key: cord-258602-dnzqiq8k
authors: Cortegiani, A.; Ippolito, M.; Greco, M.; Granone, V.; Protti, A.; Gregoretti, C.; Giarratano, A.; Einav, S.; Cecconi, M.
title: Rationale and Evidence on the use of Tocilizumab in COVID-19: A Systematic Review
date: 2020-07-20
journal: Pulmonology
DOI: 10.1016/j.pulmoe.2020.07.003
sha: 
doc_id: 258602
cord_uid: dnzqiq8k

BACKGROUND: Tocilizumab is an IL-6 receptor-blocking agent proposed for the treatment of severe COVID-19. The aim of this systematic review was to describe the rationale for the use of tocilizumab for the treatment of COVID-19 and to summarize the available evidence regarding its efficacy and safety. METHODS: MEDLINE, PubMed, EMBASE, pre-print repositories (bioRxiv and medRxiv) and two trial Registries were searched for studies on the use of tocilizumab in COVID-19 or SARS-CoV-2 infection, viral pneumonia, and/or sepsis until 20(th) June 2020. RESULTS: We identified 3 indirect pre-clinical studies and 28 clinical studies including 5776 patients with COVID-19 (13 with a comparison group, 15 single-arm). To date, no randomized trials have been published. We retrieved no studies at low risk of bias. Forty-five ongoing studies were retrieved from trial registries. CONCLUSIONS: There is insufficient evidence regarding the clinical efficacy and safety of tocilizumab in patients with COVID-19. Its use should be considered experimental, requiring ethical approval and clinical trial oversight.

The search for the holy grail of medical treatment for COVID-19 (Coronavirus Disease-2019) has led researchers to propose, among other options, the use of IL-6 receptor blocking agents for treatment of symptomatic patients 1 . With a death toll of nearly 400.000 worldwide and nearly 7 million known cases 2,3 the current lack of targeted effective medication and ongoing reliance on supportive treatment alone remains a major cause of concern 1 . J o u r n a l P r e -p r o o f Patients with the most severe COVID-19 symptoms (i.e. severe lung damage, septic shock and multiple organ failure) also exhibit what seems to be a hyper-inflammatory syndrome 4 . Early serology analyses identified higher IL-6 serum levels in patients with severe COVID-19 (particularly non-survivors) when compared to patients with mild and moderate disease 5,6 . As it has been proposed that elevated IL-6 levels may be associated with greater disease severity, the assumption is that they are also associated with worse clinical outcomes 7 and vice versa. This assumption underlies the current interest in anti-inflammatory therapies for the treatment of COVID-19 8 .

One of the IL-6 receptor blocking agents proposed for treatment of COVID-19, tocilizumab, was introduced in the early 2000's for treatment of autoimmune disorders such as refractory rheumatoid arthritis and systemic juvenile idiopathic arthritis (sJIA) 9 ,10 and has been approved by the FDA since 2017 for treatment of the cytokine release syndrome (CRS) that may occur following some forms of immunotherapy (e.g. CAR-T) 11 . The aim of this review was to describe the rationale and summarize the available evidence, direct and indirect, regarding the use of tocilizumab for treatment of SARS-CoV-2 infection and to identify and describe ongoing clinical trials with this drug.

A preliminary search conducted prior to formal study initiation suggested the evidence on the topic is likely to be limited, and yet patients are already receiving the drug, making the issue urgent. Therefore, the protocol of this systematic review was not registered.

PICO question: We sought information regarding the use of tocilizumab (I) for treatment of COVID-19, SARS-CoV-2 infection, viral pneumonia, and/or sepsis in any population (adults and children) or laboratory model (P) with or without a comparator (C).

We aimed to describe any treatment outcome whether solicited or unsolicited (O).

Search methods and article/trial inclusion/exclusion criteria: We conducted a systematic search of the MEDLINE, PubMed and EMBASE databases from inception to 20 th June 2020. We sought pre-clinical and clinical studies addressing the use of tocilizumab for treating COVID-19, SARS-CoV-2 infection, viral pneumonia, and/or sepsis.

Our search included the keywords 'tocilizumab', 'covid-19', 'coronavirus', 'sepsis, 'pneumonia, and 'viral infection' as exact phrases and a combination of subject headings according to databases syntax. We also searched the references of retrieved papers for additional potentially relevant papers. In order to find prepublication manuscripts, we surveyed the pre-print repositories biorRxiv and medRxiv from inception to 20 th June 2020 for clinical or pre-clinical studies about the use of tocilizumab in COVID-19 or SARS-CoV-2 infection, viral pneumonia, and/or sepsis. No language restrictions were imposed in any of the searches. Finally, to identify clinical trials studying treatment with tocilizumab for COVID-19, SARS-CoV-2 infection, viral pneumonia, and/or sepsis, we sought trials registered prior to 20 th June 2020 in the Chinese Clinical Trial Registry and Clinicatrial.gov. The databases and the trial registries were all screened independently and in duplicate by two of the authors (MI, VG).

In the second stage, the abstracts of all potentially relevant papers and pre-publication manuscripts were screened to identify relevant papers to be downloaded in full. After downloading potentially relevant articles, case reports, case series and reviews were excluded. Discrepancies and doubts regarding the relevance of papers downloaded in full were resolved by discussion and consensus with two additional authors (AC, MG). was used for single-arm nonrandomized studies 13 . The domains were rated in accordance with the requirements of the assessment tool used, with the lowest score achieved predominating as accepted. We used the Risk-Of-Bias VISualization (robvis) tool 14 to present the risk of bias assessments as either a plot or a table.

The initial search identified 2071 records from MEDLINE, PubMed and EM-BASE, pre-print repositories and other sources. After screening of titles and abstracts, removal of duplicates and evaluation of the additional sources retrieved, overall 31 published peer-reviewed papers and preprint non peer-reviewed papers were included (see the PRISMA flow diagram, available in Figure 1 for the study selection process).

Three papers described preclinical studies and 28 papers described clinical studies.

The characteristics of the clinical studies included were summarized (see Table 1 ). In addition, forty-five ongoing clinical studies were retrieved from the trial Registries.

These too were tabulated (see Table A .1, Appendix A).

The hypothetical justification for treating patients with tocilizumab in the context of COVID-19 stems from indirect findings. These include several pre-clinical studies describing a beneficial effect in cellular and murine models of sepsis and influenza 15-

In a cell model of sepsis (Human monocyte cell line THP-1), tocilizumab reduced the expression of TNF and IL-10, down-regulated inflammasome activation (reduced levels of NLRP3 and CASP1) and inhibited monocyte phagocytic activity. The J o u r n a l P r e -p r o o f authors of the study suggested that if suppressing the 'cytokine storm' is important when treating sepsis, these effects may be beneficial 15 .

Tocilizumab has also been evaluated in a murine model of Influenza A virus infection. Mice were anesthetized, intubated, and infected with mouse-adapted H1N1.

The tocilizumab treated group (8 mg/kg 24 hours before infection) and the controls were compared. Reduced skeletal muscle weakness (measured as digital grip strength), preserved muscle weight and increased short-term and long-term mortality were registered in the treated group, in comparison with controls. The mice manifesting distress were sacrificed and their deaths were also recorded as mortality 16 .

In a rat model of sepsis-induced acute lung and kidney injury, tocilizumab (4-8 mg/kg) reduced mortality. The authors also observed normalization of persistently high serum levels of IL-6 in septic rats after treatment with tocilizumab and improved lung wet/dry weight ratio and total protein content in the treatment group, in comparison with the sham group 17 . were multicenter studies. Thirteen studies included more than 100 patients, but in these studies the number of patients receiving tocilizumab was not large. One pub- The risk of bias assessments are shown in Figure 2 (nonrandomized studies with comparison) and in Appendix A, Table A .2 (nonrandomized single-arm studies). Ten studies were at moderate and five at serious risk of bias (ROBINS-I); thirteen studies were judged to be of "poor quality" (NOS). None of the studies were assessed as having a low risk of bias.

Tocilizumab is a humanized monoclonal antibody capable of interfering with the IL-6 soluble and membrane binding site of the receptor (IL-6R), thereby blocking the assembling of the activated complex with the transmembrane protein (gp130-IL-6-sILr). Tocilizumab is also able to block IL-6 trans-signaling 46 which is strongly related to the pro-inflammatory effects of IL-6 (e.g. release of acute phase proteins). Tocilizumab has a non-linear pharmacokinetic profile, with a dose-response curve that plateaus at an approximate dose of 800mg 46 . The half-life of tocilizumab is dose-dependent and comparable to the half-life of IgG1 47 .

IL-6 is a pleiotropic cytokine secreted by neutrophils, monocytes and macrophages and involved in the inflammatory response. It has a soluble (sIL-6R) and a membrane binding site (mIL-6R), constituting its receptors. IL-6 can bind its mIL-6R at low doses or, at higher doses, its sIL-6R (trans-signaling), creating the activated com- 

The current systematic review shows that although indirect preclinical data suggests rationale for using tocilizumab and observational studies suggest that treatment with tocilizumab may be associated with more favorable outcomes compared to standard care in patients with severe or critical COVID-19, up till now no RCTs have been published or made available pre-print regarding either the effectiveness or the safety of tocilizumab in the context of COVID-19.

The effects of tocilizumab against IL-6 related pro-inflammatory and pro-coagulant status 53 partially explain its potential role in COVID-19 54 . However, it is worth remembering that there is yet no evidence that suppressing the physiological inflammatory response to the virus is indeed beneficial. Previous experience with pharmaceutic inflammatory response modulation in patients with ARDS 55 and sepsis 56 have been notoriously unsuccessful. 

Although basic science suggests rationale for administration of IL-6 receptor antagonists to patients with COVID-19, the clinical evidence regarding the efficacy and J o u r n a l P r e -p r o o f safety of tocilizumab for COVID-19 remains observational only and is methodologically flawed. As concerns have also been raised regarding the possibility of secondary infection, the use of this drug should be limited to the context of a clinical trial and accompanied by ethical committee approval and/or informed consent, as well as appropriate monitoring for side effects.

All authors declare to have no competing interests.

AC conceived the content, drafted the manuscript, approved the final version to be submit- 

The risk of bias of the included nonrandomized studies with comparison groups is reported per single study and per domain. RoB was assessed using Risk of Bias in Nonrandomized Studies of Interventions, as appropriate. 

Pharmacologic Treatments for

Vademecum per la cura delle persone con malattia da COVID-19

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Immune-Based Therapy | Coronavirus Disease COVID-19

Clinical Management of COVID-19 -Interim guidance 27

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

None