key: cord-0796604-0mbvxoww
authors: Lu, Ling-Ying; Feng, Po-Hao; Yu, Ming-Sun; Chen, Min-Chi; Lin, Alex Jia-Hong; Chen, Justin L.; Yu, Lennex Hsueh-Lin
title: Current utilization of interferon alpha for the treatment of coronavirus disease 2019: a comprehensive review
date: 2022-01-13
journal: Cytokine Growth Factor Rev
DOI: 10.1016/j.cytogfr.2022.01.001
sha: c1c6740b60f4e51f6016c2168d8e523b3062e024
doc_id: 796604
cord_uid: 0mbvxoww

Recent studies have identified an association between perturbed type I interferon (IFN) responses and the severity of coronavirus disease 2019 (COVID-19). IFNα intervention may normalize the dysregulated innate immunity of COVID-19. However, details regarding its utilization and therapeutic evidence have yet to be systematically evaluated. The aim of this comprehensive review was to summarize the current utilization of IFNα for COVID-19 treatment and to explore the evidence on safety and efficacy. A comprehensive review of clinical studies in the literature prior to December 1(st)(,) 2021, was performed to identify the current utilization of IFNα, which included details on the route of administration, the number of patients who received the treatment, the severity at the initiation of treatment, age range, the time from the onset of symptoms to treatment, dose, frequency, and duration as well as safety and efficacy. Encouragingly, no evidence was found against the safety of IFNα treatment for COVID-19. Early intervention, either within five days from the onset of symptoms or at hospital admission, confers better clinical outcomes, whereas late intervention may result in prolonged hospitalization.

The coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, took the world by surprise towards the end of 2019. The disease has greatly impacted healthcare systems, economies, and almost every aspect of our society. Through the endeavor of researchers worldwide, we now understand more about this disease, such as the primary routes of transmission of SARS-CoV-2, which include close contact, aerosols, and respiratory droplets. The virus enters human cells primarily by binding to angiotensin-converting enzyme 2 (ACE2) and initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2). 1 However, the heterogeneity of the prognosis of COVID-19 is still not well understood, as individuals may be entirely asymptomatic yet others may suffer from severe pneumonia, cytokine storm, and multiorgan failure. 2 

While various therapeutic agents have been researched for treating COVID-19, there is yet a consensus for a treatment regimen. One therapeutic agent under investigation is interferon alpha (IFNα), a cytokine that is produced by the innate immune system in response to viral infection. IFNα is indicated for the treatment of various viral infections. 3 For example, IFNα is used for the treatment of hepatitis B and C virus (HBV and HCV) infections, condylomata acuminata due to human J o u r n a l P r e -p r o o f papillomavirus infection (HPV), and Kaposi's sarcoma due to human immunodeficiency virus (HIV) infection.

Endogenous IFNα production can be induced by interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors (PRRs), which are mediated by adaptors, tumor necrosis factor (TNF) receptor-associated factors, and IFN regulatory factors (IRFs). 4 Two key transcription factors for IFN induction are IRF3 and IRF7. IRF3 is crucial for the initial induction of IFNα-1 and IFNβ, 5 whereas IRF7 subsequently amplifies IFNα and IFNβ production via a positive feedback loop. 6 Following phosphorylation, IRF3 and/or IRF7 dimerize, translocate to the nucleus, and induce type I IFNs and IFN-stimulated genes (ISGs). 7, 8 These IFNs then bind to IFN receptors, leading to the activation of Janus-kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways, ultimately inducing the production of hundreds of different ISGs, some of which have known mechanisms related to antiviral activities. [7] [8] [9] ( Table 1) .

IFNα inhalation is part of the standard treatment in China, 18 and hence most studies reporting the use of IFNα inhalation came from China. Other studies using IFNα inhalation included Argentina, Qatar, and Russia. Subcutaneous injection of IFNα was reported in China, France, India, Turkey, the UAE, and the USA. Intramuscular injection was only reported in Cuba, which is part of their national standard treatment. 17 Wide ranges in the severity of COVID-19, age, timing of treatment initiation, and duration of treatment were observed in these studies (Table 2) .

Additionally, one study stood out because it evaluated the prophylactic efficacy and safety of IFNα nasal drops against COVID-19 in hospital workers. 95 

Inhalation/Nebulization was the most commonly reported ROA, as it is part of the national guidelines in China and was frequently reported in studies conducted by Chinese researchers. The safety of IFNα inhalation was demonstrated in two studies, which reported no difference in the proportion of COVID-19 patients receiving IFNα treatment between those with and without delayed-phase thrombocytopenia nor between survivors and non-survivors. 28, 36 Furthermore, IFNα inhalation seemed to have beneficial effects on the liver during COVID-19 infection. One retrospective J o u r n a l P r e -p r o o f cohort study showed an association between IFNα inhalation and lower risks of elevated alanine aminotransferase (>40 U/L) in patients aged between 32 and 56 with (n=86) and without nonalcoholic fatty liver disease (n=194). 60 Another cross-sectional study investigating 342 patients of a similar age range also reported that IFNα inhalation was associated with reduced risks of abnormal liver function. 125 These seemingly beneficial impacts of IFNα on the liver are somewhat intriguing, given that liver toxicity is a noted side-effect of IFN-α2. In addition, IFNα inhalation may be associated with an abnormal triglyceride-glucose index and insulin resistance (n=64). 32 As the most commonly reported ROA, what we know about the efficacy of IFNα treatment for COVID-19 disease mainly came from the experiences of IFNα inhalation. An observation that we continued to see throughout the literature was the effect of the timing of IFNα treatment, wherein early initiation of treatment (within 5 days from onset of symptom) seemed to confer favorable outcomes, whereas late initiation of treatment may have been ineffective or may have resulted in unfavorable outcomes. Another observation was that mild and moderate patients seemed to respond better to IFNα treatment, whereas quite rarely were severe patients reported to have favorable outcomes following IFNα treatment. Both the J o u r n a l P r e -p r o o f timing of treatment and the severity of patients are two important factors that should be considered. Two reports on the same cohort of 77 moderate patients showed favorable associations between IFNα inhalation and lower chest computed tomography scores, lower number of CD8+ T cells, lower serum IL-6, TNF and c-reactive protein concentrations, and shorter duration from the onset of symptoms to viral clearance; however, the timing of treatment initiation was not reported. 175, 176 A case-control study presented varying results on the effects of IFNα inhalation in reducing viral shedding time and the length of hospitalization. 52 Patients treated with IFN-α2b inhalation had significantly shorter viral shedding time and hospitalization; however, statistical significance was lost after applying the propensity score matching method. Treatment was initiated for the IFNα group (which consisted of 41 mild, 22

severe, and 5 critically ill patients) at a median of 5 days (Q1-Q3: 3-8), and no difference in the timing of treatment initiation was found when compared with the control group. Another retrospective cohort study showed that late IFNα inhalation (>5 days after admission) in a cohort mostly consisting of moderate patients was associated with late recovery. 130 Another retrospective cohort study compared the therapeutic efficacy of IFN-α2b inhalation (n=44), IFN-α2b inhalation + lopinavir/ritonavir (n=67), and control (n=12) in COVID-19 patients with different severities. 189 The study found no differences in treatment methods with SARS-CoV-2 J o u r n a l P r e -p r o o f RNA clearance or with the duration of oxygen support. However, IFN-α treatment in those patients was initiated at a median of 6 days from the onset of symptoms, which may have been the reason for the non-significant difference. The combination of patients suffering from different severities may have also influenced the outcome, although there was no difference in the proportion of severities between the cohorts.

Evidence of the inefficacy of IFNα inhalation was only observed in studies that reported treatment initiated 5 days or later from the onset of symptoms. The timing of IFNα inhalation seemed to play a role in determining the prognosis and the outcome of treatment. The majority of studies that compared early and late administration of IFNα inhalation favored early administration, which was associated with positive outcomes. A retrospective cohort study showed that early administration (n=216) within 5 days of hospital admission was associated with reduced mortality. 130 Administration within 5 days of the onset of symptoms was also correlated with a shorter viral clearance time. 86 A shorter duration of viral shedding was reported in a case-control study in 89 non-severe and 13 severe COVID-19-infected healthcare workers who received early IFNα inhalation within 5 days of the onset of symptoms. 88 Similarly, in a cohort of 852 patients who received J o u r n a l P r e -p r o o f IFNα inhalation at a median of 5 days from the onset of symptoms to admission, researchers found lower risks of disease progression, a shorter time from the onset of symptoms/admission to a negative nucleic acid test, and a shorter hospitalization time compared with patients who did not receive IFNα therapy. 152 A case-control study that included 147 non-severe and 34 severe patients analyzed these patients according to prolonged viral shedding time (n=65; 21-39 days) or short-term shedding time (n=116; 5-20 days) and discovered that a greater proportion of patients had received early IFNα inhalation in the latter group. 179 While the study found that early IFNα inhalation was associated with a faster recovery, it also identified that delayed antiviral treatment, including IFNα inhalation, was an independent factor associated with prolonged viral shedding time. 179 In contrast, a retrospective study showed that no matter whether the treatment was initiated within 7 days of symptom onset or not, there was no difference between the IFNα (n=494) and non-IFNα (n=152) groups in terms of the time from admission to discharge, intensive care unit (ICU) admission, invasive mechanical ventilation, or mortality. 137 

Subcutaneous injection of IFNα was investigated in two clinical trials and a J o u r n a l P r e -p r o o f retrospective cohort study, providing stronger evidence of the safety and efficacy of IFNα treatment. The first clinical trial was a phase II randomized controlled trial that evaluated whether an additional single dose of pegylated IFNα (1 μg/kg) could provide extra benefits in comparison to the standard of care alone. 98 The trial reported that a greater proportion of subjects in the treatment group (19/20) compared with the control group (13/19) 

Intravenous injection of IFNα was reported in one retrospective cohort study J o u r n a l P r e -p r o o f investigating the effects of bodyweight on the clinical outcomes of COVID-19. 106 That study showed that IFNα was associated with reduced mortality in overweight patients. In another study, a formulation of IFNα nasal drops was evaluated as a prophylactic measure against COVID-19. 95 A case study of a 69-year-old female patient who traveled from the US to China was found positive for SARS-CoV-2 RNA during routine screening and subsequently received IFNα-2b spray and other drugs for treatment. 185 

Several IFNα-related formulations were found to have been applied as a COVID-19 treatment. One formulation was a recombinant version of IFNα with a modified spatial configuration named recombinant super-compound IFN (rSIFN-co), which was reported to have 20 times stronger antiviral activity. 66 The formulation was evaluated and compared to traditional IFNα via nebulization in 83 moderate and 11 severe patients from 14·0-14·5 days (median) of the onset of illness. The rSIFN-co group displayed faster clinical improvement, radiological improvement, and viral nucleic acid negative conversion rates. Another formulation named novaferon was a non-natural protein created using modified DNA shuffling technology, which demonstrated more than 10 times higher antiviral potency compared to IFNα-2b. 196 J o u r n a l P r e -p r o o f Novaferon inhalation was associated with a greater rate of and shorter time to SARS-CoV-2 clearance.

The use of IFNα inhalation was reported in patients with various comorbidities and conditions, including patients with atopic dermatitis, 38 Behcet's disease, 190 and osteoporosis. 44 However, whether IFNα treatment is safe and efficacious in COVID-19 patients with these comorbidities requires further clinical studies. 

The severity of disease seems to be another key determinant of IFNα treatment.

Patients with severe COVID-19 disease did not seem to benefit from IFNα treatment. 46, 188, 195 On the contrary, a case report from the UAE suggested clinical benefits of IFNα treatment in severe patients, in which three cases received subcutaneous injections of pegylated IFNα-2a following clinical deterioration and oxygen support. 42 The timing of treatment initiation of the three reported cases were 3, 7, and 11 days after hospital admission. These male patients were respectively 61, 37, and 38 years of age. This case report serves as one of the few pieces of evidence that supports the use of IFNα in severe COVID-19 patients, two of which could be regarded as late administration. Another case report from China reported a 47-year-old male who received IFNα inhalation 7-8 days after the onset of symptoms and was discharged from the hospital after 10 days of treatment. Nevertheless, the majority of the literature that reported IFNα treatment in severe COVID-19 cases usually stated unfavorable outcomes. With less controversy, IFNα treatment showed efficacy in moderate patients, as shown in cohort studies 176, 193 and clinical trials. 98, 181 Overall, no alarming findings on the safety of IFNα agents were found in this review; 

Individuals with a perturbed IFN response, inborn errors in type I IFN immunity, or autoantibodies against type I IFNs are predisposed to life-threatening COVID-19. 12, 13 It then raises speculations on what would happen if the opposite were to occur, i.e., increase IFN concentrations prior to COVID-19 infection. The question of whether IFNα prophylaxis prevents COVID-19 infection is worth examining. A single-center study in China recruited 529 high-risk and 2,415 low-risk medical personnel who received 2-3 drops/nostril/time four times daily of IFNα for 28 days with or without subcutaneous injections of thymosin-α1. 95 During the study period, no medical personnel were infected with COVID-19. In contrast, the control group, who did not receive IFNα, from external sources during the same period in the same province J o u r n a l P r e -p r o o f recorded 1,716 confirmed cases among 3,387 medical personnel. Another piece of evidence came from the observation of patients with Behcet's syndrome in Turkey. 190 Behcet's syndrome is a rare inflammatory disorder that results in a wide range of signs and symptoms and can be treated with IFNα. Using univariate logistic regression, the researchers analyzed data from 1,037 patients and found that patients on IFNα treatment had an odds ratio of 0.12, meaning that they were 88% less likely to contract COVID-19 disease. It should be noted though that the number of patients on IFNα treatment was relatively small.

To the best of our knowledge, this is the first and most updated review that provides Some observational studies inferred certain treatments were effective or ineffective against COVID-19; however, careful assessments and interpretations are necessary as some conclusions were drawn from data that lack comparability among cohorts and/or appropriate statistical methods. Age and comorbidities are two major risk factors for severe 198 which were often the disparities among patient groups in cohort studies. The application of simple statistics in these studies could lead to incorrect conclusions. To overcome this problem, matching or regression techniques could be applied, with the latter possibly being the better option. 198 To illustrate the issue in statistical analysis, we described here a case-control study 52 that compared outcomes between patients treated with and without IFNα inhalation, in which matched and unmatched datasets were used for multivariate cox regression analysis. In unmatched analysis, IFNα inhalation was associated with reduced ICU J o u r n a l P r e -p r o o f admission, viral shedding time, and length of hospitalization as well as increased discharge rate, whereas in matched analysis, no associations were found. Although both analyses were valid, applying the cox regression method to adjust for confounders may be sufficient to draw inference, whereas there may be a risk of losing statistical power when reducing sample sizes for the purpose of matching. 198

Through this review, we have generated a number of recommendations on the study design for future clinical researchers who wish to investigate IFNα treatment for COVID-19. Firstly, it may be worthwhile to record the severity of COVID-19 at both hospital admission and at treatment initiation as well as the worst severity during hospitalization, in addition to providing a clear definition of the grading system used.

Secondly, as treatment for COVID-19 appears to be associated with the timing of treatment initiation, especially in the case of IFNα, we recommend that future studies report this information in relation to the onset of symptoms and/or hospital admission. Thirdly, for reporting IFNα treatment, it would be useful to include more explicit details, such as dose, frequency, treatment duration, and ROA. Fourthly, various confounding factors (e.g., age) could affect outcomes. To adjust for these confounders, matched data and the propensity score method may be beneficial if a We hope this review has shed some light on different aspects of the use of IFNα treatment for COVID-19. It has been said that the SARS-CoV-2 is here to stay; therefore, a further understanding of COVID-19 and an establishment of treatment and management for COVID-19 are of paramount importance for the future of mankind.

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☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alex Jia-Hong Lin, Justin L. Chen, and Lennex Hsueh-Lin Yu declare their employment status with Panco Healthcare Co., Ltd., a subsidiary of PharmaEssentia Corporation. LHY and AJL are full-time employees of Panco Healthcare Co., Ltd. JLC is a contract researcher working for Panco Healthcare Co., Ltd. Although these authors are affiliated with the industry, they declare that their contribution to this manuscript was not funded by their employer but rather driven by their passion in science and desire to contribute to the fight against the COVID-19 pandemic.

 A summary of the safety and efficacy of IFNα as a treatment for COVID-19 No evidence was found against the safety of IFNα treatment for COVID-19 Early intervention with IFNα within five days confers better clinical outcomes J o u r n a l P r e -p r o o f