Immune system modulation in COVID-19

In addition to immunosuppression, several immunomodulators are proposed in COVID-19 management and expected to restore the immunologic homeostasis in COVID-19 patients.
Interferons are cytokines-made and released by host cells in response to viral pathogens. SARS-CoV-2 could release a series of molecular anti-IFN defences to escape innate immunity early during the infection, altering intrinsic IFN’s effect in limiting viral replication and spread (Calabrese, Lenfant & Calabrese, 2020). In a retrospective cohort of 77 adults with moderate COVID-19, treatments using nebulised IFNα-2b yielded a shorter time to viral clearance from the upper respiratory tract and a reduction in systemic inflammation (Zhou et al., 2020). In a randomised controlled trial of 42 patients receiving subcutaneous IFNβ-1a on top of hydroxychloroquine/lopinavir/ritonavir or atazanavir/ritonavir therapies, IFNβ-1a significantly increased discharge rate at day-14 and reduced 28-day mortality (Davoudi-Monfared et al., 2020). Nonetheless, despite these promising results, more data investigating the effects of IFN are required due to an increasing evidence that patients with severe COVID-19 have a robust type-I IFN response, in contrasts with the delayed, possibly suppressed, IFN response in the early phase of SARS-CoV-2 infection (Lee & Shin, 2020).
Non-SARS-CoV-2 specific intravenous immunoglobulin (IVIg) is a product derived from the pooled plasma of donors that provides passive immunity against a broad range of pathogens and commonly used for treatment of primary and secondary immunodeficiencies, autoimmune/inflammatory conditions, neuro-immunologic disorders, and infection-related sequelae (Nguyen, Habiballah, Platt, Geha, Chou & McDonald, 2020). In autoimmune diseases, IVIg modulates the activation and effector functions of B and T lymphocytes, neutralises pathogenic autoantibodies, interferes with antigen presentation and therefore, has a strong anti-inflammatory effect (Bayry et al., 2003). In COVID-19, although the exact mechanism of action is unclear, it is hypothesised that IVIg exerts its beneficial effect through the modulation of inflammation, including the presence of anti-idiotypic antibodies and IgG dimers blocking the FcγR activation on innate immune effector cells (Nguyen, Habiballah, Platt, Geha, Chou & McDonald, 2020), complement scavenging, and reciprocal regulation of effector Th1, Th17 and regulatory T-cells. Moreover, IVIg also decreased plasma IL-6 and CRP levels (Galeotti, Kaveri & Bayry, 2020). A double-blind randomised placebo-controlled trial involving 59 patients with severe COVID-19 who did not respond to initial treatments reported an improvement of clinical outcome and a reduction in mortality following the administration of IVIg (Gharebaghi, Nejadrahim, Mousavi, Sadat-Ebrahimi & Hajizadeh, 2020). Similarly, several retrospective studies also reported the benefits of early IVIg in reducing the 28-day and 60-day mortality, hospital stay, inflammatory response, and improving multiorgan physiology and clinical outcome of severe COVID-19 patients (Galeotti, Kaveri & Bayry, 2020), which effects are more prominent with those having no comorbidities or treated at earlier stage (Cao et al., 2021).
Hyperimmune globulin and convalescent plasma are derived from individuals with high antibody titres to specific pathogens and can provide passive immunity (i.e., neutralising antibodies) against particular infectious agents. It was effective in treating SARS-CoV-1 and MERS-CoV infections by increasing the discharge rate and lowering mortality (Nguyen, Habiballah, Platt, Geha, Chou & McDonald, 2020). In a retrospective, propensity score-matched case-control study in 39 patients with severe or life-threatening COVID-19, convalescent plasma reduced the oxygen requirements at day-14 after transfusion and improved survivals (Liu et al., 2020). Interestingly, such observation was not documented in randomised control trials (RCTs). For instance, a meta-analysis of 10 RCTs reported that the treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes (Janiaud et al., 2021). Since the majority of the RCTs also involved moderate to severe COVID-19 patients, this finding discrepancy might not be due to the difference on the disease severity.