune diseases and other hyperinflammatory states. Several
interleukins are responsible for COVID-19-mediated cytokine storm (e.g.,
IL-1β, IL-6 and IL-18) and their inhibition could be beneficial. A
cohort of 117 patients with respiratory insufficiency and
hyperinflammation receiving either IL-1 or IL-6 inhibitors reported that
IL-1 inhibition (with anakinra) significantly reduced mortality in
COVID-19 patients with respiratory insufficiency and hyperinflammation.
Meanwhile, IL-6 inhibition (with tocilizumab or sarilumab) was only
effective in a subgroup of patients with high CRP or low lactate
dehydrogenase (Cavalli et al., 2021). Additionally, IL-6 inhibitors also
improved survivals in critically-ill COVID-19 patients receiving
intensive organ support (Investigators et al., 2021). Moreover, in a
meta-analysis of 71 (heterogenous) studies, tocilizumab was consistently
associated with a lower relative risk of mortality in prospective
studies, but effects were inconclusive for other outcomes (Khan et al.,
2021), underlining the prospective benefits of interleukin inhibition in
COVID-19.
Kinase inhibitors inhibit numerous kinases (e.g., ABL,
NAK, CDK, PI3K/AKT/mTOR, ERK/MAPK and JAK) that are important for viral
infections and predicted to be involved in mediating infection by
SARS-CoV-2 (Weisberg et al., 2020). They play important roles in viral
entry, intracellular membrane trafficking, viral replication and viral
life cycle, and possess an immunomodulatory effect that could be useful
against COVID-19-mediated hyperactive immune response. However, a recentin-vitro study showed that imatinib, an ABL inhibitor, did not
inhibit SARS-CoV-2 entry/infection and replication (Zhao, Mendenhall &
Deininger, 2020). Meanwhile, baricitinib, a JAK inhibitor, prevented
phosphorylation of key proteins involved in the signal transduction that
leads to immune activation and inflammation (e.g., the cellular response
to IL-6) (Zhang et al., 2020). In a double-blind, randomised,
placebo-controlled trial of 1033 patients, baricitinib/remdesivir was
superior to remdesivir alone in reducing recovery time and accelerating
clinical improvement, and associated with fewer serious adverse events
in COVID-19 patients receiving high-flow oxygen or non-invasive
ventilation (Kalil et al., 2021).