Tocilizumab: An Effective Therapy for Severely and Critically Ill COVID-19 Patients

INTRODUCTION

A novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the COVID-19 pathogen, is responsible for protean clinical manifestations ranging from asymptomatic to severe pneumonia and acute lung failure.¹ Coronavirus has an average incubation period of 5–6 days. The most common clinical manifestations of COVID-19-positive patients include fever, cough, shortness of breath, fatigue, loss of appetite, sputum production, joint pain, nausea, vomiting, and diarrhea. The complications of COVID-19 include pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, septic shock, disseminated intravascular coagulation, and death.^2,3

The pathogenesis of SARS-CoV-2 is initiated by viral–host cell interaction through binding of spike protein to host receptors via receptor-binding domains of angiotensin-converting enzyme 2 (ACE2).⁴ A large number of T-lymphocytes and mononuclear macrophages are subsequently activated producing cytokines, such as interleukin-6 (IL-6), that bind to the IL-6 receptor on the target cells, initiating cytokine storm and severe inflammatory responses in the lungs and other tissues. IL-6 receptor (IL-6R) has two forms: membrane-bound interleukin-6 receptor (mIL-6R) and soluble interleukin-6 receptor (sIL-6R). IL-6 binds to sIL-6R to form a complex, which then binds to glycoprotein 130 on the cell membrane to complete trans-signal transduction and play a proinflammatory role.^5–7 IL-6 is the most common cytokine reported in SARS-CoV-2 infection and has been implicated in inducing various clinical manifestations, radiological features, management modalities, and outcomes. Therefore, early identification, treatment, and prevention of a cytokine storm are essential for such patients. Tocilizumab (TCZ), a humanized monoclonal antibody against IL-6R, has been recommended in seriously ill patients with an elevated IL-6.⁸ However, there are limited data relating to the safety and efficacy of TCZ on the inflammatory overdrive activity in such severe COVID-19 patients, and subsequently the present study was designed to assess the treatment response of TCZ, an IL-6R antagonist, in severely and critically ill COVID-19 patients and the efficacy of TCZ to provide a therapeutic strategy for this disease of global concern.

METHODS

RESULTS

A total of 30 COVID-19 patients were included in the present study. The mean age of SARS-CoV-2-infected patients treated with TCZ was 49.6 years (49.6 ± 10.55). A male preponderance was observed with 63.33% males and 36.37% females (Table 1).

DISCUSSION

In the present study, the efficacy of TCZ therapy in severely or critically ill COVID-19 patients was assessed. Luo et al. had reported similar disease-ameliorating findings, suggestive of TCZ therapy being an effective treatment option for COVID-19 patients, predisposing to cytokine storms.¹⁰ Findings of the present study support the efficacy of TCZ infusion in amelioration and/or management of cytokine storm (IL-6) induced by COVID-19. The SARS-CoV-2 virus replicates rapidly triggering a storm characterized by increased levels of cytokines, such as IL-6. The raised IL-6 levels have been reported to closely correlate with the incidence of RNAaemia and COVID-19-related mortality.¹¹ IL-6 is an important proinflammatory factor in the disease process of SARS-CoV-2, contributing to COVID-19-associated cytokine storm, inducing vascular permeability with impaired organ system function. The rationale for the use of anti-IL-6 receptor antibody TCZ in COVID-19 patients is based on the appreciation of the role of IL-6 in this disease and the experience with this drug in the treatment of cytokine release syndrome caused by chimeric antigen receptor-redirected T-cells.¹² Moreover, the treatment strategy of using antivirals alone in COVID-19 may not be sufficient to reverse such deteriorating effects of IL-6.

In the present study, the efficacy of TCZ therapy, an IL-6R inhibitor, in the therapeutic response of 30 patients with severely and critically ill COVID-19 disease was assessed. The available clinical data showed that symptoms and hypoxemia improved immediately post-treatment with TCZ in most of the patients, suggesting that TCZ could be an efficient therapeutic option for the treatment of COVID-19. In the present study, all patients were symptomatic before the infusion of TCZ with cough, shortness of breath, and fever. All patients of the study group had features of hypoxemia with reduced SpO₂ and PaO₂ with subsequently increased requirement of FiO₂ for all such patients before the infusion of TCZ therapy. The majority of patients required a high mode of oxygenation including a high-flow mask and NIV as these patients could not be maintained on a low-flow mask. Eighty percentage of patients were severely ill while the remaining 20% were critically ill. As for the laboratory investigations, the mean value of hemoglobin, TLCs, and platelet counts were found to be within normal limits. Zhang, chi et al. (2020) in their study had suggested that IL-6 could play an important role in cytokine release syndrome and, if the signal transduction pathway of IL-6 could be blocked, a new definitive treatment for severe COVID-19 patients could be in the offing.¹³ The present study showed that IL-6 was raised in all patients with the majority of patients (90%) having an extremely raised serum level of IL-6 of the order of more than 10 times of ULN. IL-6 can be used to evaluate the severity of the infection and predict prognosis. IL-6 monoclonal antibody-directed COVID-19 therapy (TCZ) after its use in clinical trials has recently been incorporated into COVID-19 management guidelines, especially with extremely raised IL-6. TCZ can specifically bind to sIL-6R and mIL-6R and inhibit signal transduction and the drug is in use for rheumatoid arthritis.⁸ TCZ therapy initiated based on the serum level of IL-6 (manifold increased) and HRCT chest findings of diffuse, bilateral, homogeneous with peripheral-predominant ground-glass opacities with higher mean CT severity scores has the potential to decrease the mortality of COVID-19.

All patients were treated with a single prescribed dose of TCZ and followed sequentially for their clinical status, blood gas analysis, FiO₂ requirement, mode of oxygenation, and serum level of IL-6. Xu, Xiaoling et al. (2020) suggest that TCZ improved the clinical outcomes immediately in severe and critical COVID-19 patients and is seemingly an effective treatment to reduce mortality.¹⁴ All patients exhibited a dramatic reduction in maximum body temperature, even on the next day of TCZ infusion, with a further serial reduction of temperature that became normal within three days postinfusion. SpO₂, a rapid reflection of hypoxemia, improved immediately after TCZ infusion with the mean SpO₂ becoming more than 95% on day 5. P/F ratio also increased immediately just after the infusion of TCZ therapy with the P/F ratio being 300 on day 3. The mode of oxygenation also dramatically lightened after TCZ therapy with one patient being weaned off from NIV on day 1 of TCZ while two patients were weaned off from NIV on day 2. The requirement of high-flow oxygenation was also reduced and the majority of patients were shifted to a low-flow mask in follow-up of TCZ infusion. On day 7, only 21% of patients were oxygen dependent and the remaining patients did not require supplemental oxygen and were maintained on room air. In the follow-up HRCT scan of the chest on day 7, the majority of patients showed decreased ground-glass haziness and increased consolidation with reduced CT severity scores. Serum level of IL-6 showed a dramatic variation after infusion of TCZ with initially raised values of IL-6 followed by reduction spread across 3–5 days. IL-6 is mainly eliminated via IL-6R-mediated clearance.¹⁵ Binding of TCZ to IL-6R inhibits receptor-mediated clearance of IL-6, leading to its accumulation in serum, which is the likely explanation for raised IL-6 levels in TCZ-treated COVID-19 patients in the present study followed by a gradual decrease of IL-6 levels in the serum that could be partly due to inhibition of inflammatory activity so induced by TCZ, leading to stabilization and/or improvement of clinical outcomes. Two patients succumbed to life in the early phase of disease probably prior to the onset time so needed for a response of TCZ therapy to take place and the remaining patients were discharged within two weeks post-TCZ infusion. Henceforth, TCZ that acts by blocking of IL-6-associated febrile and inflammatory storm response could probably be effectively used to treat severe or critical patients of COVID-19.

CONCLUSION

COVID-19-infected patients with extremely high IL-6 levels are definitely at a higher risk of severe and fatal infection due to an increased inflammatory overdrive induced by cytokine storm, leading to greater mortality. IL-6 is the key molecule of cytokine release syndrome; therefore, IL-6R antagonist TCZ may be an important drug to save patients’ lives. TCZ improves the clinical symptoms and oxygenation in severely or critically ill COVID-19 patients and TCZ could act as an effective definitive management protocol in such severely and critically ill COVID-19 patients and could provide a therapeutic window for such potentially fatal infectious diseases.

ACKNOWLEDGMENTS

I would like to thank the anonymous referees for their useful suggestions. I would like to thank my professionals Dr. Abhishek Agrawal, Dr. C. L. Nawal, Dr. S. Banerjee, Dr. Prakash Keswani, Dr. Sunil Mahavar, Dr. R. S. Chejara, Dr. Vidyadhar Singh, Dr. Kapil, Dr. Amitabh Dube, Dr. Vishal Gupta, Dr. Meenu Bagarhatta, and the team of Department of General Medicine SMS Medical College and Attached Group of Hospital, Jaipur for their valuable support. and Department of Radiodiagnosis for providing radiological information of COVID-19 patients.

Limitation: There are several limitations in this study. The number of patients was limited and needs to have been studied on a large patient cohort. It is a single-center observational study and a significant bias could have possibly existed. HRCT chest data were not available for all patients.

Ethical approval: This study was approved by the ethical and research committee of SMS Medical College and Hospital, Jaipur, India.

Author contributions: S. Bhandari and G. Rankawat formulated the research questions, designed the study, developed the preliminary search strategy, and drafted the manuscript; G. Rankawat and A. Singh collected and analyzed the data for the study. G. Rankawat wrote the manuscript. S. Bhandari conducted the quality assessment. All authors critically reviewed the manuscript for relevant intellectual content. All authors have read and approved the final version of the manuscript.

Availability of data and materials: Available from the corresponding author upon reasonable request.

ARCID

Sudhir Bhandari https://orcid.org/0000-0003-2387-917X

Govind Rankawat https://orcid.org/0000-0003-3708-3068

Ajeet Singh https://orcid.org/0000-0003-3461-6420

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