Etoposide treatment adjunctive to immunosuppressants for critically ill COVID-19 patients
Authors: Montero-Baladía M, Buzón L, Astigarraga I, Delgado P, Iglesias E, Callejo F, López-Veloso M, Minguito J, Fernández-Regueras M, Ubeira M, Hermida G
Journal: Journal of Infection (2020)

In a recent article in the Journal, Cantini and colleagues1Cantini F. Niccoli L. Matarrese D. Nicastri E. Stobbione P. Goletti D Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact [published online ahead of print.J Infect. 2020; (2020;S0163-4453(20)30228-0)https://doi.org/10.1016/j.jinf.2020.04.017Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar present favorable outcomes in a small cohort of moderate COVID-19 pneumonia patients treated with lopinavir-ritonavir in addition to baricitinib, a Janus kinase inhibitor (anti-JAK). Baricitinib is a cytokine release inhibitor and is active against SARS-CoV-2 endocytosis. Current evidence suggests that systemic hyperinflammation and immune dysregulation play a key role in the development of severe lung and multiorgan damage found in critically ill COVID-19 patients.2Metha P.M. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J COVID-19: consider cytokine storm syndromes and immunosupression.Lancet. 2020; 395: 1033-1034https://doi.org/10.1016/S0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (6851) Google Scholar,3Ye Q. Wang B. Mao J The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19.J Infect. 2020; 80: 607-613https://doi.org/10.1016/j.jinf.2020.03.037Abstract Full Text Full Text PDF PubMed Scopus (2091) Google Scholar,4Vardhana S.A. Wolchok J.D. The many faces of the anti-COVID immune response.J Exp Med. 2020; 217e20200678https://doi.org/10.1084/jem.20200678Crossref PubMed Google Scholar This massive cytokine release closely resembles that of macrophage activation syndrome or secondary hemophagocytic lymphohistiocytosis, hematological conditions in which acute respiratory distress syndrome (ARDS) is also common.2Metha P.M. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J COVID-19: consider cytokine storm syndromes and immunosupression.Lancet. 2020; 395: 1033-1034https://doi.org/10.1016/S0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (6851) Google Scholar,5La Rosee P. Horne A.C. Hines M. von Bahr Greenswood T. Machowicz R. Berliner N. et al.Recommendations for the management of hemophagocytic lymphohistiocytosis in adults.Blood. 2019; 133: 2465-2477Crossref PubMed Scopus (525) Google Scholar Changes in lymphocyte sub-populations, cytokines dysregulation, presence of highly cytotoxic CD8+ T cells, and the accumulation of pro-inflammatory monocytes/macrophages in the lungs, seem to participate in the immune-mediated tissue damage.3Ye Q. Wang B. Mao J The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19.J Infect. 2020; 80: 607-613https://doi.org/10.1016/j.jinf.2020.03.037Abstract Full Text Full Text PDF PubMed Scopus (2091) Google Scholar,4Vardhana S.A. Wolchok J.D. The many faces of the anti-COVID immune response.J Exp Med. 2020; 217e20200678https://doi.org/10.1084/jem.20200678Crossref PubMed Google Scholar,6Zhou Y. Fu B. Zheng X. Wang D. Zhao C. Qi Y. et al.Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients.Nat Sci Rev. 2020; (doi.org/)https://doi.org/10.1093/nsr/nwaa041Crossref PubMed Scopus (816) Google Scholar Etoposide is a WHO Essential Medicine and powerful selective suppressor of activated T-cells and monocytes that reduces the production of inflammatory cytokines. Given its effectiveness against hyperinflammation,5La Rosee P. Horne A.C. Hines M. von Bahr Greenswood T. Machowicz R. Berliner N. et al.Recommendations for the management of hemophagocytic lymphohistiocytosis in adults.Blood. 2019; 133: 2465-2477Crossref PubMed Scopus (525) Google Scholar,7Ehl S. Astigarraga I. von Bahr Greenwood T. Hines M. Horne A.C. Ishii E. et al.Recommendations for the use of Etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society.J Allergy Clin Immunol Pract. 2018; 6: 1508-1517Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar essentially by targeting monocytes and activated T cells and by moderating the cytokine storm, we propose a rationale for its use in critically ill COVID-19 patients. In this report we review the clinical course and outcome of 11 severe COVID-19 patients treated with etoposide as salvage therapy following prior immunosuppressants. Patients eligible for etoposide treatment were older than 18 years, presented biochemical alterations suggestive of severe hyperinflammation (ferritin levels >1000 ng/ml and/or IL-6 values >50 pg/ml), ARDS (defined by PaO2/FiO2 < 300) and were not under mechanical ventilation. Prior treatment consisted on combinations of oxygen support, lopinavir-ritonavir, antimicrobials, methylprednisolone, and interleukin inhibitors. Patients not responding to a 3-day course of methylprednisolone plus Tocilizumab (IL-6 inhibitor) or Anakinra (IL-1 inhibitor) were offered etoposide. Orotracheal intubation, mechanical ventilation and prone positioning were applied when necessary according to the course of respiratory function. Prophylactic enoxaparin (40 mg per day) gas given regularly, and therapeutic anticoagulation was prescribed if thrombotic complications appeared. The study was conducted at the University Hospital of Burgos, Spain, and approved by the Local Institutional Ethics Committee (CEIm reference number, 2307) for off-label use of the drug. Informed consent from every participant (or relative) was obtained. Thirteen patients received etoposide (50–150 mg/m2) out of 709 COVID-19 patients admitted to our center during the study period (March 2 to April 10, 2020). Overall, 412/709 developed ARDS (58.1%), of which 169 received methylprednisolone plus Tocilizumab (23.8%). Two out of 13 patients receiving etoposide were excluded because they were already intubated. A total of 11 patients (1.8%), 9 males and 2 females, with a median age of 58 (range, 41 to 79) were included. Clinical characteristics are shown in Table 1. Median PaO2/FiO2 at admission was 98 (range, 52 to 174). Following etoposide treatment, the PaO2/FiO2 ratio improved an average of 195% (Fig. 1). Three patients needed mechanical ventilation. Nine patients fully recovered and were finally discharged home. Two patients died as a consequence of thrombotic complications. Patient #4 markedly improved her respiratory function allowing extubation but developed massive cerebral ischemic stroke (cardiac ultrasound detected a large thrombus in the right atrium), 2 days after ventilation withdrawal, and died 16 days after admission. Patient #5 recovered from severe ARDS with profound leukopenia, was discharged from the ICU, and died suddenly at day 24, presumably due to massive pulmonary thromboembolism, although autopsy was not performed. Apart from hematological toxicity and infection in patient #5, no other adverse effects attributable to etoposide were observed and the tolerance was good.Table 1 Patient1Patient2Patient3Patient4Patient5Patient6Patient7Patient8Patient9Patient10Patient11Patient12Patient13CharacteristicAge56416379607055576458797342SexmalemalemalemalefemalemalemalefemalemalemalemalemalemaleHypertension/obesityNoNoNoYesYesNoNoYesNoYesYesYesYespO2/FIO2 ratio15094150739896112635217463118154pCO2 (mmHg)29324436363938464548283433Ferritin (ng/mL)(**)2020149240144543131618353232305433592029169737702665CRP (ng/mL)34518194204931852438912310324412693D-dimers (μg/mL)3,45,51,87,816,51,11,21,92,30,32,810,30,6Lymphocytes abs (x10^3/μL) (***)0,30,40,40,10,30,60,61,80,50,50,20,40,1Dose of etoposide (mg/m2)*8080100501001001501501501505050174Total number of doses1121212222211Post etoposide pO2/FIO2430452435–200445287120160321180120340Etoposide administrated in ICUYESYESNOYESYESNONOYESYESNOYESNONOMechanical ventilationnoninvasivenoninvasivenoninvasiveinvasiveinvasivenoninvasivespontaneousnoninvasiveinvasivespontaneousinvasivenoninvasivespontaneousOutcomeDischargedDischargedDischargedDNRDeathDischargedDischargedDischargedDischargedDischargedHospitalizedDeathDischargedHospital stay (days)15151311131472055151432Cytopenia >2 linesNONONONOYESNONONOYESNONOYESNOInfectionsNONONONOEnterococcusNONONOHSV-1NONONONO Open table in a new tab Noticeably, in our experience, only 1–2 doses of etoposide were enough to observe clinical improvement among severely ill COVID-19 patients, in terms of inflammatory serum markers (ferritin, CRP, D-dimer), vasopressor therapy requirement and respiratory support. In fact, only 3 patients ultimately required intubation, yet 2 of which died. These preliminary results on 11 patients confirmed the safety and efficacy of etoposide as adjunctive salvage treatment for critically ill COVID-19 ARDS patients, exhibiting systemic hyperinflammation and previously treated with corticosteroids and interleukin inhibitors. A growing evidence suggests that COVID-19 disease is a biphasic disease.3Ye Q. Wang B. Mao J The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19.J Infect. 2020; 80: 607-613https://doi.org/10.1016/j.jinf.2020.03.037Abstract Full Text Full Text PDF PubMed Scopus (2091) Google Scholar,4Vardhana S.A. Wolchok J.D. The many faces of the anti-COVID immune response.J Exp Med. 2020; 217e20200678https://doi.org/10.1084/jem.20200678Crossref PubMed Google Scholar,8Jamilloux Y. Henry T. Belot A. Viel S. Fauter M. El Jammal T. et al.Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions.Autoimmun Rev. 2020 May 4; ([Epub ahead of print])102567https://doi.org/10.1016/j.autrev.2020.102567Crossref PubMed Scopus (489) Google Scholar The initial stage, at which pre-symptomatic or pauci-symptomatic patients exhibit a preliminary and reversible state of immune-suppression associated to the viral load, ideally benefits from antivirals. Later on, patients may develop more severe leucopenia (mainly lymphopenia) along with increased inflammatory markers (CRP, ferritin, IL-6) that may end in a systemic hyperinflammatory state with accompanying cytokine discharge, accumulation of activated cells responsible for the lung damage, need for mechanical ventilation, thrombotic complications, and eventual death.2Metha P.M. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J COVID-19: consider cytokine storm syndromes and immunosupression.Lancet. 2020; 395: 1033-1034https://doi.org/10.1016/S0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (6851) Google Scholar,3Ye Q. Wang B. Mao J The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19.J Infect. 2020; 80: 607-613https://doi.org/10.1016/j.jinf.2020.03.037Abstract Full Text Full Text PDF PubMed Scopus (2091) Google Scholar,4Vardhana S.A. Wolchok J.D. The many faces of the anti-COVID immune response.J Exp Med. 2020; 217e20200678https://doi.org/10.1084/jem.20200678Crossref PubMed Google Scholar,8Jamilloux Y. Henry T. Belot A. Viel S. Fauter M. El Jammal T. et al.Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions.Autoimmun Rev. 2020 May 4; ([Epub ahead of print])102567https://doi.org/10.1016/j.autrev.2020.102567Crossref PubMed Scopus (489) Google Scholar Although corticosteroid therapy in COVID-19 remains controversial, recent studies suggest a clinical benefit for severely ill COVID-19 ARDS patients in terms of mortality rate, need for mechanical ventilation, and hospital stay.9Villar J. Confalonieri M. Pastores S.M. Meduri G.U Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019.Crit Care Explor. 2020; 2 (Published 2020 Apr 29): e0111https://doi.org/10.1097/CCE.0000000000000111Crossref PubMed Scopus (89) Google Scholar,10Fadel R. Morrison A.R. Vahia A. Smith Z.R. Chaudhry Z. Bhargava P. et al.Early short course corticosteroids in hospitalized patients with COVID-19.Clin Infect Dis. 19 May 2020; (PMID: 32427279)https://doi.org/10.1093/cid/ciaa601Crossref PubMed Scopus (277) Google Scholar Regarding oxygenation parameters, we observed that many severe COVID-19 patients presented with alarming PaO2/FiO2 ratios (commonly under 150, see Table-1) that, according to Berlin ARDS criteria, were immediate candidates for orotracheal intubation and mechanical ventilation. However, many of them exhibited a relatively preserved pulmonary function (mild dyspnea with or without tachypnea), showed preserved oxygen extraction and adequate organ perfusion without lactic acidosis, and ultimately avoided intubation. We hypothesize that SARS-CoV-2 related ARDS distinct pathophysiologic features permit management of many critically ill patients with non-invasive ventilatory support, waiting for the anti-inflammatory reversal effect of etoposide plus adjunctive immunomodulators. The lack of comparison group and the low number of participants are obvious limitations of this study. Due to the severity of patients included in the study, with remarkable hyperinflammation data, all patients had received methylprednisolone and Tocilizumab or Anakinra prior to etoposide, so both drugs can be potential confounders in the interpretation of the results. However, etoposide was administered whenever patients did not respond to prior anti-inflammatory treatment, and at the stage of progressive organ dysfunction. In this preliminary experience, salvage treatment with etoposide in adjunction to immunosuppressants resulted in overall favorable outcome of a small cohort of severely ill COVID-19 ARDS patients presenting with systemic hyperinflammation. The currently ongoing clinical trial NCT04356690, started on May 8, 2020, will likely contribute to evaluate the safety and efficacy of etoposide in COVID-19 patients.