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.