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Tocilizumab/IL-6 Inhibitors

Last updated: August 24, 2020 

The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview 

In some patients who progress to severe COVID-19 disease, host immune response can lead to lung injury and multisystem organ dysfunction (Huang, January 2020Moore, May 2020). Several studies of patients with COVID-19 indicate that elevation of inflammatory markers, including proinflammatory cytokines such as interleukin-6 (IL-6), may be associated with more severe disease (Yang, February 2020Mehta, March 2020).  

Tocilizumab is an IL-6 receptor monoclonal antibody that is approved for the use of CAR-T associated cytokine release syndrome. Due to similarities in the clinical presentation of CAR-T cytokine release syndrome and the hyperinflammatory state of severe COVID-19, interest in tocilizumab for severe COVID-19 developed early in the pandemic (Mehta, March 2020)Other agents that mitigate the effects of IL-6, including sarilumab and siltuximab, have also been investigated, although to a lesser extent.   

To date, several observational studies have shown positive clinical effects with tocilizumab; however, these findings should be considered with caution as they may have been subject to a number of biases. In contrast to these observational studies, preliminary results of the Roche phase 3 randomized controlled trial of tocilizumab for severe COVID-19COVACTA, show failure to meet the primary endpoint of improved clinical status and the secondary endpoint of reduced patient mortality at week four. Similarly, Sanofi/Regeneron’s sarilumab randomized controlled trial also indicatea failure to meet similar endpoints. Additional clinical trials of IL-6 mitigating agents are underway. 

On this page: 

Guidelines 

IDSA guidelines recommend the use of tocilizumab in hospitalized patients only in the context of a clinical trial.  

Dosing 

  • Initial IV infusion of 8 mg/kg (up to a maximum dose of 800 mg).  
  • One additional dose may be given if symptoms worsen or show no improvement. 

Key Literature 

Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study (Biran, August 2020). 

Study population: 

  • Retrospective study of 764 COVID-19 patients admitted to the ICU in 13 New Jersey hospitals; 210 (27%) received tocilizumab. 
  • Propensity score-matched population included these 210 patients and 420 who did not receive tocilizumab (total of 630 patients). 
  • Tocilizumab was administered a median of 9 days (IQR 6–12) after the start of patient-­reported symptoms. 

Primary endpoint: 

  • Hospital-related mortality. 

Key findings: 

  • 358 (57%) of 630 patients diedof these, 102 (49%) received tocilizumab and 256 (61%) did not. 
  • primary multivariable Cox regression analysis with propensity matching noted an association between receiving tocilizumab and decreased hospital-related mortality (HR 0.64; p=0.0040). 
  • In post-hoc analysis of the 558 patients (89%) who had a C-reactive protein (CRP) >15 mg/dL at baseline, tocilizumab exposure was associated with decreased hospital-related mortality (HR 0.48; p=0.0025). This was not seen in patients with a CRP <15 mg/dL. 
  • The frequency of secondary bacterial infections was 17% in patients who received tocilizumab and 13% in those who did not. 

Limitations: 

  • This was a retrospective study; while propensity score matching was used, the possibility of confounding still exists.  
  • No information is given as to how patients were selected to receive tocilizumab, and a convenience sample was used; selection bias is possible.  
  • Tocilizumab start occurred well after symptoms began (median 9 days). 

Overall, in this retrospective cohort study, tocilizumab in patients with severe COVID-19 requiring ICU support was associated with a reduction in hospital­ related mortality. 

 

Tocilizumab in patients with severe COVID-19: an open-label retrospective cohort study (Guaraldi, August 2020). 

Study population: 

  • 544 hospitalized patients with severe COVID-19, of whom 365 received standard of care and 179 received tocilizumab plus standard of care. 
  • Standard of care included supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals and low molecular weight heparin. 
  • Patients with severe liver, kidney or hematologic impairments were excluded. 
  • After baseline, 53 (30%) of 179 patients treated with tocilizumab started glucocorticoids versus 61 (17%) of 365 patients in the standard of care group. 

Primary endpoint: 

  • Composite of mortality or invasive mechanical ventilation.  

Key findings: 

  • 33 (18%) of 179 patients treated with tocilizumab compared to 7 (16%) of 365 patients in the standard care group needed mechanical ventilation (p=0.41). 
  • 13 (7%) patients treated with tocilizumab compared to 73 (20%) patients in the standard care group died (p<0.0001). 
  • After adjustment for sex, age, recruiting center, duration of symptoms and Sequential Organ Failure Assessment (SOFA) Scoretocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0.61; p=0.020). 
  • Overall, 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0.0001). 

Limitations: 

  • As this was a retrospective study, confounding cannot be ruled out. 
  • Patients also received other therapies for COVID-19 
  • The treating physician determined if tocilizumab would be requested for the patient. The study was open label and used a convenience sample 
  • Shortages of tocilizumab occurred during the study period. Selection bias is possible.  
  • The participants who received standard of care only were older and therefore at higher baseline risk of invasive ventilation and death. 

Overall, in this retrospective open-label cohort study in patients with severe COVID-19, treatment with tocilizumab was associated with a reduced risk of invasive mechanical ventilation and death; however, secondary infections occurred more often in the tocilizumab group. 

 

Tocilizumab for treatment of mechanically ventilated patients with COVID-19: a retrospective cohort study (Somers, July 2020). 

Study population:  

  • Retrospective observational, controlled study of 154 patients with severe COVID-19 illness requiring mechanical ventilation at University of Michigan Medical Center. 
  • 78 patients received tocilizumab (47% treated within 24 hours of intubation; 26% >48 hours of intubation), 76 did not. 
  • Other therapeutic agents, including hydroxychloroquineremdesivir and corticosteroids, were also administered. 
  • Patients who received tocilizumab were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%) and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). 

Primary endpoint: 

  • Survival probability post-intubation. 

Key findings: 

  • In inverse probability of treatment weights (IPTW)-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR 0.5595% CI 0.33, 0.90). 
  • Tocilizumab was associated with improvement on a six-point ordinal scale that incorporated mechanical ventilation, development of superinfection and discharge from the hospital (OR 0.6; p≤0.03 for IPTW-weighted models). 
  • Patients who received tocilizumab were more than twice as likely to develop a superinfection compared to untreated controls (54% vs. 26%; p<0.001), driven primarily by a large increase in ventilator-associated pneumonia (45% vs. 20%; p<0.001). 

Limitations: 

  • As this was a retrospective study, confounding cannot be ruled out. 
  • The treating physician determined if tocilizumab would be requested for the patient; selection bias is possible. 
  • concurrent trial of sarilumab occurred at the institution during the study period. Patients who were ineligible for that trial were eligible for this study, which may limit the generalizability of the results.  
  • Patients treated with tocilizumab also received other therapeutic agents. 
  • Baseline differences in the study populations may have confounded the results.  

Overall, in this non-randomized observational study, tocilizumab use was independently associated with improved survival in patients with severe COVID-19 requiring mechanical ventilation. However, tocilizumab was associated with an increased incidence of secondary infections, primarily bacterial pneumonia.  

 

Additional Literature 

Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes (Price, June 2020). 

  • Retrospective observational study of 239 hospitalized patients with COVID-19, 104 (44%) of whom had severe COVID-19 
  • For tocilizumab-treated patients, 14-day survival was 87% and did not differ according to disease severity (83% vs. 91%; p=0.11). 

 

Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia (Capra, June 2020).  

  • Retrospective observational study of 85 hospitalized patients in Italy with COVID-19 related pneumonia and respiratory failure but not requiring mechanical ventilation 
  • Patients receiving tocilizumab showed significantly greater survival rate as compared to standard of care (hydroxychloroquinelopinavir and ritonavir; hazard ratio for death, 0.035; p=0.004), adjusting for baseline clinical characteristics. 

Safety 

Secondary infections with IL-6 inhibitors are possible and should be monitored in patients. Other common adverse reactions of anti-IL-6 agents include increased transaminase blood levels, infusion reactions and neutropenia. 

Resources

 

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