Last updated: February 26, 2021
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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.
In some patients who progress to severe COVID-19 disease, host immune response can lead to lung injury and multisystem organ dysfunction (Huang, January 2020; Moore, May 2020). Several studies of patients with COVID-19 indicate that elevation of inflammatory markers, including proinflammatory cytokines such as interleukin-6, may be associated with more severe disease (Yang, February 2020; Mehta, 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.
Although several observational studies have suggested mortality benefit (Biran, August 2020; Somers, July 2020; Guaraldi, June 2020), data from randomized clinical trials of tocilizumab in COVID-19 have not shown a benefit. The first randomized controlled trial information made publically available were preliminary results of COVACTA, the Roche phase 3 randomized controlled trial of tocilizumab for severe COVID-19, which showed a failure to meet the primary endpoint of improved clinical status and the secondary endpoint of reduced patient mortality at week four. Sanofi/Regeneron’s sarilumab randomized controlled trial also indicated a failure to meet similar endpoints. Then, preliminary results released via press release from Roche’s phase 3 EMPACTA trial noted the study’s primary endpoint had been met: hospitalized patients who received tocilizumab were 44% less likely to progress to mechanical ventilation or death compared with patients who received placebo plus standard of care. The time to hospital discharge and mortality by Day 28 was not statistically significant. As of now, 3 additional peer-reviewed randomized trials have not shown a benefit of tocilizumab in 28-day mortality or clinical improvement in critically ill patients with COVID-19 (Salvarani, October 2020; Stone, October 2020; Hermine, October 2020); each of these studies had small sample sizes and methodologic differences.
IDSA guidelines conditionally suggest the use of tocilizumab in addition to standard of care (i.e., steroids) rather than standard care alone among hospitalized patients with progressive severe or critical COVID-19.
NIH guidelines recommend against the use of anti-IL-6 receptor monoclonal antibodies (such as tocilizumab and sarilumab) or anti-IL-6 monoclonal antibody (siltuximab) for the treatment of COVID-19, except in a clinical trial.
In summary: Findings from three peer-reviewed randomized trials did not show a benefit of tocilizumab in 28-day mortality or clinical improvement in critically ill patients with COVID-19. Two industry-sponsored randomized controlled trials did not show a benefit with the use of tocilizumab or sarilumab (another IL-6 mitigating agent), and another did - however, the only data available on these studies is via press release. Of note, the primary endpoints in each of these trials were different, the sample sizes of several were small, the study populations were different, and there were methodologic differences. In addition, it is not known what the optimal timing of tocilizumab would be, if it is effective in some situations. A study with variable times to administration would be helpful. Current data does not support the routine use of tocilizumab in hospitalized patients. At least five additional randomized controlled trials evaluating tocilizumab in patients with COVID-19 are currently underway.
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomized, controlled, open-label, platform trial (RECOVERY Collaborative Group, February 2021 - preprint, not peer-reviewed).
- This study examines the use of tocilizumab (400-800 mg, weight-based) versus standard of care among 4,116 COVID-19 patients at 131 National Health Service hospitals in the U.K.
- Eligible patients either had an oxygen saturation of less than 92% on room air or were receiving supplemental oxygen, and had a C-reactive protein of ≥75 mg/L.
- The median CRP was 143 mg/dL (IQR 107-204).
- 14% of patients were receiving invasive mechanical ventilation, 41% were receiving non-invasive respiratory support, and the remaining patients (45%) were receiving supplemental oxygen.
- 2,022 patients were allocated to the tocilizumab arm, and 2,094 to the standard of care arm.
- While this study was ongoing, results of the dexamethasone arm of the RECOVERY trial were published, which led to increased use of dexamethasone in patients hospitalized with COVID-19 and requiring oxygen. Therefore, the use of dexamethasone increased in hospitalized patients in the UK during this study of tocilizumab.
- 82% of the population was receiving corticosteroids at the time of randomization.
- Mean age was 63.6 years (SD 13.6).
- All-cause mortality within 28 days of randomization.
- The median time between hospitalization and randomization for both groups was 2 days (IQR 1-5 days).
- The median days since symptom onset in the tocilizumab group was 9 days (IQR 7-13 days); in the standard of care arm it was 10 days (IQR 7-14 days).
- Patients in the tocilizumab group had a lower 28-day mortality (29%) than those in the standard of care group (33%) (RR 0.86, 95% CI 0.77-0.96).
- 54% of patients in the tocilizumab group and 47% in the standard of care group were discharged alive within 28 days (RR 1.22, 95% CI 1.12-1.34).
- In patients who were not ventilated at baseline, those who received tocilizumab were less likely to be either initiated on mechanical ventilation or die (33% vs. 38%; RR 0.85; 95% CI 0.78-0.93).
- In patients receiving corticosteroids, 28-day mortality in the tocilizumab group was 27% versus 33% in the standard of care group (RR 0.80, 95% CI 0.70-0.90).
- In patients not on corticosteroids there was no significant difference in mortality (RR 1.16, 95% CI 0.91-1.48).
- The mortality rate of patients found in this study is higher than what has been generally found in hospitalized COVID-19 patients in the United States.
- The trial is an open-label design; researchers and patients in the study knew who was receiving which treatment. This could have introduced bias into the results.
- 17% of the patients allocated to the tocilizumab group did not receive the study drug, which may have affected the results.
- Patients without a confirmed SARS-CoV-2 PCR were included; however, in a subgroup analysis of the 94% of patients with PCR confirmed-disease the results were similar to the overall results.
- Given COVID-19 mortality among hospitalized patients has declined over time it would be helpful to assess if the mortality difference seen in this study holds when examining only patients from later in the study period.
Overall, in this large open-label randomized controlled trial of hospitalized patients with COVID-19 who required oxygen, non-invasive ventilation, or mechanical ventilation and who had evidence of systemic inflammation, tocilizumab reduced 28-day mortality when compared to standard of care; 82% of the patients in the study were also receiving corticosteroids, and the effect of tocilizumab on mortality appeared to be additive to the mortality benefit of corticosteroids.
Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19 - Preliminary Report (REMAP-CAP Investigators, January 2021).
- Randomized trial of adult patients with COVID-19 within 24 hours of commencing organ support in an intensive care unit, who were randomized to receive either tocilizumab (8mg/kg) (N=353), sarilumab (400mg) (N=48), or standard of care (control) (N=402).
- Respiratory and cardiovascular organ support-free days up to day 21.
- In this composite ordinal outcome, all deaths within hospital are assigned the worst outcome (–1).
- Among survivors, respiratory and cardiovascular organ support-free days are calculated up to day 21, such that a higher number represents faster recovery.
- Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0, 16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control, respectively.
- Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control.
- Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control.
- The estimates of the treatment effect for patients treated either with tocilizumab or sarilumab and corticosteroids in combination were greater than for any intervention on its own.
- Tocilizumab and sarilumab were effective across all secondary outcomes, including 90-day survival, time to ICU and hospital discharge, and improvement according to the World Health Organization ordinal scale at day 14.
- There were 9 serious adverse events reported in the tocilizumab group including 1 secondary bacterial infection, 5 bleeds, 2 cardiac events and 1 deterioration in vision.
- There were 11 serious adverse events in the control group, 4 bleeds and 7 thromboses, and no serious adverse events in the sarilumab group.
- Open-label trial design.
- As this is a preliminary report, some data are missing, including 11 outcomes. Some patients remain hospitalized, so long-term outcomes may differ from the short-term outcomes presented here.
Overall, in critically ill adult patients with COVID-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival, according to this preliminary report.
Tocilizumab in Patients Hospitalized with COVID-19 Pneumonia (Salama, January 2021).
- Randomized, double-blind, placebo-controlled, phase 3 study of 328 patients hospitalized with COVID-19 and evidence of pneumonia, randomized to receive standard of care treatments plus one or two doses of either tocilizumab (N=249) or a placebo (N=128).
- In the tocilizumab and placebo groups, 60.2% and 57.0% of the patients were men, respectively, and the mean (±SD) age was 56.0±14.3 years and 55.6±14.9 years, respectively.
- In the tocilizumab and placebo groups, 143 patients (57.4%) and 68 patients (53.1%), respectively, were Hispanic or Latinx, 35 (14.1%) and 21 (16.4%) were Black, and 33 (13.3%) and 15 (11.7%) were American Indian or Alaska Native.
- In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 196 (78.7%) and 101 (78.9%), respectively, received antiviral treatment, 55.4% and 67.2% of the patients received dexamethasone, and 52.6% and 58.6% received remdesivir.
- Mechanical ventilation or death by day 28.
- The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was significantly lower in the tocilizumab group (12.0%; 95% confidence interval [CI], 8.5 to 16.9) than in the placebo group (19.3%; 95% CI, 13.3 to 27.4) (hazard ratio, 0.56; 95% CI, 0.33 to 0.97; P=0.04 by the log-rank test).
- Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points: 95% CI, –5.2 to 7.8).
- In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group.
- Death occurred in 29 patients (11.6%) in the tocilizumab group and 15 patients (11.8%) in the placebo group.
- A slightly higher number of patients in the placebo group received steroids (which have been shown to lower mortality in patients with serious COVID-19 disease) compared to the tocilizumab group.
- Patients in both groups received standard of care, which may have impacted outcomes.
Overall, in this randomized, controlled trial of hospitalized patients with COVID-19 plus pneumonia, tocilizumab plus standard care was more effective than placebo plus standard care in reducing the likelihood of the composite outcome of progression to mechanical ventilation or death among hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation; however, there was no difference in the incidence of death from any cause.
Efficacy of Tocilizumab in Patients Hospitalized with COVID-19 (Stone, October 2020).
- 243 patients with confirmed COVID-19 (via PCR or IgM), hyperinflammatory states,
- AND at least two of the following signs:
- Fever (body temperature >38°C);
- Pulmonary infiltrates;
- Need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%.
- AND at least one of the following:
- CRP > 50 mg/L;
- Ferritin > 500 ng/mL;
- D-dimer level > 1000 ng/mL;
- LDH > 250 U/L.
- AND at least two of the following signs:
- Patients were randomized to receive tocilizumab or placebo in a 2:1 ratio.
- 58% of the population were men, and the median age was 59.8 years (IQR 21.7 - 85.4).
- 45% of the sample was Hispanic or Latino.
- 51% had a BMI of ≥30; 49% of the patients had hypertension, and 31% had diabetes.
- Intubation or death assessed in a time-to-event analysis.
- The HR for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI 0.38 to 1.81).
- The HR for disease worsening was 1.11 at 14 days (95% CI, 0.59 to 2.10).
- The median time to discontinuation of supplemental oxygen was 5.0 days in the tocilizumab group and 4.9 days in the placebo group (P=0.69).
- Serious infections occurred less in the tocilizumab group than placebo (8.1% vs.17.3%; P=0.03).
- Single-center study with relatively small sample size.
- Median time from symptom onset to randomization was not discussed; it is unclear when in the disease course patients received tocilizumab. They may have been ill for a prolonged period of time, or they may have been early in their disease course.
- Patients with a positive IgM were included and may have received tocilizumab later in their course of disease compared to patients who were diagnosed via PCR.
- Patients received other potentially efficacious agents, such as remdesivir and non-dexamethasone glucocorticoids. 18 patients in the tocilizumab group and 5 in the placebo group received steroids.
- The confidence intervals were wide.
Overall, in this randomized, double-blind placebo-controlled trial, the use of tocilizumab in patients with elevated inflammatory markers and severe disease did not reduce rates of intubation or death. The findings may be limited by a lack of clarity about where in the disease course patients were randomized.
Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial (Hermine, October 2020).
- Patients in 9 French hospitals with confirmed SARS-CoV-2 infection with moderate, severe, or critical pneumonia.
- Of 130 patients, 63 patients were randomly assigned to the tocilizumab group and 67 to the standard of care group.
- 42 were women (32%) and the median age was 64 years (IQR 57.1-74.3).
- In the tocilizumab group. antiviral drugs were administered in 11% of patients, glucocorticoids in 33%, and prophylactic or therapeutic anticoagulants in 94%.
- In the standard of care group, antiviral drugs were administered in 24% of patients, glucocorticoids in 61%, and preventive or therapeutic anticoagulants in 91%.
- The proportion of patients dead or needing noninvasive or mechanical ventilation on day 4 (score of >5 on the WHO ordinal scale (WHO-CPS).
- Survival with no need for noninvasive or mechanical ventilation at day 14.
- On day 4, 12 of 63 patients randomized to receive tocilizumab had a WHO-CPS score > 5 (19%), compared with 19 of 67 patients in the standard of care group (28%) [median posterior absolute risk difference (ARD), −9%; 90% CrI, –21 to 3].
- The posterior probability of negative ARD (tocilizumab better than standard of care) was 89.0% and ARD less than −5.5% was 68.4%.
- On day 14, at least 1 event (noninvasive ventilation, high-flow oxygen, mechanical ventilation, or death) had occurred in 15 patients in the tocilizumab group (24%) (cumulative incidence of event 24%; 95% CI, 13% to 35%) and 24 patients in the standard of care group (cumulative incidence 36%; 95% CI, 33%-58%).
- The posterior probability of any efficacy of tocilizumab (HR<1) was 95.0%, and of moderate or greater efficacy (HR<0.85) was 87.4% (posterior median HR, 0.58; 90% CrI, 0.33-1.00).
- The number of patients with mechanical ventilation or death at Day 14 was 11 in the tocilizumab group (17%) and 18 in the standard of care group (27%). The posterior probabilities of HR less than 1 and HR less than 0.85 were 92.5% and 84.4%, respectively (posterior median HR, 0.58; 90% CrI, 0.30-1.09).
- The HR for mechanical ventilation or death was 0.58 (90% CrI, 0.30 to 1.09).
- At day 28, 7 patients had died in the tocilizumab group and 8 in the standard of care group (adjusted HR, 0.92; 95% CI 0.33-2.53).
- Serious adverse events occurred in 20 patients in the tocilizumab group (32%) and 29 in the standard of care group (43%) (P = 0.21).
- The sample size was small.
- Unblinded study, which could have led to measurement bias.
- There was no placebo.
- Patients may have received antiviral agents, anticoagulants, and corticosteroids.
- An analysis of patients with moderate vs severe disease separately was not performed, just ICU vs non-ICU.
- Includes a narrow segment of the COVID-19 patient population (patients with a WHO-CPS score of exactly 5 and requiring at least 3 L/min oxygen) - these results may not be generalizable to other populations.
- The median time from symptom onset to randomization is not discussed; it is thus unclear when the patient received tocilizumab in their disease course. They may have been ill for a prolonged period of time, or they may have been early in their disease course.
Overall, in this small randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, tocilizumab did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of noninvasive ventilation, mechanical ventilation, or death by day 14. Results showed no difference in day-28 mortality. The findings may be limited by a lack of clarity around where the patients were in their disease course when randomized.
Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial (Salvarani, October 2020).
- Prospective, open-label, randomized clinical trial of 126 patients in 24 hospitals in Italy with confirmed COVID-19 pneumonia and Pao₂/Fio₂ ratio between 200 and 300 mm Hg and either fever or a CRP ≥10 mg/dL and/or CRP level increased to at least twice the admission measurement.
- Patients were excluded if they had advanced age or multiple comorbidities, or if the treating physician deemed the patient wouldn’t receive ICU care.
- 60 patients randomized to tocilizumab; 63 randomized to the control group (intention-to-treat).
- The median age was 60.0 years (IQR 53.0-72.0), and 61.1% of patients were male.
- Patients in the control arm had lower C-reactive protein levels, IL-6, ferritin, and D-dimer levels and were more frequently treated with antivirals compared with patients in the tocilizumab group at baseline, despite randomization.
- Primary composite outcome including: entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao₂/Fio₂ ratio less than 150 mm Hg, whichever came first.
- 17 of 60 patients in the tocilizumab arm (28.3%) and 17 of 63 patients in the standard of care group (27.0%) showed clinical worsening within 14 days after randomization (rate ratio, 1.05; 95% CI, 0.59-1.86).
- 11 patients in total were admitted to ICU, all within 14 days after randomization, with no major differences between the 2 arms (10.0% vs. 7.9%; rate ratio, 1.26; 95% CI, 0.41-3.91).
- Mortality was comparable at 14 days (1.7% vs. 1.6%; rate ratio, 1.05; 95% CI, 0.07-16.4) and at 30 days (3.3% vs. 1.6%; rate ratio, 2.10; 95% CI, 0.20-22.6) between the 2 groups.
- The tocilizumab group did not have increased infections compared to the control group.
- Small sample size.
- Lack of a placebo, unblinded study.
- The mortality rate in the study was much lower than the general rate in Italy (2.4% vs. 13.2%).
- Because 14 patients in the control group received tocilizumab after they reached the primary endpoint, subsequent secondary outcomes may have been affected.
- Clinical characteristics differed in the 2 groups, although they were not statistically significant.
- The median time from symptom onset to randomization is not discussed; it is thus unclear when the patient received tocilizumab in their disease course. They may have been ill for a prolonged period of time, or they may have been early in their disease course. It is also not known what the optimal timing of tocilizumab would be, if it is effective in some situations. A study with variable times to administration would be helpful.
Overall, in this small randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao₂/Fio₂ ratio between 200 and 300 mm Hg who received tocilizumab, there was no observed benefit in disease progression compared with standard of care. The findings may be limited by a lack of clarity around where the patients were in their disease course when randomized.
Association Between Early Treatment with Tocilizumab and Mortality Among Critically Ill Patients With COVID-19 (Gupta, October 2020).
- Retrospective multicenter cohort study of 3924 adults admitted with COVID-19 to 68 U.S. hospital ICUs from March 4 to May 10, 2020.
- Patients were randomized within the first 2 days of intensive care unit admission.
- The median age was 62 years (IQR, 52-71 years).
- 433 patients received tocilizumab within the first 2 days of ICU admission (11.0%).
- Tocilizumab-treated patients were younger (median age, 58 [IQR, 48-65] years vs. 63 [IQR, 52-72] years) and generally had fewer comorbidities than the non-tocilizumab group:
- Hypertension, 234 (54.0%) vs. 2186 (62.6%);
- Coronary artery disease, 39 (9.0%) vs. 504 (14.4%);
- Congestive heart failure, 23 (5.3%) vs. 386 (11.1%).
- After applying inverse probability weighting, baseline and acute severity-of-illness characteristics were well-balanced between groups.
- Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.
- A total of 2,058 patients were discharged alive (52.4%); 1,544 died (39.3%), and 322 remained hospitalized at last follow-up (8.2%).
- The 1,544 patients who died included 125 of the 433 patients treated with tocilizumab (28.9%) and 1,419 of the 3,491 patients not treated with tocilizumab (40.6%) (unadjusted HR, 0.64; 95% CI, 0.54-0.77).
- In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92).
- The estimated 30-day mortality was 27.5% in the tocilizumab-treated patients (95% CI, 21.2%-33.8%) and 37.1% in the non-tocilizumab-treated patients (95% CI, 35.5%-38.7%) (risk difference, 9.6%; 95% CI, 3.1%-16.0%).
- Retrospective study.
- The treatment groups differed at baseline before applying inverse probability weighting, with tocilizumab-treated patients younger and having fewer comorbidities.
- Data collection did not include the number of administered doses of tocilizumab or other administered agents, such as corticosteroids.
- Patients who were hospitalized for 1 week or more before ICU admission were excluded; this could limit the generalizability of the results.
Overall, this multicenter retrospective cohort study of critically ill patients with COVID-19 found an association of lower in-hospital mortality risk in patients treated with tocilizumab within the first 2 days of ICU admission, compared with patients whose treatment did not include early use of tocilizumab. However, these findings may be affected by unmeasured confounding.
Decreased mortality in COVID-19 patients treated with Tocilizumab: a rapid systematic review and meta-analysis of observational studies (Malgie, September 2020).
- Patients with COVID-19 included in studiews that examined tocilizumab use vs no tocilizumab use; studies where tocilizumab was reserved for severe disease or cytokine release syndrome were excluded.
- 10 studies comprising 1358 patients were included.
- 4 studies were from Italy, 3 were from the USA, 2 were from Spain and one was from France.
- Mortality, expressed as the number of patients who died within the study period.
- 9 of the 10 studies were considered high quality.
- Of the 1358 patients, 554 patients received tocilizumab and 804 patients did not.
- There were 95 deaths in the tocilizumab group and 222 deaths in the control group.
- The risk ratio was 0.27 (95% CI 0.12 - 0.59); the risk difference was 12% (95% CI 4.6% - 20%) in favor of the tocilizumab group.
- Based on the higher CRP and the lower PaO₂-FiO₂ ratio for the TCZ group, the TCZ group appeared to be more severely affected by COVID-19 at baseline than the control group.
- There was substantial heterogeneity with respect to the primary endpoint, with an I2 of 61%; it appeared this was due to one study. When this study was excluded the I2 was 19%.
- In studies that used glucocorticoids the treatment effect of tocilizumab on mortality was smaller compared to studies that did not use glucocorticoids (I2=33%).
- The individual studies included in the meta-analysis were observational, and thus at risk for bias.
- Multiple confounders exist in the studie included, such as the use of medications for COVID-19, including immune supperive medications, differences in the study populations, the dose and timing of tocilizumab, etc.
- The authors used crude risks for the calculation of RR and RD, which does not allow control of baseline imbalances by treatment group.
IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections (preprint) (Kimmig, September 2020).
- Retrospective study of 111 critically ill COVID-19 patients at a single center in Chicago, of whom 54 received tocilizumab, as per inter-hospital COVID-19 guidance.
- Histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy were also included.
- The mean age in the tocilizumab group was 64.5 years (IQR 50.9-78.1); 68.5% were male.
- The mean age in the non-tocilizumab group was 61.8 years (IQR 78.4-45.2); 43.9% were male.
- During an 8-week span, the prevalence of secondary infection and outcomes were compared in patients who did and did not receive tocilizumab.
- Among 54 patients who received tocilizumab, 44 patients (81%) received 400 mg X 1; the rest received doses ranging between 160-800 mg.
- Secondary infections were defined by positive culture data or clinical suspicion resulting in the initiation of antimicrobials.
- Receiving tocilizumab was associated with a higher incidence of secondary bacterial infections including hospital-acquired pneumonia and ventilator-associated pneumonia (26 (48.1%) vs. 16 (28.1%). p=0.021).
- Diagnosis of infection was made approximately 5 days after the administration of tocilizumab (4.9±3.0 days, 95% CI 3.67-6.17).
- Patients who received tocilizumab had higher mortality (35.2% vs. 19.3%, p=0.020).
- Tocilizumab use was independently positively associated with the development of bacterial infections with an odds ratio of 2.76 (95% CI 1.11-7.20) p=0.0295.
- 7 cases underwent autopsy. In 3 patients who received tocilizumab, there was evidence of pneumonia on pathology. Of the 4 patients who had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage.
- This is a retrospective study with a lack of randomization; bias is possible.
- The decision to use tocilizumab was at the discretion of the primary team; it is therefore possible there was heterogeneity with determination to use.
- The authors report the higher mortality seen in patients who received tocilizumab was related to secondary infections, but as the use of tocilizumab was not standardized it is possible patient characteristics not measured in the study made them more likely to receive tocilizumab.
- 19% of the patietns who received tocilizumab received non-standard doses (as defined by inter-institutional guidance); the risk for adverse events may have been differed by dose.
- The authors note a higher use of immunosuppressive agents in the tocilizumab group 13%) but do not provide further details; the authors note that after removing these patients from the analysis more patients in the tocilizumab group had bacterial infections, but given the small numbers in the study it is difficult to interpret this analysis.
Overall, in this small retrospective study of patients with COVID-19, there was a higher incidence of secondary bacterial infections and fungal infections in those that received tocilizumab compared to those not receiving tocilizumab; however, the use of tocilizumab was at the discretion of the primary team, which limits the study findings.
Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study (Biran, August 2020).
- 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.
- Hospital-related mortality.
- 358 (57%) of 630 patients died; of these, 102 (49%) received tocilizumab and 256 (61%) did not.
- A 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.
- 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).
- 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.
- Composite of mortality or invasive mechanical ventilation.
- 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) Score, tocilizumab 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).
- 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).
- 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 hydroxychloroquine, remdesivir 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).
- Survival probability post-intubation.
- In inverse probability of treatment weights (IPTW)-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR 0.55; 95% 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).
- 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.
- A 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.
Tocilizumab in nonventilated patients hospitalized with COVID-19 pneumonia (Salama, October 2020). Nonventilated patients hospitalized with COVID-19 pneumonia were randomized to tocilizumab (8 mg/kg IV) or placebo plus standard of care. Of these, 249 patients received tocilizumab and 128 received placebo (2:1). The cumulative proportion (CI 95%) of patients who had required mechanical ventilation or died by day 28 was 12% (8.52% to 16.86%) and 19.3% (13.34% to 27.36%) for the tocilizumab and placebo arms, respectively (log-rank p=0.0360; hazard ratio, 0.56 [95% CI, 0.33 to 0.97]). All-cause mortality by day 28 was 10.4% with tocilizumab and 8.6% with placebo (weighted difference, 2.0% [95% CI, -5.2% to 7.8%]).
Observational study on off-label use of tocilizumab in patients with severe COVID-19 (Albertini, September 2020). In this single-center observational cohort study of 44 patients hospitalized with COVID-19, 22 patients diagnosed with COVID-19 were treated with tocilizumab and were compared with 22 patients not treated with tocilizumab. The average respiratory rate was lower in the tocilizumab group than in the control group (21.5 vs. 25.5 breaths/min at day 14, 95% CI −7.5 to −0.4; p=0.03). Patients tended to be intubated less during the course of the disease (2/22 vs. 6/22, 95% CI −0.4 to 0.1; p=0.12).
Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes (Price, June 2020). In this retrospective observational study of 239 hospitalized patients with COVID-19, 104 (44%) of whom had severe COVID-19, in153 patients who received tocilizumab, 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). In this retrospective observational study of 85 hospitalized patients in Italy with COVID-19 with respiratory failure not requiring mechanical ventilation, 62 received tocilizumab; these patients showed significantly greater survival rate as compared to standard of care (hydroxychloroquine, lopinavir and ritonavir; hazard ratio for death, 0.035; p=0.004), adjusting for baseline clinical characteristics.
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.