Introduction
The 2019 coronavirus disease (COVID-19) is caused by severe acute
respiratory syndrome-associated coronavirus type-2 (SARS-CoV-2)
infection. In the first year of its appearance, COVID-19 has affected
more than 120 million individuals and killed 2 million people worldwide.
In some countries, the numbers are still soaring, while in some of the
others, the cases are resurging, entering the second and third waves.
Such increase could be attributed to several determinants, including the
emergence of novel SARS-CoV-2 variants (e.g., N501Y, E484K, B117),
psychological exhaustions (pandemic fatigue) altering the adherence to
health protocols, viral reinfection, vaccination delay and the
non-existence of potent pharmacological treatments for COVID-19. In most
of the contracted patients, COVID-19 is asymptomatic or only causes mild
to moderate non-life-threatening symptoms. However, in high-risk
individuals, it can cause serious conditions, leading to severe acute
respiratory failure, multiorgan dysfunction and death. Therefore, having
safe and effective pharmacological agents for COVID-19 is essential to
prevent mortality and COVID-19-associated complications (e.g., long
COVID).
The pandemic has triggered numerous global initiatives to tackle the
newly emerging disease, including the development of SARS-CoV-2 vaccines
and the attempt to discover potential pharmacological therapies.
Nonetheless, despite the success of SARS-CoV-2 vaccines development, the
COVID-19 therapy remains challenging. Several repurposed drugs that were
documented to be useful in small clinical trials were ineffective in
larger studies. For example, the antimalarial drug chloroquine and
antimicrobial azithromycin were effective in reducing
COVID-19-associated mortality in 2541 multi-centre patients (Arshad et
al., 2020). However, in a meta-analysis, the chloroquine and
azithromycin-treated group displayed no significant difference in
mortality compared to standard care (Ghazy et al., 2020). Moreover,
those drugs were associated with greater adverse effects, including the
occurrence of malignant arrhythmias (Sutanto & Heijman, 2020).
Similarly, the use of human immunodeficiency virus (HIV) protease
inhibitors ritonavir/lopinavir was no longer recommended following
studies reporting no benefit compared to standard care (Cao et al.,
2020; Group, 2020). Meanwhile, inconclusive findings were documented for
antiparasitic ivermectin (Lopez-Medina et al., 2021; Rajter, Sherman,
Fatteh, Vogel, Sacks & Rajter, 2021) and antiviral favipiravir (Cai et
al., 2020; Solaymani-Dodaran et al., 2021). To date, only antiviral
remdesivir was shown to facilitate significant clinical improvements and
has been authorised for COVID-19 by major drug safety regulators (Beigel
et al., 2020; Garibaldi et al., 2021).
Likewise, the pathophysiology and key determinants of the disease have
not been fully elucidated. Several evidences pointed toward the strong
involvement of proinflammatory mediators, with clear evidences of
cytokine storm, which is essential to induce multiorgan dysfunction,
worsening the prognosis of COVID-19 (Tang, Liu, Zhang, Xu, Ji & Wen,
2020). Therefore, immunosuppression could potentially be beneficial in
the COVID-19 management. However, previous systematic review reported
that immunocompromised patients with COVID-19 had higher comorbidities,
rates of intensive care and hospital mortality (Belsky, Tullius, Lamb,
Sayegh, Stanek & Auletta, 2021), indicating the potential risk of
immunosuppression in COVID-19. Thus, in this narrative review, we
explore the documented effects of immunosuppressive medications (e.g.,
corticosteroids, interleukin (IL)-1 inhibitors, IL-6 inhibitors and
kinase inhibitors) and immunomodulators (e.g., interferon alpha (IFNα),
interferon beta (IFNβ), non-SARS-CoV-2 specific immunoglobulin and
convalescent plasma) in COVID-19, and propose some potential immunologic
targets to test in the foreseeable future (Figure 1 ).