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      Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy

      research-article
      Author(s): b , 1 , a , * , a , a , c , b , a , a , c , c , c , d , a , a , a , e , a , a , b , a , c , d , a , a , a , a , b , a , b , a
      Publication date (Electronic):
      Journal: European Journal of Internal Medicine
      Publisher: European Federation of Internal Medicine. Published by Elsevier B.V.
      Keywords: COVID-19, tocilizumab, IL-6 inhibitors, COVID-19, CoronaVirus Disease (COVID)-19, SARS-CoV-2, Severe acute respiratory syndrome-Coronavirus-2, ARDS, Acute respiratory distress syndrome, IQR, interquartile rate, CPAP, Continuous positive airway pressure, ICU, intensive care unit, sHLH, haemophagocytic lymphohistiocytosis

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          Graphical abstract

          Figure 4 modified: A curves showing survival of participants with severe COVID-19 pneumonia treated with tocilizumab: B. Kaplan-meier survival curves in patients with severe COVID-19 stratified according to ventilation ststus at baseline. B. Incidence of bloodstream infections over the study period.

          Abstract

          Background

          Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19.

          Methods

          In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days.

          Results

          Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count ( p<0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p=0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%).

          Conclusion

          Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Chaolin Huang, Yeming Wang, Xingwang Li … (2020)
          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Fei Zhou, Ting Yu, Ronghui Du … (2020)
            Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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              A Novel Coronavirus from Patients with Pneumonia in China, 2019

              Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
              Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
              Article 0 comments Cited 12693 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Laura Milazzo
                Journal
                Journal ID (nlm-ta): Eur J Intern Med
                Journal ID (iso-abbrev): Eur. J. Intern. Med
                Title: European Journal of Internal Medicine
                Publisher: European Federation of Internal Medicine. Published by Elsevier B.V.
                ISSN (Print): 0953-6205
                ISSN (Electronic): 1879-0828
                Publication date PMC-release: 21 May 2020
                Publication date (Electronic): 21 May 2020
                Affiliations
                [a ]Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy
                [b ]Luigi Sacco Department of Biomedical and Clinical Sciences, University of Milan, Italy
                [c ]Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
                [d ]Microbiology, Virology and Bioemergence Diagnostics, ASST Fatebenefratelli Sacco, Milan, Italy
                [e ]Clinical Pathology Laboratory, ASST Fatebenefratelli Sacco, Milan, Italy
                Author notes
                [* ]Corresponding author at: Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Via GB Grassi 74, 20157, Milan, Italy. laura.milazzo@ 123456unimi.it
                [1]

                These authors contributed equally to the work.

                Article
                Publisher ID: S0953-6205(20)30196-5
                DOI: 10.1016/j.ejim.2020.05.011
                PMC ID: 7241995
                PubMed ID: 32448770
                SO-VID: 1d798ced-57a0-4c02-ad60-e2f2381a491f
                Copyright © © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 24 April 2020
                Date revision received : 5 May 2020
                Date accepted : 6 May 2020
                Categories
                Subject: Article

                Keywords: covid-19,tocilizumab,il-6 inhibitors,covid-19, coronavirus disease (covid)-19,sars-cov-2, severe acute respiratory syndrome-coronavirus-2,ards, acute respiratory distress syndrome,iqr, interquartile rate,cpap, continuous positive airway pressure,icu, intensive care unit,shlh, haemophagocytic lymphohistiocytosis
                Data availability:
                Keywords: covid-19, tocilizumab, il-6 inhibitors, covid-19, coronavirus disease (covid)-19, sars-cov-2, severe acute respiratory syndrome-coronavirus-2, ards, acute respiratory distress syndrome, iqr, interquartile rate, cpap, continuous positive airway pressure, icu, intensive care unit, shlh, haemophagocytic lymphohistiocytosis

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