Cytokine-Directed Therapy in COVID-19

Recombinant IFN as an Antiviral Treatment
One of the first defenses of the human body against RNA viruses like SARS-CoV-2 is the release of types I and III IFNs. It is important to note that type I IFN (IFNα/β) receptors are ubiquitously expressed, so IFNα/β signaling can result in not only antiviral effects, but also the activation of immune cells that potentially exacerbate pathogenesis. In contrast, type III IFN (also known as IFNλ) signals mainly in epithelial cells, as well as in a restricted pool of immune cells. Because type III IFNs have immunomodulatory functions, subsequent signaling could induce a potent antiviral effect without enhancing pathogenic inflammation (Andreakos et al., 2017, Prokunina-Olsson et al., 2020).
Recently, there has been a growing interest in the potential therapeutic impact of modulating the IFN response to disable COVID-19 pathogenesis. Before the current pandemic, groups have studied the role of IFNs in other betacoronavirus infections. One study of 40 patients with SARS-CoV-1 infection described unresolved elevated type I IFNs and ISGs in those with poor outcomes (Cameron et al., 2007). Others report that exogenous type I IFN does not improve outcomes when given with ribavirin in patients with MERS-CoV infection (Arabi et al., 2020), suggesting that the role of IFN as a therapeutic or prophylactic option may be strain or species specific (Sheahan et al., 2020). Interestingly, a recent study by Mount Sinai virology groups revealed that type I IFN signaling is impaired in the early response to SARS-CoV-2; in vitro, SARS-CoV-2 may be more susceptible to type I IFN than SARS-CoV-1 is (Blanco-Melo et al., 2020). Based on additional evidence that IFN responses to betacoronaviruses are altered as compared to other respiratory viruses (Blanco-Melo et al., 2020, Channappanavar et al., 2016, Okabayashi et al., 2006), trials of IFN-I/III administration have been initiated (NCT04343976, NCT04331899).

Cytokine Blockade
Hyperinflammatory responses and elevated levels of inflammatory cytokines, including IL-6, -8, and -10, have been shown to correlate with COVID-19 severity (Chen et al., 2020h, Diao et al., 2020, Gong et al., 2020, Moore and June, 2020, Wan et al., 2020a, Xu et al., 2020b). The drivers of this cytokine storm remain to be established, but they are likely triggered initially by a combination of viral PAMPs and host danger signals. The heterogeneous response between patients suggests other factors are involved, possibly including the SARS-CoV-2 receptor, ACE2 (Hirano and Murakami, 2020).
Several studies have begun to report the cellular programs that may contribute to the cytokine storm detected in COVID-19 patients. One group reported that in the context of generalized lymphopenia, certain subsets of CD4 T cells that express GM-CSF and IL-6 are more abundant in severe COVID-19 patients than in COVID-19 patients who do not require intensive care (Zhou et al., 2020b). Reports that other major proinflammatory cytokines (TNF-α, IFN-ɣ, IL-2) and chemokines (CCL2, CCL3, CCL4) are elevated underscore a potentially pathogenic TH1/2 program in COVID-19 (Diao et al., 2020, Giamarellos-Bourboulis et al., 2020). Histological and single-cell analyses identified monocytes and macrophages as other potent sources of inflammatory cytokines in COVID-19 cytokine storm (Chen et al., 2020h, Giamarellos-Bourboulis et al., 2020, Law et al., 2005, Moore and June, 2020, Zhou et al., 2020b). Studies of other betacoronavirus infections, including SARS-CoV-1 and MERS-CoV, have also identified similar hyperactivation of monocytes, macrophages, and DCs as a driver of cytokine-mediated immunopathology in humans (Cheung et al., 2005, Chien et al., 2006, Huang et al., 2020c, Konig et al., 2020, Wang et al., 2005, Wong et al., 2004, Xu et al., 2020b, Zhou et al., 2020b).
Following preliminary reports of IL-6 as a critical cytokine in COVID-19-associated CRS, monoclonal antibodies that target the IL-6 signaling pathway have been proposed as therapeutic candidates (Moore and June, 2020) (Figure 6C). The commercial anti-IL-6R antibodies tocilizumab (Actemra) and sarilumab (Kevzara) and the anti-IL-6 antibody siltuximab (Sylvant) are now being tested for efficacy in managing COVID-19 CRS and pneumonia in 13 ongoing clinical trials (Table 2 ). To date, only one group has reported preliminary results from a cohort of 20 COVID-19 patients treated with a single administration of tocilizumab (400 mg, i.v.), along with lopinavir, methylprednisolone, and oxygen therapy (ChiCTR2000029765) (Xu et al., 2020b). The single observation study found recuperated lymphocyte counts in 10 of 19 patients and resolution of lung opacities in 19 of 20 patients on chest CT; 19 of 20 patients were discharged. All patients experienced an improvement in symptoms, and no subsequent pulmonary infections were reported. A second report described an association between use of tocilizumab and reduced likelihood of ICU admission and mechanical ventilation. Still, in 30 declining patients with severe COVID-19 pneumonia, this retrospective study did not report significant improvement in mortality on weighted analysis (Roumier et al., 2020). Nevertheless, these studies are encouraging, but like other treatment approaches, larger RCTs are needed.
Table 2 Clinical Trials Evaluating the Efficacy of IL-6/IL-6R Blockade Therapy
Clinical Trial Intervention
NCT04331795 (COVIDOSE)NCT04320615 (COVACTA)NCT04332913 (TOSCA)NCT04317092 (TOCOVID-19)NCT04335071 (CORON-ACT)NCT04315480ChiCTR2000029765 tocilizumab
NCT04315298 sarilumab
NCT04310228 tocilizumabfavipiravir
NCT04306705 (TACOS) tocilizumabcontinuous renal replacement therapystandard of care
NCT04332094 (TOCOVID) tocilizumabazithromycinhydroxychloroquine
NCT04341870 (CORIMUNO-VIRO) sarilumabazithromycinhydroxychloroquine
NCT0433z638 (COV-AID) tocilizumabsiltuximabanakinrastandard of care
In addition to the IL-6 signaling pathway, other cytokine- and chemokine-associated elements, including IL-1R, GM-CSF, and the chemokine receptor CCR5, have been proposed as potential targets for blockade to manage COVID-19 CRS (Figure 6C). Finally, complement activation was shown to be overactivated in lungs of COVID-19 patients. Although results from the randomized trial are not yet published, anti-C5a monoclonal antibody therapy showed benefits in two critically ill COVID-19 patients (Gao et al., 2020d).