key: cord-1023468-9tus5wlw authors: Nakhlband, Ailar; Fakhari, Ali; Azizi, Hosein title: Interferon‐alpha position in combating with COVID‐19: A systematic review date: 2021-06-08 journal: J Med Virol DOI: 10.1002/jmv.27072 sha: 20210688feab401d20ee6b66dc36d6235a419493 doc_id: 1023468 cord_uid: 9tus5wlw The newborn coronaivus disease 2019 (COVID‐19) pandemic has become the foremost concern of health system worldwide. Interferon typeI (IFN‐I) are among the well‐known antiviruses. Hence IFN‐α have gained much attention as a treatment for COVID‐19 recently. To sum up the efficiency of IFN‐α against COVID‐19, we searched PubMed, SCOPUS, and EMBASE, from the date of genesis to the 1st of October 2020. Discharge from hospital and virus clearance considered as primary and secondary outcomes, respectively. We compared the aforementioned outcomes of patients treated with standard care protocol and the patients treated with IFN‐α in addition to standard care protocol. Out of 356 identified records, 14 studies were subjected for full‐text screening. Finally, a systematic review was performed with inclusion of five studies. Majority of the participants were males (ranged from 43.50% to 90.0%). We found that time of viral clearance and polymerase chain reaction negative (days) in most studies were decreased in the INF‐α + standard care group. The mean days of virus's clearance in INF‐α group and standard group reported 27.3 and 32.43. Likewise, the average days of hospitalization was found also lower in INF‐α group (18.55 vs. 24.36). This study provides a stand to conclude that early administration of INF‐α may be accounted as a promising treatment of COVID‐19. Latest pandemic well known as coronavirus disease 2019 has caused the foremost health and economic challenges all over the world. 1 Several research works have been conducted worldwide addressing this newborn concern but to date no efficient antiviral intervention have been approved. Clues arise from investigating molecular patho-mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) (virus causing . Interferons (IFNs) are well known for their action of interfering with virus replication and resulted in antiviral functions. 2 Moreover, type I IFNs support immune system in viral clearance via several mechanisms. But regretfully production and function of type I IFNs attenuated notably in COVID-19 patients since circulating levels of IFNs type I presented to define the stage of the condition. Deterioration of patients' clinical symptoms occurs following a decrease in plasma levels of IFNs type I. Therefore, type I IFNs insufficiency could be a sign of severe stages of COVID-19 and may help identify a high-risk population. Among type I IFNs, IFN-α is the first-line therapy of viral diseases, including hepatitis B and C infections. IFN-α revealed beneficial effects on resolution of lung abnormalities in hospitalized patients with SARS during 2003 SARS-CoV outbreak in Canada and China. 3, 4 In our previous conducted systematic review and meta-analysis study of clinical trials we presented that early administration of IFN-β with antiviral drugs is a promising treatment against COVID- 19. 5 Moreover, it was reported that nasal drops of IFN-α had protective function against COVID-19 among healthcare workers. 16 IFN-α can be efficient as preventive and therapeutic medicine for COVID-19, not only for its antiviral activity but also owing to its role in regulating inflammatory factors. Thereafter IFN-α seems a promising candidate to manage several stages of COVID- 19. In such a situation where finding a way to control and treatment of COVID-19 is urgent, thorough review and analysis of the studies and Records independently selected by two authors (HA, AN) and appropriate information gathered. Disagreements and doubted records were solved by consent of two more authors. All information about included records, such as article character, therapeutic impact of IFN, sign and symptoms release, hospital discharge, mortality, other relevant information and expected outcomes, as well as intervention, were gathered in the predesigned EXCELL form with brief details. We compared standard care protocol of laboratory-confirmed and hospitalized patients with COVID-19, with standard care combination with IFN-α. We considered patients who received standard antiviral treatment (lopinavir/ritonavir/arbidol) as control group and (antiviral treatment + IFN-α/IFN-β) as intervention group. The primary and secondary outcomes were considered as virus clearance (mean days) and hospitalization days (length of stay), respectively. The time (days) of treatment initiation (with IFN) from symptom onsets was evaluated in the studies if reported, to identify the association between the golden time of IFN-α therapy after symptoms beginning. Inflammatory factors as well as symptoms release, including fever resolve, adverse reactions, blood cells count, and disease level were studied and assessed in all included studies. Table 1 . Majority of the patients were males in most of the articles. The percentage of male patients ranged from 43.50% to 60.0%. The mean age of the patients in most studies was more than 41. All of included records were performed in China. 6, 7 In all studies, hospitalized patients with mild to severe COVID-19 had been investigated. The time of treatment onset from symptom onset were between 5 and 10 days. The shortest time (<5 days) to IFN administration after initiation of symptoms was reported in the Yan Zuo study. 8 Table 2 10±2.9 days compared with delayed intervention group. 9 However, some studies did not reported death and hospitalization days. 7 The average duration of viral clearance ranged from 5 to 21 days. The shortest duration of virus clearance (5 days) was reported by Yan Zuo study for patients who started antiviral treatment. 8 In the RCT study from China (Yin- Qiu Huang) , no death was reported among study groups. This study did not have any control group (without IFN-α) but the results indicated that after 4 days fever of all patients had subsided and the median days of hospitalization reported were 17 days (Table 2 ). 10 One other open-label single-arm clinical trial, reported only one death after 45 days of hospitalization. 11 A noncontrolled study reported that fever disappeared in all patients within the first seven days. 6 In the majority of included studies there was no important difference in the adverse effect compared between two groups. 9,10 In most of the studies, 5 micrograms/ml (12 million IU/ml) of IFN-α were administered twice per day for two consecutive weeks or until discharge. IFN-α administrated subcutaneously in Bo Wang study whereas other studies administered IFN-α by aerosol inhalation ( It should be taken into consideration that auto-antibodies (auto-Abs) against type I IFNs have been adverted in some patients. Some studies did not balance standard characteristics of the two groups, which can lead to overestimation of the IFN efficiency. Additionally, the effects of comorbidities have been ignored in stu- The peer review history for this article is available at https://publons. 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Interferon-alpha position in combating with COVID-19: A systematic review