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Abkürzungen
ACEI
Angiotension converting enzyme inhibitors
ARB
Angiotension receptors blockers
ARDS
Acute respiratory distress syndrome
COVID-19
Coronavirus disease 2019
CI
Confidence intervals
CRS
Cytokine release syndrome
FiO2
Fraction of inspired oxygen
ICU
Intensive care unit
IL-6
Interleukin-6
IMV
Invasive mechanical ventilation
NSAID
Non-steroidal anti-inflammatory drugs
NIV
Non- invasive Ventilation
OR
Odds ratio
PaO2
Partial pressure of oxygen
SaO2
Oxygen saturation
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
The current coronavirus disease 2019 (COVID-19) pandemic induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused a global increase in hospitalizations and deaths. Unfortunately, effective medicines to fight this disease, especially in the severely ill patients, are still lacking [1]. Tocilizumab, a humanized monoclonal antibody used in rheumatoid arthritis treatment, might also be effective in treating severe COVID-19 as it could selectively target the interleukin-6 (IL-6) receptor [2]. Considering the uncertain efficacy of tocilizumab treatment in severe COVID-19, we conducted a systematic review and meta-analysis to clarify this added effect of tocilizumab.
We performed a systematic search of PubMed, Embase, Medline, Cochrane, and CNKI database through 25 July 2020, using the following search terms alone or in combination: (1) “COVID-19,” (2) “coronavirus,” (3) “SARS-CoV-2,” (4) “COVID,” (5) “anti-interleukin-6 receptor antibodies,” (6) “anti-IL-6 receptor antibodies,” (7) “anti-IL-6,” (8) “tocilizumab,” (9)“sarilumab,” and (10) “siltuximab.” Clinical trials regarding tocilizumab as a therapeutic intervention were selected. Two independent investigators selected eligible trials and extracted data from articles. Discrepancies in screening/data extraction were addressed by group discussion. Proportional variables were measured by odds ratio (OR) and corresponding 95% confidence intervals (CI). P values < 0.05 were considered statistically significant. Significant heterogeneity (P < 0.10 or I2 ≥ 50%) was evaluated by chi-square and I2 tests in a fixed-effect model. The comparison of the outcome between tocilizumab and control was conducted by using Review Manager 5.4 (Revman, The Cochrane Collaboration, Oxford, UK).
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Finally, 10 studies involving 1675 severe COVID-19 patients were included, among which only one trial was a randomized controlled trial, while the rest were all retrospective cohort studies. These studies included COVID-19 patients who were older/elderly (mean/median age ≥ 52 years) in America, Europe, and India, among whom 675 patients received tocilizumab, while 1000 patients underwent standard care. Severe COVID-19 patients received tocilizumab via intravenous or subcutaneous formulation, while doses and administration time points varied. Standard care included hydroxychloroquine, lopinavir/ritonavir, remdesivir, azithromycin, low weight heparin, and/or methylprednisolone, among others (Table 1). Our meta-analysis result revealed a significant difference in mortality between tocilizumab group (132/675, 19.5%) and control group (283/1000, 28.3%) in the fixed-effect model (OR, 0.47; 95%Cl, 0.36–0.60; P < 0.00001), suggesting efficacy of tocilizumab treatment for severe COVID-19. However, high heterogeneity was also observed (I2 = 74%, P < 0.0001) as shown in Fig. 1. SARS-CoV-2 infection might cause a hyperimmune response associated with acute respiratory distress (ARDS), the latteris a leading cause of death for severe COVID-19 [3]. Uncontrolled immune activation would result in cytokine storm, also known as cytokine release syndrome (CRS), appearing as overproduction of pro-inflammatory cytokines and chemokines [4]. Severe COVID-19 patients always present elevated inflammatory markers, among which the elevation of IL-6 is associated with severity of COVID-19 [5]. Besides, the upregulated expression of IL-6 receptor (IL-6R) was also detected in COVID-19 patients [6]. Therefore, IL-6/IL6R might serve as a messenger not only for transmitting inflammatory signals throughout the lung and other organs but also by activating cellular signal pathway, thus causing ARDS and multiple organ dysfunction. It is reasonable to speculate that IL-6 blockade is beneficial for avoiding poor prognosis.
Table 1
Study characteristics and demographics of included severely ill coronavirus disease 2019 (COVID-19) patients
COVID-19 with oxygen saturation of 94% or less despite giving supplemental oxygen of 15 L/min via non-rebreathing mask or PaO2/FiO2 ratio of less than 200
Death
Guaraldi G
Lancet Rheumatol
2020
Retrospective observational cohort study
Italy
544
69 (control)
64 (tocilizumab)
Oxygen supply to target SaO2 reaching at least 90%, hydroxychloroquine, azithromycin at the physician’s discretion when suspecting a bacterial respiratory super-infection, lopinavir–ritonavir or darunavir–cobicistat, low molecular weight heparin
Intravenous tocilizumab was administered at 8 mg/kg bodyweight (up to a maximum of 800 mg) administered twice, 12 h apart; the subcutaneous formulation was used when there was a shortage of the intravenous formulation, at a dose of 162 mg administered in two simultaneous doses, one in each thigh
Severe pneumonia defined at least one of the following: presence of a respiratory rate of 30 or more breaths per minute, peripheral blood SaO2 of less than 93% in room air, a ratio of PaO2 to FiO2 of less than 300 mmHg in room air, and lung infiltrates of more than 50% within 24–48 h, according to Chinese management guidelines for COVID-19
Death or invasive mechanical ventilation
Klopfenstein T Med Mal Infect
2020
Retrospective case-control study
France
45
71 (control)
77 (tocilizumab)
Hydroxychloroquine or lopinavir-ritonavir, antibiotics, less commonly corticosteroids
1 or 2 doses (no detail was reported)
All critically COVID-19 patients in tocilizumab group, fewer critically ill patients in control
Death and/or ICU admissions
Moreno-Pérez O
J Autoimmun
2020
Retrospective cohort study
Spain
236
57 (control)
62 (tocilizumab)
No detail was reported
Initial 600 mg, with a second or third dose (400 mg) in case of persistent or progressive disease
The standard tocilizumab dose was 8 mg/kg (maximum 800 mg) × 1, additional doses were discouraged
Severe COVID-19 patients requiring mechanical ventilation
Survival probability after intubation
Fig. 1
Forest plot of pooled mortality of severely ill coronavirus disease 2019 (COVID-19) patients from included studies
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Our meta-analysis had several limitations: (1) most included studies were retrospective analysis of cases, resulting in poor quality of the included studies; (2) the uniformity of the diagnostic criteria for severe COVID-19 needs to be improved, and the extraction of related factors is limited; and (3) extraction of the original data is incomplete, and some data cannot be converted due to the lack of relevant data.
In summary, this is the first meta-analysis demonstrating the efficacy of tocilizumab treatment in severely ill COVID-19 patients.
Acknowledgements
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Ethics approval and consent to participate
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Consent for publication
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Competing interests
The authors declare no conflict of interest.
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