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      Reconsideration of interferon treatment for viral diseases: lessons from SARS, MERS, and COVID-19

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          Abstract

          Periodic pandemics of coronavirus (CoV)-related pneumonia have been a major challenging issue since the outbreak of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012. The ongoing pandemic of CoV disease (COVID-19) poses a substantial threat to public health. As for the treatment options, only limited antiviral agents have been approved hitherto, and clinicians mainly focus on currently available drugs including the conventional antiviral interferons (IFNs). In clinical practice, IFNs, when used either alone or in combination with ribavirin and/or lopinavir/ritonavir, have shown promising outcomes, to some extent, in SARS-CoV or MERS-CoV treatment. Although the efficacy and safety of IFNs in COVID-19 treatment remain unclear, their possible use merits further evaluation. We present a review that summarizes current evidence of IFNs treatment for COVID-19 and elaborates on other challenges in terms of the timing of IFN treatment initiation, treatment duration, and IFN type to be used. The review findings suggested that IFN acts by directly inhibiting viral replication and activating immune cell subsets. However, there is a lack of well-designed and controlled clinical trials providing firm evidence for the efficacy or safety of IFN therapy for CoVs. Additionally, critically ill patients with multiple immunosuppression-associated comorbidities may not benefit from IFN therapy, necessitating screening of those patients who would most benefit from IFN treatment.

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          Most cited references82

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          Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

          A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.
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            Coronavirus infections and immune responses

            Abstract Coronaviruses (CoVs) are by far the largest group of known positive‐sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV‐induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.
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              Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

              Summary Background Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19. Methods This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688. Findings Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI 1·86–10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study. Interpretation Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted. Funding The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
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                Author and article information

                Journal
                Int Immunopharmacol
                Int Immunopharmacol
                International Immunopharmacology
                Published by Elsevier B.V.
                1567-5769
                1878-1705
                16 June 2023
                16 June 2023
                : 110485
                Affiliations
                [a ]Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, GuiZhou, China
                [b ]Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, GuiZhou, China
                [c ]Department of Pharmacy, Tongji hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
                Author notes
                [* ]Corresponding authors.
                [1]

                contributed equally to this work

                Article
                S1567-5769(23)00808-1 110485
                10.1016/j.intimp.2023.110485
                10272952
                6018bd2c-4abc-4a0e-8605-f4bd76562b2c
                © 2023 Published by Elsevier B.V.

                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
                : 4 April 2023
                : 1 June 2023
                : 9 June 2023
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                interferon,coronavirus,pneumonia,viral replication,efficacy
                Pharmacology & Pharmaceutical medicine
                interferon, coronavirus, pneumonia, viral replication, efficacy

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