. 2021 Sep 17;94(1):63–81. doi: 10.1002/jmv.27317

Table 1.

Clinical implication of interferon‐1 in the context of COVID‐19

Title	First author	Date of publication	Country	Type of study	Sample number	Mean age of patients	Intervention	Outcomes
The triple combination of interferon beta‐1b, lopinavir‐ritonavir, and Ribavirin in the Treatment of patients admitted to hospital with COVID‐19: an open‐label, randomized, phase 2 trial ⁸¹	Ivan Fan‐Ngai Hung	May 8, 2020	China	Clinical Trial	Combination group: 86 Control group: 41	Combination Group: 51 Control Group:52	Combination group: lopinavir, ritonavir, ribavirin and interferon beta‐1b Control group: lopinavir and ritonavir	(1) Combination therapy suppressed the shedding of SARS‐CoV‐2 in all clinical specimens (by day 8) and reduced the duration of in‐hospital stay (2) Combination therapy significantly reduced the duration of positive RT‐PCR and viral load
A Randomized Clinical Trial of the Efficacy and Safety of Interferon β−1a in Treatment of Severe COVID‐19 ¹⁰⁵	Effat Davoudi‐Monfared	August 20, 2020	Iran	Randomized Controlled Trial	Interferon group: 42 Control group: 39	Interferon group: 56.50 Control group: 61.00	Interferon group: Interferon β−1a and national protocol (hydroxychloroquine plus lopinavir‐ritonavir or atazanavir‐ritonavir) Control group: national protocol	(1) Adding IFN to the national protocol medications did not change the time of clinical improvement. (2) IFN significantly improved the discharge rate by day 14. (3) The 28‐day mortality was significantly lower in the IFN group. (4) Patients who received IFN in the early phase of the disease experienced significantly more benefits from the Treatment.
Interferon‐α2b Treatment for COVID‐19 ⁸	Qiong Zhou	May 15, 2020	China	Uncontrolled, exploratory cohort study	Interferon group: 7 Arbidol group: 24 Combination group: 46	Interferon group: 41.3 Arbidol group: 64.5 Combination group: 40.4	Interferon group: Nebulized IFN‐α2b Arbidol group: arbidol hydrochloride Combination group: IFN‐α2b and Arbidol	IFNα2b therapy, with or without Arbidol, appears to: (1) Reduce the duration of detectable virus in the upper respiratory tract (2) Shorten the duration of viral shedding (3) Decrease the markers of acute inflammation such as CRP and IL‐6.
Interferon β−1b in Treatment of severe COVID‐19: A randomized clinical trial ¹⁰⁵	Hamid Rahmani	August 24, 2020	Iran	Randomized Controlled Trial	Interferon group: 33 Control group: 33	Interferon group: 60 Control group: 61	Interferon group: Interferon β−1b Control group: lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine	(1) Interferon decreased time to clinical improvement, increased the discharge rate at Day 14, and reduced the need for ICU admission. (2) There was no difference in duration of hospitalization, intubation rate, length of ICU stay, and all‐cause 28‐day mortality (3) Incidence rates of common and serious adverse events were higher in the control group compared with the IFN group.
Arbidol/IFN‐α2b therapy for patients with coronavirus disease 2019 a retrospective multicenter cohort study ¹¹³	Ping Xu	May 20, 2020	China	Retrospective Cohort Study	Combination group: 71 Interferon group: 70	Combination group: 50.9 Interferon group: 53.2	Combination group: Arbidol and IFN‐ α2b Interferon group: IFN‐ α2b	(1) The median days of CT improvement in the combination group were less than that of the IFN‐a2b, the only group. (2) Combination group has potential effects on inhibiting COVID‐19 lung inflammation in mild cases without invasive ventilation, but no effects on RNA clearance and hospitalization days.
Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID‐19 Patients ¹²⁰	Nan Wang	September 9, 2020	China	Retrospective Cohort Study	Early IFN group: 216 No IFN group: 204 Late IFN group: 26	Early IFN group: 50 No IFN group: 49 Late IFN group: 51.5	Early IFN group: 83 patients received IFN + lopinavir/ritonavir (LPV/r), 94 patients received IFN + umifenovir (UFV), 39 patients received IFN alone No IFN group: 122 patients received LPV/r, 82 patients received UFV Late IFN group: 26	(1) Patients in the early IFN‐a2b administration group showed a lower mortality rate than those with no IFN‐a2b admission. (2) Patients who received late administration of IFN‐a2b experienced increased mortality. (3) Late IFN‐a2b administration was associated with delayed recovery among survivors. (4) Early IFN‐a2b and Umifenovir alone or in combination were associated with reduced mortality and a faster recovery in comparison with Treatment with lopinavir/ritonavir (LPV/r) alone.
No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon‐Alpha, Lopinavir/Ritonavir Plus Interferon‐Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon‐Alpha in Patients With Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open‐Labeled Prospective Study ⁹⁷	Yin‐Qiu Huang	July 14, 2020	China	Clinical Trial	Ribavirin (RBV) and interferon α group: 33 Lopinavir/ritonavir (LPV/r) and IFN α group: 36 RBV, LPV/r and IFN α group: 32	Ribavirin (RBV) and interferon α group: 40.3 Lopinavir/ritonavir (LPV/r) and IFN α group: 43.3 RBV, LPV/r and IFN α group: 43.8	First group: ribavirin (RBV) and interferon α Second group: Lopinavir/ritonavir (LPV/r) and IFN α Third group: RBV, LPV/r and IFN α	There were no significant differences among the three regimens regarding antiviral effectiveness in patients with mild to moderate COVID‐19.
Therapeutic effectiveness of interferon‐alpha 2b against COVID‐19: the Cuban experience ¹⁰⁸	Ricardo Pereda	June 9, 2020	Cuba	Prospective cohort study	Interferon group: 761 Control group: 53	Interferon group: 42.9 Control group: 66.9	Interferon group: Heberon® Alpha R (IFN‐α2b, liquid formulation) and Cuban COVID protocol (lopinavir/ritonavir and chloroquine) Control group: Cuban COVID protocol	The use of Heberon® Alpha R may contribute to recovery from COVID‐19 and improving both the rates of recovery and case fatalities.
Therapeutic effectiveness of interferon‐alpha 2b treatment for COVID‐19 patient recovery ¹¹¹	Ricardo Pereda	August 4, 2020	Cuba	Prospective cohort study	Interferon group: 2165 Control group: 130	Interferon group: 44 Control group: 68	Interferon group: IFN‐α2b and Cuban COVID protocol (lopinavir/ritonavir and chloroquine) Control group: Cuban COVID protocol	Interferon‐alpha 2b is effective for critical patient survival and decreases disease progression to severe stages.
Effect of combination of interferon alpha‐2b and interferon‐gamma or interferon alpha2b alone for the elimination of SARS‐CoV‐2 viral RNA. Preliminary results of a randomized controlled clinical trial. ¹¹⁸	Idelsis Esquivel‐Moynelo	August 4, 2020	Cuba	Randomized controlled clinical trial	Combination group: 30 Control group:33	Combination group: 42 Control group: 31	Combination group: IFN‐α2b and IFN‐γ (HeberFERON), lopinavir‐ritonavir and chloroquine Control group: IFN‐α2b (Heberon Alpha R), lopinavir‐ritonavir and chloroquine	HeberFERON was a safe treatment, superior to Heberon Alpha R in shortening the time to SARS‐CoV‐2 viral RNA elimination, with more than 95% of patients negative for SARS‐CoV‐2 within five days of Treatment.
Clinical evaluation of IFNbeta1b in COVID‐19 pneumonia: a retrospective study ¹⁰⁶	Miriam Estébanez	May 21, 2020	Spain	Retrospective cohort study	Interferon group: 106 Control group: 150	Interferon group: 61.9 Control group: 64.83	Interferon group: beta1b (Betaferon) and antivirals (lopinavir/ritonavir, and/or hydroxychloroquine or chloroquine), and/or anti‐inflammatory drugs (steroids and/or tocilizumab) Control group: antivirals (lopinavir/ritonavir, and/or hydroxychloroquine or chloroquine), and/or anti‐inflammatory drugs (steroids and/or tocilizumab)	The interferon beta1b treatment had no significant effect on in‐hospital survival. Because most patients in both treatment groups received other potential drugs such as hydroxychloroquine or Azithromycin, it was difficult to evaluate the treatment's effectiveness individually.
An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area ¹²¹	Zhongji Meng	May 7, 2020	China	Clinical trial	Low‐risk group: 2415 High risk group: 529	Low‐risk group: 35.13 High risk group: 32.87	Low‐risk group: rhIFN‐α (recombinant human interferon alpha) nasal drops with first‐level protection High‐risk group: rhIFN‐α nasal drops combined with thymosin‐α1 along with secondary‐level or third‐level protection	If standard first‐ and second‐level protections are strictly implemented, the IFN‐α nasal drops could significantly prevent medical staff at low exposure level from COVID‐19 pneumonia. Besides, IFN‐α nasal drops combined with weekly thymosin‐α1 could prevent medical staff at high exposure levels from developing the disease over a period of 28 days.
Repurposed antiviral drugs for COVID‐19 –interim WHO SOLIDARITY trial results ¹⁰⁹	Hongchao Pan	October 15, 2020	Multi National (30 countries)	WHO Solidarity trial consortium	Remdesivir group: 2743 Hydroxychloroquine group: 947 Lopinavir‐ritonavir group: 1399 Interferon‐β1a group: 2050 Control group: 4088		Remdesivir group Hydroxychloroquine group Lopinavir‐ritonavir group Interferon‐β1a group Control group: no study drug	The main outcomes of mortality, initiation of ventilation, and hospitalization duration were not clearly decreased by any type of study drugs (Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon).
Safety and efficacy of inhaled nebulized interferon beta‐1a (SNG001) for Treatment of SARS‐CoV‐2 infection: a randomized, double‐blind, placebo‐controlled, phase 2 trial ¹⁰³	Phillip D Monk	November 12, 2020	United Kingdom	Randomized, controlled, phase 2 trial	Interferon group: 48 Control group: 50	Interferon group: 57.8 Control group: 56.5	Interferon group: Inhaled nebulized interferon beta‐1a (SNG001) Control group: placebo	(1) Greater improvement in the SNG001 group (2) More rapid recovery in the SNG001 group (3) Greater improvement in breathlessness and total BCSS over the treatment period in the SNG001 group (4) No significant differences in time to hospital discharge between treatment groups
Engineered interferon‐alpha effectively improves clinical outcomes of COVID‐19 patients¹²⁴	Chuan Li		China	Randomized controlled trial	rSIFN‐co group: 46 Interferon‐alpha group: 48	rSIFN‐co group: 51 Interferon‐alpha group: 56	rSIFN‐co group: Recombinant super‐compound interferon combined with baseline antiviral agents (lopinavir–ritonavir or umifenovir) interferon‐alpha combined with baseline antiviral agents (lopinavir–ritonavir or umifenovir)	(1) rSIFN‐co combined with antiviral agents significantly improved the recovery in moderate‐to‐severe COVID‐19 patients compared to combination of traditional interferon‐alpha and antiviral agents. (2) rSIFN‐co‐lead to a shorter time to clinical improvement, radiological improvement, and virus nucleic acid negative conversion (3) Higher clinical improvement rate on day 28 in rSIFN‐co group
Combination therapy of IFNβ1 with lopinavir–ritonavir, increases oxygenation, survival and discharging of sever COVID‐19 infected inpatients ¹¹²	P. Baghaei	December 26, 2020	Iran	Retrospective cohort study	IFN group: 152 Control group: 304	IFN group: 56 Control group: 56	IFN group: IFN‐β1‐a, lopinavir and ritonavir Control group: lopinavir and ritonavir	Combination therapy resulted in reduced risk of mortality. IFN‐β1‐a can lower mortality rate, invasive ventilation, comorbidity, and improve requirement of oxygen.
Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta‐1b in hospitalized patients with moderate to severe COVID‐19 pneumonia ¹⁰⁷	F. Khamis	November 4, 2020	Oman	Randomized, open label controlled trial	Combination group: 44 Standard group: 45	Combination group: 54 Standard group: 56	Combination group: Favipiravir with interferon beta‐1b Standard group:Hydroxychloroquine	Neither clinical outcomes nor inflammatory markers were different between 2 groups.
Role of Interferon Therapy in Severe COVID‐19: The COVIFERON Randomized Controlled Trial ¹¹⁹	Darazam, I.A.	April 13, 2021	Iran	Randomized controlled trial	Intervention group 1: 20 Intervention group 2: 20 Control group: 20	Intervention group 1: 71.5 Intervention group 2: 65 Control group: 76	Intervention group 1: IFNβ1a + Lopinavir/Ritonavir and Hydroxychloroquine Intervention group 2: IFNβ1b + Lopinavir/Ritonavir and Hydroxychloroquine Control group: Lopinavir/Ritonavir and Hydroxychloroquine	Time to clinical improvement was significantly lower in the IFNβ1a group relative to the control group.
Clinical outcomes of different therapeutic options for COVID‐19 in two Chinese case cohorts: A propensity‐score analysis ¹¹⁴	C.K.H. Wong	February 13, 2021	China	Propensity‐score analysis	Lopinavir‐ritonavir: 994 Ribavirin: 377 Umifenovir: 217 Corticosteroids: 1044 Interferon‐alpha‐2b: 495 Antibiotics: 2179 Chinese medicines: 565 Interferon‐beta‐1b: 161 Interferon‐beta‐1b and ribavirin: 634 Interferon‐beta‐1b and ribavirin and lopinavir‐ritonavir: 408 Interferon‐beta‐1b and lopinavir‐ritonavir: 752		Lopinavir‐ritonavir Ribavirin Umifenovir Corticosteroids Interferon‐alpha‐2b Antibiotics Chinese medicines Interferon‐beta‐1b Interferon‐beta‐1b and ribavirin Interferon‐beta‐1b and ribavirin and lopinavir‐ritonavir Interferon‐beta‐1b and lopinavir‐ritonavir	Among all types of medications, interferon‐beta‐1b monotherapy along with interferon‐beta‐1b combined with oral ribavirin showed clinical improvement. Interferon‐beta‐1b combined with oral ribavirin considered to be more beneficial regarding clinical outcomes and hospitalization time.
Interferon‐α2b Treatment for COVID‐19 Is Associated with Improvements in Lung Abnormalities ¹¹⁷	Zhou, Q	December 30, 2020	China	Uncontrolled, exploratory cohort study	Interferon group: 7 Arbidol group: 24 Combination group: 46	Interferon group: 41.3 Arbidol group: 64.5 Combination group: 40.4	Interferon group: Nebulized IFN‐α2b Arbidol group: arbidol hydrochloride Combination group: IFN‐α2b and Arbidol	IFN therapy lead to reduced lung abnormalities in COVID‐19 patients. IFN increased CD8 + cells level and lowered TNF‐α and IL‐6.

The table summarizes valuable information on study design, types of interventions, and most importantly, outcomes from cited articles. Most of the studies shown here have compared the efficacy of IFN‐I presence or absence in specific antiviral regimens, while a few have explored its pure effectiveness either in nebulized or injective form. Utilizing nebulization is gaining lots of attention, with a considerable number of studies are yet to be carried out and published on this specific topic.