Assessment of Tocilizumab (Humanized Monoclonal Antibody) for Therapeutic Efficacy and Clinical Safety in Patients with Coronavirus Disease (COVID-19)

Abstract

Background and objectives: COVID-19 patients exhibit a broad range of manifestations, presenting with a flu-like respiratory tract infection that can advance to a systemic and severe disease characterized by pneumonia, pulmonary edema, severe damage to the airways, and acute respiratory distress syndrome (ARDS, causing fatality in 70% of COVID-19 cases). A ‘cytokine storm’ profile is found in most severely influenced COVID-19 patients. The treatment protocol of the disease also includes tocilizumab, which is a humanized monoclonal antibody used to treat autoimmune and inflammatory conditions. This study was designed (1) to assess the role of tocilizumab in COVID-19 patients regarding therapeutic efficacy through evaluation of cytokine release syndrome (CRS) resolution and anticoagulant effect, analyzing clinical safety via monitoring of associated adverse effects profile; and (2) to compare the clinical safety and therapeutic efficacy of institutional treatment regimen (alone) versus tocilizumab added to an institutional treatment module in COVID-19 patients. Materials and Methods: In this study, the endpoints parametric assessment of severely diseased patients of COVID-19 was performed (total n = 172, control group (institutional protocol treatment provided), n = 101 and test group (tocilizumab provided), n = 71) at the Khyber Teaching Institution, MTI, Peshawar. The assessments were compared using non-parametric analyses at baseline and after a follow-up of 12–18 days until the patient discharged or expired. Results: Results of the study revealed an insignificant difference among the control vs. test group in resolving inflammatory parameters (C-reactive protein (CRP) 21.30 vs. 50.07; p = 0.470, ferritin 482.9 vs. 211.5; p = 0.612, lactate dehydrogenase (LDH) 29.12 vs.18.8; p = 0.0863, and D-dimer 464 vs.164.4; p = 0.131). However, a statistically significant difference was found between the control group and test group regarding coagulation parameters (international normalized ratio (INR) 0.12 vs. −0.07; p ≤ 0.001; activated partial thromboplastin time (aPTT) 0.42 vs. −1.16; p ≤ 0.001; prothrombin time (PT) 0.31 vs. −0.96; p ≤ 0.001; platelet count −12.34 vs. −1.47; p = 0.012) and clinical survival rate (89.10 vs. 90.14; p < 0.001). Furthermore, there was significantly higher infection rates and raised alanine aminotransferase (ALT) and alkaline phosphatase (ALP) associated with the tocilizumab group as compared to those receiving institutional treatment (bacterial infections: 0.99% vs. 15.49%; p ≤ 0.01, ALT: 3.96% vs. 28.16%; p ≤ 0.01, ALP: 1.98% vs. 22.53%; p ≤ 0.01). Conclusions: From this study, it was concluded that tocilizumab can be a better drug of choice in terms of efficacy, particularly in resolving coagulopathy in severe COVID-19 patients.

Artificial intelligence assessment of the potential of tocilizumab along with corticosteroids therapy for the management of COVID-19 evoked acute respiratory distress syndrome

“…Despite our data compilation did not categorize endothelial pathology as a separated item and our models were not build specifically focusing on endothelial or coagulation processes, our results highlight the involvement of several endothelial and coagulation mediators in the mechanisms of action of the drugs, specifically found to be modulated by dexamethasone (SELE, SELP) and tocilizumab (ACE2, AGT1R, ANGPT2, CDH5, EGFR, FN1, TGFA and VEGFA). As commented, the study by Ullah et al [ 67 ], highlights the role of tocilizumab in improving performance on an institutional treatment including dexamethasone over coagulopathy control, supporting our model results. Furthermore, the evidence regarding the use of biologics targeting IL-6R –including tocilizumab–and IL-6 downstream JAK proteins since we started this study has increased [ 40 , 41 , 86 – 90 ], to the point that its use is recommended in the NIH guidelines for treatment of hospitalized patients requiring oxygen or assisted ventilation or oxygenation, in combination to dexamethasone [ 91 ] The methodology employed for the modelling, considering the whole human protein network and a wide range of drug-pathology relationships for the training ( S4 Table ), allow the TPMS-based models to infer biological and functional information on not-so-well documented therapeutic areas by connecting a wider biological knowledge spectrum, as shown in previous studies [ 47 , 55 , 83 , 84 ].Therefore, while the models and conclusions could be updated over time as new information is generated, potentially improving accuracy of the results and allowing exploring unanswered questions in COVID-19 evoked ARDS, our approach has provided results that are in agreement with current molecular pathophysiological and clinical knowledge, providing protein candidates as response biomarkers and supporting the role of the approach in exploring mechanistic insights on the effects of current available therapies.…”

“…A recent study in critically ill patients treated with dexamethasone show that inflammatory markers, such as the C-reactive protein (CRP), lactate dehydrogenase, ferritin and the neutrophil-lymphocyte ratio were reduced upon tocilizumab treatment (in patients treated with a treatment combination including corticosteroids) [ 66 ]. In another study comparing the change from baseline between adding tocilizumab or not, although they found a greater reduction in CRP and ferritin levels when adding tocilizumab, the reduction was not significantly different than the reduction induced by the treatment without tocilizumab [ 67 ]; they did find, however, a significant difference when evaluating coagulation parameters, such as activated partial thromboplastin time, prothrombin time and platelet levels. Interestingly, Ponthieux et al [ 68 ], although noting reduced CRP levels, found an increase in IL-1β, -2, -4, -10, -12p70, -18, and sIL-6R days 2–4 after tocilizumab alone treatment in a small cohort of 15 critically ill patients, supporting the relevance of the combination with corticosteroids for an additive anti-inflammatory effect.…”

Effect of Tocilizumab on Mortality in Patients with SARS-CoV-2 Pneumonia Caused by Delta or Omicron Variants: A Propensity-Matched Analysis in Nimes University Hospital, France

“…Unfortunately, in numerous countries, several factors have limited the use of tocilizumab, such as drug shortages, high cost or late approval (December 2021 in Europe, December 2022 in the USA). Therefore, real-life data on tocilizumab treatment remain scarce, especially in patients infected with delta or omicron VOCs [13][14][15]. Moreover, its use is questionable in omicron cases.…”

The association between tocilizumab therapy and the development of thrombosis in critically ill patients with COVID-19: a multicenter, cohort study

“…Sami Ullah et al, conducted an open-label, randomized clinical trial to investigate the impact of TCZ in patients with COVID-19 while focusing on the remission of the cytokine release syndrome. The study did not reveal any statistically significant difference between the TCZ and control group in inflammatory markers (CRP, ferritin, D-dimer or LDH) while the coagulation parameters showed a significant difference in the median change from baseline between the TCZ and control group (INR 0.12 vs. − 0.07; p ≤ 0.001; aPTT 0.42 vs. − 1.16; p ≤ 0.001; prothrombin time (PT) 0.31 vs. − 0.96; p ≤ 0.001; and platelet count − 12.34 vs. − 1.47; p = 0.012) 24 . In the Atallah et al 20 case series, they observed a decline in inflammatory markers, such as D-dimer and fibrinogen, in hospitalized patients with COVID-19 while being on TCZ therapy.…”