key: cord-1027827-3od9m8gh
authors: Khiali, Sajad; Khani, Elnaz; Entezari‐Maleki, Taher
title: A Comprehensive Review on Tocilizumab in COVID‐19 Acute Respiratory Distress Syndrome
date: 2020-06-18
journal: J Clin Pharmacol
DOI: 10.1002/jcph.1693
sha: 51cf27a74cc6a01dad5dd7f9ad91c7c61e5d9e9a
doc_id: 1027827
cord_uid: 3od9m8gh

Currently, the world is facing the pandemic of a novel strain of beta‐coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Acute respiratory distress syndrome (ARDS) is the most devastating complication of SARS‐CoV‐2. It was indicated that cytokine release syndrome (CRS) and dominantly IL‐6 play a central role in the pathophysiology of ARDS related to the novel 2019 coronavirus disease (COVID‐19). Despite the global emergency of the disease, at this time, there are no proven therapies for the management of the disease. Tocilizumab is a potential recombinant monoclonal antibody against IL‐6 and currently is under investigation for the management of ARDS in patients with COVID‐19. Given these points, we reviewed the current evidence regarding the potential therapeutic role of tocilizumab and its important clinical issues in the treatment of ARDS related to COVID‐19. This article is protected by copyright. All rights reserved

Coronaviruses are a large family of RNA viruses with a widely found in nature. Generally, coronaviruses are animal pathogens, but in humans, six types of coronaviruses were known to cause respiratory tract infections ranged from mild to severe disease. The outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV), in 2012 were two severe types of infections caused by beta-coronaviruses with 11-35% mortality. [1] [2] [3] Late in December 2019, a novel strain of beta-coronavirus was recognized to cause a cluster of cases of acute pneumonia in Wuhan, Hubei province, China. Unlike with SARS-CoV and MERS-CoV, the novel virus has a lower rate of mortality, but a higher rate of transmissibility and infectivity that rapidly spread throughout the globe. The World Health Organization (WHO) declared a pandemic outbreak and named the disease as coronavirus disease 2019 . Along with, the International Committee on Taxonomy of Viruses (ICTV) called the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of writing this manuscript, globally more than 7,410,000 confirmed cases of COVID-19 with more than 418,000 deaths have been reported. [1] [2] [3] Person to person spread is the main route of virus transmission, which occurs by respiratory droplets. Notably, inhaled aerosols are another proposed pathway for transmission of SARS-CoV-2. It is indicated that viable viruses could be detected in aerosols up to 3 hours after aerosolization. Transmission of the virus can take place with the contact of contaminated surfaces or objects with the eyes, nose, and mouth. 4, 5 Classically, the well-known symptoms of COVID-19 include fever, cough, and shortness of breath. A recently pooled meta-analysis of 43 studies involving 3600 patients with COVID-19, showed that the most common clinical manifestation of the disease was fever Sarilumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptor with high affinity and is Food and Drug Administration (FDA) approved for the treatment of Rheumatoid Arthritis (RA). Siltuximab is a chimeric, human-murine immunoglobulin monoclonal bind directly to human IL-6 to neutralize it. The only labeled indication of siltuximab is for the treatment of Castleman disease. Tocilizumab is the first marketed IL-6 blocker that has been widely used in the treatment of patients with inflammatory diseases. Importantly, it is the only monoclonal antibody drug with FDA approval for the treatment of CAR T-cell induced CRS. 1-6, 12, 13 Based on the potential role of tocilizumab in the management of CRS, the main role of IL-6 in CRS, and the marked role of CRS in the pathophysiology of ARDS of SARS-CoV-2, we aimed to review the current evidence concerning to safety and efficacy of the use of tocilizumab in the management of ARDS in the patients with COVID-19.

The SARS-CoV-2 spike glycoprotein (S) binds the host cell surface via angiotensinconverting enzyme-2 (ACE-2) receptor allowing virus cell entry and replication. 14 It is indicated that SARS-CoV-2 recognizes the human ACE-2 receptor more efficiently than SARS-CoV. Moreover, it has a strong binding affinity to the human ACE-2 receptor. 10 Expression of the ACE-2 receptor is found in the heart, kidney, endothelium, and intestine, with a higher ratio in pulmonary tissues. Evaluating normal lung tissue from eight adult donors showed that 83% of ACE-2-expressing cells were alveolar epithelial type II cells.

Accordingly, these cells are a reservoir for SARS-CoV-2 invasion. 15 

The pathological features of SARS-CoV-2 are similar to SARS-CoV and MERS-CoV infections. 21 Furthermore, the envelope proteins (E proteins) involved in the viral assembly of SARS-CoV-2 and SARS-CoV share 95% homology and mediate the host immune reaction to coronaviruses. 22, 23 It is believed that the delayed type-I interferon (INF) response plays a role in the process of SARS-CoV infection. In the initial phase, the virus evades patternrecognition receptors and antagonizes the type-I INF response in the airway and alveolar epithelial cells, which leads to rapid viral replication. However, plasmacytoid dendritic cells and macrophages' response to SARS-CoV leads to a strong but delayed type-I INF response as well as releasing other inflammatory cytokines. The activation of type-I INF signaling cascades attracts neutrophils, inflammatory monocyte-macrophages, dendritic cells, and natural killer (NK) cells to the lung and a cytokine-driven vicious cycle occurs. The uncontrollable proinflammatory cytokines production such as IL-6 leads to diffuse alveolar damage with epithelial and endothelial apoptosis, dysregulated coagulation, and pulmonary fibrinolysis. [24] [25] [26] [27] In some cases of SARS-CoV, it was showed that ARDS can take place independently from viral load suggesting the important role of inherent properties of the host immune system rather than viral virulence on tissue. 1, 5, 28 The SARS-CoV-2 activates the immune system through binding to the alveolar epithelial cells and leads to the release of cytokines, mainly IL-6. Consequently, alveolar-capillary permeability to fluid, proteins, and blood cells is increased and respiratory failure occurs. [29] [30] [31] Evaluating the immune system of patients with COVID-19 showed that activation of abnormal pathogenic T-cells lead to the production of a large number of cytokines importantly IL-6 as well as induction of an inflammatory storm. In addition to IL-6, higher plasma levels of other cytokines including, IL-2, IL-7, IL-10, tumor necrosis factor-α (TNFα), macrophage inflammatory protein-1 alpha (MIP-1α), granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) were observed in intensive care unit (ICU) patients. Furthermore, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) play the key roles in the inflammatory storm, which probably leads to pulmonary fibrosis and organ failure through impairment of gas exchange across the alveolar-capillary membrane. 10, 11, Analyzing peripheral blood samples indicated that T cells and monocytes in severe/critical COVID-19 patients are significantly lower than healthy patients. Moreover, inflammatory monocyte with CD14+CD16+ phenotype and high IL-6 expression as well as Pathogenic Th1 cells with high expression of GM-CSF and IFN-γ exist in both peripheral blood and biopsy samples at autopsy of COVID-19 patients. Indeed, these inflammatory monocytes and pathogenic T cells stimulate the immune system and cause end-organ damage. 32 Postmortem examination of a patient who died of confirmed infection with COVID-19 demonstrated a bilateral diffuse alveolar damage with cellular fibromyxoid exudates. Besides, mononuclear inflammatory lymphocytes were observed in both lungs. Moreover, the characteristic viral cytopathic changes such as multinucleated syncytial cells with atypical enlarged pneumocytes in the intra-alveolar spaces were observed. 33 Interleukin 6 and cytokine release syndrome IL-6 is a multi-functional cytokine and has an important role in acute inflammation. 34 It has an essential role in the differentiation of B cells and the production of antibodies. 35 IL-6 is a pro-inflammatory regulator of T-cells that induce cytotoxic T-lymphocyte activity, stimulates T-helper 17 cell lineage and function as well as the development of self-reactive proinflammatory CD4 T-cell response, and inhibits the induction of regulatory T-cell stimulate. [36] [37] [38] Also, IL-6 stimulates the differentiation of osteoclasts and angiogenesis. 39 CRS is a severe and life-threatening acute systemic inflammatory syndrome characterized by multi-organ damage and fever that often takes place in the patients received immunotherapy or haploidentical allogeneic hematopoietic cell transplantation and associated with a sharp increase of inflammatory cytokine levels; however, it can occur via viral infections. Clinical manifestations can range from the flu-like syndrome to circulatory collapse, pulmonary edema, hypoxia, peripheral edema, hypotension, and multiorgan system failure. [40] [41] [42] [43] In the pathogenesis of T-cell engaging immunotherapy, released INF-γ by activated T-cells activates macrophages. Afterwards, the activated macrophages releases TNF-α, IL-6, and IL-10. Furthermore, serum levels of IL-8, IL-5, and IL-1 are elevated in CSR and are thought to contribute to its clinical manifestations. TNF-α is associated with flu-like symptoms as well as malaise, fever, diarrhea, lung damage, cardiomyopathy, and vascular leakage. INF-γ is associated with fatigue, dizziness, headache, fever, and chills; and IL-6 is associated cardiomyopathy, activate of the complement and coagulation cascades, cardiomyopathy, and disseminated intravascular coagulation. [44] [45] [46] [47] [48] In the CAR T-cell therapy associated CRS, IL-6 is considered to be a key driver symptom and its levels increase dramatically (more than 100fold). No studies have been carried out to evaluate the effects of tocilizumab for CAR-T associated CRS; however, rapid clinical improvement in several patient cohorts led to rapid FDA approval in August 2017. Also, tocilizumab is used in the treatment of severe CRS due to BiTE therapy. 49, 50 IL-6 plays an important role in the inflammatory storm in patients with COVID-19, and combining antiviral with anti-inflammatory treatments should be considered. 51 as an early indicator of CRS like reactions in COVID-19-infected pneumonia. 72.7% of patients had CRS like characteristics such as fever, pulmonary inflammation, an increase of IL-6, and multi-organ dysfunction. 53 Another study in patients with COVID-19 found that high levels of IL-6 are associated with the severity of pneumonia. 54 Besides, a retrospective multicenter study of 150 patients with COVID-19 pneumonia showed elevated levels of inflammatory factors such as ferritin (p<0.001), and IL-6 (p<0.0001) in the blood are the predictors of the mortality outcome. 55 CAR T-cell induced CRS and role of IL-6 briefly are shown in Figure 1 . showed that early administration of methylprednisolone (0.25 to .5 mg/kg) twice daily for 3 days is associated with clinical outcomes improvement. Indeed, the occurrence of the composite endpoint was significantly lower in the early corticosteroid received group compared to the non-treated group (34.9% vs. 54.3%, p=0.005). Moreover, a single-center retrospective cohort study was done in 463 patients with COVID-19 pneumonia to determine the role of steroids in in-hospital mortality. Results indicated that the survival rate was higher in patients who received glucocorticoids compared to those not received. Furthermore, no statistically significant difference was observed in the mortality rate between the initial regimens of methylprednisolone (1 mg/kg/day) or equivalent and pulses of glucocorticoid. In (Table 1) . 67 The published papers lack a clear analytical approach and show poor methodological quality.

A retrospective, single-center, case series was carried out in 21 Chinese patients with critical (19%) and severe (81%) COVID-19. Critical COVID-19 defined as requiring mechanical ventilation or organ support in ICU. Severe COVID-19 included patients with tachypnea and/or respiratory failure. The mean age of patients was 56.8 ± 16.5 years, and 85.7 % of them were male. The mean level of IL-6 was 132.4 ± 278.5 pg/mL. All patients received standard care including lopinavir, methylprednisolone, other symptom relievers, and oxygen therapy. In addition to standard care, all patients received a single dose of intravenous tocilizumab 400mg, three patients received a second administration of tocilizumab 400mg with 12 hours interval. It is important to mention that seven days before treatment with tocilizumab, all of the patients had received routine treatment; however, no improvement had been observed in symptoms, hypoxemia, and CT images. Results showed immediate improvement of symptoms, CT opacity changes, and hypoxemia after tocilizumab administration. Patients' fever improved completely within 24 hours post-administration.

Radiological improvement in ground-glass opacities took place in 91% of patients. Notably, blood and oxygenation results were reported in 19 patients. Mean C-reactive protein (CRP) level decreased from 75.1 ± 66.8 mg/mL to 2.72 ± 3.6 mg/mL on day 5 after treatment.

Furthermore, oxygen saturations of patients improved statistically significant within five days after treatment. One patient no longer needed supplementary oxygen; 15 had decreased oxygen support; one began the ventilator weaning process, and two were extubated. Finally, 19 patients discharged, and 2 were in a stable condition in the hospital. 68 According to the National Health Commission of China, clinical classification of the COVID-19 is as follow: mild ( slight clinical symptoms but no imaging presentations of pneumonia); moderate (fever, respiratory symptoms and pneumonia performance on chest X-ray or CT); severe (respiratory distress with respiratory rate > 30 times/minutes, or oxygen saturation at rest <93%, or atrial partial pressure of oxygen/fraction of inspiration O2 (PaO2/FiO2) ratio <300 mmHg (1 mmHg=0.133 kPa); critically severe ( respiratory failure needs ventilation, or shock, or combined with other organ failure, patients need intensive care unit monitoring and treatment). 69 Another retrospective, single-center, case series was done in 15 Chinese patients with moderately ill (13.3%), seriously ill (40%), and critically ill (46.7%) COVID-19. The median age of patients was 73 years, with a male majority of 75%. Baseline comorbidities of patients included diabetes mellitus, hypertension, and previous cerebrovascular accident (CVA) in 27%, 60%, and 20%, respectively. All patients were This article is protected by copyright. All rights reserved. administered at least one dose of tocilizumab (80 to 600 mg) of either alone (47%) or in combination with methylprednisolone (53%). Notably, 33% of patients received subsequent doses of tocilizumab. By day seven post-treatment, 67% of patients were clinically stable, 13% had deterioration of their disease, and 20% died. The baseline levels of IL-6 ranged from 16.4 to 627.1 pg/mL. A mild rise of 74.8 pg/mL (-0.8-175.6) in median IL-6 level was observed after tocilizumab administration in ten clinically stabilized patients, while the remaining 5 patients experienced a dramatic rise of 3581.2 pg/mL (591.9-4983.6); however, the CRP levels rapidly, and significantly dropped from 126.9 mg/L (10.7-257.9) to 11.2 mg/L (0.02-113.7) after tocilizumab administration (P < .01). It is in accordance with the fact that CRP is an appropriate surrogate marker for tocilizumab levels and IL-6 bioactivity. 70 A prospective, multi-center, case series was carried out in 63 patients with severe COVID-19.

The mean age of the patients was 62.0 ± 12.5 years (mean ± SD), and 88.8% were male.

Patients with polymerase chain reaction-confirmed COVID-19, pulmonary involvement (oxygen saturation <93% or Pao2 / Fio2 < 300 mm Hg), and at least three of the following Also, the levels of CRP, ferritin, D-dimer, and lymphocyte count improved; however, no significant change in LDH levels was observed. Notably, the mean baseline D-dimer level was predictor of death (HR 5.01; 95%CI 1.04-29.17). Finally, results showed that tocilizumab decreased chance of mortality within six days of treatment (HR 2.2 95%CI 1.3-6.7, p<0.05). 71 A prospective, single-center case series was carried out in 100 patients with severe COVID-19. The median age of patients was 62 years, with a male majority of 82%.

The severity of respiratory disease was evaluated using the Brescia COVID-19 Respiratory Severity Scale (BCRSS). 72 Base on China's National Health Commission recommendation, tocilizumab should be considered for the treatment of patients infected with COVID-19, with elevated IL-6 levels and serious lung damage. 75 The FDA has approved a randomized, double-blinded, placebocontrolled phase 3 trial called COVACTA to evaluate the efficacy and safety of intravenous tocilizumab 8 mg/kg (up to the maximum dose of 800 mg per dose) in patients with COVID-19 pneumonia. In this study, patients are allowed to receive an additional dose based on their clinical conditions. The inclusion criteria are hospitalized patients with COVID-19 pneumonia according to WHO criteria chest X-ray or CT scan. 76 Moreover, the Italian Regulatory Agency (AIFA) has approved a multicenter study to evaluate the efficacy and safety of tocilizumab 8 mg/kg (up to a maximum of 800 mg per dose) in the treatment of COVID-19 pneumonia patients. Patients can receive second administration (same dose) after 12 hours. Notably, the study project includes a parallel observational cohort study, and a single-arm phase 2 study. The inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection, and oxygen saturation ≤93% in ambient air. In addition, patients with intubation less than 24 hours before registration are enrolled in phase 2, and those with intubation more than 24 hours before registration in an observational cohort. Patients are evaluated regarding laboratory data (blood count, bilirubin, aspartate aminotransferase (AST), ALT, creatinine, prothrombin time (PT), partial thromboplastin time (PTT), LDH, Ddimer), atrial blood pressure, 12-lead electrocardiogram, vital signs, SOAF score, radiologic findings, a respiratory assistant during the study period. A one-month mortality rate is the primary endpoint of the study. The secondary endpoints of the study include the duration of hospitalization, evaluation of CRP and IL-6 levels in correlation with treatment outcomes, respiratory symptoms, time to invasive mechanical ventilation, definitive extubation, and independence from oxygen therapy, radiological response, trends of PaO2/FiO2 ratio, SOFA score, and lymphocyte count, and tocilizumab toxicity. The Italian guideline recommended the presence of at least one of the following criteria before tocilizumab administration; IL-6 levels >40 pg/mL (or D-dimer >1000 mg/L), PaO2/FiO2 ratio <300 mmHg, respiratory gas exchange rapid worsening. According to the University of Michigan recommendations, tocilizumab should be considered in COVID-19 patients with abnormalities in chest imaging, rapid worsening of gas exchange requiring >6 L/min O2, laboratory parameters of CRS, need for supplemental O2 to maintain PaO2/FiO2 <300 mmHg or saturations oxygen <92%, and at least two laboratory abnormalities ( lymphocyte count < 600/mm3, D-dimer > 1000 mg/L, ferritin >500 mg/L, LDH >250 units/L, or CRP >100 mg/L or >50 but doubled in past 48 hours). [77] [78] [79] Because immune system antiviral activity is vital to recovering from SARS-CoV-2 infection, the pros and cons of using tocilizumab on these patients should be considered with caution. randomized, placebo-controlled, parallel-group phase III study, 623 patients with RA were randomized to receive intravenously tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) every 4 weeks, with fixed doses of methotrexate. The results showed serious infections, as the most common serious adverse events, were observed in six, three, and two patients, respectively. 82 The tocilizumab safety data was collected from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study. A total of 4,199 patients included patients were categorized based on tocilizumab administration, and dose as follow: resource-limited countries, homelessness should be tested before tocilizumab administration.

Moreover, suspected patients for strongyloides should be treated empirically with ivermectin, if receiving tocilizumab. Furthermore, IL-6 serum level should be measured before the tocilizumab administration. Besides, the Italian guidelines recommended measurement of CRP, D-dimer, and ferritin with or without IL-6 levels before, and after each administration.

Finally, exclusion criteria include hypersensitivity to tocilizumab or its excipients, concomitant immunomodulators or anti-rejection drugs, active infections, platelets <50.000 / mm 3 , neutrophils <500 /mm 3 , ALT or AST > 5 times the upper limit of the normality, bowel diverticulitis or perforation, and other contraindications of tocilizumab. [76] [77] [78] [79] It is important to mention that IL-6 elevation is not an accurate indicator to reflect its functional downstream effects. CRP as a marker of IL-6 bioactivity is synthesized through IL-6-dependent hepatic biosynthesis. 84 Tocilizumab administration increases the serum levels of soluble IL-6 receptor due to the longer elimination half-life of tocilizumab with soluble IL-6 receptor immune complex compared with the soluble IL-6 receptor. In addition, IL-6 level increase after tocilizumab administration through inhibition of IL-6 consumption.

Importantly, it is indicated that the administration of tocilizumab does not increase the production of IL-6. According to the published data in COVID-19, regardless of clinical outcome, the administration of tocilizumab is associated with CRP serum levels reduction.

Conversely, after the administration of tocilizumab, a mild increase of IL-6 serum level was observed in all patients followed by a dramatic increase in patients with disease aggravation or mortality ( Table 3 ).

The disease-related conditions in COVID-19, clinical condition of the patient, and treatment duration may influence the incidence of adverse events. A retrospective analysis of patients with CAR T-cell induced CRS showed no adverse events with tocilizumab, suggesting its safety in both adults and pediatrics. 86 Notably, tocilizumab adverse events were assessed on patients with different demographic and clinical characteristics. As an example, patients in CAR T-cell induced CRS trials were younger than sever COVID-19. To date, no welldesigned clinical trial has been published regarding tocilizumab safety in patients with COVID-19. In the case series by Toniati and colleagues, three severe adverse events were observed during the 10-day follow-up. Among them, two patients died due to septic shock, and one experienced gastrointestinal perforation. In the study by Sciascia et al, the safety of tocilizumab was evaluated as the primary endpoint in patients with severe COVID-19, and no moderate to severe adverse events related to the drug were reported. Also, no adverse reactions were reported in other studies. 68, [70] [71] [72] [73] Finally, drug interactions of tocilizumab should be considered. It may enhance the effects of other immunosuppressants. Importantly, tocilizumab is a cytochrome P450 enzyme inducer and may decrease the serum concentration of cytochrome P450 3A4 substrates. Consequently, it is recommended that rivaroxaban and apixaban should not be used in those receiving tocilizumab. Besides, dose adjustments of warfarin is also recommended in these patients. Notably, warfarin is primary metabolized via cytochrome P450 2C9. The proposed mechanism of action of drug interactions is the effect on decreasing the effect of IL-6 and thus an upregulation of transporters and drug metabolism enzymes. [87] [88] [89] [90] [91] [92] Taken together, according to the limited data, one-or two-times administration of both intravenous and subcutaneous tocilizumab in the mentioned doses is considered to be safe in patients with severe/critical COVID-19; however, the tocilizumab safety data in other conditions should be considered in determining exclusion criteria in the future clinical trials and practice.

This review may include some limitations. First, the treatment of COVID-19 is fluid with the discovery of new knowledge about disease-modifying treatment plans. Next, we reference some documents in pre-print status that are not peer-reviewed at the time of writing this manuscript. So, caution should be used in referencing these documents until the publication.

To date, data about the use of tocilizumab in the treatment of acute lung injury in patients 

The authors have nothing to disclose.

This article is protected by copyright. All rights reserved. 

Review of the 2019 Novel Coronavirus (COVID-19) based on current evidence

World Health Organization. Coronavirus disease 2019(COVID-19) Situation Report-144

WHO Director-General's remarks at the media briefing on 2019-nCoV on 11

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Consideration of the Aerosol Transmission for COVID-19 and Public Health

Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis

COVID-19 Data from the National Center for Health Statistics

Clinical course and outcomes of critically ill patients with SARS-CoV2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

European Patients With Mild to Moderate COVID-19

Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in sever e pulmonary syndrome patients of a new coronavirus

Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients

Cytokine release syndrome (CRS)

Review of siltuximab in the treatment of multicentric

Castleman's disease

Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan COVID-19

Angiotensin-converting enzyme 2 is an essential regulator of heart function

Essential role for collectrin in renal amino acid transport

Multiple organ infection and the pathogenesis of SARS

Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis

The clinical pathology of severe acute respiratory syndrome (SARS): a report from China

Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis

Coronavirus envelope protein: current knowledge

Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoVinfected mice

Chemokine up-regulation in SARS-coronavirusinfected, monocyte-derived human dendritic cells

Lung pathology of fatal severe acute respiratory syndrome

Analysis of serum cytokines in patients with severe acute respiratory syndrome

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense

The micromechanics of lung alveoli: structure and function of surfactant and tissue components

Pulmonary epithelial barrier function: some new players and mechanisms

Why tocilizumab could be an effective treatment for severe COVID-19?

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Interleukin-6 and its receptor: from bench to bedside

Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene

IL-6: a cytokine at the crossroads of autoimmunity

IL-6: regulator of Treg/Th17 balance

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

IL-6 as a keystone cytokine in health and disease

Cytokine release syndrome

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

Cytokine storms in infectious diseases Seminars in immunopathology

Cytokine storm and sepsis disease pathogenesis Seminars in immunopathology

CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia

Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia

Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia

Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function

Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome

Management of cytokine release syndrome related to CAR-T cell therapy

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19: combining antiviral and antiinflammatory treatments

The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis

Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study

How Does COVID-19 Kill? Uncertainty Is Hampering Doctors' Ability to Choose Treatments

COVID-19) Treatment Guidelines

COVID19 Treatment Guidelines by Massachusetts General Hospital

SARSCoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis

Short Course Corticosteroids in Hospitalized Patients with COVID-19

SARS-COV-2 INFECTION MORTALITY: A RETROSPECTIVE CONTROLLED COHORT STUDY (2020)

Activation Syndrome: Reanalysis of a Prior Phase III Trial

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study

Could ferritin help the screening for COVID-19 in hemodialysis patients? Kidney Int

First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab

Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report

Effective treatment of severe COVID-19 patients with tocilizumab

for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 5

Tocilizumab treatment in COVID-19: A single center experience

Pilot Prospective Open, Single-Arm Multicentre Study on Off-Label Use of Tocilizumab in Patients With Severe COVID-19

Tocilizumab for the Treatment of Severe

Pneumonia With Hyperinflammatory Syndrome and Acute Respiratory Failure: A Single Center Study of 100 Patients in

Tocilizumab is associated with reduced risk of ICU admission and mortality in patients with SARS-CoV-2 infection

Systematic review and meta-analysis of predictive symptoms and comorbidities for severe COVID-19 infection

National Health Committee of the People's Republic of China. China's National Health Commission treatment guidelines 7th version

A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA)

Anti-IL6R role in treatment of COVID-19-related ARDS

pdf?lang=en-US 79. Tocilizumab in COVID-19 Pneumonia

The immunology of COVID-19: is immune modulation an option for treatment? Lancet Rheumatol

A Comprehensive Updated Review on SARS-CoV-2 and COVID-19

Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial

Integrated safety in tocilizumab clinical trials

Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five longterm extensions

Cardiovascular safety of tocilizumab: A systematic review and network meta-analysis

FDA Approval Summary: Tocilizumab for Treatment of

Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome

Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes: potential implications on IL-6 bioactivity

Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials

Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

Last Updated

Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic

Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

Inflammation-induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis With Implications for Personalized Medicine

COVID-19, coronavirus disease 2019; IV, intravenous; SC, subcutaneous; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

intensive care unit; WHO, word health organization

macrophage activation syndrome; SOFA, Sequential Organ Failure Assessment, PaO2/FiO2; atrial partial pressure of oxygen / fraction of inspiration O2, IGRA; Interferon Gamma Release Assay, IL; interleukin, CRRT; continuous renal replacement therapy

Soluble Interleukin-6 receptor