key: cord-0712282-6k8196p2 authors: Yu, Chengjun; Kang, Lian; Chen, Jiadong; Zang, Na title: Evaluation of safety, efficacy, tolerability, and treatment-related outcomes of type I interferons for Human coronaviruses (HCoVs) infection in clinical practice: An updated critical systematic review and meta-analysis date: 2020-06-25 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2020.106740 sha: 406f2cac81b03243feb4c9694d0e69078aeda7ba doc_id: 712282 cord_uid: 6k8196p2 BACKGROUND: There is no vaccine or specific antiviral treatment for HCoVs infection. The use of type I interferons for coronavirus is still under great debate in clinical practice. MATERIALS AND METHODS: A literature search of all relevant studies published on PubMed, Cochrane library, Web of Science database, Science Direct, Wanfang Data, and China National Knowledge Infrastructure (CNKI) until February 2020 was performed. RESULTS: Of the 1081 identified articles, only 15 studies were included in the final analysis. Comorbidities and delay in diagnosis were significantly associated with case mortality. Type I interferons seem to improve respiratory distress, relieve lung abnormalities, present better saturation, reduce needs for supplemental oxygen support. Type I interferons seem to be well tolerated, and don’t increase life threating adverse effects. Data on IFNs in HCoVs are limited, heterogenous and mainly observational. CONCLUSIONS: Current data do not allow making regarding robust commendations for the use of IFNs in HCoVs in general or in specific subtype. But we still recommend type I interferons serving as first-line antivirals in HCoVs infections within local protocols, and interferons may be adopted to the treatments of the SARS-CoV-2 as well. Well-designed large-scale prospective randomized control trials are greatly needed to provide more robust evidence on this topic. Coronaviruses are single -stranded and positive -sense RNA viruses. Among Both SARS-CoV and MERS-CoV caused outbreaks affecting multiple countries, severe disease, and global threatening, for its widespread infectivity, rapid progress, high variance and mortality rate, and nonspecial treatment, somewhat the same as SARS-CoV-2 in Wuhan, China 5 . As for treatments, currently there is no defined primary remedy, vaccination or prophylaxis. Nowadays, treatments for such cases range from supportive treatment (including fluid balance, nutrition support, invasive ventilation, renal replacement therapy, vasopressors, corticosteroids, immunoglobulins, etc.) to antiviral treatment, or both [6] [7] [8] [9] [10] . The specific antiviral treatments were interferons (IFN), ribavirin, lopinavir, and other related antiviral agents. Clinically, the use of specific antivirals, especially the utility of IFNs, is still under great debate, for its efficacy, safety, and treatment-related adverse effects. Initial in vitro investigations demonstrated type I interferons (IFN-α, IFN-β) to inhibit replication of SARS coronavirus (SARS-CoV) 11 . Based on previous studies, Morgenstern et al. investigated the combination effect of IFN-β and ribavirin to prevent SARS-CoV, and yield potential benefits of the ribavirin plus IFN-β for the treatment of SARS 12 . Illuminated by the possible antiviral treatment for SARS, several in vitro studies determined a possible efficacious effect of IFN-α2b and ribavirin in the treatment of MERS-COV infection 13, 14 . Subsequently, the same investigators further examined the efficacy of these drugs in an animal study (macaques), 8 hours after they were inoculated with MERS-CoV with favorable outcomes 15 could make contributions to increase survival rate, improve oxygen saturation and associated with a more rapid resolution of pyrexia or radiographic lung opacities and respiratory improvements 17-21 , or even prophylaxis efficacy 22, 23 . A review of such anecdotal experiences is greatly needed for the more rational use of type I IFNs for coronavirus. Therefore, we conducted this updated systematic review and meta-analysis to recapitulate relevant studies to evaluate the safety, efficacy, tolerability and treatment-related outcomes of type I IFNs for coronavirus infection in clinical practice, with expectation to provide more robust evidence whether IFNs should be served as first-line agents for coronavirus infection, including the SARS-CoV-2. This study was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 24 . The systematic literature search of databases was conducted by two independent reviewers on February, 2020. These articles that contained relevant information on IFN and coronavirus were initially searched on PubMed, Cochrane Library, Web of Science Database, Science Direct, Wanfang Data, and China National Knowledge Infrastructure (CNKI), without time period, language, and region restriction. A MeSH terms search and keywords search were combined. The references of the included studies and reviews were also manually searched. We used the following search terms using the Boolean operators: #1 "interferon" OR "IFN" OR "antivir*" OR "drug effect" OR "drug ther*" OR "combination drug ther*" AND #2 "coronavirus" OR "Middle East Respiratory Syndrome: OR "MERS-CoV" OR "MERS virus*" OR "SARS" OR "severe acute respiratory syndrome" OR "SARS-CoV" (1) Clinical trials regarding type I IFN (IFN-α, IFN-β) solely or combinationally for the treatment of coronavirus infections or prophylaxis; (2) Human studies, regardless of randomized controlled trial (RCT), case-control studies, observational study, cohort studies or case series; (3) Compared the treatment outcomes of IFN and other remedies (supportive treatment only, corticosteroids, or between IFNs). (1) In vitro studies or animal models; (2) Cellular, molecular, histological, or pathological mechanism studies or hypothesis; (3) Pharmaceutical mechanism or toxicology hypothesis addressing IFN or related agents on coronavirus; (4) Other antiviral therapies that do not include type I IFN; (5) Repeated studies, staged trials or studies without comparison information; (6) Reviews, comments or letters. Two investigators independently reviewed the electronically and manually retrieved articles. After screening the titles and abstracts, potentially relevant studies were selected, and a full-text review was performed. All disagreements were solved by discussion or, still unsolved, by a third supervisor. Each included article was thoroughly reviewed, and the following baseline information were extracted (Table 1) : first author, publication year, region, study type, participants, diagnostic method of coronavirus, data collection method, time from admission to treatment start, time from diagnosis to treatment start, primary endpoints, and treatment-related adverse effects. In addition, the study design, treatment plan (including IFN dosage, frequency and duration), main findings and conclusions were extracted in detail in Table 2 . Data on total mortality rate, 14-day survival, 28-day survival, 3-month survival, transferring rate to intensive care unit (ICU), required intubation and mechanical ventilation, resolution of pyrexia, and respiratory improvement (days) were recorded for possible meta-analysis. For better understanding of severity and case mortality rate of coronavirus, we divided these patients into critically ill patients and mild ill patient. Critically ill defined as coronavirus-infected patients with other severe comorbidities, respiratory distress or failure, directly or indirectly transferred to ICU, needing intubation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO), when admitted to primary treatment. Mild ill patients defined as these real-time polymerase chain reaction (RT-PCR) or other laboratory confirmed coronavirus infected asymptomatic or otherwise laboratory well patients. Dichotomous variables were analyzed using Review Manager version 5.3 (Cochrane Collaboration, Oxford, United Kingdom) and the Mantel-Haenszel method. The crude ORs and their 95% confidence intervals (CIs) were calculated. For continuous variables, mean difference (MD) with 95% CI was applied. The single-rate meta-analysis was performed using STATA 15.0 software (Stata Corporation, College Station, Texas, USA), which assigned a weight to each study based on both withinstudy variance and between-study heterogeneity. Heterogeneity of these manuscripts was tested using both the chi-square test (with a low p-value indicating high heterogeneity, and p-value ≥0.1 indicating low heterogeneity) and I 2 index statistics (0% indicating no inter-study heterogeneity) 25 . When I 2 was < 50%, the fixed effects model was applied; otherwise, the random effects model was applied 26 . In all analysis, P-value less than 0.05 was considered significant. The initial database search yielded 1073articles ( Figure 1 ). In addition, six articles were added by manual searching from retrieved study lists and relevant reviews, and two papers added by expert suggestion. After eliminating 161 duplicate articles, 920 titles and abstracts were screened. After comprehensively screening 38 full texts, only 15 studies complied with the eligibility criteria and were included at last. Among these, three were RCTs 18, 22 , one of which has not published yet 27 , four were retrospective cohort studies 6, 20, 28, 29 , four were case series 6, 19, 21, 23 , one prospective cohort study 30 , one open-label preliminary study 17 , one open-label prospective randomized study 31 , and one retrospective observational study 32 . Turner et al. firstly explored whether the prophylactic recombinant IFNs could decrease CoV-229E catch rate or reduce the severity of coronavirus cold symptoms in 1986 in a well-design randomized placebo-control study 22 . They recruited absolutely healthy volunteers for participants. In their study, they found that the cold-catch rate, the mean nasal symptom score, the mean total symptom score, and the mean number of days with total symptom score ＞4 were much lower in IFNs prophylaxis group than placebo group, all reached significant difference ( Table 2) On account of insufficient data, inconsistent initial study design, and complexity of human bodies and case variance, statistical synthesizing was impossible regarding abovementioned parameters ( Table 1) . As for total mortality rate, we investigated the variance between critically and mild ill patients. On the basis of our analysis, the mortality rate was 69.0% (95% confidence interval: 61.2%-76.8%, I 2 =71.1%) and 11 .2% (95% confidence interval: 1.9%-20.5%, I 2 =98.5%) in critically and mild ill coronavirus-infected patients. Both presented high heterogeneity and the random effect model was used (Figure 2 ). Our study systematically investigated the application of type I interferons for HCoVs infection in clinical practice. According to our review, IFNs mainly acted a vital role in rapid resolution of lung abnormalities, respiratory improvements, better oxygen saturation, reduced needs for supplemental oxygen support, and less of an increase in creatine kinase level, which are indispensable for advanced life support and further increase survival. In the meantime, several adverse effects were detected, including drop in platelet, drop in hemoglobin, rise in lipase or bilirubin, and emergency of pancreatitis (only one critically ill case at terminal phage of disease), but these treatment-related outcomes couldn't rule out the effects of other agents like ribavirin, and still need further investigation 33 . These side effects were not life threating, and much easier to solve compared with respiratory distress, intractable hyoxemia, or rapid progress of renal or hepatic failure. The tolerability of type I IFNs was acceptable, and no premature discontinuation of IFN secondary to adverse effects was found in all case. Apart from remedy effect of IFN in coronavirus infection described above, we also found the prophylaxis efficacy of IFN in coronavirus infection 22, 23 , which increased and enhanced the utility of IFN in clinical practice. Al-Tawfiq et al. reported their experience of five critically ill patients that were all died of multi-organ failure after treatment of IFN plus ribavirin and concluded that combination antivirals may not contribute to MERS-CoV-infected patients 32 , as preclinical data suggested. In addition, vast majority of adverse effects were reported by them. We think this conclusion may be not objective. They included only critically ill patients with multiple comorbidities, all under mechanical ventilation and, most importantly, diagnosed late in admission. The mortality rate was significantly related with comorbidities, like chronic renal failure, diabetes mellitus, coronary artery disease, hypotension, elevated creatinine, anemia, etc., and age more than 50-year 20, 28 . What's more, severity of illness was the greatest predictor of reduced survival in the multivariate analysis 20 . As for adverse effects, this couldn't absolutely ascribe to IFN alone, critically ill patients may suffer from respiratory abnormality, internal environment disturbance, and other disease-related complications. Beyond this, some side effects, at least drop in hemoglobin level, was found related with ribavirin, for its temporal toxicity 21, 33 . Cheng et al. concluded from their research that even with steroid therapy alone, the mortality rate appeared to be low when compared with conservative treatment for pneumonia caused by SARS-CoV, and the combination of an effective antiviral and steroid was associated with a better outcome 34 . The same results from Omrani et al., a retrospective cohort study, IFN plus ribavirin have a decreased mortality rate than supportive treatment only, and didn't significantly increase adverse effects. Apart from antiviral therapy, management should primarily focus on strict lungprotective ventilation 35 . Our analysis indicated that the overall mortality rate of coronavirus-infected critically ill patients was about 69.0%, and 11.2% in mild ill patients, in accordance with Imran Khalid's conclusion that delay in remedy would increase mortality 35 . But this caculated mortality rate may be higher that its actual level, for publication bias. As a consequence, early dignosis and intervention would greatly improve outcomes 19 . This also suggested us paying attention to early screen of close contacts and suspected patients of such disease was equally crucial. Clinically, combination of IFN and ribavirin are reletively widely adopted to coronavirus onfection, though lack of robust evidence 3 . One well-designed randomized placebo-control trial regarding effects of recombinant IFN-β1b plus opinavir/ritonavir was registed in 2018 and still pending completion 27 . In this RCT, primary and secondary outcomes are mortality in the ICU, mortality in the hospital and 28-day mortality, 90-day mortality, sequential organ failure assessment scores at baseline and on study days 1, 3, 7, 14, 21 and 28. This seems to be the best conceived trial to determine the efficacy of antivirals in coronavirus infection. We are looking forward to the successful administration of this clinical trial, and calling for largescale prospective randomized studies to assess the role of antivirals for the treatments of coronavirus, to better guide clinical practice. In conclusion, type I interferons seem to improve respiratory distress, relieve lung abnormalities, present better saturation, reduce needs for supplemental oxygen support. Type I interferons seem to be well tolerated, and don't increase life threating adverse effects. We still recommend type I interferons serving as first-line antivirals in coronavirus infections within local protocols, with timely administration and monitoring of adverse events. And interferons may be used to treat SARS-CoV-2 infected patients. Well-designed large-scale prospective randomized control trials are greatly needed to provide more robust evidence on this topic. No financial or nonfinancial benefits have been received or will be received from any Table 2 The study designs, treatment strategies, and outcomes of included studies for evaluation of safety, efficacy, tolerability, and treatment-related outcomes of interferon for coronavirus infection in clinical practice The severe acute respiratory syndrome Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study. Clinical microbiology and infection : the official publication of the Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia A Novel Coronavirus from Patients with Pneumonia in China Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission Middle East respiratory syndrome coronavirus in children Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection A hospital outbreak of severe acute respiratory syndrome in Guangzhou Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs Ribavirin and interferon-beta synergistically inhibit SARSassociated coronavirus replication in animal and human cell lines Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment Treatment with interferon-α2b and ribavirin improves outcome in None. The study was supported by the Foundation of Children's Hospital of Chongqing Overseas Retureness (cx2018150). Not required.