key: cord-1052289-uz4s6w7v authors: Hashimoto, S.; Kitajima, H.; Arai, T.; Tamura, Y.; Nagai, T.; Morishita, H.; Matsuoka, H.; Han, Y.; Minamoto, S.; Hirashima, T.; Yamada, T.; Kashiwa, Y.; Kameda, M.; Yamaguchi, S.; Uno, K.; Nakayama, E.; Shioda, T.; Yoshizaki, K.; Kang, S.; Kishimoto, T.; Tanaka, T. title: A retrospective study evaluating efficacy and safety of compassionate use of tocilizumab in 13 patients with severe-to-critically ill COVID-19: analysis of well-responding cases and rapidly-worsening cases after tocilizumab administration date: 2020-06-30 journal: nan DOI: 10.1101/2020.06.24.20134288 sha: d6321dd7f37a6a2c009666bd25635680c77a016c doc_id: 1052289 cord_uid: uz4s6w7v We administered tocilizumab into 13 severe-to-critically ill patients with coronavirus disease 2019 (COVID-19) for compassionate use in combination with potential anti-viral agents in those who required an oxygen supply and showed increased laboratory inflammatory markers such as C-reactive protein (CRP) and ferritin. One injection of tocilizumab led to rapid improvements in clinical features, inflammatory findings, and oxygen supply in seven patients with severe COVID-19 and substantial amelioration in two patients who were critically ill, whereas four patients, who exhibited rapidly worsened respiratory function, required artificial ventilatory support even after tocilizumab treatment. Three of these four patients ultimately recovered from deterioration after methylprednisolone treatment. Administration of tocilizumab did not affect viral elimination nor IgG production specific for the virus. Compared with well-responding patients, rapidly-worsened patients showed a significantly higher ratio of ferritin vs. CRP. These findings suggest that tocilizumab has beneficial effects in severe-to-critically ill patients with COVID-19; however, in some cases, addition of methylprednisolone is required for disease rescue. Coronavirus disease 2019 , caused by severe acute respiratory syndromes coronavirus-2 (SARS-CoV-2), has rapidly spread worldwide. 1-4 By the end of May 2020, more than 6 million people were diagnosed with COVID-19, with a mortality rate of approximately 6%. Thus, vaccines and therapeutic drugs are urgently needed to stop the spread of the disease and decrease mortality; however, no vaccines and drugs except for All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint 3 remdesivir as an emergency use drug have been developed and approved. 5 Various studies have indicated that a cytokine storm, also known as hyperinflammation, is a pathological mechanism underlying the development of severe disease, leading to a critically ill state of patients including acute respiratory distress syndrome, multiple organ dysfunction syndrome, and shock. 6-8 Among the cytokines involved in severe and critical cases of COVID-19, interleukin (IL)-6 is highly elevated and can be used a prognostic marker. [9] [10] [11] Additionally, IL-6 plays a major pathological role in disease worsening. Several case series and case reports have demonstrated the beneficial effects of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, in patients with Based on recent findings regarding the clinical and laboratory features of COVID-19, 1-4,9,10 our hospital developed a therapeutic protocol for managing COVID-19 and used tocilizumab to treat severe-to-critically ill patients with COVID-19. Here, we report our experience using tocilizumab to treat patients with COVID-19. Seventy patients with COVID-19 were admitted to our hospital by the end of May 2020. Among them, 13 patients were diagnosed as severe-to-critically ill, as they required oxygen supply because of severe pneumonia and were intravenously administered tocilizumab at 400 mg once in combination with anti-SARS-CoV-2 drugs such as lopinavir/ritonavir, ciclesonide, or favipiravir. All patients provided written informed consent, and the off-label compassionate use of tocilizumab was approved by the Ethics Committee of Osaka Habikino Medical Center (Approved ID: 150-7). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint Based on various previous reports of characterizations patients with COVID-19, the inclusion criteria of off-label indication of tocilizumab were set as follows: 1. Elevated inflammatory findings: C-reactive protein (CRP) level >5 mg/dL or ferritin >1000 ng/mL 2. Requirement of oxygen supply or rapid progression according to chest image evaluation (more than 50% increase in infiltrates over 24-48 hours) Patients with elevated procalcitonin and patients who also had bacterial infections were excluded. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint The serum levels of IgM and IgG class antibodies specific for SARS-CoV-2 were determined by using the Corona Virus COVID-19 Antibody Rapid Detection kit according to the manufacturer's instructions (Healgen Scientific Ltd.). 17 The test samples in an individual patient included all of the sera collected before and 1-2 and 3-4 weeks after tocilizumab injection, or in some cases at 4-5 weeks after injection, depending on the availability. The significance of the difference between well-responding group and rapidly-worsening group was evaluated using the Man-Whitney U test. A value of P <0.05 was considered as statistically significant. The patients' characteristic features and clinical courses are shown in Table 1 . Eleven male patients and two female patients with a mean age of 63 years were evaluated. Five patients were complicated with diabetes mellitus, five with hypertension, and two with chronic obstructive pulmonary disease. At admission, two patients were critically ill and required artificial ventilator management before tocilizumab injection, and severe disease was diagnosed in 11 patients. The clinical course of each patient is shown in Table 1 . Tocilizumab caused no adverse events. Seven patients promptly recovered from fever and malaise and lowered their oxygen support, and were free of oxygen support within a week on average (well-responding group). PCR analysis of the nasopharyngeal specimens showed negative results for SARS-CoV-2 10-25 days (15.4 days as average) and the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint patients were discharged 12-27 days (17 days as average) after tocilizumab administration. However, four patients showed further worsening of respiratory function and required artificial ventilatory support (rapidly-worsening group); these patients were administered methylprednisolone and recovered from such a support within a week. Two patients were discharged from the hospital, and one patient died because of sudden laryngotracheal stenosis. Two patients who were critically ill and required artificial ventilator management before tocilizumab injection were ameliorated in respiratory function. Analysis of clinical outcomes showed that by 1 week after tocilizumab treatment, eight (62%), 1 (8%), and 4 (31%) patients improved, had no change, and worsened, respectively, whereas nine (69%), 3 (23%), and 1 patient (8%) were cured, improved, and died, respectively, by 1 month after treatment. A representative case that responded well to tocilizumab and a case that worsened despite tocilizumab injection are shown in Figures 1 and 2 , respectively. The changes in laboratory parameters are shown in Figure 3 . Tocilizumab injection rapidly decreased serum CRP levels followed by a gradual decrease in ferritin and increase in the number of peripheral lymphocytes. Respiratory disturbance acutely progressed in some patients with severe disease. 1-3 The clear difference in the clinical features between the well-responding group and the rapidly-worsening group was not observed. In the laboratory results, there was no difference in the basal levels of CRP and ferritin or in number of peripheral lymphocytes between groups, whereas the ratio of ferritin/CRP was significantly higher in the rapidlyworsening group than in the well-responding group (373.1±346.8 vs. 83.7±56.7, p = 0.01) ( Table 2) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint Because IL-6 plays a crucial role in the host defense against pathogens and promotes T cell and B cell activation and differentiation, 18, 19 we next evaluated whether tocilizumab injection affects elimination of SARS-CoV-2 and specific antibody production. Three out of nine patients tested showed viremia, and their viral load transiently increased at 2-3 days after tocilizumab injection but then decreased (Figure 4) . In addition, we detected IgG class antibody in all nine patients, whose sera were available for the test at 1-2 weeks after tocilizumab administration. These results suggest that tocilizumab in combination with anti-viral drugs did not suppress viral elimination or induction of the IgG class antibody specific for SARS-CoV-2. We describe our experience in which tocilizumab was administered to 13 severe-tocritically ill patients with COVID-19. Seven patients promptly improved in response to tocilizumab (well-responding group), whereas four patients showed worsened respiratory function and required artificial ventilation (rapidly-worsening group). Recent various case series and case reports have demonstrated the promising efficacy of tocilizumab for severe-to-critically ill COVID-19 either monotherapy or its combination with corticosteroids, 12-16,20-23 although opposite results were observed in some other studies. 24,25 According to our experience with 13 patients with COVID-19 patients, it is due to the clinical status and the timing of tocilizumab administration. Compared with patients with non-severe COVID-19, those with severe-to-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. IL-6 is a cytokine that helps maintain homeostasis. When infections occur, IL-6 is promptly produced and plays a major role against infectious agents by producing acute phase proteins and activating T cells and B cells, leading to their differentiation into All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.24.20134288 doi: medRxiv preprint effector T cells and Ig production, respectively. 18, 19 Therefore, an important concern is that tocilizumab may suppress viral elimination and humoral immunity for the virus. However, our experience suggests that this is not the case when tocilizumab is administered with potential anti-viral drugs. Rather, flow cytometric analysis of immune cells from patients with COVID-19 showed that impaired immune cell cytotoxicity in severe cases was IL-6-dependent and thus targeting IL-6 may restore anti-viral activity. 30 This report has several limitations. The sample size was small, and the data were analyzed retrospectively. Moreover, the treatment protocol involved combination therapy of tocilizumab with anti-viral drugs, so the direct effect of tocilizumab could not be evaluated. Further evaluation using a randomized controlled trial design is essential. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 30, 2020. The dotted line represents the data from the rapidly-worsening group. The dotted line represents the data from the rapidly-worsening group. Tocilizumab treatment in COVID-19: A single center experience Tocilizumab, an anti-IL-6 receptor antibody, to treat Covid-19-related respiratory failure: A case report First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab Off-label use of tocilizumab in patients with SARS-CoV-2 infection Immunotherapeutic implications of IL-6 blockade for cytokine storm Targeting interleukin-6 signaling in clinic Pilot prospective open, single-arm multicenter study on off-label use of tocilizumab in severe patients with COVID-19 Tocilizumab for the treatment of severe coronavirus diseases 2019 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.