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Tocilizumab for severe COVID-19: A promising intervention affecting inflammation and coagulation

  • Marcel Levi
    Correspondence
    Corresponding author at: University College London Hospitals, 250 Euston Road, London NW1 2PG, UK
    Affiliations
    University College London Hospitals NHS Foundation Trust, Department of Medicine, London, UK

    Cardio-metabolic Programme-NIHR UCLH/UCL BRC, London, UK
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      The COVID-19 pandemic is causing significant morbidity and mortality worldwide. Although most patients experience predominantly a respiratory tract infection, a proportion of patients progresses to a more severe and systemic disease, characterised by treatment-resistant pyrexia, acute lung injury with adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction, associated with substantial mortality [
      • Bhatraju P.K.
      • Ghassemieh B.J.
      • Nichols M.
      • et al.
      Covid-19 in critically ill patients in the seattle region - case series.
      ,

      Roberts C.M., Levi M., Schilling R., Lim W.S., Grocott M.P.W., McKee M.Covid-19: a complex multisystem clinical syndrome BMJ2020; on line.

      ].
      Severe COVID-19 infection is associated with increased levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and several interleukins (IL), as well as other chemokines, inflammatory mediators, and damage-associated molecular patterns (DAMPs) [
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ]. In a subset of the most severely affected COVID-19 patients, a cytokine ‘storm’ profile can be found, characterized by high levels of proinflammatory cytokines and remarkably increased levels of TNF-α, IL-2, IL-6, granulocyte-colony stimulating factor, and several chemokines [
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ]. A cytokine storm is a hyper-immune phenomenon leading to an uncontrolled release of pro-inflammatory cytokines that will cause a systemic inflammatory state. It has been hypothesized that this pattern mimics secondary haemophagocytic lymphohistiocytosis (sHLH), an under-recognised, hyper-inflammatory syndrome characterized by fulminant hyper-cytokinaemia, excessive coagulation activation and multi-organ failure [
      • Valade S.
      • Mariotte E.
      • Azoulay E.
      Coagulation disorders in hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
      ].
      In the pathogenesis of severe COVID-19 the cytokine IL-6 seems to play a dominant role. Plasma levels of IL-6 are higher than usually seen in severe (bacterial) sepsis. In addition, increased IL-6 levels are a strong predictor of mortality and IL-6 levels were found to be related to more severe lung injury [
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Liu T.
      The potential role of IL-6 in monitoring severe cases of coronavirus disease.
      ]. In a meta-analysis of 9 studies in patients with severe COVID-19 IL-6 levels closely correlated to the severity of the disease and –again- mortality [
      • Aziz M.
      • Fatima R.
      • Assaly R.
      Elevated interleukin-6 and severe COVID-19: a meta-analysis.
      ]. This has also observed in other coronavirus infections, such as severe adult respiratory syndrome (SARS) or influenza A infection [
      • de Jong M.D.
      • Simmons C.P.
      • Thanh T.T.
      • et al.
      Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.
      ]. In view of this central role of IL-6 in the pathogenesis of severe COVID-9 infection, therapies specifically directed against this cytokine may be considered.
      Tocilizumab is a monoclonal anti-soluble IL-6 receptor antibody an has been licensed for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and giant cell arteritis. It is also established treatment for Castleman's disease and the cytokine release syndrome that is seen as a complication of CAR-T cell therapy for lymphoproliferative malignancies and other cancer [
      • Campochiaroa C.
      • Della-Torrea E.
      • Cavallia G.
      • et al.
      Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.
      ]. Interestingly, cytokine release syndrome is the consequence of an uncontrolled immune activation characterized by the occurrence of a ‘cytokine storm’ which is not very different from the one seen in the most severe COVID-19 patients [
      • Lee D.W.
      • Gardner R.
      • Porter D.L.
      • et al.
      Current concepts in the diagnosis and management of cytokine release syndrome.
      ]. Hence, tocilizumab has been proposed for patients with severe COVID-19 as well [
      • Ortiz-Martinez Y.
      Tocilizumab: a new opportunity in the possible therapeutic arsenal against COVID-19.
      ]. Initial clinical observations from China have shown an improvement in pneumonia and associated symptoms in patients with COVID-19 treated with tocilizumab [
      • Luo P.
      • Liu Y.
      • Qiu L.
      • Liu X.
      • Liu D.
      • Li J.
      Tocilizumab treatment in COVID-19: A single center experience.
      ]. Subsequently, several retrospective cohort studies have focused on the efficacy and safety of this treatment.
      In this issue of the European Journal of Internal Medicine three groups of authors report on the use of tocilizumab in patients with severe COVID-19. Campochiaro et al. studied 65 patients with COVID-19 that were admitted to the hospital, of which 32 received tocilizumab [
      • Campochiaroa C.
      • Della-Torrea E.
      • Cavallia G.
      • et al.
      Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.
      ]. It is not clear what determined the treatment with the antibody, as this was at the discretion of the attending physician. They observed a non-significant lower mortality in tocilizumab-treated patients (16% versus 33% in non-treated patients). In another study, Capra et al. included 85 patients with COVID-9 and respiratory failure and in this series 62 patients received tocilizumab, as soon as the antibody became available [
      • Capra R.
      • De Rossi N.
      • Mattioli F.
      • et al.
      Impact of low-dose tocilizumab on mortality rate in patient with COVID-19 related pneumonia.
      ]. They observed a lower mortality (2 out of 62 patients (3.2%) in the tocilizumab group compared to 11 out of 23 patients (47.8%) in the untreated group. It should be mentioned, however, the untreated group should be considered as historic controls and it cannot be excluded that increasing insights in the optimal treatment of severe COVID-19 may have contributed to the result. Lastly, Morena et al. observed in 51 patients with severe COVID-19 that after initiation of tocilizumab there was a lowering of the body temperature, normalization of C-reactive protein (CRP) and a restoration of lymphopenia [
      • Morena V.
      • Milazzo L.
      • Oreni L.
      • et al.
      Off-lable use of tocilizumab for the treatment of SARS-Cov-2 pneumonia in Milan, Italy.
      ]. In this study side effects of tocilizumab were systematically assessed and the authors found hepatic enzyme elevation in 29%, thrombocytopenia in 14% and bacterial or fungal infections in 27% of patients.
      These studies (and similar observations in the literature) suggest that tocilizumab may be a promising candidate to improve the outcome of patients with severe COVID-19 infections. However, these results need confirmation in a prospective and properly controlled randomized trial before this treatment can be advocated. Genentech has recently announced a phase III randomized controlled clinical trial with tocilizumab for severe COVID-19. In addition, side effects of tocilizumab seem significant and will not only need systematic evaluation but also proper offset against potential benefits of tocilizumab.
      It is tempting to speculate why specific anti-IL-6 targeted treatment would be more effective than more general anti-inflammatory interventions, such as corticosteroids, intravenous immunoglobulin, or other cytokine blockers (such as anakinra). Apart from the prominent role of IL-6 in the host-defense response in COVID19 it may be that specific beneficial effects of tocilizumab on the coagulation abnormalities associated with COVID-19 are also relevant. Many patients with severe COVID-19 infections present with a coagulopathy that is reminiscent but also distinct of other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation or thrombotic microangiopathy [
      • Thachil J.
      • Wada H.
      • Gando S.
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID-19.
      ,
      • Levi M.
      • Thachil J.
      • Iba T.
      • Levy J.
      Coagulation abnormalities and thrombosis in patients with COVID-19 infection.
      ]. The occurrence of this coagulopathy in COVID-19 infected patients is associated with a higher risk of death. In addition, patients with this coagulopathy have a very high risk of thromboembolic complications [
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ]. In experimental and clinical studies in bacterial sepsis IL-6 was shown to be the pivotal cytokine in the upregulation and expression of tissue factor on mononuclear cells and possibly endothelial cells [
      • Levi M.
      • van der Poll T.
      • Buller H.R.
      Bidirectional relation between inflammation and coagulation.
      ]. Infusion of a monoclonal anti-IL-6 antibody resulted in the complete abrogation of coagulation activation in experimental sepsis [
      • van der Poll T.
      • Levi M.
      • Hack C.E.
      • et al.
      Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees.
      ]. In addition, studies in cancer patients receiving recombinant IL-6 indicated that indeed thrombin is generated following the injection of this cytokine [
      • Stouthard J.M.
      • Levi M.
      • Hack C.E.
      • et al.
      Interleukin-6 stimulates coagulation, not fibrinolysis, in humans.
      ]. It might therefore be hypothesized that blockage of IL-6 activity in COVID-19 not only benefits the inflammatory response but also the activation of coagulation in these patients.
      As there is at present not yet a specific and unequivocally effective treatment for COVID-19 it is important to develop and evaluate adjuvant treatment options. In view of its specific anti-inflammatory (and potentially coagulation-modulating) properties, tocilizumab is an interesting and potentially promising treatment modality that requires further evaluation regarding its efficacy and safety for severe COVID-19.

      Declaration of Competing Interest

      None.

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