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      Successful treatment of tocilizumab and ivermectin for a patient with ARDS due to COVID-19

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          Abstract

          Dear Editor: Acute respiratory distress syndrome (ARDS) is one of the consequences of the cytokine release syndrome (CRS) triggered by coronavirus disease 2019 (COVID-19). 1 Tocilizumab (TCZ), a recombinant IL-6 inhibitor, is a potentially beneficial treatment for CRS caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 2 Ivermectin, an antiparasitic drug, acts as a potential inhibitor of the coronavirus. 3 The combination of TCZ and Ivermectin could be a potential treatment for COVID-19-related ARDS. A 68-y/o female was admitted to the hospital for COVID-19 after returning from Indonesia. The chest radiograph revealed bilateral subpleural infiltrates (Fig. 1 A). She was tested positive for SARS-CoV-2 and treated with hydroxychloroquine and azithromycin on hospital day 2. ARDS (Fig. 1B) had developed on hospital day 4/ICU day 1, and intubation with lung protective-strategy and prone positioning was performed due to PaO2/FiO2 ratio at 60 mmHg. Both hydroxychloroquine and azithromycin were discontinued due to QTc prolongation (709 ms) on hospital day 9/ICU day 6. We prescribed single dose of TCZ 240 mg for ARDS and checked for hyper-inflammatory response, including C-reactive protein (CRP) at 30.42 mg/dL (reference range: 0–0.5 mg/dL), lactate dehydrogenase (LDH) at 667 U/L (reference range: 125–220 U/L) and ferritin at 4125.77 ng/mL (reference range: 4.63–204 ng/mL) on hospital day 10/ICU day 7. Single dose of Ivermectin 12 mg was given on hospital day 12/ICU day 9 due to positive result of SARS-CoV-2 in sputum collected on hospital day 10/ICU day 7. After the Ivermectin treatment, the patient had 3 negative results on consecutive sputum examinations during hospital days 15–17/ICU days 12–14, and the PaO2/FiO2 ratio increased gradually (from 91, 154 to 230 mmHg). Her chest radiograph (Fig. 1C) showed improvement and hyper-inflammatory markers decreased gradually (CRP from 30.42 to 0.48 mg/dL, LDH from 667 to 342 IU, and ferritin from 4125.77 to 1000 ng/mL), which all confirmed our suspicion that the CRS induced by SARS-CoV-2 was the cause of ARDS. She had a smooth hospital discharge, but living with subpleural fibrosis (Fig. 1D). Figure 1 Serial chest radiographs revealed changes from bilateral subpleural infiltration (A) to bilateral subpleural patch of consolidation with ARDS (B), then turned to bilateral subpleural nodular infiltration (C), and chest CT scan showed subpleural fibrosis (D). Figure 1 During the initial stage of infection, SARS-CoV-2 could trigger an adaptive immune response to fight against virus in our body and lead to a phase of CRS that cause ARDS. 1 Previous reports demonstrated that, in addition to CRP, LDH and ferritin, the IL-6 levels were elevated during SARS-CoV-2 infection. 2 CRP, LDH and ferritin could be used to predict the acuteness, severity and prognosis of COVID-19, and considered as a surrogate marker for IL-6 level. 2 , 4 The hypothesized mechanism of Ivermectin was implicated in the blockade of viral protein transport in the nucleus of target cell, and significantly reducing the coronaviral RNA by more than 90% in 24 h. However, the report of clinical trials on Ivermectin for the treatment of COVID-19 are not yet available. 3 In this case, Ivermectin was the only one choice that could possibly treat SARS-CoV-2 in our patient under the circumstances of limited availability of Lopinavir/Ritonavir and Remdesivir, as well as the adverse effects in hydroxychloroquine and azithromycin. 5 The rationale of combination with Ivermectin and TCZ is to stop the coronavirus and to deal with the CRS-induced ARDS. To our knowledge, this is the first and unique reported case of successful treatment in the combination of TCZ and Ivermectin for ARDS induced by COVID-19. The combination therapy of IL-6 inhibitor and potential anti-coronavirus agent deserves further investigation in SARS-CoV-2 related ARDS.

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          Is Open Access

          The COVID-19 Cytokine Storm; What We Know So Far

          COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called “cytokine storm” induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.
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            Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy

            A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24–72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0–2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.
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              Treatment options for COVID-19: the reality and challenges

              An outbreak related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019. An extremely high potential for dissemination resulted in the global coronavirus disease 2019 (COVID-19) pandemic in 2020. Despite the worsening trends of COVID-19, no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale studies. Remdesivir is considered the most promising antiviral agent; it works by inhibiting the activity of RNA-dependent RNA polymerase (RdRp). A large-scale study investigating the clinical efficacy of remdesivir (200 mg on day 1, followed by 100 mg once daily) is on-going. The other excellent anti-influenza RdRp inhibitor favipiravir is also being clinically evaluated for its efficacy in COVID-19 patients. The protease inhibitor lopinavir/ritonavir (LPV/RTV) alone is not shown to provide better antiviral efficacy than standard care. However, the regimen of LPV/RTV plus ribavirin was shown to be effective against SARS-CoV in vitro. Another promising alternative is hydroxychloroquine (200 mg thrice daily) plus azithromycin (500 mg on day 1, followed by 250 mg once daily on day 2-5), which showed excellent clinical efficacy on Chinese COVID-19 patients and anti-SARS-CoV-2 potency in vitro. The roles of teicoplanin (which inhibits the viral genome exposure in cytoplasm) and monoclonal and polyclonal antibodies in the treatment of SARS-CoV-2 are under investigation. Avoiding the prescription of non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, or angiotensin II type I receptor blockers is advised for COVID-19 patients.
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                Author and article information

                Journal
                J Microbiol Immunol Infect
                J Microbiol Immunol Infect
                Journal of Microbiology, Immunology, and Infection
                Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC.
                1684-1182
                1995-9133
                3 October 2020
                3 October 2020
                Affiliations
                [1]Division of Pulmonary Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [2]Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
                [3]Division of Critical Care Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [4]Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
                [5]Division of Critical Care Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [6]Division of Pulmonary Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [7]Division of Pulmonary Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [8]Department of Family Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
                [9]Share Hope Medicine Co.,Ltd., Taoyuan, Taiwan
                Author notes
                []Corresponding author. Division of Pulmonary Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan.
                Article
                S1684-1182(20)30241-3
                10.1016/j.jmii.2020.09.007
                7837228
                e4783902-4b26-41e0-b21e-dd7309ffe062
                © 2020 Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC.

                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
                : 23 May 2020
                : 21 September 2020
                : 30 September 2020
                Categories
                Correspondence

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