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).