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).