key: cord-259691-3bo4md44 authors: Zhao, Ming title: Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies date: 2020-04-16 journal: Int J Antimicrob Agents DOI: 10.1016/j.ijantimicag.2020.105982 sha: doc_id: 259691 cord_uid: 3bo4md44 • Discussion of the role of immunomodulatory agents to reduce the cytokine storm in severe cases of COVID-19. • Potential immunomodulatory agents currently used in the treatment of COVID-19 (chloroquine, hydroxychloroquine and tocilizumab) are discussed. • Other immunomodulatory agents with good safety profiles may be considered for use in combination with antiviral drugs for the treatment of severe or critical cases of COVID-19. required to have a significant impact on clinical outcome. Immunomodulatory therapy to down-regulate the cytokine storm may provide insights into the treatment of COVID-19. Combined use of an immunomodulatory agentto reduce the cytokine stormwith an antiviral agent may give physicians more time to provide supportive treatment for patients with Corticosteroids are among the most commonly used drugs for immunomodulatory therapy of infectious diseases. However, the use of corticosteroids in the treatment of COVID-19 can cause host immune suppression and delay viral clearance. Recent study results have provided information to help handle this dilemma. A study at Xi'an Jiaotong-Liverpool University found that the use of corticosteroids did not influence viral clearance time, length of hospital stay or duration of symptoms in patients with mild COVID-19 [5] . This study, which included 201 patients with COVID-19, found that treatment with methylprednisolone decreased the risk of death (hazard ratio 0.38, 95% confidence interval 0.20-0.72) among patients with acute respiratory distress syndrome (ARDS). Based on these findings, the use of corticosteroids is considered beneficial in severe cases of COVID-19 (especially in partients with ARDS), but not in mild cases [6] . According to treatment experiences in China, cautious use of corticosteroids is only recommended in certain critically ill patients (e.g. those with hypoxaemia) at low-to-moderate doses (no more than 1-2 mg/kg/day methylprednisolone or equivalent) for a short duration (3-5 days), as stated in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). issued by the National Health Commission of China [7] . Recently, chloroquine and its derivative hydroxychloroquine have been used in the treatment of COVID-19. In February 2020, results from more than 100 Chinese patients with COVID-19 showed that chloroquine phosphate had good efficacy [8] . French doctors conducted an open-label non-randomized clinical trial, and 20 patients with COVID-19 who received hydroxychloroquine treatment showed good efficacy [9] . Both chloroquine and hydroxychloroquine are weak bases and are able to accumulate in acidic organelles (e.g. lysosomes); as such, they can increase endosomal/lysosomal pH and inhibit viral replication [10] . In addition to their antimalarial and antiviral effects, their anti-inflammatory properties have been demonstrated in the treatment of autoimmune diseases such as rheumatoid arthritis and lupus erythematosus. Chloroquine and hydroxychloroquine can inhibit major histocompatibility complex class II expression, antigen presentation and immune activation (reducing CD154 expression by T cells) via Toll-like receptor signalling and cGAS stimulation of interferon genes [11] . Thus, chloroquine and hydroxychloroquine can reduce the production of various pro-inflammatory cytokines, such as IL-1, IL-6, interferon-α and tumour necrosis factor, which are involved in the cytokine storm [11] . These immunomodulatory effects synergize their antiviral effects in the treatment of COVID-19. Immunomodulatory agents that directly target the key cytokines involved in COVID-19 may also help to alleviate hyperinflammation symptoms in severe cases [12] . Elevated levels of the inflammatory indicator IL-6 in the blood have been reported to be predictive of a fatal outcome in patients with COVID-19 [13] . Tocilizumab, a specific monoclonal antibody that blocks IL-6, has been recommended for use in severe or critically ill patients with extensive lesions in bilateral lungs and a confirmed elevated level of IL-6 in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) issued by the National Health Commission of China [7] . A retrospective analysis on 20 severe cases of COVID-10 showed that treatment with tocilizumab led to a reduction in fever and lung lesion opacity, and recovered the percentage of lymphocytes in peripheral blood [14] . IL-6 can bind to transmembrane IL-6 receptors (mIL6R) and soluble IL-6 receptors (sIL-6R), and the resulting complex can combine with signal transducing component gp130 to activate the inflammatory response. Tocilizumab can bind specifically to sIL-6R and mIL-6R, and block signal transduction [15] . Tocilizumab is a good therapeutic option for cytokine release syndrome in chimeric antigen receptor T-cell immunotherapy. However, clinical experience with tocilizumab in viral disease is very limited. In a retrospective study on patients with juvenile idiopathic arthritis infected with influenza A, reduced fever and a reduced level of C-reactive protein were observed in patients who received tocilizumab compared with patients who did not receive tocilizumab [16] . Meanwhile, IL-6 inhibition by tocilizumab did not exacerbate or increase susceptibility to influenza virus infection [16] . However, there are well documented warnings on increased risk of opportunistic infections (including tuberculosis, fungal or other viral infections) caused by anti-IL-6 monoclonal antibodies during the treatment of rheumatoid arthritis [17] . High costs and safety risks may be a barrier for the wide use of tocilizumab in the treatment of COVID-19. In early March 2020, Chinese clinicians investigated the use of other immunomodulatory agents, such as ulinastatin, for treatment of the cytokine storm for COVID-19 [18] . Ulinastatin is a serine protease inhibitor with anti-inflammatory properties (including inhibition of IL-6), and it has been used in the treatment of acute pancreatitis and sepsis in Japan and China [19] . Expert consensus from Shanghai was that ulinastatin is recommended in patients with exacerbated lung lesions [18] . Overall, certain immunomodulatory agents with good safety profiles may be considered for use in combination with antiviral drugs for the treatment of severe or critical cases of COVID-19. Competing interests: None declared. Ethical approval: Not required. This article has been edited extensivelyplease check the proof carefully to ensure that your meaning has not been altered Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Pathological findings of COVID-19 associated with acute respiratory distress syndrome A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 Impact of corticosteroid treatment in patients with coronavirus disease 2019 Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China National Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7) Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology COVID-19: consider cytokine storm syndromes and immunosuppression Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Effective treatment of severe COVID-19 patients with tocilizumab Immunotherapeutic implications of IL-6 blockade for cytokine storm Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis Comprehensive treatment and management of corona virus disease 2019: expert consensus statement from Shanghai Effect of ulinastatin on interleukins and pulmonary function in bypass patients: a meta-analysis of randomized controlled trials