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What data are there to support use of tocilizumab in critically ill patients with COVID-19?

Background

Cytokine storm syndrome is an inflammatory condition that can develop in a subset of critically ill patients who are infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the virus implicated in causing coronavirus disease 2019 (COVID-19).1 These patients develop an inflammatory syndrome with rapidly worsening pulmonary infiltrates, failure of multiple organ systems, and associated increases in inflammatory markers. Initial reports on patients with COVID-19 from Wuhan, China showed that patients with the most severe disease had significantly elevated serum levels of inflammatory markers, such as C-reactive protein,  interleukins (IL) 2, 6, 8, and 10, and tumor necrosis factor alpha; patients with more severe disease also had significantly higher mortality rates.2-4 Betacoronaviruses, such as SARS-CoV-2, infect immune cells including monocytes, dendritic cells, and macrophages. Once these cells are activated, various inflammatory cytokines are released, which cause a cascade reaction activating other inflammatory mediators and ultimately leading to vascular leakage, development of hypotension, and acute respiratory distress syndrome.5

Given the association between elevated inflammatory markers, COVID-19 disease severity, and mortality, these inflammatory pathways are currently being investigated as potential therapeutic targets in the treatment of COVID-19. A recent meta-analysis conducted in China evaluating IL-6 levels in 1,426 patients with COVID-19 from 9 observational studies found that patients with severe disease had significantly higher mean serum IL-6 levels compared to those with non-severe disease (mean difference 38.6 pg/mL; 95% confidence interval [CI], 24.3 to 52.9; p<0.001).6 Meta-regression from 5 of these studies with mortality data showed a significantly higher mortality risk among patients with higher serum IL-6 levels at admission (regression coefficient, 0.01; 95% CI, 0.01 to 0.03; p=0.03). Tocilizumab is an IL-6 receptor antagonist that is currently Food and Drug Administration-approved for use in patients with various inflammatory conditions including rheumatoid and juvenile idiopathic arthritis, giant cell arteritis, and cytokine release syndrome associated with chimeric antigen receptor T cell-induced cytokine release syndrome.7 Due to its mechanism of action against IL-6 and proven efficacy in other inflammatory conditions, tocilizumab is currently being investigated as a potential treatment option for COVID-19 in critically ill patients.

Guidelines

Currently, guidelines on management of COVID-19 from major organizations including the National Institutes of Health, Infectious Diseases Society of America, and Surviving Sepsis Campaign do not make specific recommendations on use of IL-6 inhibitors in patients with COVID-19 due to a lack of sufficient data.8-10 Therefore, the purpose of this FAQ is to summarize literature on the use of tocilizumab in critically ill patients with COVID-19.

Literature Summary

A literature search was performed to identify clinical trials investigating the efficacy or safety of tocilizumab in patients with COVID-19 who are critically ill; 8 observational studies were identified at the time the search was performed.11-18 Of the trials, which are further described below in the Table below, 2 were prospective, the remainder were retrospective, and 3 had control groups. None of the studies were randomized or blinded, and the largest population studied included 112 patients.

Of the 3 studies which included control groups, tocilizumab had mixed effects, with 2 studies finding it to be associated with a significant reduction in mortality and 1 study showing no difference in mortality or intensive care unit admission rates between tocilizumab and standard care.11-13 The remaining, uncontrolled studies generally showed that patients who were administered tocilizumab displayed clinical improvement, as evidenced by improved respiratory status, discontinuation of mechanical ventilation, and relatively low mortality rates; however, it is difficult to determine the true effect of tocilizumab from these studies since a control group was not used. Patients in many of the trials also received standard care, often in addition to tocilizumab.14-18 Standard care was somewhat variable from study to study and included different drugs.11-15,17 This was potentially due to differences in country-specific guidance on management of COVID-19 and the time frame that the study was conducted in relation to the start of the pandemic. Many of the drugs that were included as standard care (eg, hydroxychloroquine, azithromycin, lopinavir/ritonavir) are also currently under investigation as treatment options for COVID-19, which could have impacted the results of the trials (especially uncontrolled trials). When described, the administered dose and route of tocilizumab also varied, with single doses as low as 80 mg and as high as 800 mg and administration via either the intravenous or subcutaneous route.11,12,14-18 It is also unclear which patients are most appropriate for treatment with tocilizumab since the eligibility criteria varied among trials and definitions of “severe” illness also differed.11-18

Table 1. Studies evaluating the use of tocilizumab in critically ill patients with COVID-19.11-18
Study design Subjects

 		InterventionsaResultsAuthors’ conclusions
Capra 202011 

Retrospective, single center, non-randomized  observational study

N=85 patients consecutively admitted to a single hospital in Italy with COVID-19 pneumonia and acute respiratory syndrome that did not require mechanical ventilation but had one of the following indicating severe respiratory syndrome: SaO2 ≤93% or PaO2/FiO2 ≤ 300 mmHgTCZb + standard care  (n=62)

Standard care (n=23)

Standard care patients were admitted to the hospital prior to availability of tocilizumab and received treatment with hydroxychloroquine and  lopinavir/ritonavir		Patients treated with TCZ were significantly more likely to survive. In the TCZ group, 3.22% of patients died compared to 47.8% of patients in the control group (HR for death, 0.035; 95% CI, 0.004 to 0.347; p=0.004)

92% of patients treated with TCZ were discharged from the hospital vs 42.1% of control patients		While the results of this trial seem to support low-dose TCZ to reduce mortality and prevent respiratory distress in patients with COVID-19, randomized clinical trials are needed
Colaneri 202012

Retrospective, non-randomized,  single center  database study

N=112 patients admitted to a referral hospital in Italy with a confirmed diagnosis of COVID-19TCZ 8 mg/kg (max 800 mg); repeated at 12 hours if no side effects associated with first dose (n=21)

Standard care (n=91)

To be eligible for treatment with TCZ  patients were required to have a CRP >5 mg/dL, PCT <0.5 ng/mL, PaO2/FiO2 <300 mmHg and ALT <500 U/L.

Standard care patients were treated with hydroxychloroquine, azithromycin, heparin prophylaxis, and a 10-day methylprednisolone taper		Patients treated with TCZ did not have significant differences in 7-day mortality or admission to the ICUThis study suggests that treatment with TCZ does not improve mortality or ICU admission rates in patients with COVID-19; however, additional data are needed
Klopfenstein 202013

Retrospective, single center, non-randomized, case-control study

N=45 patients at a single hospital in France with confirmed COVID-19, symptom onset within 7 days, at least 2 laboratory indicators of inflammation or markers which may indicate higher risk for mortality (eg, high lactate dehydrogenase), and >25% lung damage visible on CT scan requiring at least 5 L/min of oxygenTCZ (1 or 2 doses) + standard care

Standard care

Standard care consisted of hydroxychloroquine or lopinavir-ritonavir, antibiotics, and occasional corticosteroids		The combined outcome of death and/or ICU admission was significantly higher with standard treatment (72%) vs TCZ (25%; p=0.002)

When separated, ICU admission was significantly higher with standard treatment (44%) vs TCZ (0%; p<0.001). Mortality was elevated in patients who received standard treatment (48%) vs TCZ (25%); however, this difference was not statistically significant.		When combined with standard treatment, TCZ reduced ICU admissions and/or mortality
Alattar 202014

Retrospective, non-randomized,  uncontrolled,  observational study

N=25 patients admitted to the ICU with COVID-19 who received ≥1 dose of TCZ and completed ≥14 days of follow upTCZ 400 mg (most common) or 600 mg

Patients with elevated CRP levels that required ICU admission were eligible for TCZ

All patients received standard care. Those with severe disease also received treatment with hydroxychloroquine, azithromycin, lopinavir/ritonavir, ribavirin and/or interferon α 2a		At day 14, 9 patients (36%) were discharged alive from the ICU, 3 (12%) died, and 13 (52%) remained in the ICU

The proportion of patients requiring mechanical ventilation decreased from 84% when TCZ was initiated to 60% on day 7 (p=0.31) and 28% on day 14 (p=0.001)

The most frequently experienced adverse events were anemia (64%), ALT increase (44%), and prolonged QT interval (20%)		Although the effects on inflammatory markers and need for ventilatory support are encouraging, adequately powered RCTs must be conducted to confirm these findings
Toniati 202015

Prospective, non-randomized, uncontrolled, single center  observational study		N=100 consecutive patients at a single hospital in Italy with severe COVID-19 infectionTCZ 8 mg/kg (max 800 mg) x2  IV infusions 12 hours apart. A third infusion (24 hours after the second) was optional

Patients were eligible for TCZ if they had rapidly progressive respiratory failure that was refractory to pharmacologic treatment and ventilatory support

All patients also received standard care with an antiviral (lopinavir/ritonavir or remdesivir), antibiotic prophylaxis (azithromycin, ceftriaxone, or piperacillin/tazobactam), hydroxychloroquine, and dexamethasone		By 24 to 72 hours post-TCZ administration, 58% of patients showed rapid improvement of clinical and respiratory symptoms, 37% stabilized, and 5% worsened

By 10 days post-TCZ, 77% of patients improved or stabilized, 61% had significant improvement upon chest x-ray, and 15% were discharged from the hospital

Among patients treated in the ICU (N=43), 74% improved, 2% stabilized, and 24% died		Tocilizumab may be considered as a rescue treatment option after failure or inaccessibility of other treatments; however, efficacy should be validated in large clinical trials
Sciascia 202016

Prospective, multicenter, non-randomized uncontrolled study

N=63 patients hospitalized in Italy with confirmed severe COVID-19 infection with pulmonary involvement (SaO2 <93% or PaO2/FiO2 <300 mmHg), and pro-inflammatory or pro-thrombotic markers out of rangeTCZ 8 mg/kg IV or 324 mg SC x 1 to 2 doses, separated by 24 hours7 patients (11%) died by day 14; mortality rates were similar between those that received IV and SC TCZ

No reports of moderate to severe AE were observed

Increased likelihood of survival noted in patients who received TCZ within 6 days of admission (HR, 2.2; 95% CI, 1.3 to 6.7; p<0.05)		TCZ may be a safe option to treat patients with severe COVID-19 who are hospitalized; controlled trials are needed to support these findings
Xu 202017

Retrospective, multicenter, non-randomized,  uncontrolled   observational study

N=21 patients in China with severe (respiratory rate ≥30 breaths/min, SaO2 ≤93% or PaO2/FiO2 ≤300 mmHg)  or critical (documented respiratory failure requiring mechanical ventilation, shock, other organ failure, or need for ICU admission) COVID-19TCZ 4 to 8 mg/kg IV x1 (recommended dose 400 mg; max 800 mg)

Additional dose given within 12 hours if fever present

All patients received standard care with lopinavir/ritonavir, inferferon α, and ribavirin, a glucocorticoid, and other agents to manage symptoms as needed		All patients had normalization of body temperature within 1 day after initiation of TCZ; 15 patients (75%) required less oxygen within 5 days after treatment

By day 5, the percentage of patients with abnormal laboratory values (WBC count, lymphocyte percentage, CRP, and procalcitonin) decreased; 100% of patients had elevated IL-6 levels throughout treatment

CT scans showed absorption of lesions in 90.5% of patients after treatment with TCZ		Patients treated with TCZ had an improvement in clinical symptoms and were protected from deterioration related to COVID-19 infection
Luo 202018

Retrospective, single center, uncontrolled  observational study

N=15 patients at a single hospital in China with confirmed COVID-19TCZ (doses ranged between 80 and 480 mg on day 0; a few patients received subsequent doses on day 1 (n=3), day 2 (n=3), and day 3 (n=1))On first draw after administration of TCZ, CRP levels were significantly decreased from baseline (126.9 mg/L to 11.2 mg/L; p<0.01)

Serum IL-6 levels generally spiked initially and then decreased		While the study showed that patients had a positive response to TCZ, the results of this study should be interpreted with caution due to the small number of cases, short duration of treatment, and challenge associated with use of laboratory parameters as a surrogate marker for disease activity
Abbreviations: AE=adverse effects; ALT=alanine aminotransferase; CI=confidence interval; COVID-19=coronavirus disease 2019; CRP=C-reactive protein; CT=computed tomography; FiO2=fractional inspired oxygen; HR=hazard ratio; ICU=intensive care unit; IL=interleukin; IV=intravenous; PaO2=arterial partial pressure of oxygen; PCT=procalcitonin; RCT=randomized controlled trial; SaO2=oxygen saturation; SC=subcutaneous; TCZ=tocilizumab; WBC=white blood cell
aDose provided when indicated in the study
bThe first 2 patients admitted received a dose of 800 mg IV, 33 patients received 400 mg IV x1 dose, and 27 patients received 324 mg SC x1 dose

Clinical considerations

Based on the observational trials described above, an optimal dose for tocilizumab has not yet been established, and it is unclear whether additional doses should be administered. Guidance from China suggests that an initial dose between 4 and 8 mg/kg (recommended dose 400 mg) can be given over at least 1 hour in patients with severe COVID-19 who have elevated serum IL-6 levels and extensive lung lesions.19 A single extra dose (same dose as initially given) may be administered (max 800 mg) if the first dose is ineffective. While the existing literature has some variability in the dosages of tocilizumab administered, they generally fall within this recommended range. There is no clear definition as to what might constitute an “ineffective dose” to warrant administration of a second dose. A randomized, double-blinded, controlled study that is underway to evaluate tocilizumab in COVID-19 states that a second dose may be given if clinical symptoms do not improve or worsen.20 Most of the trials described above did not specify criteria for administration of a second dose; one study described administration of a second dose if fever was present 12 hours after administration of the first dose.17

Adverse effects that have been reported in clinical trials of tocilizumab for other indications include infection risk, gastrointestinal perforation, infusion reactions, anaphylaxis, immunogenicity, malignancies, and abnormal laboratory findings including thrombocytopenia and elevated liver enzymes and lipids.7 Although tocilizumab is administered differently for other conditions, clinicians should monitor for these adverse effects when treating a patient with COVID-19 with tocilizumab. Case reports of patients with COVID-19 who received treatment with tocilizumab have reported some of these adverse effects, including candidemia, intestinal perforation, and hypertriglyceridemia.21-23

Ongoing clinical trials

As noted by the authors of most of the observational studies described above, larger, randomized, double-blinded, controlled trials are needed to fully elucidate the role of tocilizumab in the treatment of critically ill patients with COVID-19. To date, there are a number of clinical trials with these attributes underway, including 3 large, randomized, controlled, double-blinded, multicenter trials (NCT04356937,  NCT04372186, and NCT04320615). As more high-quality data becomes available, tocilizumab’s role in the treatment of COVID-19 will be more apparent.

Conclusion

A subset of critically ill patients with COVID-19 may develop cytokine storm syndrome, an inflammatory condition that can result in rapid clinical deterioration. Abnormally elevated serum levels of IL-6 have been noted in these patients, which may be a therapeutic target of interest. Tocilizumab, an IL-6 inhibitor, has shown efficacy in other inflammatory conditions, and is currently being investigated for treatment of critically ill patients with COVID-19. To date, only observational trials have been conducted to assess the efficacy of tocilizumab for COVID-19, many of which are uncontrolled. Although this literature shows that tocilizumab may potentially lead to more rapid clinical improvement and reductions in mortality when administered to critically ill patients with COVID-19, there are a number of limitations that reduce the applicability of these results. Multiple larger, randomized, controlled trials are currently underway which will better elucidate the potential role of tocilizumab in critically ill patients with COVID-19.

References

  1. England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes Blood Rev. Published online May 15, 2020. doi: 10.1016/j.blre.2020.100707
  2. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846‐848. doi: 10.1007/s00134-020-05991-x
  3. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. doi: 10.1136/bmj.m1091
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  8. Immune-based therapy under evaluation for treatment of COVID-19. National Institutes of Health COVID-19 treatment guidelines. Updated May 12, 2020. Accessed May 20, 2020. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/
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  11. Capra R, De Rossi N, Mattioli F, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med. Published online May 13, 2020. doi: 10.1016/j.ejim.2020.05.009
  12. Colaneri M, Bogliolo L, Valsecchi P, et al. Tocilizumab for treatment of severe COVID-19 patients: Preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms. 2020;8(5):E695. doi: 10.3390/microorganisms8050695
  13. Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect. Published online May 6, 2020. doi: 10.1016/j.medmal.2020.05.001
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  15. Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. Published online May 3, 2020. doi: 10.1016/j.autrev.2020.102568
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  22. Gonzálvez Guardiola P, Díez Ares JÁ, Peris Tomás N, Sebastián Tomás JC, Navarro Martínez S. Intestinal perforation in patient with COVID-19 infection treated with tocilizumab and corticosteroids. Report of a clinical case. Cir Esp. Published online April 29, 2020. doi:10.1016/j.ciresp.2020.04.030
  23. Morrison AR, Johnson JM, Ramesh M, Bradley P, Jennings J, Smith ZR. Letter to the editor: Acute hypertriglyceridemia in patients with COVID-19 receiving tocilizumab. J Med Virol. Published online April 21, 2020. doi:10.1002/jmv.25907

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
June 2020

The information presented is current as of May 19, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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