10
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Tocilizumab has been reported to attenuate the “cytokine storm” in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI–7.19%–21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 ( P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI–99.17% to–17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

          Electronic Supplementary Material

          Supplementary material is available in the online version of this article at 10.1007/s11684-020-0824-3 and is accessible for authorized users.

          Related collections

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: not found

          Pathological findings of COVID-19 associated with acute respiratory distress syndrome

          Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Effective treatment of severe COVID-19 patients with tocilizumab

            Significance In patients with coronavirus disease 2019, a large number of T lymphocytes and mononuclear macrophages are activated, producing cytokines such as interleukin-6 (IL-6), which bind to the IL-6 receptor on the target cells, causing the cytokine storm and severe inflammatory responses in lungs and other tissues and organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6 receptor with high affinity, thus preventing IL-6 itself from binding to its receptor, rendering it incapable of immune damage to target cells, and alleviating the inflammatory responses.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Cytokine release syndrome in severe COVID-19

                Bookmark

                Author and article information

                Contributors
                ustcwhm@ustc.edu.cn
                xxlahh8@ustc.edu.cn
                Journal
                Front Med
                Front Med
                Frontiers of Medicine
                Higher Education Press (Beijing )
                2095-0217
                2095-0225
                9 March 2021
                : 1-9
                Affiliations
                [1 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Pulmonary and Critical Care Medicine, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                [2 ]GRID grid.59053.3a, ISNI 0000000121679639, Division of Life Sciences and Medicine, , University of Science and Technology of China, ; Hefei, 230027 China
                [3 ]GRID grid.59053.3a, ISNI 0000000121679639, Intensive Care Unit, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                [4 ]GRID grid.59053.3a, ISNI 0000000121679639, Drug Clinical Trail Institution, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Division of Life Sciences and Medicine, , University of Science and Technology of China, ; Hefei, 230001 China
                [5 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Infectious Diseases, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430000 China
                [6 ]Department of Respiratory Medicine, the Second People’s Hospital of Fuyang, Fuyang, 236000 China
                [7 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Xiangya Lung Cancer Center, Xiangya Hospital, , Central South University, Hunan Provincial Clinical Research Center for Respiratory Diseases, ; Changsha, 410000 China
                [8 ]GRID grid.186775.a, ISNI 0000 0000 9490 772X, Lu’an People’s Hospital Affiliated to Anhui Medical University, ; Lu’an, 237005 China
                [9 ]GRID grid.414884.5, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Bengbu Medical College, , Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, ; Bengbu, 233004 China
                [10 ]GRID grid.186775.a, ISNI 0000 0000 9490 772X, Department of Respiratory Medicine, , Anqing Hospital Affiliated to Anhui Medical University, ; Anqing, 246000 China
                [11 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210000 China
                [12 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Rheumatology and Immunology, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                [13 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Oncology, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                [14 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Endocrinology, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                [15 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Hematology, , the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), ; Hefei, 230001 China
                Article
                824
                10.1007/s11684-020-0824-3
                7940448
                33687643
                9d6675c9-bfc6-4da6-820a-209af5df806d
                © Higher Education Press 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 12 October 2020
                : 16 October 2020
                Categories
                Research Article

                tocilizumab,coronavirus disease 2019 (covid-19),cytokine storm

                Comments

                Comment on this article