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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 189-191

Tocilizumab: A potent immunomodulatory agent in the treatment of COVID-19 pneumonia


1 Department of Pulmonary Medicine, Apollo Specialty Hospitals, Bengaluru, Karnataka, India
2 Department of Rheumatology, Apollo Specialty Hospitals, Bengaluru, Karnataka, India

Date of Submission30-Jul-2021
Date of Decision30-Jul-2021
Date of Acceptance03-Aug-2021
Date of Web Publication07-Sep-2021

Correspondence Address:
Ravindra M Mehta
Chief of Pulmonary and Critical Care, Apollo Specialty Hospitals, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_88_21

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  Abstract 


Inflammation plays a major role in the pathophysiology of COVID-19, and corticosteroids are validated as initial potent broad-spectrum anti-inflammatory agents. IL-6 is one of the culprit pro-inflammatory cytokines identified for this cytokine storm. Tocilizumab is a recombinant humanized monoclonal antibody that inhibits binding of interleukin (IL)-6 to both membrane and soluble IL-6 receptors. The role of tocilizumab was controversial with conflicting evidence, but recent data validate the use of this agent under specific circumstances of rapidly worsening COVID acute respiratory distress syndrome with escalating respiratory support or gradually worsening COVID-19 pneumonia in a hospital setting. One of the benchmark tocilizumab studies is the REMAP-CAP trial that showed the benefit of IL-6 antagonists in terms of survival, number of organ support-free days, and even probability of discharge from the hospital. This benefit was seen when tocilizumab was administered within 24 h of patients requiring either respiratory or hemodynamic support. A recently concluded meta-analysis showed that tocilizumab treatment predicts better overall survival in COVID-19 patients (hazard ratio [HR] =0.45, 95% confidence interval [CI]: 0.24–0.84, P = 0.01), especially in severe cases (HR = 0.58, 95% CI: 0.49–0.68, P < 0.00001).

Keywords: COVID-19, interleukin 6, tocilizumab


How to cite this article:
Bansal S, Karjigi U, Mehta RM. Tocilizumab: A potent immunomodulatory agent in the treatment of COVID-19 pneumonia. Apollo Med 2021;18:189-91

How to cite this URL:
Bansal S, Karjigi U, Mehta RM. Tocilizumab: A potent immunomodulatory agent in the treatment of COVID-19 pneumonia. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:189-91. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/189/325680




  Introduction Top


Inflammation in the 2nd week of disease is cardinal to the pathophysiology of COVID-19. Dexamethasone was the first broad-spectrum anti-inflammatory to impact on mortality in COVID19.[1] The downstream cascade of inflammation includes interleukin (IL)-6 as one of the main cytokines responsible for the cytokine release syndrome seen in severe and critically ill COVID patients and has been a target for intervention due to the availability of IL-6 antagonists.[2] There are several IL-6 antagonists such as tocilizumab, sarilumab, and itolizumab. Tocilizumab is one of the earliest repurposed and most extensively studied IL-6 antagonists in moderate to severe COVID-19 pneumonia. While some studies showed a possible benefit with the drug, other randomized control trials (RCTs) failed to demonstrate any advantage with respect to the holy grail of clinical progression and mortality, till recent data showed positive results.


  Discussion Top


Tocilizumab has been extensively used in the management of systemic inflammatory disorders by rheumatologists for around a decade now. Its role as an immunomodulator has been promising in controlling inflammation, with a good safety profile.

The following literature trail shows how data on tocilizumab evolved in the past 1 year. One of the earliest observational studies in 2020 by Gupta et al. showed a reduced risk of death at 30 days in patients treated with tocilizumab.[3] However, its use was restricted to patients with IL-6 levels at least 50–100-fold higher with worsening of other inflammatory markers, deteriorating clinical condition, and no evidence of secondary infections.

As a next step, the earliest RCT by Salvarani et al. compared tocilizumab with standard of care (SOC) for its impact on clinical worsening in hospitalized patients with COVID-19. Patients received tocilizumab within 8 h of randomization. However, no benefit on disease progression was observed when compared with standard care (28.3% in the tocilizumab arm and 27.0% in the standard care group showed clinical worsening within 14 days after randomization [rate ratio odds ratio [OR]: 1.05; 95% confidence interval [CI]: 0.59–1.86]).[4] The CORIMUNO-19 TOCI-1 study by Hermine et al. included 131 hospitalized hypoxic patients, not on mechanical ventilator or admitted to ICU. Tocilizumab did not reduce WHO-clinical progression scale scores but showed a trend toward reduced risk of progression to noninvasive ventilation (NIV), mechanical ventilation (MV), or death by day 14. No difference on day 28 mortality was found.[5]

The EMPACTA study was the first RCT which showed significant reduction in MV by day 28.[6] The cumulative percentage of patients who received MV or died by day 28 was 12.0% (95% CI: 8.5–16.9) in the tocilizumab group and 19.3% (95% CI, 13.3–27.4) in the placebo group (hazard ratio [HR] for MV or death: 0.56; 95% CI: 0.33–0.97; P = 0.04 by the log-rank test). However, there was no mortality benefit.

The TOCIBRAS study group RCT across 9 centers in Brazil included 129 severe and critically ill COVID-19 patients. It concluded that tocilizumab plus SOC was not superior to SOC alone in improving clinical outcomes at day 15, and in fact, it may increase mortality.[7]

Another recent industry-sponsored study, COVACTA, was conducted across North America and Europe. It reported failure to meet predefined efficacy thresholds and no mortality difference at day 28. Tocilizumab-treated patients had reduced hospital length of stay, but other secondary outcomes were negative.[8]

Interestingly, only Salvarani et al.[4] commented on the timing of tocilizumab, i.e., within 8 h of randomization. The game-changer REMAP-CAP trial published in April 2021 randomized 803 patients to receive either tocilizumab, sarilumab or placebo within 24 h of commencing organ support, i.e., respiratory or hemodynamic support. Patients treated with IL-6 antagonists had significantly higher organ support free days (10 vs. 0) and improved survival at 90 days (HR: 1.61 [95% Cl: 1.25–2.08]).[9] In addition, the probability of discharge from the ICU or the hospital was higher than the placebo group.

This benefit was later reiterated by the meta-analysis published by Wei et al. They compared 25 publications on tocilizumab and found significantly better clinical outcomes in the tocilizumab treatment group when compared to the standard care group (OR = 0.70, 95% confidential interval [C]: 0.54–0.90, P = 0.007). The pooled HR for tocilizumab showed significant benefit with regard to mortality (HR: 0.79 [95% CI: 0.70, 0.90]), progression to MV (HR: 0.90 [95% CI: 0.83, 0.97]), and discharge from hospital (HR: 1.18 [95% CI: 1.05, 1.34]).[10]

A recently concluded meta-analysis of 27 RCTs by the WHO rapid evidence appraisal for COVID-19 therapies working group showed a reduced ORs for 28-day all-cause mortality – OR: 0.86 (P 0.003).[11] This benefit was better in those receiving corticosteroids – OR: 0.77 (95% CI: 0.68–0.87). The OR for the association with progression to invasive MV or death compared with usual care or placebo was 0.77 (95% CI: 0.70–0.85).

The current role of tocilizumab endorsed by most guidelines is within the first 24 h of organ (respiratory/cardiovascular) support with particular reference to patients with rapid worsening requiring high flow O2, NIV/high flow nasal cannula or MV, or in the situation of gradual respiratory worsening in the hospital setting with elevated inflammatory markers (C-reactive protein ≥75 mg%). However, IL-6 measurement is not a prerequisite and more of an ancillary test, with repeat levels not indicated.


  Conclusion Top


Tocilizumab when given timely in specific situations of initial rapid worsening or escalating respiratory compromise in critically ill COVID19 pneumonia improves overall outcomes and survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Recovery Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021;384:693-704.   Back to cited text no. 1
    
2.
Chen LY, Hoiland RL, Stukas S, Wellington CL, Sekhon MS. Assessing the importance of interleukin-6 in COVID-19. Lancet Respir Med 2021;9:e13.  Back to cited text no. 2
    
3.
Gupta S, Wang W, Hayek SS, Chan L, Mathews KS, Melamed ML, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med 2021;181:41-51.  Back to cited text no. 3
    
4.
Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: A randomized clinical trial. JAMA Intern Med 2021;181:24-31.  Back to cited text no. 4
    
5.
Hermine O, Mariette X, Tharaux P, Resche-Rigon M, Porcher R, Ravaud P, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia. JAMA Internal Med 2021;181:32.  Back to cited text no. 5
    
6.
Salama C, Han J, Yau L, Reiss W, Kramer B, Neidhart J, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med 2021;384:20-30.  Back to cited text no. 6
    
7.
Veiga VC, Prats JA, Farias DL, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: Randomised controlled trial. BMJ 2021;372:n84.  Back to cited text no. 7
    
8.
Rosas I, Bräu N, Waters M, Go R, Hunter B, Bhagani S, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med 2021;384:1503-16.  Back to cited text no. 8
    
9.
REMAP-CAP Investigators; Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med 2021;384:1491-502.  Back to cited text no. 9
    
10.
Wei Q, Lin H, Wei RG, Chen N, He F, Zou DH, et al. Tocilizumab treatment for COVID-19 patients: A systematic review and meta-analysis. Infect Dis Poverty 2021;10:71.  Back to cited text no. 10
    
11.
Domingo P, Mur I, Mateo G, Gutierrez M, Pomar V, de Benito N et al. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19. JAMA. 2021. 326:499-518.  Back to cited text no. 11
    




 

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