Review on therapeutic targets for COVID-19: insights from cytokine storm

Abstract

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been caused the greatest pandemic of our century. Many of the deaths related to it are due to a systemic inflammatory response, which has been called ‘cytokine storm’. Objectives We developed a comprehensive review of the pathophysiology mechanisms of COVID-19 and of the rationale for drugs and therapeutics that have been tested in clinical trials. Methods A narrative review of the literature was conducted using PubMed, SciELO, Bireme, Google Scholar and ClinicalTrials. Results SARS-CoV-2 has evolutive mechanisms that made it spread all around the globe, as a higher latency period and a lesser lethality than other coronaviruses. SARS-CoV-2 causes a delay in the innate immune response and it disarranges the immune system leading to an overwhelming inflammatory reaction (the ‘cytokine storm’). In this scenario, high levels of interleukins (IL), notably IL-6 and IL-1, create a positive feedback of chemokines and immune responses, and powers pulmonary and systemic tissue damage, leading to capillary leakage and SARS, the main cause of death in patients with COVID-19. On 17 July 2020, there were 1450 entries on ClinicalTrials.gov of ongoing studies on COVID-19. The mechanisms of the main therapeutic approaches were comprehensively reviewed throughout the text. Therapies focus on blocking viral entry (remdesivir, umifenovir, among others) and blocking of immune system for cytokine storm control (IL-1 and IL-6 inhibitors, glucocorticoids, convalescent plasma, among others). Conclusions Understanding of action mechanisms of SARS-CoV-2 enables us to direct efforts on effective therapeutic targets. This comprehensive review helps to interpret the clinical results of the several trials ongoing.

Caspase-4/11 exacerbates disease severity in SARS–CoV-2 infection by promoting inflammation and immunothrombosis

“…However, the contribution of these pathogen-sensing pathways and other inflammasome components in mediating host defense versus immune-mediated pathology and thrombosis during SARS–CoV-2 infection in vivo remains unclear ( 7 ). While effector molecules downstream of infection-sensing pathways, such as specific inflammatory cytokines, have been targeted in attempts to limit virus-induced tissue damage, most of these strategies failed to exert major benefits in human clinical trials ( 8 ). Therefore, strategies targeting molecules upstream of multiple inflammatory cytokines or chemokines may be more effective, though this remains to be experimentally tested.…”

“…Once cleaved, the GSDMD N-terminal fragment inserts into the plasma membrane of eukaryotic cells to form pores that allow the release of IL-1β and other molecules and that can lead to cell lysis and death, known as pyroptosis ( 12 ). Interestingly, roles for GSDMD downstream of caspases have been posited to mediate inflammatory pathology during SARS–CoV-2 infection ( 13 ), though clinical trials testing inhibitors of GSDMD in COVID-19 patients were not promising ( 8 ) and SARS–CoV-2 infection studies in GSDMD genetically deficient animal models have not yet been performed. Likewise, the role of CASP4/11 in viral infections has not been explored, despite the induction of these proteins by the antiviral type I and II IFNs ( 8 ).…”

“…Interestingly, roles for GSDMD downstream of caspases have been posited to mediate inflammatory pathology during SARS–CoV-2 infection ( 13 ), though clinical trials testing inhibitors of GSDMD in COVID-19 patients were not promising ( 8 ) and SARS–CoV-2 infection studies in GSDMD genetically deficient animal models have not yet been performed. Likewise, the role of CASP4/11 in viral infections has not been explored, despite the induction of these proteins by the antiviral type I and II IFNs ( 8 ). This notable induction by IFNs and the broad roles of CASP4/11 in regulating diverse inflammatory pathways ( 10 ) prompted us to investigate its role in SARS–CoV-2 infections.…”

重症COVID–19患者における侵襲的人工呼吸管理中のステロイドの投与終了と28日死亡率の関連の検討，後方視的コホート研究(Association between corticosteroid treatment termination during invasive mechanical ventilation and 28–day mortality in severe COVID–19 patients, a retrospective cohort study)

“…本研究でステロイドを投与終了したほうが予後不良であった理由として，重症COVID–19患者で生じる過剰な免疫反応の抑制がステロイドの10日間の投与では困難であった可能性がある。COVID–19患者の重症化には過剰な免疫反応が関与しているとされ 8) ，その抑制にステロイドの投与は有効であるとされる 9) 。ステロイドは人工呼吸管理を要するような患者でとくに効果的であるとされること 1) や，CRPが高値であった患者でより効果的であったとする報告があること 10) から，重症度の高い患者や炎症が高度である患者ほど効果的であることが予想される。本研究の対象者は重症COVID–19患者の中でも人工呼吸期間の中央値が15日を超えるような臨床的にとくに重症度が高い患者であり，過剰な免疫反応が生じていた可能性は否定できずステロイドの必要性が高かったと考えられる。ステロイドの適切な投与期間に関しては不明な点が多いが，本研究で対象にしたような重症の患者では過剰な免疫反応が遷延していることが予想されステロイドの投与期間は10日間では不足していた可能性が示唆される。…”

Editorial: Tocilizumab, a Humanized Therapeutic IL-6 Receptor (IL-6R) Monoclonal Antibody, and Future Combination Therapies for Severe COVID-19

“…For example, in February 2021, data from the RECOVERY collaboration group controlled clinical trial (NCT04381936) showed that patients who were hospitalized with COVID-19, who were receiving either invasive mechanical ventilation or oxygen and treated with dexamethasone, had a significantly reduced 28-day mortality when compared with patients given usual care [ 8 ]. Dexamethasone reduces systemic inflammation, or the ‘cytokine storm,’ an exaggerated or unregulated immune response associated with excessive release of inflammatory cytokines, resulting in multi-organ damage and increased patient mortality [ 7 ].…”