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 ).