Tocilizumab Treatment in Patients With COVID-19

In December 2019, a group of patients with the acute respiratory disease was detected in Wuhan, Hubei Province of China. A month later, a new beta-coronavirus was identified as the cause of the 2019 coronavirus infection. Despite China's efforts to contain the disease, it spread rapidly outside the continent. Currently, Mexico is one of the countries that is facing this world health problem with a dynamic and exponential increase in the number of confirmed cases.

SARS-CoV-2 is a coronavirus that belongs to the group of β-coronaviruses of the subgenus Coronaviridae. The SARS-CoV-2 is the third known zoonotic coronavirus disease after severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS). The diagnosis of SARS-CoV-2 recommended by the WHO, CDC is the collection of a sample from the upper respiratory tract (nasal and oropharyngeal exudate) or from the lower respiratory tract such as expectoration of endotracheal aspirate and bronchioloalveolar lavage and its analysis using the test of real-time polymerase chain reaction (qRT-PCR).

The clinical manifestations of the patients are heterogeneous presenting asymptomatic symptoms, mild respiratory disease, severe pneumonia, acute respiratory failure syndrome (ARDS), and even death. According to the Berlin definition, ARDS is an acute lung injury that occurs within 7 days after the triggering event and is characterized by bilateral lung infiltrates and severe progressive hypoxemia, as well as non-cardiogenic pulmonary edema. The mortality associated with ARDS depends on its severity: mild 27%, moderate 32%, and severe 45%. In patients with SARS and SARS-CoV-2, the average duration of mechanical ventilation was reported in 10 (7-12) days, achieving extubation in 6/18 (33%) of which their meantime under mechanical ventilation was 11 (7-12) days. Of these patients, none received treatment with tocilizumab, only 1 patient received hydroxychloroquine, and another patient was treated with lopinavir-ritonavir. Therefore, the present study proposes that the use of Tocilizamab will shorten the time to improve, so an evaluation of the ARDS will be carried out at 7 days.

Initial reports suggest that SARS-CoV-2 is associated with a severe illness that requires the intensive care unit in approximately 5% of confirmed infections. In the CDC report from China, the clinical manifestations of the disease were divided into:

Mild: Mild respiratory symptoms (cough, malaise, temperature> 37.5, runny nose) with or without pneumonia data by an imaging study (up to 81% cases) Severe: dyspnea, increase in respiratory rate ≥ 30 breaths / min, oxygen saturation ≤ 93%, PaO2 / FiO2 <300 mmHg, and image lung infiltrates> 50% within 24 to 48 hours of symptom onset (up to 14 % of the cases) Critical: respiratory failure, septic shock and/or multiple organ failure (up to 5% of cases)

China's mortality rate from SARS-CoV-2 was 2.84%, with a ratio of male to female deaths of 3.25: 1. The average age of death was 75 years, and the average time from the first symptom to death was 14 days. For people age 70 and older, the average time from first symptoms to death was shorter than for people younger than age 70. In another retrospective study of 99 cases, 17% of patients developed Acute Respiratory Failure Syndrome (ARDS), and 11% worsened in a few days and died. Critical case mortality has been documented to reach 60.5%, however, Mexico still does not exist epidemiological data because is not yet reached the zenith of the pandemic.

The SARS-CoV-2 infection causes dysregulation of the immune response mediated by cytokines and chemokines. An increase in inflammation-related cytokines including IL-2, IL-7, and IL-10, colony-stimulating factor (G-CSF), protein 10 inducible interferon g (IP10), protein, was reported in plasma samples from patients. monocyte chemoattractant (MCP1), macrophage inflammatory protein 1 alpha (MIP1A), and tumor necrosis factor-alpha (TNF-a), especially in severe patients. This suggests that SARS-CoV-2 patients have a large infiltrate of inflammatory immune cells and severe lung inflammation. IL-6 and IL-10 expression levels increase the risk of progression to a critical condition.

Cytokine storm syndrome is a phenomenon during which there is an immune dysregulation due to the increase of proinflammatory cytokines in response to stimulation by microorganisms or drugs.

Under homeostasis conditions, the body's pro-inflammatory and anti-inflammatory cytokine concentrations remain relatively balanced. Before infection, there may be abnormal and dysregulated activation of dendritic cells, macrophages, lymphocytes, and NK cells. The release and action of a large number of proinflammatory cytokines facilitate a positive feedback loop. After a certain threshold, there may be a cytokine storm. Patients will present with fever, diffuse intravascular coagulation (DIC), shock, and organ failure. The transition from mild to severe disease in COVID-19 patients may be caused by a cytokine storm.

Manifestations of a dysregulated inflammatory response have been identified in patients with COVID-19. The cardinal features of this syndrome include constant fever, cytopenias, and hyperferritinemia. Pulmonary involvement, including ARDS, occurs in approximately 50% of patients. A cytokine profile that resembles LHHS has been associated with COVID-19 disease severity.

At the time of infection, immune mechanisms are activated, including specific and non-specific immune responses. Endogenous viral protein synthesized within infected cells can activate virus-specific CD8 + T cells through the major pathway of the histocompatibility complex-I (MHC-I). There is then proliferation, differentiation, and effector responses of CD8 + T cells (24). Increased IL-2, IL-7, granulocyte colony-stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and necrosis factor have been observed in severe cases tumor-α. Continuous and dysregulated amplification exacerbates the manifestations associated with infection, while hypoxia and necrosis eventually lead to an uncontrolled inflammatory response and will trigger cytokine storms. There is a probability that immunosuppression is beneficial in a hyper-inflammatory state.

Therapeutic options include steroids, intravenous immunoglobulin, selective cytokine blockade (eg, Anakinra or Tocilizumab), JAK inhibition, vaccines, reinfusion of serum from recovered patients, progenitor therapy, elimination of immune cells (eg. , Alendizumab, Rituximab), among others.

All patients with severe COVID - 19 should undergo tests for hyper inflammation using laboratory tests such as ferritin levels, platelet count, globulin sedimentation rate, and H score measurement in order to determine the subgroup of patients to whom the immunosuppression may improve the risk of mortality.

A study carried out to identify the immune characteristics of those infected with SARS-CoV-2 showed that patients in the intensive care unit had a significant decrease in hemoglobin and albumin, with an increase in concentrations of the c-reactive protein (PCR), alanine aminotransfer (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (DHL). The total number of leukocytes did not show significant differences, while the number of lymphocytes decreased significantly. Furthermore, they found an increase in the number of G-CSF and in IL-6, suggesting a high risk of monocyte-mediated release of inflammatory cytokines that can migrate to the lung and produce severe clinical manifestations and even death.

The management of the critically ill adult patient with SARS-CoV-2 is not standardizing, however, the panel of experts from the "Surviving Sepsis Campaign" has published 54 recommendations for the management of the patient with severe SARS-CoV-2 and ARDS. The recommendations focus on hemodynamic support, fluid therapy, use of vasoactive agents, invasive mechanical ventilation, as well as management of the "cytokine storm" syndrome.

One of the proposals for the treatment of cytokine storm and macrophage activation in severe or critical stages of SARS-CoV-2 is the use of drugs that inhibit the interaction of IL-6 with its receptor. Tocilizumab (TCZ) is a humanized recombinant monoclonal antibody of the IgG1 immunoglobulin subclass, is directed against soluble or membrane IL-6 receptors (IL-6R). TCZ inhibits the binding of IL-6 to its receptor by reducing pro-inflammatory activity.

The use of TCZ in patients with severe/critical SARS-CoV-2 was first reported in China. Patients received TCZ treatment at an initial dose of 400 mg with an additional dose in the patient with persistent fever (maximum of two doses). The patients presented a rapid reduction in fever and in the supplemental oxygen requirement in the days after receiving the medication. Despite the promising results of this study, there is currently no solid evidence demonstrating the safety and efficacy of TCZ for the clinical treatment of SARS-CoV-2 pneumonia. The FDA recently approved a randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the safety and efficacy of TCZ (ActemraMR) added to standard care in hospitalized adult patients with severe SARS-CoV-2 disease, which will be held in the United States of America (ClinicalTrials.gov Identifier: NCT04320615). Likewise, Italy is recruiting patients for a phase II study with a single TCZ treatment arm in critically ill patients (ClinicalTrials.gov Identifier: NCT04317092, NCT04315480). China is conducting a study with Tocilizumab vs. renal replacement therapy for the management of cytokine release syndrome (ClinicalTrials.gov Identifier: NCT04306705). In patients with mild-moderate SARS-CoV-2, the US will initiate a phase 2 study in 50 patients to assess its efficacy (ClinicalTrials.gov Identifier: NCT04331795). As well as its comparison with other medications (hydroxychloroquine and azithromycin, ClinicalTrials.gov Identifier: NCT04332094) and combinations (Favipiravir + Tocilizumab vs Favipiravir and Tocilizumab ClinicalTrials.gov Identifier: NCT04310228).