key: cord-0872355-nadcsiii
authors: Coomes, E. A.; Haghbayan, H.
title: Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
date: 2020-04-03
journal: nan
DOI: 10.1101/2020.03.30.20048058
sha: 5a1cfee3acc1c0c1863e32f155417f69b111700e
doc_id: 872355
cord_uid: nadcsiii

Purpose: Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field. Methods: We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models. Results: Eight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed. Conclusions: In patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application.

A novel coronavirus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), emerged in December 2019 from Wuhan, China.1,2 Causing a febrile respiratory illness known as coronavirus disease 2019 , this is the third zoonotic coronavirus to infect humans in the past two decades.3 Compared to its predecessors, COVID-19 has demonstrated rapid capacity for dissemination, having already infected over 500,000 patients worldwide. 4 Such transmission has been fuelled by the high intrinsic reproductive number of 2-2.5,5-7 burgeoning community transmission,8-10 and potential occult transmission during the pre-symptomatic incubation period. [11] [12] [13] In China, nearly one-fifth of infected patients experience severe or critical illness,14

with an overall 2.3% case fatality rate and up to 6.1% of patients experiencing severe complications. 15 As preventative vaccines and effective antivirals remain unavailable, hostdirected therapeutics employing existing immunomodulatory agents must be explored. 16, 17 Coronaviruses have been observed to activate excessive and dysregulated host immune The biologic agent tocilizumab is a humanized monoclonal antibody targeting IL-6 receptors, blocking downstream pro-inflammatory effects of IL-6. It is approved by the Food and Drug Association for CRS induced by chimeric antigen receptor-T cell therapies and immunemediated rheumatic diseases. 21, 22 Exploratory studies have suggested that IL-6 inhibition may be beneficial in patients with severe COVID-19 and, despite the absence of definitive evidence, very high drug cost, and unclear potential for harm, it has already been incorporated into COVID-19 management guidelines generated in China and Italy. 23, 24 This may thus incite clinical use without definitive evidence supporting its safety in COVID-19. We therefore designed a systematic review and meta-analysis to assess the evidence describing IL-6 response in patients with COVID-19 and the existing and planned studies investigating the efficacy of tocilizumab to guide patient management, clarify guideline development, and inform future trials in this field.

We undertook a systematic review and meta-analysis investigating IL-6 dysregulation in patients diagnosed with COVID-19, and the potential role of IL-6 suppression with the administration of tocilizumab. Articles eligible for inclusion were observational cohort, casecontrol, or randomized controlled trials (RCTs) characterizing either serum IL-6 dynamics or therapeutic response to tocilizumab in adult or pediatric patients diagnosed with COVID-19.

This systematic review was undertaken with methodology in accordance with Cochrane Handbook,25 and reporting consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).26 An a priori protocol was designed and registered (PROSPERO identification: CRD42020175879).

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We designed a high sensitivity search strategy combining free text and keyword search term synonym clusters for COVID-19, combined with clusters for either IL-6 or tocilizumab. We then systematically searched for published articles in Ovid Medline Embase, pre-publication manuscripts in pre-print servers (Biorxiv, Medrxiv, and Chinxiv), and Google Scholar, and for planned trials in clinical trial registries (clinicaltrials.gov and the Chinese Clinical Trial Registry). All searches spanned January 1, 2019 to March 15, 2020 ; no exclusions were made for language, disease severity, or outcomes reported. We then conducted an expanded Ovid Medline and Embase database search from January 1, 2020 to March 15, 2020 for all published cohort studies reporting COVID-19 patient characteristics and outcomes (see Appendix for full search strategy) to ensure all studies reporting IL-6 levels in COVID-19 were identified. Reference lists of all included articles were also reviewed for potential eligibility of citations.

Two reviewers (E.A.C. and H.H.) independently undertook two-step selection, with studies screened via titles and abstracts followed by full-text review. Studies were included if they were RCTs, observational cohorts, or case-control in design, describing two or more patients diagnosed with COVID-19, and reported either measures of cytokine levels (with a focus on IL-6) or tocilizumab administration.

Data extraction was undertaken in duplicate (E.A.C. and H.H.) via standardized data extraction tables. Data were extracted from article text, tables, and graphs (employing figure analysis tools to quantitatively estimate curves for data). Data were collected for study design and setting, patient demographics, disease characteristics, levels of immune markers and . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03. 30.20048058 doi: medRxiv preprint indicators of systemic inflammation (inflammatory markers and cytokine levels), immunomodulatory agents administered (corticosteroids and intravenous immunoglobulin (IVIg)), and outcomes consistent with complicated infection (hospitalization, intensive care unit (ICU) admission, ARDS, invasive mechanical ventilation, renal replacement therapy, severe disease on clinical scoring tools (such as the Chinese New Coronavirus Pneumonia Prevention and Control Program or any others), or death). Conflicts were resolved by consensus discussion.

Count data and nominal variables are presented as proportions with percentages while continuous data are presented as means and standard deviations (SDs), or medians and interquartile ranges (IQR) or range. Measures of association relating clinical characteristics or receipt of tocilizumab with downstream clinical outcomes are presented in both unadjusted and adjusted forms, as availability of data permitted.

Results are described and summarized quantitatively and semi-qualitatively; for data deemed adequately homogenous in terms of patient characteristics, interventions, and clinical outcomes, meta-analysis was undertaken using random effects models. For statistical homogeneity, medians and IQRs were converted to means with SDs to maximize the number of studies eligible for meta-analysis.27 For such continuous data, we computed ratio of means (RoM) for each study and undertook meta-analysis via generic inverse variance methods (DerSimonian and Laird) to produce pooled measures of association, corresponding 95% confidence intervals (95%CI), and forest plots.25,28,29 Pre-specified subgroup analyses were conducted in regard to individual sub-definitions of complicated disease (as defined by primary studies investigators).

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Following removal of duplicates, our database search identified 1,219 unique citations, of which 112 articles were assessed via full text and eight studies were eligible for inclusion ( Figure   1 ). An additional three articles were identified via pre-print server searches; five planned or inprocess clinical trials were identified via clinical trial registry searches. A total of 16 articles were therefore eligible for inclusion, with eleven (n=1819) contributing to qualitative synthesis and six (n=1302) undergoing quantitative synthesis (meta-analysis) ( Figure 1 ).

Individual study characteristics and patient demographics are presented in Table 1 , and inflammatory markers, therapeutic interventions, and disease complications are presented in Table 2 . The summary of registered clinical trials planned or underway investigating tocilizumab treatment for COVID-19 is presented in Table 3 .

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Ten cohort studies (n=1798) described the immunological response to SARS-CoV-2 in patients diagnosed with COVID-19; mean age was 54.8±14.4 and 42% were female. All studies were set in China and all but one exclusively recruited hospital inpatients. Of studies reporting the use of immunomodulatory therapies, corticosteroids were the most commonly administered agents and were received by 32% of patients. In studies reporting survival, global mortality was 22% among patients diagnosed with COVID-19 (Tables 1 and 2 CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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One study examined the clinical impact of tocilizumab on severe COVID-19 disease.43 In a non-randomized, open-label, clinical trial, 21 patients with severe or critical COVID-19 were treated with tocilizumab. Mean age was 56.8 years and 14% of patients were female; critical disease was identified in four patients (19%). All patients received institutional standard of care including lopinavir and methylprednisolone, as well as tocilizumab 400 mg intravenously in one to two doses. Eighteen patients (85.7%) received tocilizumab once, and three patients (14.3%)

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 3) . Of these, all are based in China; one has since been cancelled by the principal investigator and one is planned but not yet recruiting. Two of the studies underway are multi-centre RCTs, with a third RCT pending recruitment. The cumulative anticipated sample size for the four planned studies will be n=518 and the methodological designs are complementary in target patient populations (all-comers, allcomers with elevated IL-6, severe cases with elevated IL-6, and severe cases with elevated IL-6 meeting diagnostic criteria for grade 2-3 CRS) and comparators (supportive therapy, favipiravir, continuous renal replacement therapy).

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In cohort studies assessing inflammatory response in COVID- 19 Figure 1) ;34 this was mostly driven by lack of control for confounding and potential inconsistencies in the measurement of the inflammatory mediators under study. For the assessment of tocilizumab treatment for COVID-19,43 risk of bias was determined to be severe following assessment by the ROBINS-I tool.32

In this systematic review and meta-analysis, we demonstrate that serum levels of IL-6 are significantly elevated in the setting of severe COVID-19 disease. Meta-analysis of the available data indicates that such increased levels are significantly associated with adverse clinical outcomes, including ICU admission, ARDS, and death. Patients with such complicated forms of COVID-19 had nearly three-fold higher serum IL-6 levels than those with non-complicated disease. In the single, non-randomized study published investigating the effect of tocilizumab treatment, decreased levels of serum IL-6, improved clinical and radiological status, and the absence of mortality were observed.

It is increasingly recognized that a dysregulated host immune response to foreign infectious pathogens is integral to the development of target organ dysfunction and a major contributor to morbidity and mortality. Specifically, the systemic inflammatory response in sepsis has been demonstrated to overlap with that of CRS;44,45 in patients with COVID-19 complicated by ARDS, such a hyperactivation of the humoral immune system with a prominent IL-6 response may suggest that part of the pathogenesis of complicated disease involves a . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Although designed and reported in accordance with standardized systematic review methodology25,26 and employing a highly sensitive search strategy, including the grey literature, this study has important limitations, much of which is inherent to the methodological quality of the included primary studies. All primary studies eligible for inclusion were conducted in China,

with several studies recruiting participants from the same centres; while none of the included studies described their data as having been previously published, this remains a theoretical possibility.55

We encountered high levels of statistical heterogeneity in our meta-analysis comparing IL-6 levels between patients with complicated and non-complicated disease; although we performed pre-specified sensitivity analyses, these failed to sufficiently explain this heterogeneity. Such residual heterogeneity may have arisen from multiple sources of variability between studies, most prominently due to likely differences in patient characteristics, lack of consecutive enrolment, variable timing of IL-6 measurement, the absence of a set definition of "supportive care", and differences in adjuvant immunomodulatory medications received, such as corticosteroids and IVIg, which may have affected both IL-6 response and patient outcomes.

Most studies included in this review were rated at moderate or high risk of bias, reflecting generally low methodological quality. This was primarily driven by a lack of control for confounding, inconsistencies or unclarity of the context in which IL-6 measurements were performed, and potential for selection bias due to lack of consecutive patient enrolment. Lastly, we identified only a single, non-randomized, single-arm study investigating the effect of tocilizumab treatment in patients with COVID-19; while promising, this provides only low-level . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03. 30.20048058 doi: medRxiv preprint evidence for the efficacy and safety of this drug for the treatment of severe COVID-19 and should be primarily considered hypothesis-generating at this time.

In this systematic review and meta-analysis, we demonstrate serum levels of IL-6 to be significantly elevated in the setting of complicated COVID-19 disease, and increased IL-6 levels to be in turn significantly associated with adverse clinical outcomes. This suggests that the . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03. 30.20048058 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint .

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is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03. 30.20048058 doi: medRxiv preprint 

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