key: cord-0839240-xos48rkr
authors: Samaee, Hamidreza; Mohsenzadegan, Monireh; Ala, Shahram; Sedigh Maroufi, Shahnam; Moradimajd, Parisa
title: Tocilizumab for treatment patients with COVID-19: recommended medication for novel disease
date: 2020-09-16
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2020.107018
sha: 6018c30e518bac96f65821ac6ed0c60ba96ee408
doc_id: 839240
cord_uid: xos48rkr

The coronavirus disease 2019 (COVID-19) virus has spread all over the world. Scientists are trying to discover drugs as effective treatment for patients with COVID-19. So far about 30 drugs have been introduced that one of them is Tocilizumab. Recently Tocilizumab has been introduced to treat patients with COVID-19 and researchers are investigating further the efficacy of this drug for different are patients. In Iran and China, some reports showed a positive effect of Tocilizumab on Saturation of Peripheral Oxygen (SPO2) but results of CT scan in patients in different. In some patients, CT scan showed reduced infiltration, however in other no change was observed. Unfortunately, until now there has been no definitive and effective treatment for patients with COVID-19. Although Tocilizumab has been accepted by China Health Commission to treat infected patients, its positive effects still cannot be predicted in all patients. Based on evidence of the Tocilizumab’s effect on the SARS COV 2, researchers hope this drug will make effective and promising treatment to improve lung tissue inflammation in patients with the fatal COVID-19 virus. The present study provides an overview of respiratory inflammation with COVID-19 and probable effect of Tocilizumab on SARS-COV 2.

generate granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytokine environment provides inflammatory monocytes with a high production of inflammatory cytokines such as IL-6 (14) . In the observations, large amounts of inflammatory cells infiltrate into the lungs of patients with COVID-19. This process may be responsible for an immune damaging and causing lung functional injuries and quick mortality (15) .

According to the studies in ICU patients with COVID-19, higher plasma levels of cytokines including IL-6, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon-γinducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1 alpha (MIP1A), and tumor necrosis factor alpha (TNFα ) were found (7, 16) . This increase of inflammatory cytokine levels occurs as cytokine storm and is related to the severity and prognosis of the disease (16) .

IL-6 is produced in response to tissue injuries and various types of infections and contributes to host defense through activation of immune responses and stimulation of acute phase reactions. IL-6 is of great importance in the pathogenesis of various inflammatory diseases including infectious inflammations associated with tissue fibrosis and for this reason, tocilizumab, anti-IL-6 receptor antibody, has been developed. IL-6 binds to the membrane IL-6 receptor (IL-6R) which is only expressed on hepatocytes and some of the leukocytes and leads to classical signaling through the membrane-bound β-receptor glycoprotein 130 (gp130) (17, 18) . There is another pathway, called trans-signaling, such that IL-6 binds to soluble forms of the IL-6R (sIL-6R), and this complex, IL-6/sIL-6R, can activate all of the tissue cells due to the expression of gp130 on all cells (17, 19) . In this section, we review the role of IL-6 in lung inflammation and fibrosis.

Saito and colleagues revealed the significance of IL-6 production in the infiltration of inflammatory cells in Broncho alveolar lavage fluid of wild-type and IL-6-deficient mice were treated with bleomycin. The number of neutrophils and macrophages decreased in BAL fluid in IL-6-deficient mice. In addition, lung pathology showed a decrease of the accumulation of inflammatory cells in IL-6-deficient mice compared with wild type. These findings revealed the significant role of IL-6 in the pathogenesis of bleomycin-induced lung injury and lung fibrosis (17) . of this study showed that IL-6 could have a bidirectional role in the pathogenesis of lung fibrosis in animal models (19) .

Tocilizumab known as traditional Actemra and Atlizumab is an immunosuppressive humanized monoclonal antibody drug . This drug is mainly used for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (21, 22) . Tocilizumab selectively and competitively binds to soluble expressing the IL-6 receptor (IL-6) and then blocking the signaling caused by IL-6 (21). This drug displays dose-dependent, nonlinear pharmacokinetics and has a long elimination half-life (22) . Mechanism of Tocilizumab for inhibiting IL-6 receptors is shown in fig 1. The elimination of Tocilizumab has been relatively slow and dependent on concentration. After saturating the IL6 receptors, clearance of dependent begins by the mononuclear phagocyte system.

It has been shown that increase of the dose leads to prolongation of the half-life, but it should be considered that the elimination of Tocilizumab is capacity limited (6) . In a review study of Sheppard and colleagues (2017), effects of gender, age, ethnicity, mild renal failure and treatment with methotrexate, NSAIDs or corticosteroids on the pharmacokinetics of Tocilizumab were unclear (22) .

Tocilizumab is prescribed to treat moderate to severe active arthritis in adults, Giant cell arthritis, Polyarticular juvenile idiopathic arthritis and cytokine release syndrome in patients 2 years of age older with active disease (23, 24) . The recommended dose of Tocilizumab is 4-8 mg/kg administered as a single 60-minute intravenous infusion every 4 weeks. This drug should be stored refrigerated at 2 to 8 c (36 to 46 F) (24) .

Individuals with active infections should not be treated with Tocilizumab. There are no adequate studies of Tocilizumab in the pregnant women. Also, it is not known whether Tocilizumab is excreted in breast milk (23) .

We can categories side effects into 1) common side effects (respiratory tract infections, headache, hypertension, elevation in liver test), 2) reactions of injection site (rash, redness, swelling, itching),

studies (hyper sensitivity reactions, developed cancer, reactivation of herpes zoster, gastrointestinal perforation in patients with diverticulitis) (22, 24) .

About side effects of Tocilizumab in infected patient with coronavirus, initial researches did not reveal any side effects. Although may be reported longer time side effects.

Tocilizumab inhibits IL-6-receptor, witch as described above is a key cytokine leading to an inflammatory storm which may result in increased alveolar-capillary blood-gas exchange dysfunction, especially impaired oxygen diffusion, and eventually lead to pulmonary fibrosis and organ failure. We estimate that many of studies haves mentioned positive effect of Tocilizumab in treatment of COVID-19 but recent studies doubt about its effects.

The probable reason for the serious deterioration and the loss of some organs in coronavirus disease are cytokines, known as cytokine release syndrome (CRS) (1, 27) . Therefore, drugs used in the past for the CRS have been considered as effective drugs for treating patients with COVID-19 (13) . Recently Tocilizumab has been introduced to treat patients with COVID-19 and researchers are investigating further the efficacy of this drug for different patients (13) . Therefore, we can assert that continuous accurate protocol and method of treatment with Tocilizumab is not found and physicians prescribe this drug with trial and error.

In some studies observed positive effect of Tocilizumab with combination of antiviral drugs such as lopinavir/ritonavir (400 mg/100 mg twice a day) or remdesivir 100 mg/day and corticosteroids able to improve clinical manifestations of patients. In this studies other drugs were different, for example in chinies and Italian clinical trials some drugs such as glucocorticoid, interferon α2, and antibiotic were used. Therefore, maybe antiviral drug, especially lopinavir/ritonavir (400 mg/100 mg twice a day) with Tocilizumab reduced mortality in severe COVID-19 patients.

Timing for prescribing Tocilizumab and selecting suitable patients for treatment is also an important question. All of the reviewed studies included patients in severe phase of disease. Some researchers claim that the optimal time to prescribing Tocilizumab is in beginning of inflammation and first steps of dropping O2 saturation. But still accurate time and infection stage to start this drug is unclear.

Comparison the clinical differences between effective (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) and ineffective (47) There have been few reports about side effects after use of Tocilizumab. For example study of Campochiaro and colleagues Bacterial/fungal infection showed side effects only in 13% of patients who received this drug (42) .In another study, Rojas-Marte and colleagues, reported bacteremia, fever, cough and shortness of breath (45) . Majority of studies did not find any side effects after use of Tocilizumab in patients affected with COVID-19 until with twice prescribing (46, 48) . Due to the current pandemic situation and three speed of resource dissemination, there may be side effects but they are not reported. On the other hand, taking drugs at the same time makes it difficult to judge the side effects.

We should know that Tocilizumab is not an anti-viral drug and may only be effective in a group of patients with inflammation and lung damage caused by the coronavirus. Another important point is that excessive production and activity of Tocilizumab can cause autoimmune diseases and damage body tissues (26) (27) (28) (29) . This drug is very sensitive and can be used in a specific age and certain patients. As a result of review of the published data and based on the mechanism of action of Tocilizumab, we may be able to claim that this drug can be a better or more suitable choice to be used for in patients with higher IL-6 level than normal.

Although Tocilizumab has been accepted by China Health Commission and also recommended by some other health commissions all over the world, its positive effects cannot be predicted in all patients.

Tocilizumab may have a positive effect on improving immune damaging, lung functional injuries and arterial oxygen saturation. Researchers who had the successful experience of using this drug for treating inflammation lungs diseases, hope it will make effective and promising treatment to improve lung tissue inflammation in patients with fatal COVID-19 virus. However, further accurate clinical trial studies are needed to determine its efficacy in patients with specific characteristics such as age, level of IL-6, and different clinical symptoms.

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 Tocilizumab is a suggested anti-inflammatory drug to treatment COVID-19

Our study is immunopharmacology review that can be suitable for now  Tocilizumab is effective treatment in patients with severe COVID-19