key: cord-0958192-4buq4k4l authors: Corominas, Hèctor; Castellví, Ivan; Pomar, Virginia; Antonijoan, Rosa; Mur, Isabel; Matas, Laia; Gich, Ignasi; de Benito, Natividad; Laiz, Ana; Castillo, Diego; Villamarin, Laura; Filella, David; Millán, Ana Milena; Quijada, María Ángeles; Puig, Mireia; Casademont, Jordi; Domingo, Pere title: Effectiveness and safety of intravenous tocilizumab to treat COVID-19-associated hyperinflammatory syndrome: Covizumab-6 observational cohort() date: 2020-11-12 journal: Clin Immunol DOI: 10.1016/j.clim.2020.108631 sha: e8bb17214ba85d0c3e706125fc4b8be26d69de37 doc_id: 958192 cord_uid: 4buq4k4l Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications. Hèctor Corominas PhD 1,9,* Hcorominas@santpau.cat, Ivan Castellví PhD 1, 9 , Virginia Pomar PhD 2,9 , Rosa Antonijoan PhD 3, 9 , Isabel Mur MD 2 , Laia Matas PhD 2,9 , Ignasi Gich PhD 4,9 , Natividad de Benito PhD 2,9 , Ana Laiz PhD 1,9 , Diego Castillo MD 5, 9 , Laura Villamarin MD 6 Autònoma de Barcelona (UAB) Barcelona, Catalonia, Spain. 8 As of December 2019, SARS-CoV2 outbreak that causes COVID-19 has rapidly spread from Wuhan, China all over, to almost every country in the world, leading to the World Health Organization (WHO) to describe COVID-19 as a pandemic on 11 March 2020 1-6 . Accumulating evidence suggests that a subset of patients with severe COVID-19 develop an acute and fast release of different cytokines as a severe immune activation response ("cytokine release syndrome" CRS), leading to acute respiratory distress syndrome (ARDS). This sepsis-like storm may lead to a life-threatening multi-organ failure. CRS, firstly described in previous epidemic processes in patients with Severe Acute Respiratory Syndrome (SARS) 7 , 8 Middle East Respiratory Syndrome (MERS-CoV) diseases, both caused by coronaviruses, can be triggered by infections, trauma or therapeutic interventions, such as chimeric antigen receptor (CAR)-T cell therapy. Dysregulation of immune response has also been reported in COVID-19. Interestingly, IL-2, IL-7, IL-10, IL-12, interferon-γ, macrophage inflammatory protein 1-α, and tumor necrosis factor-α, play a role in this cytokine comprehensive storm, meanwhile it seems that the outstanding cytokine is IL-6 9. IL-6 is a cytokine with pleiotropic activity. When produced mainly by macrophages, fibroblasts, and dendritic cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), performs a protective function against the virus healing damaged tissue through induction of this acute phase and immune responses. Beside higher plasma levels of those inflammatory cytokines, granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1 alpha J o u r n a l P r e -p r o o f Journal Pre-proof (MIP1A), has been found in most severe COVID-19 cases 2 ,3, 7 , suggesting that presence of CRS. Ending up, among the inflammatory cytokines, IL-6 may enter the pulmonary circulation in large numbers, triggering lung functional disability and death 9 Nowadays, it is widely accepted that after the initial viral acute replication phase, there is a hyper-inflammatory process that might be targeted for the treatment of the severe disease phase. This opened the window of opportunity for the possible recommendations of biological disease modifying antirheumatic drugs (bDMARD´s) such as IL-6R antagonists (tocilizumab, sarilumab) and IL-6 blocker (siltuximab) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib) to be used to stop the CRS. Different guidelines from all over suggested various drugs and strategies according to their availability, stock and self-experience with those therapies 10 ,11 Intravenous (iv) Tocilizumab (TCZ), a recombinant humanized an¬tiinterleukin-6 receptor (IL-6R) monoclonal antibody that blocks IL-6 from binding to the soluble and membrane-bound IL-6R emerged as an available option to use in the present outbreak. Based on methodologically weak, but positive results of tocilizumab in the treatment of severe COVID-19 patients from observational studies 12, 13 , case reports 14, 15 and the experience of tocilizumab in inducing rapid reversal of CAR T cell-induced CRS 16 , several clinical trials We did a single-centre, observational cohort analysis of patients who received iv TCZ treatment and were admitted while the pandemic in Barcelona, Spain at the university Hospital de la Santa Creu i Sant Pau. All patients aged 18 years or older with at least a real-time reverse transcription polymerase chain reaction (RT-PCR) positive test for SARS CoV2, and suspicion of CRS were initially included in this study. We reviewed electronic medical charts of all patients admitted to hospital due of Covid-19. We collected demographics, baseline comorbidities predisposing factors, ICU admission and mortality rates. Laboratory results including haemoglobin, liver function tests, ferritin, D-dimer, white blood cell count, platelets, CRP, LDH and respiratory lung function parameters such as PaO2/FiO2 and SpO2/FiO a) at baseline, b) before the first infusion of TCZ and c) before discharge were also evaluated. All data collected on paper forms were entered into an electronic database using double entry for quality control. All patients with SARS-CoV-2 infection were treated as a first step with hydroxychloroquine 400mg/12h (1d) followed by 200mg/12h (4 more days) plus azithromycin 500mg/d (3 days). Selected patients who presented fast radiological progression, increased oxygen needs, and progressive increase of CRP, D-dimer, ferritin, AST, ALT levels and marked lymphopenia were labeled as candidates for bad prognosis and suitable to receive iv TCZ to prevent severe CRS. An expert committee evaluated the suitability of iv TCZ considering risk/benefit ratio and prescribed the therapy short early in the course of clinical onset of CRS, according to more than one of the following (Figure 1 ). Interestingly, CRP before discharge showed the fastest decrease almost back to normal due to the effect of the blockade of IL6-R and the progressive effect on liver protein synthesis function (p<0,001). Details of main serological changes observed at baseline, before infusion and after the treatment are shown in Table 2 . The main objective respiratory function parameters determined were oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) and ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (PaO2/FiO2). Our patients at baseline presented a moderate mean rate of SpO2/FiO2: 392·3 (SD 91·8) and PaO2/FiO2: 278·1 (SD 71·9). When the disease progressed from moderate to severe impairment parallel with the demand of oxygen, at day 7 (SD 2) presented a crude decrease in blood saturation that brought to a SpO2/FiO: 231·7 (SD 80·8) (p<0·001) and a PaO2/FiO2: 201·3 (SD 78·1). From that point, those selected patients according to Age-adjusted Charlson<4, and IL-6 levels, received iv TCZ leading to a progressive change and improvement of both lung function test parameters, which measured just before discharge showed a SpO2/FiO2: 407·5 (SD 67·0), with a PaO2/FiO2: 231 (SD 207) (when available) (p<0·001) Table 2 The second study, that included 15 patients, has reported that CRP levels ameliorated and, in most patients, (66·7 %) IL-6 levels showed an initial spike followed by a gradual decrease 13 The erratic elevation of D-Dimer describes a subset of patients with a higher probability of thrombosis, mainly in lung, that runs independent from TCZ treatment and could persist or even increase for a short period of time after the infusion, to later normalize. Similarly, as observed in systemic lupus erythematosus when they are active, patients with Covid-19 present with a decrease of lymphocyte count, that improved when they present a positive response to IL-6R antagonists such as TCZ or when the disease heals when viral load clears. We knew beforehand that using an antagonist of IL-6R, IL-6 levels would increase after infusion as observed in RA treated patients, thus we did not request IL-6 levels after treatment, while is not efficient and does not lead to changes in the management and treatment. Our study has limitations. First of all, in the context of a world health emergency, we did not design the study as RCT, neither a case control study. And on the other hand, we have some few missing data in the final analysis. It has to be taken into account that we were more than a hundred different J o u r n a l P r e -p r o o f Journal Pre-proof specialists (dermatologists, cardiologist, rehabilitation, gynecologists etc.), attending COVID-19 patients in hospital units lead by internists, infectious disease specialists and rheumatologists. Our tertiary hospital has diagnosed to date with RT-PCR or serology 2093 patients with Covid-19 with a mean age of 61 years. Of these, 1343 (68%) with a mean age of 67 years needed hospitalization in one of the 12 hospital units we organized to face the peak. During the outbreak we had a general inhospital population-based death rate of 11%, taking into account that 150 were directly admitted in ICU. This brings us to reinforce the rationale that our critically ill patients were on jeopardy. Thus, in the absence of globally accepted guidelines and recommendations, we decided to use iv TCZ. Even though within TCZ treated patients we had 22 patients admitted to ICU, we solely had a 5·8% of mortality (6 patients) surprisingly low considering the emergency context and the severity of the cases. TCZ has demonstrated to be effective and safe for the treatment of CRS in SARS CoV-2 infected patients in a context of global emergency. This observational study might help to place TCZ as an alternative treatment until RCT (like ours COV20/00070) or further case control studies still ongoing give the answer of which are the first, and second line treatments among the two different phases of the Covid-19 infection. 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PaO2/FiO2: ratio of arterial oxygen partial pressure We thank Cristina Anglès for her fast work managing patient database. We also thank all medical services and departments of Hospital de Santa Creu i Sant Pau, who helped to fight against the SARS-CoV-2 (Covid-19) outbreak in Barcelona.