key: cord-0966799-vd1gjna8
authors: Saleki, Kiarash; Yaribash, Shakila; Banazadeh, Mohammad; Hajihosseinlou, Ehsan; Gouravani, Mahdi; Saghazadeh, Amene; Rezaei, Nima
title: Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies
date: 2021-06-12
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2021.174248
sha: d5442dcad92528fc2a4867134cf60729546cfe0d
doc_id: 966799
cord_uid: vd1gjna8

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR=-0.05, 95% CI: (-0.71,0.62), I(2) =44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR=-0.44, 95% CI: (-1.13,0.25), I(2) =31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

Coronaviruses (CoVs) are single-stranded, positive-sense, RNA containing, and enveloped viruses responsible for several major global outbreaks (Poutanen, 2012; Raoult et al., 2020) .

Global epidemics of atypical pneumonia were first caused by SARS-CoV1 and MERS-CoV in 2002 , respectively (Al-Osail and Al-Wazzah, 2017 Huang, 2004) , and continued to affect the globe with MERS-CoV reappearing in South Korea in 2015 (Ki, 2015) . Recently, coronavirus disease 2019 (COVID-19), a disease caused by a novel variant of SARS-CoV known as SARS-CoV2, emerged in Wuhan, China (Cascella et al., 2020; . While showing a lower mortality rate (2.3%) compared to MERS-CoV (9.5%) and SARS-CoV1 (34.4%), the COVID-19 pandemic has raised significant concern. The concern is partly due to the high spreading potential of SARS-CoV2, which influences and causes mortality in a significantly larger population (Petrosillo et al., 2020) . The novel virus has an undetermined clinical presentation , as the recent evidence has suggested non-respiratory and asymptomatic presentations . Hence, the diversity in the presentations and hurdles in detecting the virus (Basiri et al., 2020a) suggests the high importance of an effective onset-to-treat period regarding the treatment of COVID-19 patients (Saleki et al., 2020a) .

Numerous novel efforts have been carried out in the fields of drug discovery, vaccine Nevertheless, several protocols of past curatives are being used for COVID-19 patients due to a lack of effective treatments or alternatives when extreme adverse drug events (ADE) are indicated. The innate immune system comprises inflammasomes (Rasoulinejad et al., 2020) , cytokines, and IFNs which help to clear viral disease and provide multi-system immunological protection (Kopitar-Jerala, 2017; Rostamtabar et al., 2021) . It has been shown that SARS-CoV2 is sensitive to type I IFN therapy in human cell lines (Mantlo et al., 2020) . A strong association between low type I IFN production and COVID-19 severity has been reported (Bastard et al., 2020; Bost et al., 2020; Zhang et al., 2020b) . Nuclear factor-kappa light chain enhancer B (NF-kB) activation in the dendritic cells is crucial for large scale type I IFN production. In a study of COVID-19 by or 2 mutations required hospitalization (Meyts et al., 2021) , highlighting the functional role of IFNs. Administration with subcutaneous IFN β-1a has been shown to reduce morbidity in COVID-19 infected patients (Davoudi-Monfared et al., 2020) . Lung infection in COVID-19 may evolve into systemic involvement. Also, IFNs specially IFN-α2b are capable of preventing lung abnormalities in such patients (Zhou et al., 2021) . All of these statements emphasize the role of IFN therapy in severe acute CoVs disease. In addition to lungs, other organs like kidneys (Han and Ye, 2021) , liver , and the brain (Baig et al., 2020; Saleki et al., 2020b) are also involved. A major entry pathway for SARS-CoV2 is angiotensin-converting enzyme 2 (ACE2), which is present in multiple systems throughout the body. Research has shown IFNs can significantly alter ACE2 profile. ACE2 is regarded as an interferon-stimulated gene (ISG) (Ziegler et al., 2020) . Thus, interferon-induced alteration in ACE2 production may be crucial for liability to COVID-19 or its corresponding adverse outcomes (Onabajo et al., 2020) . Taken together, noteworthy for future research is that IFNs could play a J o u r n a l P r e -p r o o f crucial role in multi-organ involvement prevention of patients with COVID-19. The probable role of IFNs in the multi-organ involvement situation has been enlaced in Fig. 1 . Intriguingly, despite contradicting in vitro and in vivo studies and the absence of sufficient high-quality randomized controlled trials (RCTs) for the use of IFNs to treat SARS-CoV2, and that several studies indicate that it is not suggested for COVID-19 therapy, antivirals such as RBV have been commonly used in combination with IFN during epidemics (Arabi et al., 2020; Morra et al., 2018; Totura and Bavari, 2019) . Also, combination therapies in RCTs have been undertaken for the novel CoV (e.g., NCT04276688). Surprisingly, current Chinese guidelines include IFNs as an alternative for combination therapy (WHO, 2020) . Such efforts have led to rapidly increasing clinical data on IFN administration for COVID-19 cases. Notably, CoV outbreaks share remarkable similarities, and hence, investigating the experience with the previous spreading of SARS-and MERS-CoVs may assist in discovering an effective treatment or help determine if a candidate should be removed from treatment protocols . To our knowledge, there have not been any updated systematic reviews of the literature shedding light on the effectiveness of IFN therapy with the past outbreaks in mind. In the present systematic review and quantitative analysis of the evidence, we describe the characteristics of hospitalized cases with MERS-CoV, SARS-CoV1, and SARS-CoV2 patients and assess important treatment outcomes and ADEs of various combinational and non-combinational IFN treatments.

The present systematic review has been conducted compatible with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (Table S1 ). We designed the J o u r n a l P r e -p r o o f protocol to determine our scope, inclusion and exclusion criteria, and outcomes of evaluated studies. The protocol for the present study is provided in further detail in Supplementary Material.

The present study aimed to assess the outcomes of IFN treatments or IFN combination therapies in hospitalized patients infected with MERS-CoV, SARS-CoV, and SARS-CoV2.

Comparator therapies comprised placebo, sham therapy, and no intervention. Moreover, researches involving no comparator group were included. Outcome measures were selected according to our protocol. We assessed the efficacy of IFN therapies with or without combination with other pharmacotherapy options. As efficacy comprises numerous parameters, we took account many clinical outcomes, including mortality, discharge, CXR, hospital durations, inflammatory state, ADEs, and disease severity. Due to limited data and the emerging situation of the COVID-19 pandemic, both published and unpublished works were included. No restrictions were considered for the date of publication and language. Our classification for treatment regimens was in line with World Health Organization (WHO) Guidelines. For SARS-CoV, these groups included RBV, LPV/RTV (Kaletra), corticosteroids, IFN, convalescent plasma, and intravenous immunoglobulin (IVIG), which have been previously utilized in similar studies (Stockman et al., 2006) . MERS-CoV treatments included IFNs, RBV, LPV/RTV, polyclonal anti-MERS-CoV human immunoglobulins, humanized murine anti-S monoclonal antibodies, nucleoside viral RNA polymerase inhibitors (e.g., REM), peptide inhibitors (e.g., HR2P-M2), and mycophenolate mofetil (MMF) (Organization, 2019) . Moreover, possible SARS-CoV2 interventions according to WHO and Centers for Disease Control and Prevention (CDC) Guidelines comprised hydroxychloroquine, chloroquine, REM, oseltamivir, J o u r n a l P r e -p r o o f tocilizumab, LPV/RTV, IFN-β, convalescent plasma, IVIG, and corticosteroids (Organization, 2011) . Treatments were selected if used in combination with IFN. We included human studies designed as randomized and non-randomized clinical trials, observational clinical studies (e.g., retrospective and prospective cohorts), case reports, and case series.

In May 2020, five reviewers (K.S., S.Y., E.H., M.B., M.G.) performed a systematic search.

PubMed, Scopus, Cochrane's library, Web of Science (WoS), Global Index Medicus (WHO library), Google Scholar, and Scopus were searched for articles. An additional search was done for unpublished work (e.g., from BioRxiv, MedRxiv), and Reference lists were also screened (grey literature). Unpublished articles were checked, and updated with the published version of each, if available. For all articles, corrections and retractions were also checked. For Google Scholar, the following search strings were developed with the help of a skilled librarian:

("interferon" OR "IFN") AND ("Middle East respiratory syndrome" OR "Middle Eastern Respiratory Syndrome" OR "MERS-CoV" OR "Severe Acute Respiratory Syndrome" OR "SARS-CoV" OR "COVID-19") AND ("Patient" OR "Case" OR "Human") AND (clinical OR case) -"in vitro" -review -"narrative review" -monkey -"rat model" -mouse -polymorphism, String #2 "Ribavirin and interferon" AND ("Middle East respiratory syndrome" OR "Middle Eastern respiratory syndrome" OR "MERS-CoV" OR "Severe Acute Respiratory Syndrome" OR "SARS-CoV")), and String 3# ("Interferon Alfacon-1" AND "SARS-COV" OR "MERS-COV") -monkey -"review article".

We used hyphen, "-", to exclude phrases associated with preclinical research, as hyphen equals NOT operator in Google Scholar. All final records were imported into EndNote X9 software (Thomson Reuters, San Francisco, CA) . Results were collected after duplicate removal by J o u r n a l P r e -p r o o f authors (K.S., S.Y., E.H., M.B, M.G.). A three-step screening was followed to determine eligible results by examining each title, abstract, and full-text. Five reviewers (K.S., S.Y., E.H., M.B, M.G.) screened records separately, and disagreements were solved by referring to a third author (A.S.). All included studies were updated until March 2021 (2020; Fan et al., 2021; Zhang et al., 2020a; Zhou et al., 2020a) . Further detail for the search strategy is provided in Supplementary Material.

The following information was retrieved for each study: first author's name, year of publication, location, type of study, the period of data collection, personnel, setting, essential intervals (e.g., onset to treat period), number of patients, gender, disease severity, contact history, comorbidities, diagnostic methods, symptoms, drug information (e.g., name, dosage, duration, along with route and frequency of administration), and non-drug interventions. The extracted outcomes of interest were mortality, the number of discharged patients, inflammatory cytokines, ADEs, and chest imaging results. Table S2 is the table of data extraction.

To assess the risk of bias, the following tools were used for each study design: Cochrane risk of bias tool for randomized clinical trials (Sterne et al., 2019) , risk of bias in non-randomized studies of interventions (ROBINS-I) tool for non-randomized trials (Sterne et al., 2016) , J o u r n a l P r e -p r o o f Newcastle-Ottawa Scale (NOS) for Cohort Studies (Penson et al., 2018) , National Institute of Health (NIH) tool for case-series and descriptive cross-sectional studies (National Heart), and a recently suggested tool for case reports (Murad et al., 2018) .

The studies were further assessed according to the U.S. Preventive Services Task Force scoring protocol, in which Level of Evidence (LOE) is determined as follows (Mohamed et al., 2020a) :

Level I: Evidence acquired from a minimum of one properly designed RCT;

Level II-1: Evidence acquired from properly-designed controlled trials with no randomization;

Level II-2: Evidence acquired from a properly-designed cohort or case-control analytic research, preferably from more than one center or study group; Level II-3: Evidence acquired from multiple time series, both with or without the intervention. Dramatic outcomes in uncontrolled trials may also be taken as such kind of evidence;

Level III: Opinions of validated authorities, in accordance with clinical experience, descriptive research, or reports of expert groups.

The protocol details methods used for narrative and quantitative syntheses (Supplementary Material) (College Station).

The tool developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group (www.gradeworkinggroup.org) was selected for evaluation of bias across studies eligible for meta-analysis. GRADE enables consistent evaluation of the J o u r n a l P r e -p r o o f certainty of evidence. It also allows recommendations based on high-quality observational studies. GRADE initially ranks the evidence-based on study design. Studies are then promoted or downgraded according to criteria, including the risk of bias, indirectness, and imprecision (GradePro, 2020).

Our search strategy produced 2693 results from all six databases. Moreover, in addition to 42 initially included articles, our updated electronic search results identified 20 relevant results. An additional search yielded seven results. For five studies, full-text could not be obtained ( Fig. 2 ) (Gao et al., 2003; Qing et al., 2005; Wu et al., 2003a; Wu et al., 2003b; Xu et al., 2008) . Due to a lack of multilingual collaborators, we used online translators for foreign studies. All foreign articles were sufficiently translatable via online translators and hence were included (Rui et al., 2020a; Xu et al., 2008) .

Fifty-five distinct publications were included in line with our eligibility criteria. Classified by etiology, there were 29 eligible clinical studies for SARS-CoV2 (Cai et al., 2020a; Chen et al., 2020; Cheng et al., 2020; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Pan et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhou et al., 2020b) , 26 studies for MERS-CoV (24 distinct reports) (Al  J o u r n a l P r e -p r o o f Al-Hameed et al., 2016; Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Arabi et al., 2017; Arabi et al., 2019; Cha et al., 2016; Choi et al., 2016; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Rhee et al., 2016; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017) , and seven studies for SARS-CoV1 from which two articles could be retrieved in fulltext (Loutfy et al., 2003; Zhao et al., 2003) . Three studies reported on a similar population of patients. There, they were merged Arabi et al., 2019; Shalhoub et al., 2018) .

More specifically, the report by Shalhoub et al. was based on a cohort of 32 cases derived from 330 cases previously described by Arabi et al. in 2017 in a conference paper .

The multi-center cohort by Arabi et al. (2019) is an extended version that includes 349 cases, most of whom were previously described in earlier publications. As a result, the three studies were merged according to the 2019 report by Arabi et al. . A sum of 1122 cases, 1665 (53.3 %) males and (46.7%) 1457 females, with either suspected or confirmed COVID-19, was explored in 29 distinct reports. The mean age for COVID-19 patients was 47.12 (n = 1046) for 12 studies Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020b; Jin et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Qiu et al., 2020; Sun et al., 2020; Wang et al., 2020a; Yu et al., 2020; Zhou et al., 2020b) . After calculating the point estimate of the mean for the rest of the studies, which did not report study setting (Weir et al., 2018) , the mean age for all COVID-19 cases reached 51.26 (n = 3122) (Cai et al., 2020a; Chen et al., 2020; Cheng et al., 2020; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020;  J o u r n a l P r e -p r o o f Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Pan et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhou et al., 2020b) . In 24 distinct MERS publications, 1196 patients, including 587 males, 269 females, and 340 whose gender was not reported, were investigated ( Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Rhee et al., 2016; Shalhoub et al., 2015; Sherbini et al., 2017) .

Two studies did not report the age of 18 and 8 cases , respectively. A SARS study reported a mean age of 28.6 (n = 190) for one study (Zhao et al., J o u r n a l P r e -p r o o f 13 2003). The overall mean of both studies was 30.39 (n = 212) after calculating the mean for the other study (Loutfy et al., 2003; Zhao et al., 2003) .

All studies used nucleic acid real-time polymerase chain reaction (RT-PCR) test to detect the presence of CoVs in respiratory (e.g., nasopharyngeal, throat, upper respiratory swab) or urinary specimen (Al Al-Hameed et al., 2016; Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Arabi et al., 2017; Arabi et al., 2019; Cai et al., 2020a; Cha et al., 2016; Chen et al., 2020; Cheng et al., 2020; Choi et al., 2016; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Garout et al., 2018; Habib et al., 2019; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Pan et al., 2020; Rhee et al., 2016; Rui et al., 2020b; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhou et al., 2020b) , except for SARS-CoV1-infected patients who were included according to clinical inclusion criteria and IgG testing (Loutfy et al., 2003; Zhao et al., 2003) . A both positive and clear contact history with suspected or confirmed CoV cases or travelling to epidemic areas was reported in 20 (Cai et al., 2020a; Chen et al., 2020; Du et al., 2020; Fan et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Lo et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan Ghamdi et al., 2016; Al-Hameed et al., 2016; Cha et al., 2016; Choi et al., 2016; Garout et al., 2018; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Malik et al., 2016; Oh et al., 2015; Rhee et al., 2016; Shalhoub et al., 2015; Sherbini et al., 2017) , and 2 (Loutfy et al., 2003; Zhao et al., 2003) studies for COVID-19, MERS, and SARS infections, respectively. Moreover, a descriptive study divided COVID-19 patients into cases with "clear" and "unclear" contact history but did not determine whether the "clear" cases had a positive or negative contact history with a SARS-CoV2 patient or a high prevalence area (Pan et al., 2020) . Cai et al., 2020a; Cha et al., 2016; Chen et al., 2020; Cheng et al., 2020; Choi et al., 2016; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Garout et al., 2018; Habib et al., 2019; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Loutfy et al., 2003; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Pan et al., 2020; Qiu et al., 2020; Rhee et al., 2016; Rui et al., 2020b; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et J o u r n a l P r e -p r o o f al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhao et al., 2003; Zhou et al., 2020b) . Non-IFN pharmacological treatments comprised antivirals such as Umifenovir, also called Arbidol (ARB), Du et al., 2020; Fan et al., 2020; Huang et al., 2020b; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liu et al., 2020a; Wang et al., 2020a; Wang et al., 2020b; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhou et al., 2020b) , REM , Oseltamivir Fan et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Liu et al., 2020b; Sun et al., 2020; Yu et al., 2020) , Ganciclovir Cheng et al., 2020; Yu et al., 2020) , LPV and RTV (or Kaletra (LPV/RTV)) Cai et al., 2020a; Chen et al., 2020; Cheng et al., 2020; Choi et al., 2016; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Kim et al., 2017; Kim et al., 2016; Liu et al., 2020a; Lo et al., 2020; Pan et al., 2020; Qiu et al., 2020; Rhee et al., 2016; Rui et al., 2020b; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et al., 2020; Yuan et al., 2020) , FPV , and RBV (Al Al-Hameed et al., 2016; Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Arabi et al., 2017; Arabi et al., 2019; Cha et al., 2016; Chen et al., 2020; Cheng et al., 2020; Choi et al., 2016; Du et al., 2020; Fan et al., 2020; Garout et al., 2018; Habib et al., 2019; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Liu et al., 2020b; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Rhee et al., 2016; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017; Yuan et al., 2020; Zhao et al., 2003) . Administered curatives also included IVIG Chen et al., 2020; Choi et al., 2016; Du et al., 2020;  J o u r n a l P r e -p r o o f 2020; Wan et al., 2020; Yu et al., 2020) . Several studies reported patients' initial symptoms on admission, including fever, cough, shortness of breath, sputum or phlegm production, runny nose, nose obstruction, sore throat, myalgia, headache, dizziness, asthenia, and GI symptoms (e.g., diarrhea, nausea, and vomiting) (Al Al-Hameed et al., 2016; Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Cha et al., 2016; Chen et al., 2020; Cheng et al., 2020; Choi et al., 2016; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Habib et al., 2019; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jiang et al., 2020; Jin et al., 2020; Khalid et al., 2016; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Liao et al., 2020; Liu et al., 2020a; Lo et al., 2020; Malik et al., 2016; Oh et al., 2015; Pan et al., 2020; Qiu et al., 2020; Rhee et al., 2016; Rui et al., 2020b; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017; Sun et al., 2020; Wang et al., 2020c; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020; Zhao et al., 2003; Zhou et al., 2020b) . COVID-19, MERS, and SARS studies mentioned 20 Liao et al., 2020; Liu et al., 2020a; Lo et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Wang et al., 2020a) , 42 Choi et al., 2016; Khalid et al., 2014) , and no asymptomatic patients, respectively. Among MERS studies, one excluded the symptomatic cases (n = 38) from further analysis .

Furthermore, study characteristics including country, study design, age of participants, comorbidities, symptoms on admission, and type, dosage, and administration route of both IFN and non-IFN treatments have been summarized (Tables 1-3 ).

J o u r n a l P r e -p r o o f 2020) were also assessed. Results showed seven to be of good quality, while four had a fair quality Liao et al., 2020; Liu et al., 2020b; Xiao-Wei et al., 2020) , and one was of poor quality (Jian-ya, 2020). Importantly, a case-series was pre-printed , but was later published with a comparator group. The published version showed poor quality due to a lack of comparability according the NOS tool . The only included case report was of a high risk of bias (Tables 4-8) .

From 26 studies of MERS (Al Al-Hameed et al., 2016; Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Arabi et al., 2017; Arabi et al., 2019; Cha et al., 2016; Choi et al., 2016; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015; Omrani et al., 2014; Rhee et al., 2016; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017) , two were good quality caseseries Rhee et al., 2016) . There were 11 cohorts (Al Al-Hameed et al., 2016; Alfaraj et al., 2019; Arabi et al., 2019; Choi et al., 2016; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Omrani et al., 2014; Shalhoub et al., 2015; Sherbini et al., 2017) , two of which were good quality Shalhoub et al., 2015) , while the other nine were of poor quality, mostly due to low comparability scores and not adjusting for confounding factors (Al Al-Hameed et al., 2016; Alfaraj et al., 2019; Choi et al., 2016; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Omrani et al., 2014; Sherbini et al., 2017) . From 11 case reports in MERS Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Cha et al., 2016; Khalid et al., 2015; Kim et al., 2017; Kim et al., 2016; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015) , ten were of a high J o u r n a l P r e -p r o o f risk of bias, mainly because of lacking any description of suitable selection processes Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Cha et al., 2016; Khalid et al., 2015; Kim et al., 2016; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015) .

Furthermore, only one study had a low risk of bias .

Two studies were included in SARS (Loutfy et al., 2003; Zhao et al., 2003) . One was a randomized clinical trial (Zhao et al., 2003) with a high risk of bias, and the other was a cohort study of good quality (Loutfy et al., 2003) .

Finally, we provided the results for the quality of evidence by the LOE tool (Tables 1-3 ). For COVID-19 studies, only one study declared a conflict of interest , and others did not have any competing interests to declare. For MERS studies, two studies declared the existence of a conflict of interest (Arabi et al., 2020; Omrani et al., 2014) . Finally, SARS studies declared no conflict of interest. A few studies did not mention whether competing interests were present (Table S2) .

Out of 29 clinical COVID-19 studies, three did not specify mortality (Cai et al., 2020a; Fan et al., 2020; Zhou et al., 2020b) . A total of 414 cases expired in 26 studies Du et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Pan et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2020c; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020) . Interestingly, 14 studies J o u r n a l P r e -p r o o f reported no mortality Hung et al., 2020; Jiang et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Wang et al., 2020a; Xiao-Wei et al., 2020; Yu et al., 2020; Yuan et al., 2020) , and all cases in three studies died Du et al., 2020; Huang et al., 2020b) . This was, in part, due to that some studies strictly sampled cases with a fatal outcome or survivors.

Interestingly a study of 101 non-survivors was published with 134 cases, comprising a new comparator group of 33 survivors .

A recent open-label RCT showed no mortality in both LPV/RTV + RBV + IFN-β (n = 86) and LPV/RTV groups (n = 41) (P = 1.00) . A double-blind, placebo-controlled, multicenter RCT included 158 and 78 cases as intention-to-treat population in REM + IFN and Placebo + IFN groups, respectively. Results showed a 28-day Mortality of 22 (14%) in REM group (for REM + IFN: 29 (18%)) and 10 (13%) in the placebo group (for placebo + IFN: 15 (19%)) (risk difference=1·1%, 95% CI: (-8·1,10·3)) (Wang et al., 2020c). . The combination therapy of IFN/RBV was not associated with death in a recent cohort . Another study reported a CFR of 31.5% in patients who received IFN treatments, and a CFR of 40% in patients who did not receive IFN (P = 0.698) .

In two studies, 12 (5.67%) patients died (Loutfy et al., 2003; Zhao et al., 2003) . A randomized trial of 190 patients treated SARS cases with the following regimens: Group A (n = 40): RBV and Cefoperazone/Sulbactam, and oxygen therapy; Group B: fluoroquinolone, rIFN-α and restricted steroid use (n = 30); Group C (n = 60): quinolone, azithromycin, rIFN-α for some patients, and steroids when symptoms worsened; and Group D (n = 60): levofloxacin, azithromycin, 45 patients were given rIFN-α, high-dose methylprednisolone was given when infiltrates affected more than one pulmonary segment or when consolidation was expanded, and broad-spectrum antibiotics if a bacterial infection was confirmed after culture. In four groups, 2 (5%), 2 (6.67%), 7 (11.67%), and 0 (0%) patients died, respectively (Zhao et al., 2003) . In the other SARS study, 1 (7.7%) patient in the corticosteroid group (n = 13) died, while all patients in the corticosteroid + IFN-Alfacon-1 group (n = 9) survived (Loutfy et al., 2003) .

953 hospital discharges were reported in 24 studies Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; J o u r n a l P r e -p r o o f 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a) . Blurred edges were also reported by one study (Rui et al., 2020b) . Speckles and patchy shadows were observed in nine studies Huang et al., 2020a; Liao et al., 2020; Liu et al., 2020a; Lo et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a) . Thickening or disorder of textures was observed in three distinct reports Jian-ya, 2020; Rui et al., 2020b) . Other reported categories included unilateral or bilateral CXR involvement, pleural effusion, pneumothorax, white lung appearance, lung streak shadow, single lobe lesions, multiple solid nodules, visible band shadows, and bronchial shadow with air (Cai et al., 2020a; Cheng et al., 2020; Du et al., 2020; Fan et al., 2020; Fernández-Ruiz et al., 2020; Huang et al., 2020a; Huang et al., 2020b; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Liu et al., 2020b; Lo et al., 2020; Pan et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020b; Xiao-Wei et al., 2020; Yu et al., 2020; Zhou et al., 2020b) .

A recent non-randomized open-label trial investigated the efficacy of combination therapy of IFN with FPV, and included a total of 80 patients, who received IFN-α1b in two arms of the study (FPV + IFN group (n = 35), LPV/RTV + IFN (n = 45). The results showed that CT scan scores (median, range) were 12 (4.0-14.0) for FPV + IFN group, and 10 (4.5-13.5) for the LPV/RTV + IFN group (P = 0.78). Chest CT changes showed improvement in 32 cases (91.43%) vs. 28 (62.22%) cases, deterioration in 1 case (3.23%) vs. 9 (20.00%) cases, and was constant in 2 cases J o u r n a l P r e -p r o o f (6.45%) vs. 8 (17.78%) cases in FPV + IFN group and LPV/RTV + IFN group after 2 weeks, respectively (P = 0.004) (Cai et al., 2020a) .

Of 24 distinct reports, lung consolidation was present in 12 studies Al-Tawfiq and Hinedi, 2018; Arabi et al., 2019; Choi et al., 2016; Kim et al., 2017; Lee et al., 2017; Malik et al., 2016; Oh et al., 2015; Rhee et al., 2016; Sherbini et al., 2017) , while 11 studies showed infiltrates (Al Al-Tawfiq and Hinedi, 2018; Arabi et al., 2019; Cha et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2016; Lee et al., 2017; Oh et al., 2015; Rhee et al., 2016) . Eight studies reported ground glass shadows Choi et al., 2016; Khalid et al., 2015; Kim et al., 2017; Lee et al., 2017; Oh et al., 2015; Rhee et al., 2016; Sherbini et al., 2017) . Patchy shadows were observed in two studies (Al-Tawfiq and Hinedi, 2018; Oh et al., 2015) . Other reported categorizations included atelectasis, hilar vascular shadow, bronchovascular marking, acute pulmonary embolism, multiple solid nodules, single or multiple lobe lesion, and pleural effusion Cha et al., 2016; Choi et al., 2016; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2017; Kim et al., 2016; Malik et al., 2016; Rhee et al., 2016; Sherbini et al., 2017) .

In a randomized trial with four treatment groups (described in the SARS mortality section), the number of cases with unabsorbed pulmonary infiltrates was 12, 11, 13, and 4 for groups A, B, C, and D, respectively. Moreover, the difference between groups was significant (P = 0.003). This study also reported infiltrates localized in one pulmonary segment, signs in one pulmonary J o u r n a l P r e -p r o o f field, the involvement of both lungs, diffuse damage, as well as reported cases with only interstitial changes (Zhao et al., 2003) . In a recent preliminary study, patients were treated with IFN-Alfacon-1 + corticosteroid or corticosteroid alone. In this study, all cases in both groups showed abnormal chest imaging (P > 0.99). Eighteen patients did not show a full resolution of CXR abnormalities. Interestingly, the IFN-Alfacon-1 treatment group showed a reduced duration to 50% resolution of lung imaging abnormalities. The median for this duration was 4 in the IFN-Alfacon-1 + corticosteroid group vs. 9 in the corticosteroid only group (P = 0.001) (Loutfy et al., 2003) .

Seven studies that did not report the number of severe and non-severe cases Fernández-Ruiz et al., 2020; Huang et al., 2020b; Liu et al., 2020b; Wang et al., 2020b; Xiao-Wei et al., 2020; Yu et al., 2020) were excluded. 22 distinct reports, including 766 severe and 2007 non-severe cases, were studied (Cai et al., 2020a; Cheng et al., 2020; Du et al., 2020; Fan et al., 2020; Huang et al., 2020a; Hung et al., 2020; Jian-ya, 2020; Jiang et al., 2020; Jin et al., 2020; Liao et al., 2020; Liu et al., 2020a; Lo et al., 2020; Pan et al., 2020; Qiu et al., 2020; Rui et al., 2020b; Sun et al., 2020; Wan et al., 2020; Wang et al., 2020a; Wang et al., 2020c; Yuan et al., 2020; Zhou et al., 2020b) .

A retrospective cohort reported mean IFN treatment durations (days) in various levels of COVID-19 severity were 10.88, 95% CI: (8.00,13.75) in the mild group (n = 8), 14.24, 95% CI:

(13.45,15.03) in the moderate group (n = 75), and 15.55, 95% CI: (13.84,17.25) in the severe group (n = 11), which were significantly different (one-way ANOVA, P = 0.01) .

The number of non-severe (n = 52) and severe (n = 8) patients receiving various combination IFN regimens were reported in a trial. Among cases treated with IFN-β + LPV/RTV, 39 (80%)

were non-severe and 3 (38%) were severe (P = 0.045). Also, among cases treated with IFN-β + LPV/RTV + ARB, 10 (19%) were non-severe and 5 (63%) were severe (P = 0.019) (Jiang et al., 2020 ).

454 severe cases were reported in 10 studies Arabi et al., 2019; Cha et al., 2016; Choi et al., 2016; Kim et al., 2017; Lee et al., 2017; Omrani et al., 2014; Rhee et al., 2016) . The rest of studies had an unclear number of severe cases (Al Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Khalid et al., 2015; Khalid et al., 2014; Kim et al., 2016; Malik et al., 2016; Oh et al., 2015; Shalhoub et al., 2015; Sherbini et al., 2017) . In total, 9 non-severe cases were also reported in 10 studies Arabi et al., 2019; Cha et al., 2016; Choi et al., 2016; Khalid et al., 2015; Kim et al., 2017; Lee et al., 2017; Omrani et al., 2014; Rhee et al., 2016) , and the rest of studies had an unclear number of non-severe cases (Al Al-Tawfiq and Hinedi, 2018; Al-Tawfiq et al., 2014; Alfaraj et al., 2019; Garout et al., 2018; Habib et al., 2019; Khalid et al., 2016; Khalid et al., 2014; Kim et al., 2016; Malik et al., 2016; Oh et al., 2015; Shalhoub et al., 2018; Shalhoub et al., 2015; Sherbini et al., 2017) .

Univariable analysis of the influence of severity of disease on medications administered showed a significant negative risk association of -4.62, 95% CI: (−8.40,−0.84) (P = 0.018) for IFN-α, and a negative but non-significant risk association of -1.24, 95% CI: (−6.71,4.24) (P = 0.652) for IFN-J o u r n a l P r e -p r o o f β. Moreover, a multivariable analysis, which included a biomarker of disease severity, showed a strong association between disease severity and decreased survival, and no association between treatment with IFN-β and mortality (OR = 0.68, 95% CI: (0.04,10.28)) (P = 0.778) (Al . However, another study that did not discuss the severity of included patients showed a reduction in mortality was significantly associated with IFN-α (OR = 0.16, 95% CI: (0.02,1.38)) (P = 0.09). The lower mortality did not reach statistical significance for IFN-β (OR=0.28, 95% CI (0.03,2.33)) (P = 0.24) .

A cohort study showed that during the time interval of day 0-20 (upon onset of symptoms), on average, cases receiving the ARB only regimen had higher CRP levels than cases treated with IFN alone or both IFN and ARB, by 25.7 mg/L. Also, over the time interval between day 12 and day 42 (upon onset of symptoms), on average, cases receiving the ARB only regimen showed higher IL-6 levels than the cases who received IFN alone or both IFN and ARB, by 33.5 pg/ml. These effects were not influenced by co-morbidities for IL-6 (P = 0.456), or CRP (P = 0.420) levels . In a recent phase II trial, IL-6 levels (log10 pg/ml, median, (Q1,Q3)) were 1·4, (1·0-1·4) in LPV/RTV + RBV + IFN-β group (n = 86), and 1·4, (1·0-1·6) in LPV/RTV group (n = 41). These results did not show any significant differences between the trial arms (P = 0.43). Also, in this trial, TNF-α levels were measured for both trial arms (P = 1.00) . In another clinical study, CRP (mg/dl, median, (Q1,Q3) level was 18.6 (5.0-20.0) for all patients (n = 80). CRP levels were 15.0, (3.0-19.2) and 21.4, (5.0-23.2) in the FPV + IFN-α (n = 35) and LPV/RTV + IFN-α arm (n =45) of the study, respectively (P = 0.33). IL-6 (ng/l, median, J o u r n a l P r e -p r o o f (Q1,Q3)) was 13.4, (4.4-16.2) in all patients. IL-6 levels were 14.0, (3.5-11 .0) and 12.9, (5. 3-16.8) in FPV + IFN-α and LPV/RTV + IFN-α arm, respectively (P = 0.77) (Cai et al., 2020b) .

There were higher CRP levels (mg/l, median, (Q1,Q3)) in cases treated with IFN-α (n = 13) (86.5, (25,226)) compared to cases treated with (19.3, 346) ); However, this difference did not reach statistical significance (P = 0.61) .

In a recent cohort, duration from the symptom onset to hospital admission (days, median, (Q1,Q3)) was 8.0, (5.5, 15.5), 6.5, (3.0, 10.0), and 10.0, (4.5, 19.5) for IFN, IFN + ARB, and ARB groups, respectively. This difference, however, was not statistically significant (P = 0.087) . A placebo-controlled RCT of IFN therapy in combination with REM showed a similar duration of hospitalization (days, median, (Q1,Q3)) in the two arms of the trial 25·0, (16·0,38·0) in intention-to-treat populations of REM group (for REM + IFN: 29 (18%)) vs. 24·0 (18·0,36·0) in placebo group (for placebo + IFN: 15 (19%)) (risk difference=0·0, 95% CI: (-4·0,4·0)) . A lately surfaced cohort indicated that the duration of hospitalization was significantly correlated with PCR negative conversion durations in the IFN-α + LPV/RTV + RBV group (P = 0.0215), as well as the IFN-α + LPV/RTV group (P = 0.012) (Yuan et al., 2020) . A recent study divided the cohort of study into patients who experienced symptoms for more or less than ten days; Furthermore, 15 (45.5%) cases with symptoms lasting longer than ten days and 19 (65.5%) cases with symptoms lasting shorter than or equal to 10 days received IFN alone or in combination with ARB, RBV, or LPV/RTV . In a J o u r n a l P r e -p r o o f recent phase II RCT, the duration of hospital stay (days, median (Q1,Q3)) was significantly lower in the LPV/RTV + RBV + IFN-β 9·0, (7·0-13·0), compared with 14·5, (9·3-16·0) in the LPV/RTV (control) group (P = 0·016) .

The length of hospital stay (days, median, (Q1,Q3)) in a recent multi-center study was reported 17 (10, 28) in RBV/IFN group compared to 20 (10, 36) in the no RBV/IFN group (P = 0.48) .

In a randomized trial of 4 treatment groups (regimens were described in SARS mortality section), time to discharge (days, (S.D.)) was 24·8, (5·5) in group A, 24·8, (6·4) in group B, 22·4, (5·9) in group C, and 20·7, (4·6) in group D. Also, the difference between groups was not reported significant (Zhao et al., 2003) .

The total number of ADEs were significantly lower in the FPV + IFN-α (4) compared to the LPV/RTV arm of the trial (25) (P = 0.001); Also, nausea in patients in the FPV + IFN-α group was lower significantly in the FPV + IFN-α (0) compared to the LPV/RTV arm of the trial (6) (P = 0.03) (Cai et al., 2020a) . In another study, self-limited nausea and diarrhea were similar between the two groups. Furthermore, in this study, ADEs were reported by 41 (48%) of cases in the LPV/RTV + RBV + IFN group and 20 (49%) of cases in the LPV/RTV group . A placebo-controlled multi-center trial for the efficacy of REM + IFN compared with placebo + IFN found that ADEs were reported in 102 (66%) of REM receivers compared to 50 (64%) of placebo J o u r n a l P r e -p r o o f receivers. Importantly, REM was stopped early because of ADEs in 18 (12%) cases compared to 4 (5%) patients who discontinued placebo early . Finally, ADEs have been provided (Table S2 ).

MERS patients showed several ADEs during treatment with IFNs and other drugs. ADEs also included pancreatitis, which was reported in one patient , kidney injuries (e.g., AKI) in 5 cases , and renal failure in 3 cases .

Hepatic jaundice occurred in one patient during therapy . Changes in laboratory data were mentioned in some studies. Alterations in the laboratory profile of patients included increased amylase and lipase in seven patients who were treated with IFN Rhee et al., 2016) , increased bilirubin , decrease in Hb in 45 cases Omrani et al., 2014) , Scr and AST-ALT elevation in one patient with IFN therapy , thrombocytopenia in 2 patients Cha et al., 2016) , anemia in 46 cases Omrani et al., 2014) , and hemodynamic instability in 3 patients during treatment with IFN and other drugs were reported as ADEs . Fever was mentioned in one IFN receiver . Also, multiorgan damage as a severe side effect was reported in 5 cases treated with IFN ).

In SARS patients, fever, neutropenia with an absolute neutrophil count (ANC) of less than 1000/μl on the last day of treatment, a minor transient decrease in ANC, and elevation of J o u r n a l P r e -p r o o f serum transaminase levels were reported during IFN therapy in both IFN-Alfacon-1 and corticosteroid alone groups (Loutfy et al., 2003) .

Three observational COVID-19 investigations were eligible for meta-analysis of IFN treatment and severity. The studies showed moderate certainty (Table 9 ). Fixed-effects (Mantel-Haenszel) (I 2 <35%) approach was employed. Results showed the relation between receiving IFN and severity to be inconclusive. Effect size in all three studies crossed the line of no effect, indicating inconclusiveness of the current data (log OR=-0.44, 95% CI: (-1.13,0.25), I 2 =31.42%) (Fig. 3) .

Six MERS-CoV cohorts were included in the quantitative synthesis. Evaluation of the risk of bias across studies via GRADE showed the evidence was low certainty, indicating that further research could change our estimation (Table 10) . Random-effects (DerSimonian-Laird) (I 2 >35%) approach was selected. Mortality was not clearly affected by the administration of RBV/IFN treatment vs. no RBV/IFN (log OR=-0.05, 95% CI: (-0.71,0.62), I 2 =44.71%) (Fig. 4) . Publication bias was not analyzed due to the insufficient number of studies (n < 10). Finally, summary of findings table for GRADE assessments for narrative synthesis outcomes were conducted according to a new study (Murad et al., 2017) , and results were provided in Tables 11, 12, and   13 for COVID-19, MERS, and SARS, respectively.

The ongoing COVID-19 pandemic has led the scientific community to consider repurposing previously approved treatments such as convalescent plasma, antivirals like IFN, and LPV/RTV, and the clinical reapplication of the experience learned from previous global epidemics caused by hCoVs (Guy et al., 2020) . The present research has systematically investigated the efficacy of combinational or mere IFN therapy. We have reviewed the clinical literature regarding the clinical efficacy of IFN for three deadly human CoVs by analyzing the mortality, discharge, CXR presentations, onset-to-treatment duration, ADEs, and other clinically essential outcomes.

Understandably, mortality is of high clinical interest. Mortality in COVID-19 and SARS cases was not significantly affected by IFN therapy, as studies reported no mortality in all study subgroups of similar mortality. Moreover, a poor-quality cohort of SARS patients showed lower mortality and faster CXR improvement in patients receiving IFN-Alfacon-1 compared to IFN-Alfacon-1 + corticosteroids group. However, the results of this uncontrolled study should be taken with its small sample size and lack of randomization in mind. The higher discharge was indicated in a high-quality trial for combinational IFN therapy with REM vs. IFN alone in COVID-19. However, lower discharge rates for taking RBV/IFN were indicated in a poor-quality cohort. In addition to a lack of high-quality evidence backing up the use of RBV/IFN for COVID-19 patients, the calculated effect size for six MERS-CoV studies shows that IFN/RBV treatment did not prove beneficial compared with no RBV/IFN in terms of mortality. Cytokine storm in COVID-19 cases has been known for inducing a destructive immune response and is possibly responsible for unfavored clinical outcomes in COVID-19 (Nile et al., 2020) . For COVID-19, inflammatory cytokines (e.g., IL-6, TNF-α, and CRP) were lower in patients who received IFN with or without J o u r n a l P r e -p r o o f ARB. The quality of this study was good. Moreover, a randomized trial of a high risk of bias indicated no difference between inflammatory cytokine levels. Furthermore, our results should be interpreted in light of competing interests of included literature.

Also, a comparison between the anti-inflammatory potential of two IFN types was not significant in MERS patients. A wide range of chest radiography presentations was found in both COVID-19 and MERS patients. Interestingly, a moderately biased trial by Cai et al. showed a significant improvement in CXRs in FPV + IFN-α group vs. LPV/RTV +IFN-α group (P = 0.004), while also showing significantly fewer ADEs (P < 0.001). The median for onset-to-treat times was mostly under two weeks for both MERS and COVID-19. Interestingly, combination ARB + IFN treatment was clinically effective in a cohort via reducing inflammatory cytokines despite the relatively long onset-to-treatment interval (days, median (Q1,Q3)) 17.0 (10.0, 22.0). ADEs were mostly reported for IFN in combination with other antivirals. Therefore, despite that some studies showed certain combinations are less likely to result in ADEs, they were inconclusive for the use of IFN.

Studies strictly including patients according to a strictly fatal or non-fatal outcome do not help compare drug effects. In general, we indicate that although IFN has been commonly given in combination with antiviral therapies (e.g., with RBV in MERS cases), most studies have not reported a definitive benefit for the inclusion of IFN in administered regimens. Therefore, we suggest that more placebo-controlled RCTs with larger populations are required to clarify further the efficacy of IFN for a reduction in improving clinical status, and more importantly, mortality in COVID-19 patients. Also, we recommend that in order to reduce bias and increase J o u r n a l P r e -p r o o f usability in practice, comparative observational studies should control for confounding factors, especially severity.

The major restriction in our synthesis was the high risk of bias in many observational studies.

Also, most articles were observational studies, many of which were case reports or case series, and did not include a control group. Also, many cohort studies did not control any confounders, resulting in a high risk of bias. Most studies used a combination of pharmacological and nonpharmacological treatments, and utilized highly varied administration protocols along with IFN therapy or did not report outcomes classified by receiving IFN, complicating the distinguish of IFN-related harms or benefits from other interventions. MERS studies mostly reported RBV/IFN treatment groups, which does not assess the net effect of IFN therapy. Despite calling authors, six of SARS studies could not be retrieved due to the unavailability of the full-text. A limitation in SARS studies was using solely clinical criteria for inclusion rather than confirmed laboratory results. This may lead to the dampening of any actual treatment effects of antiviral therapeutics. We highlighted our assessments in light of lessons that can be learned from past CoVs, as they share principal similarities with the novel SARS-CoV2 (Gilbert, 2020; Peeri et al., 2020) . However, though IFN treatments may hold significant potential for the management of hospitalized COVID-19 patients, it is challenging to approximate their worldwide acceptance in regards to evidence of this treatment, irrespective of the efficacy of such therapeutics in past outbreaks.

In conclusion, the present systematic review reveals that the efficacy of IFN alone has not been investigated sufficiently for three deadly human CoVs. Still, we found that combination therapy of IFN with antivirals such as FPV, ARB, REM, or corticosteroids can have potential benefits (e.g., faster CXR improvement, lower level of inflammatory cytokines). These potentials need to be tested in larger RCTs. Also, the data regarding mortality, a crucially determining clinical outcome, seem insufficient for assessing treatment efficacy. Further investigation considering potential benefits and harms (e.g., ADEs) discussed in the present research can shed light on the path, leading to more successful conclusive trials in the strict time researchers possess during rapidly evolving outbreaks.

It is notable that many of the available therapeutic options are not specific to the COVID-19 condition and the death tolls are rising . This lack of specificity has brought about numerous efforts towards understanding the origin of the virus (Lundstrom et al., 2020; Sharifkashani et al., 2020) and discovering more targeted approaches for treatment of the disease Fathi and Rezaei, 2020; Lotfi et al., 2020; Rabiee et al., 2020; Rezaei, 2020b; Saghazadeh and Rezaei, 2020b; Seyedpour et al., 2020; Sharifkashani et al., 2020) , and the management of comorbid diseases . Definitely, such efforts need great scientific collaborations to occur and get presented (Mohamed et al., 2020b; Momtazmanesh et al., 2020; Moradian et al., 2020; Rzymski et al., 2020) . During this pandemic in which people are at risk of infection and re-infection and social distancing is the most important method of prevention, utilization of hybrid methods for J o u r n a l P r e -p r o o f holding scientific events might help the data to be shared and the information to be exchanged Samieefar et al., 2020) .

J o u r n a l P r e -p r o o f . 1 Role of IFNs and other innate immunity elements in multi-system CoV disease Among innate elements, inflammasomes, ILs, and IFNs are of high importance (Rasoulinejad et al., 2020) . Innate immunity helps to prevent the spread of viruses and affects ACE2  a major entry path for SARS-CoV2. Therefore, impairments in these elements may contribute to severe clinical disease. COVID-19 similar to its ancestors, may utilize ACE2, which can be mediated by IFN secretion. IFN may inhibit the replication chain. Retrograde synaptic pathway through which SARS-CoV2 infects the central nervous system (CNS) also involves ACE2. Here, dissemination of COVID-19 and its replication have been illustrated (indigo, I-IX). Also, the activation of innate pathways that upregulate IFNs, inflammasome elements, and cytokines has been illustrated (blue, I-VII). Created with BioRender.com. 

A RCT using a six-category ordinal scale previously defined by the authors showed that at the first level of the scale

A total of 33 cases were discharged in 18 studies

A recent observation, in which all cases were either discharged or deceased by the end of the study period

2% in the no RBV + IFN-α group (n = 17

Jian-ya, SARS-CoV, MERS-CoV, and SARS-CoV2 are human CoVs (hCoVs) that have been the cause of three outbreaks during the last two decades

Sadeghmousavi and Rezaei

Supporting this, inborn errors of immunity have not been shown to increase the risk of developing severe COVID-19 and dying from that. However, there are sporadic reports of death in patients with combined immunodeficiency

For this, anti-inflammatory and immunomodulatory treatments along with monoclonal antibodies appear as potential candidates (Basiri et al., 2020b; Fathi and Rezaei

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Characteristics and outcomes of Middle East respiratory syndrome coronavirus patients admitted to an intensive care unit in Jeddah, Saudi Arabia

The history and epidemiology of Middle East respiratory syndrome corona virus

The most effective therapeutic regimen for patients with severe Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection

The calm before the storm: clinical observations of Middle East respiratory syndrome (MERS) patients

Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study

Clinical predictors of mortality of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: A cohort study

Effect of ribavirin and interferon on the outcome of critically ill patients with mers. American journal of respiratory and critical care medicine

Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study

Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study

Primary Immunodeficiency Diseases in COVID-19 Pandemic: A Predisposing or Protective Factor? The American journal of the medical sciences

Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

Microfluidic devices for detection of RNA viruses

Regenerative Medicine in COVID-19 Treatment: Real Opportunities and Range of Promises

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Host-viral infection maps reveal signatures of severe COVID-19 patients

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A case report of a Middle East respiratory syndrome survivor with kidney biopsy results

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Not applicable J o u r n a l P r e -p r o o f

The authors declare that they have no competing interests.

There is no funding for the present study.

K.S. conceptualized the study, performed data curation and analysis, and prepared the initial draft. S.Y. conceptualized the study, performed data curation, and prepared the initial draft.M.B. conceptualized the study and performed data curation. E.H. conceptualized the study and performed data curation. M.G. conceptualized the study and performed data curation.A.S. conceptualized the study, designed the project, and prepared the final draft. N.R.conceptualized the study, supervised the project, and critically appraised the manuscript.