key: cord-0760134-5j08s078
authors: Arasteh, Omid; Khalili, Hossein
title: Do interferons play a role in COVID‐19?
date: 2021-10-20
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14721
sha: e25eec0a2da45c6082987a512f1b4726c37c6e76
doc_id: 760134
cord_uid: 5j08s078

nan

piratory syndrome-related coronavirus (MERS-CoV). While the infection is rapidly spreading worldwide, the WHO declared COVID-19 as a pandemic disease on 12 March 2020, only three months after the emergence of the virus. The infection has now become a global concern around the world. 1, 2 Coronaviruses belong to a large family of viruses affecting both animal and human subjects. 3 

through similar mechanisms. The receptor-binding domain of these two viruses shares 72% similarity in the structure. 4 Coronaviruses interact with the human cells through a structural protein known as spike protein. 5 It suppresses the production of type 1 interferones (IFNs) especially IFNα and IFNβ. 1 IFNs play a vital role here and limit the viral replication before the development of the body adaptive immune responses. 1, 6 Interaction of IFNs through the IFNα/β receptor on infected cells is associated with the expression of different genes. Following phosphorylation of these receptors, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway will activate. As a result, IFN-stimulated genes (ISGs) will express. ISGs play an important role in antiviral activity of IFNs. Among the ISGs, myxovirus resistance protein A has a potential activity against various viruses. On the other hand, the main consequence of a viral infection is reducing type-1 IFN level in an infected person, which led to a reduction of the innate immune system activity. [6] [7] [8] [9] Both IFNα and IFNβ showed non-specific broadspectrum antiviral activity against different viruses. These IFNs have been used extensively in the treatment of some viral infections such as hepatitis B and C virus infections. However, IFNβ was more active against SARS-CoV. 7, 8 There are some preclinical (in-vitro and animal studies) and clinical (observational studies) evidence regarding the efficacy of IFNs on SARS-CoA and MERS-CoA viruses. [10] [11] [12] [13] [14] [15] [16] The results are controversial and the efficacy of IFNs has not been confirmed yet. Both IFNα (mostly) and IFNβ were examined. In an in vitro study, IFNβ showed a more potent inhibitory effect on the replication of coronavirus than IFNα. 11 This may be because of the higher capability of IFNβ to induce the production of MxA protein. Additionally, in a retrospective cohort study, the efficacy of IFN preparations was investigated in MERS-CoV patients. In this study, patients who received IFNβ experienced a lower mortality rate than IFNα. However, neither of the IFNs preparations (IFN-β1a, IFN-α2a) reduced MERS-CoV mortality significantly. Nonetheless, it should be considered that the results attained from an observational study with a small sample size. Also, older patients with several concomitants comorbidities were included which may be affected response to IFNs. 13 IFNs did not show any beneficial effect in patients with severe MERS-CoV infection. 10, 15, 16 It seems that patients with mild to mod- SARS-CoV-2 may be more sensitive to IFNs in comparison with other coronaviruses. Also, it seems that IFNβ is more effective than IFNα for the treatment of COVID-19. 17 IFNβ has two subgroups, named IFN-β1a and IFN-β1b. In an in vitro study, antiviral activity of IFN-β1a was 14 times more than IFN-β1b. 14 Therefore, to interpret the efficacy of IFNs, the type of IFN formulation should be considered.

Recently few clinical studies regarding the efficacy of IFNs in the treatment of patients with COVID-19 were published. Early administration IFNs (within 7-10 days after the onset of the symptoms) is critical to fight against coronavirus infections. 18, 19 Additionally, in another retrospective multicentre cohort study, early administration of IFN-α2b (≤5 days after admission) was associated with favourable outcome and reduced in-hospital mortality. Whereas, delayed administration of IFN-α2b was associated with increased mortality. 20 As a result of the probable antiviral activity of IFNs in the initial phase of the viral infections, they may be considered as a preventive strategy too. In a prospective, open-label study, 2944 medical staff received nasal IFNα as prophylaxis against COVID-19 (2-3 drops/ nostril/time, four times daily) for 28 days. In the high-risk individuals who had direct exposure with COVID-19 patients, the results were promising. None of them were infected. 21 In a cohort study, 7, 46 and 24 patients with mild COVID-19 received IFN-α2b alone, IFN-α2b plus arbidol or arbidol alone, respectively. The viral clearance was considered a primary outcome. The administration of IFN-α2b with or without arbidol was associated with better virological response. 22 In another retrospective cohort study, 256 hospitalised patients with moderate to severe COVID-19 pneumonia were enrolled. In-hospital mortality was considered a primary outcome. In the multivariate analysis, treatment with IFN-β1b did not reduce in-hospital mortality. 23 Recently, in an open-label, randomised clinical trial 127 patients with confirmed pneumonia because of SARS-CoV2 were included. Patients in the control group received lopinavir/ritonavir 400/100 mg every 12 hours for 14 days. Patients in the treatment group received a 14-day course of lopinavir/ritonavir 400/100 mg every 12 hours and ribavirin 400 mg every 12 hours and three doses of 8 million international units of IFN-β1a every other day. The primary outcome was time for a negative test for SARS-CoV2. The median time to negative test was 7 and 12 days in the treatment and control groups, respectively. Therefore, IFN-β1a as add-on therapy caused a more rapid virological response and shorter duration of hospitalisation. 24 In another randomised clinical trial, the efficacy and safety of IFN-β1a in severe COVID-19 patients were evaluated.

In this study, the primary outcome was time to clinical response.

Secondary outcomes were complications during hospitalisation and mortality. Forty-two patients and 39 patients were included in treatment and control groups, respectively. Patients in the control group have received standard of care and patients in the treatment group received IFN-β1a plus the standard of care. The dose of interferon was 12 million IU as subcutaneous injections three times weekly for two weeks. Although the time to clinical response was not significantly different but 28-day overall mortality was significantly lower in the IFN group than in the control group. Furthermore, the early administration of IFN (within 7-10 days after onset of symptoms) has been associated with significantly lower mortality compared with the late administration. 19 Supportive care is the cornerstone of the treatment for COVID-19. However, some broad-spectrum antivirals may be helpful. 2 Various combinations of lopinavir/ritonavir, chloroquine phosphate, oseltamivir, arbidol and ribavirin are under examination. 2, 25 According to the evidence, one of the potential treatment options for COVID-19 is recombinant human interferons (rhIFNs). 10, 13, 15, 16 Considering pharmacodynamics and pharmacokinetic characteristics, these compounds have lower cardiovascular adverse effects and weaker drug interactions than under-trial medications. Flu-like symptoms (fever, fatigue, chills and myalgia) are the common adverse effects. 7, 26, 27 Serious adverse effects such as neutropenia, thrombocytopenia, hyper-and hypothyroidism, pancreatitis and irreversible pulmonary hypertension have also been reported with IFNs. Nevertheless, most of them were reported following prolonged administration of IFNs. 7 The duration of IFNs administration for COVID-19 is shorter than other indications.

In the recent version of the NIH guideline, the use of IFNs is not recommended in the treatment of patients with severe or critical COVID-19 unless in clinical trials. Also because of insufficient data no recommendation was made either for or against the use of IFNs in treatment of patients with mild to moderate COVID-19. 28 In the IDSA guideline, no clear recommendation regarding the use of IFNs in the treatment of COVID-19 was provided. Nevertheless, it was noted that early administration of IFNs in combination with other antivirals may show beneficial effects in some patients with 30 Accordingly, further studies are required to confirm the efficacy of IFNs in the treatment of patients with different severity of COVID-19.

Considering the pathophysiology of the disease, early administration of rhIFNs especially rhIFN-β1a may be a potential antivirals for the treatment of patients with COVID-19. According to the current evidence, the use of IFNs is not recommended for the treatment of patients with severe or critical COVID-19. There are insufficient data to recommend either for or against the use of IFNs for the treatment of patients with mild or moderate COVID-19.

Fu n ding info r mat io n The authors did not receive any fund for this work.

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