key: cord-0885711-7xsuvpfv
authors: Corominas, Hèctor; Castellví, Ivan; Diaz-Torné, César; Matas, Laia; de la Rosa, David; Mangues, Maria Antònia; Moya, Patricia; Pomar, Virginia; Benito, Natividad; Moga, Ester; Sosa, Nerea Hernandez-de; Casademont, Jordi; Domingo, Pere
title: Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2
date: 2021-05-14
journal: Medicine (Baltimore)
DOI: 10.1097/md.0000000000025923
sha: d9442ef7dbddc6d96c1004ad5426ad3124ae5ef0
doc_id: 885711
cord_uid: 7xsuvpfv

Blocking IL-6 pathways with sarilumab, a fully human anti–IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used “off-label” sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome.

Facing the second wave of this COVID-19 outbreak, the spread of positive cases worldwide has brought a landscape of fear and respect with a maddening increase of cases over 122,036,229 and 2,694,915 deaths at March 15th. [1] [2] [3] However, several trials are ongoing to consider biological therapy as an alternative for unresponsive and life-threatening cases of cytokine release syndrome (CRS). [4] [5] [6] [7] 

We recently hypothesized that blocking IL-6 pathways with (sarilumab/(Kevzara), a fully human anti-IL-6R antagonist monoclonal antibody that binds membrane bound and soluble human IL-6R with high affinity, may potentially curb the inflammatory storm. [8, 9] In the present emergency, according to our hospital guidelines we used "off-label" sarilumab in cases of critically advanced CRS, considering the higher 10-fold increase affinity for the receptor that sarilumab presents over tocilizumab. [10, 11] 

In this retrospective, single-centre observational report, we describe a case-series of 5 patients with severe, progressive and life-threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) infection. All patients or their legal representatives gave oral informed consent. An expert committee prescribed the therapy according to more than one of the following criteria:

1. Age-adjusted Charlson Comorbidity Index scores <4, [12] 2. Interstitial pneumonia with severe respiratory failure (score = 2), 3. rapid respiratory worsening requiring noninvasive or invasive ventilation (score ≥3 on the COVID respiratory severity scale),

Editor: Jianli Tao.

This study was part of a fully supported research grant (COV20/00070) from ISCIII Spain.

The authors have no conflicts of interests to disclose.

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party. The datasets generated during and/or analyzed during the current study are publicly available.

the presence of severe systemic inflammatory response criteria was fully present: high levels of D-dimer (>1500 ng/mL) or progressively increasing D-dimer or alternatively high levels of IL-6 (>40 pg/mL).

General exclusion criteria for IL-6R antagonist therapy were: AST/ALT values greater than 5 times the upper limit of normality, neutrophils <500 cells/mm, platelets <50000 cells/ mmc, documented sepsis by pathogens other than SARS-CoV-2, presence of comorbidity that can lead, according to clinical judgment, to a poor prognosis, complicated diverticulitis or intestinal perforation, or ongoing skin infection (uncontrolled pyodermitis with antibiotic treatment). The use of IL-6R was approved in strict compliance with the Hospital Ethics Committee with the given code (IRS-TOC-2020-01).

Our 5 SARS-CoV-2 elderly patients, 3 men and 2 women, (median age: 72-2, [range: 62-79], with good quality of life age adjusted Charlson <4) previous to the outbreak, when first admitted to hospital received hydroxychloroquine plus azithromycin. When they presented radiological progression, increased oxygen needs, and/or worsening of biological parameters, they were considered candidates to sarilumab.

Four of them were on noninvasive ventilation (NIV), and 1 was on invasive mechanical ventilation. An average median peak of the blood markers present before receiving sarilumab: CRP: Table 1 . Two patients died; one with previous chronic obstructive pulmonary disease and obesity, and the other with high chronic kidney disease grade. Among both we observed the highest CRP: 480 (mg/dl), ferritin level: 3394 (mg/L), D-Dimer: 83275 (ng/mL), IL-6: 380 (pg/mL) and the lowest lymphocyte count: 0,45 (x109/L). In the follow-up 3 patients fully recovered and were discharged home with improvement in the control chest X-Ray.

Sarilumab, is a fully human anti-IL-6R antagonist monoclonal antibody that binds membrane bound and soluble human IL-6R with high affinity to treat adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to 1 or more disease-modifying antirheumatic drugs. [10] Sarilumab, Inhibits IL-6-mediated signaling pathway which involves ubiquitous signal-transducing glycoprotein 130 (gp130) and the Signal Transducer and Activator of Transcription-3, only in the presence of IL-6. IL-6 also stimulates diverse cellular responses such as proliferation, differentiation, survival, and apoptosis and can activate hepatocytes to release acute-phase proteins, including C-reactive protein (CRP) and serum amyloid. [9] Scarce existing evidence supports its use in the case of CRS, and has only been described in 4 previous reports in COVID-19. [13] [14] [15] [16] [17] Those 5 patients were in life-threatening critical condition not candidates to further active measures, neither to tocilizumab therapy because of comorbidities, limited access or temporary lack Table 1 XXXX. of stock. Therefore, sarilumab treatment was then started. Three out of 5 patients fully recovered and were later discharged home. We may argue the role that NIV and invasive ventilation played, but considering the worsening of those not treated with sarilumab, we assume the importance of the blockade of IL-6R. Interestingly, all blood active phase reactants improved after 24 hour. The crux of matter was the patients were treated late enough to avoid invasive ventilation measures. Thus, since they had an ominous clinical picture, advanced age and a late stage of the disease, our belief is that sarilumab therapy helped to reverse their CRS loop.

Currently, the optimal treatment for SARS CoV-2 pneumonia has not been defined yet. In a context of international emergency, we believed sarilumab therapy was a rationale option to minimize or reverse CRS in these critically ill patients. Ideally, we could have treated these patients sooner, but the emergency situation and the lack of recommendations for treating elderly patients prompted us to use sarilumab. Hopefully, in the near future we expect to have randomized controlled trials (23 studies registered in NCT, including ours) and data from observational studies (IIBSP-COV-2020-28) to support clinical decisions.

In summary, we suggest that sarilumab can be useful in a global context of IL-6R antagonist indication, as an alternative to tocilizumab or other therapies targeted to modulate mild to severe COVID-19-associated CRS.

Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Why tocilizumab could be an effective treatment for severe COVID-19?

A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Corticosteroid therapy for critically Ill patients with Middle East Respiratory Syndrome

Effectiveness and safety of intravenous tocilizumab to treat COVID-19-associated hyperinflammatory syndrome: covizumab-6 observational cohort

Facing the SARS-CoV-2 (COVID-19) outbreak with IL-6R antagonists

Sarilumab, a fully human monoclonal antibody against IL-6Ra in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor (il-6r) alpha

Age-adjusted charlson comorbidity index and 30-day morbidity in pelvic surgeries

Overview on the use of IL-6 agents in the treatment of patients with cytokine release syndrome (CRS) and pneumonitis related to COVID-19 disease

Study Group; SARI-RAF Study Group members. Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study

A comprehensive review on sarilumab in COVID-19

Sarilumab versus standard of care for the early treatment of COVID-19 pneumonia in hospitalized patients: SARTRE: a structured summary of a study protocol for a randomised controlled trial

Subcutaneous Sarilumab in hospitalised patients with moderate-severe COVID-19 infection compared to the standard of care (SARCOVID): a structured summary of a study protocol for a randomised controlled trial

Medicine (2021) 100:19 www.md-journal