Optimal use of tocilizumab for severe and critical COVID-19: a systematic review and meta-analysis

Introduction

In December 2019, a novel virus named Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) that causes Coronavirus Disease-19 (COVID-19) began to spread worldwide and it become a pandemic globally¹. COVID-19 manifestation ranges broadly from mild symptoms to severe illness. Several studies probed multiple types of inflammatory cytokine levels and found higher levels of interleukin (IL)-1β, IL-1RA, IL-6, IL-7, IL-8, IL-10, IFN-γ, monocyte chemoattractant peptide-1, macrophage inflammatory protein (MIP)-1A, MIP-1B, granulocyte-colony stimulating factor, and tumor necrosis factor-alpha in severe COVID-19 patients^2,3. COVID-19 causes severe illness due to activation of the cytokine cascade leading to cytokine release syndrome (CRS), which is delineated by systemic inflammation and multiple organ failure. Therefore, prompt strategies for treating CRS are essential for COVID-19 patients^3–5.

IL-6 is a proinflammatory cytokine that plays an essential role in CRS. Activation and secretion of IL-6 by infected monocytes, macrophages, and dendritic cells cause two main effects; a plethora effect on immune cells and the innate immune system, and increased vascular permeability due to secretion of vascular endothelial growth factor (VEGF), resulting in hypotension and acute respiratory distress syndrome^3,5,6.

Tocilizumab, a humanized monoclonal antibody interleukin-6 receptor (IL-6R) inhibitor, is recommended by the National Health Commission of China for treating severe and critically ill patients with elevated IL-6⁷. Recently, several case reports demonstrated tocilizumab could improve the clinical manifestations of seriously ill COVID-19 patients. Several retrospective case-control, single-armed studies and randomized clinical trials declared promising results of tocilizumab treatment in SARS CoV-2 infection. Nevertheless, some systematic reviews and meta-analyses showed an unclear risk of bias and reported debatable results about tocilizumab's benefit as a treatment^6,8–13. We performed a systematic review and meta-analysis to research the risks and benefits of tocilizumab and investigate outcomes from different baseline criteria for administration of tocilizumab as a treatment for severe and critically ill COVID-19 patients.

Methods

Literature search

The search strategy¹⁶, using medical subject headings (MeSH) terms, involved the use of a combination of the following keywords: (tocilizumab) OR (anti-IL-6 monoclonal antibody) OR (IL-6 blockade) OR (IL-6 receptor antagonist) AND severe AND critical ill AND (COVID-19) OR (novel coronavirus disease) OR (SARS-CoV-2). The search was performed by two authors (BAM and CW) in PubMed, Embase, Medline, and Cochrane (March 1^st to October 31^st 2020, last searched 2^nd November 2020) and the language was limited to English. We selected 606 full text and free full text articles from PubMed, included all article types, then we excluded them based on the exclusion criteria of case reports, reviews, editorials, letters, duplicate records, and studies with incomplete data. From filter selection of clinical trials, meta analyses, randomized control trials and systematic reviews within one year we got 42 articles after removing 655 articles (see Figure 1).

Figure 1. Study selection.

Results

Outcomes of tocilizumab treatment

There is a significant difference between the SOC group and tocilizumab group (RR: 1.65; 95% CI = 1.37, 2.00) from all-cause mortality events (Figure 2) and days until death (time to death after first intervention) (MD: 6.03; 95% CI: 0.31, 11.76). There is no significant difference between the length of stay (MD: -2.05; 95% CI: -5.25, 1.16). All outcomes showed evidence of heterogeneity and the random effect model was adopted.

Figure 2. Forest plot outcome between SOC group and TCZ group.

A) All-cause mortality event; B) Subgroup CRP >100 mg/L; C) Subgroup PaO2:FiO2 200-300 mmHg; D) Subgroup PaO2:FiO2 <200 mmHg. SOC, standard of care; TCZ, tocilizumab; CRP, C-reactive protein; SD, standard deviation; CI, confidence intervals.

Subgroup analysis

There is a significant difference in all-cause mortality events for patients with CRP level >100 mg/L (RR: 1.78; 95% CI: 1.35, 2.34); P/F ratio 200–300 mmHg (RR: 1.84; 95% CI: 1.35, 2.50); and P/F ratio <200 mmHg (RR: 1.44; 95% CI: 1.28, 1.63). For length of stay in hospital, CRP level <100 mg/L showed a significant difference (MD: -7.75; 95% CI: -10.31, -5.20) (Figure 3).

Figure 3. A forest plot length of stay baseline criteria for administration of tocilizumab CRP < 100 mg/L.

SOC, standard of care; TCZ, tocilizumab; CRP, C-reactive protein; SD, standard deviation; CI, confidence intervals.

Within the subgroup analysis, evidence of homogeneity was found and we used the fixed effect model for all-cause mortality events for P/F ratio <200 mmHg and length of stay for CRP level ≥100 mg/L, CRP level <100 mg/L, and P/F ratio 200–300 mmHg. The other parameters were analyzed using the random effect model.

Discussion

To the best of our knowledge, this is the first meta-analysis investigating the optimal use of tocilizumab in severe and critically ill COVID-19 patients. The 26 studies analysed, mostly retrospective studies with only two clinical trials (Salvarini et al. and Somerset al.), suggest that treatment with tocilizumab gives fewer all-cause mortality events than the SOC^18–43. Lan et al. showed that tocilizumab could not provide additional benefits for clinical outcomes of severe COVID-19, but the mortality rate was lower than the SOC, although this was not statistically different¹⁰. Studies from Kaye et al., Zhao, J et al., and Zhao, M et al., reported that tocilizumab showed a statistically significant reduction in mortality and fatality than the SOC, similar to our results^9,11,13.

Nevertheless, hospital and ICU lengths of stay did not differ between tocilizumab and SOC^{20–26,31,32,35,40,43}. Only one study (Eimer et al.) showed that length of stay in hospital on tocilizumab was shorter than the SOC and it was able to shorten the duration of use of a ventilator. However, for the variable days until death, intervention with tocilizumab resulted in a shorter duration until death than the SOC due to secondary infections after tocilizumab treatment²⁰.

Selection criteria from included studies for using tocilizumab treatment for COVID-19 mostly included similiar clinical manifestations but baseline laboratory parameters varied. Clinical manifestations for tocilizumab treatment eligibility were frequency of respiration ≥30 breaths/min and peripheral capillary oxygen saturation (SpO2) <93% while breathing ambient air. Laboratory markers for tocilizumab treatment eligiblity were P/F ratio, CRP, ferritin, LDH and IL-6. In most studies, baseline criteria for administration of tocilizumab were level of CRP ≥100 mg/L (normal values <6 mg/L), ferritin ≥900 ng/mL (normal value <400 ng/mL), LDH >220 U/L, and P/R ratio 200–300 mmHg^{18–20,24,36,39,40,42}. .However, several studies used baseline criteria for administration of tocilizumab of CRP <100 mg/L and P/F ratio <200 mmHg^{23,30–34,36,43,44}.

The SMACORE study used baseline criteria for administration of tocilizumab of CRP >50 mg/l, procalcitonin <0.5 ng/mL and P/F ratio <300 mmHg in seriously ill COVID-19 patients. Tocilizumab was first administered at 8 mg/kg (up to a maximum 800 mg per dose) intravenously, repeated after 12 hours if no side effects were reported after the first dose. The result from this study was that tocilizumab administration did not reduce mortality rate or ICU admissions²³.

Similar selection criteria were used by Masia et al.; the eligible participants had CRP >50 mg/l and tocilizumab was given at an initial dose of 600 mg intravenously for a weight of >75 kg or 400 mg when the weight was <75 kg. If their condition worsened, treatment was reevaluated following 24 hours. A second dose of tocilizumab (400 mg) was given if there was no clinical response. The result from this study was that tocilizumab administration significantly reduced the mortality rate³².

In the randomized trial by Salvarini et al., the selection criteria for tocilizumab treatment were P/F ratio of 200–300 mmHg. Tocilizumab was given intravenously at a starting dose of 8mg/kg until 800 mg within eight hours of randomization, and a second dose administered after 12 hours. This study showed no benefit on disease progression in the tocilizumab group compared with the SOC group⁴².

According to the Moreno-Perez study, candidates for tocilizumab treatment had poor prognostic factors or worsening disease. One of indication for worsening condition was CRP level >100 mg/L or P/F ratio <200 mmHg³⁴.

Our subgroup analysis showed tocilizumab had a good result when CRP levels were ≥100 mg/L and P/F ratio was 200–300 mmHg or <200 mmHg. Administration of tocilizumab for CRP levels <100 mg/L did not reduce mortality and showed a longer length of stay in hospital.

There are various types of administration of tocilizumab treatment among studies. Tocilizumab can be administrated at a low dose (400 mg or 4 mg/kg) or high dose (800 mg or 8 mg/kg), as a single-dose and then continue with the second dose if clinical condition worsens in 24 hours (maximum 800 mg per dose), intravenously or subcutaneously.

Strengths and limitations of the analysis

Meta-analysis on this topic has not been previously conducted; only mortality events and ICU admissions have been reported by previous studies^9–11,13. In our study, we evaluate all-cause mortality events, length of stay in hospital, and days until death (time to death after first intervention) and carry out subgroup analysis of baseline criteria for administration of tocilizumab treatment. This study has a larger sample size; 2112 patients in the tocilizumab group and 6160 patients in the SOC group.

The limitations of this study are that we didn’t perform subgroup analysis outcomes according to the dosage and route of administration tocilizumab and didn’t analyze secondary outcomes after tocilizumab treatment like bacterial or fungal infections, thrombotic events, major bleeding, or requirement of invasive mechanical ventilation requirement. The results of our study should be used carefully because most studies included were retrospective and only two were randomized clinical trials, since it has been difficult to perform randomized trial during this pandemic. A meta-analysis of more clinical trial data will provide a more precise result for tocilizumab treatment in severe and critically ill COVID-19 patients.

Conclusion

Our study provides meaningful data regarding the effect of tocilizumab in severe and critically ill confirmed COVID-19 patients. Tocilizumab is a treatment option for severe and critically ill COVID-19 patients and it appears to reduce mortality events, especially when CRP level >100 mg/L, P/F ratio 200–300 mmHg, and P/F ratio <200 mmHg. However, tocilizumab should be used cautiously according to proper selection criteria to achieve optimal results and its use should be tailored according to the eligibility of the patients. Further studies are still required, especially regarding optimal dosage and administration route of tocilizumab in COVID-19 patients.

Data availability