Journal of Clinical Immunology https://doi.org/10.1007/s10875-021-01068-6 COMMENTARY Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β Donald C. Vinh 1 & Laurent Abel 2,3,4 & Paul Bastard 2,3,4 & Matthew P. Cheng 1 & Antonio Condino-Neto 5 & Peter K. Gregersen 6 & Filomeen Haerynck 7 & Maria-Pia Cicalese 8 & David Hagin 9 & Pere Soler-Palacín 10 & Anna M. Planas 11 & Aurora Pujol 12,13 & Luigi D. Notarangelo 14 & Qian Zhang 2 & Helen C. Su 14 & Jean-Laurent Casanova 2,3,4,15 & Isabelle Meyts 16,17 & On behalf of the COVID Human Genetic Effort Received: 26 March 2021 / Accepted: 17 May 2021 # The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Introduction errors of TLR3- and IRF7-dependent type I IFN production or amplification underlie severe disease in ~3% of a cohort of Since December 2019, over 150 million individuals have been relatively young adult patients analyzed by the COVID infected with SARS-CoV-2 globally. While most cases Human Genetic Effort (COVIDhge.com) [3]. In at least an (>95%) are asymptomatic or mild, a small proportion develop additional 10% of cases, high levels of pre-existing auto-anti- moderate, severe, or critical COVID-19 pneumonia requiring bodies (auto-Abs) neutralizing most type I IFNs, but rarely hospitalization, at times in the intensive care unit [1]. At least IFN-β, abrogate type I IFN–dependent control of SARS- 2 million patients have already died [2]. The main epidemio- CoV-2 replication in vitro, thereby underlying critical disease logical risk factor associated with critical pneumonia or death in vivo [3, 4, 9, 10]. This observation was replicated in other is age > 65 years; however, life-threatening COVID-19 has cohorts [11–15]. The mean age of patients with inborn errors also affected younger people, albeit sporadically. Studies have was 48 years, while that of patients with auto-Abs was 65 suggested that type I interferon (IFN) immunity contributes to years. These findings support a two-step model of COVID- the control of SARS-CoV-2 infection [3–8]. Notably, inborn 19 pathogenesis: defective type I IFN immunity in the first * Isabelle Meyts 9 Allergy and Clinical Immunology Unit, Department of Medicine, Tel isabelle.meyts@uzleuven.be Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel 1 McGill University Health Centre, Montreal, Canada 10 Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital 2 St Giles Laboratory of Human Genetics of Infectious Diseases, Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall Rockefeller Branch, Rockefeller University, New York, NY 10065, d’Hebron Barcelona Hospital Campus, Universitat Autònoma de USA Barcelona (UAB), Barcelona, Catalonia, Spain 3 Laboratory of Human Genetics of Infectious Diseases, Necker 11 IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 12 75015 Paris, France Neurometabolic Diseases Laboratory, IDIBELL–Hospital Duran I 4 Reynals; Catalan Institution for Research and Advanced Studies University of Paris, Imagine Institute, 75015 Paris, France (ICREA), Barcelona, Catalonia, Spain 5 University of São Paulo, São Paulo, Brazil 13 CIBERER U759, ISCiii, Madrid, Spain 6 Feinstein Institute for Medical Research, Northwell Health USA, 14 Manhasset, NY, USA Laboratory of Clinical Immunology and Microbiology, National 7 Institutes of Health, Bethesda, MD, USA Department of Paediatric Immunology and Pulmonology, Centre for 15 Primary Immunodeficiency Ghent (CPIG), PID Research Lab, Howard Hughes Medical Institute, New York, NY, USA Jeffrey Modell Diagnosis and Research Centre, Ghent University 16 Hospital, Ghent University, Ghent, Belgium Department of Pediatrics, University Hospitals Leuven, 8 Leuven, Belgium Pediatric Immunohematology and Bone Marrow Transplantation 17 Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Laboratory for Inborn Errors of Immunity, KU Leuven, IRCCS San Raffaele Scientific Institute, Milan, Italy Leuven, Belgium J Clin Immunol hours and days of infection leads to uncontrolled viral repli- Abs versus the general population? Although reports from cation with spread to the lungs and other tissues, with subse- patients with genetic type I IFN defects have not raised con- quent excessive leukocyte recruitment, underlying uncon- cerns about impaired vaccine responses, longitudinal data will trolled inflammation [5]. This model of early deficient type I be required to more definitively address these questions [20, IFN function provides a framework for novel preventive and 21]. The COVIDhge data also open new considerations on therapeutic approaches of COVID-19. Here, we explore two safety. As some type I IFN pathway defects, especially auto- therapeutic routes that aim to restore protective type I IFN somal recessive (AR) deficiency of STAT2, IFNAR1, and immunity: [1] the early administration of IFN-β in ambulatory IFNAR2, predispose to severe disease with live attenuated subjects, including exposed individuals prior to infection, pre- vaccine (LAV), and as anti-type I IFN auto-Abs can underlie symptomatic infected individuals and symptomatic individ- disease caused by the yellow fever vaccine, special caution uals, and [2] the removal of auto-Abs to type I IFN in hospi- will be needed with SARS-CoV-2 vaccine strategies that use talized patients. We also discuss the implications of these LAV [22]. We must also recognize that, as SARS-CoV-2 findings for other preventive and therapeutic interventions, variants with potential to escape vaccine coverage emerge, it including B cell depletion, JAK inhibitors, intravenous immu- is possible that individuals with monogenic or auto-Ab- noglobulins, the use of convalescent plasma and virus-specific mediated impairment of type I IFN responses continue to re- mAbs, and vaccination. This discussion is timely, as more main at risk for severe disease, despite vaccination. The cor- than one year into the pandemic, we are still in the dark about ollary would propose that individuals who develop COVID- the best prevention and treatment for severe COVID-19 pneu- 19 disease following vaccination, and perhaps those who are monia, while the emergence of more contagious viral variants, repeatedly re-infected as well, may harbor known or novel causing more severe disease, raises concerns regarding the inborn errors of immunity. efficacy of the nascent vaccination programs [16, 17]. Convalescent Plasma and mAbs Vaccines for COVID-19: Where Do We Stand? Convalescent plasma (CP) from recovered patients is being Currently, several COVID-19 vaccines are in use, and numer- administered in severe and critical COVID-19, prompted by ous others are in different phases of development. Despite historical experience with SARS-CoV, MERS-CoV, and their excellent efficacy and safety profile, the finding that sera 1918 Spanish flu [23, 24]. The rationale is that passive immu- from vaccinated individuals showed reduced in vitro neutral- nization against SARS-CoV-2 can ameliorate disease by de- ization of 5 of 10 pseudoviruses representing circulating creasing virus spread and replication. It is expected to be ben- SARS-CoV-2 strains is concerning [18]. Moreover, protection eficial mainly in the initial phases of disease. Risks of CP from vaccines may wane and not all people will be able to therapy include those of standard plasma infusions; for in- tolerate the vaccines or mount protective responses. For in- stance, volume overload and transfusion-related acute lung stance, a word of caution is needed for the use of mRNA injury require special care [23, 25]. A theoretical risk is vaccines in patients with interferonopathies (i.e., antibody-dependent enhancement, in which non-neutralizing autoinflammatory conditions due to excessive type I IFN ac- antibodies against SARS-CoV-2 worsen disease by engaging tivity), as these vaccines may potentially induce exaggerated Fc receptors which modulate effector functions of monocytes/ type I IFN responses, despite the introduction of macrophages and mediate cytokine release [26]. Eight ran- pseudouridine instead of uridine to reduce recognition by domized clinical trials (RCTs) using CP have been reported nucleic acid sensors. Overall, surveillance studies and most failed to show a beneficial effect on clinical status or documenting both safety and efficacy are critically needed in mortality, conflicting with the observational studies [27–29]. patients with inborn errors of immunity and their phenocopies. Subsequently, an additional double-blind placebo-controlled Germane to the COVIDhge findings of deficient type I IFN clinical trial showed no efficacy in improving morbidity/ activity in severe COVID-19, more specific questions arise. mortality in patients with severe COVID-19 when adminis- First, is vaccine efficiency maintained in patients with a ge- tered at a median of 8 days after symptom onset, whereas netic or auto-immune phenocopy of type I IFN defect? Indeed, another double-blind placebo-controlled clinical trial showed type I IFN has been described to enhance antibody responses decreased disease progression in mildly affected patients and isotype switching by effects on dendritic cells [19]. Do the when administered within 72 h after symptom onset [30, current vaccines induce sufficient adaptive immunity to com- 31]. There are over 100 ongoing studies evaluating CP. pensate for a patient’s innate defect in type I IFN or for the These studies need to teach us [1] the minimum levels of pre-existing anti-type I IFN auto-Abs? Is the clinical effective- anti-SARS-CoV-2 neutralizing antibodies needed to prevent ness of the vaccines comparable between those with genetic or abort development of severe disease; [2] the optimal timing defects of type I IFN response pathway and those with auto- of plasma collection from donors after disease resolution; and J Clin Immunol [3] the optimal dosing and timing of infusions relative to [39–45]. A retrospective multicenter study conducted in symptom onset in recipients [32, 33]. China reported reduced mortality at day 28 in critically ill In the context of the findings of the COVIDhge, the main COVID-19 patients treated with high-dose IVIG [46]. Two concern is that CP, if harvested from severely ill or hospital- RCTs with high-dose IVIG were recently published. The first ized COVID-19 patients, may contain neutralizing type I IFN study compared 1.2 g/kg IVIG plus hydroxychloroquine and auto-Abs [15]. In that case, CP therapy could worsen disease lopinavir/ritonavir to the latter treatment alone, and its results in the recipient. Thus, CP should only be collected from did not support the use of IVIG [47]. A smaller study, with 30 asymptomatic or mildly ill COVID-19 patients and must be patients in each treatment arm, showed a decreased mortality tested for neutralizing auto-Abs against type I IFN, even in patients with severe COVID-19 treated with IVIG [48]. though at present, the threshold of auto-Abs that leads to crit- More RCTs are needed to define efficacy, dosing, and timing ical COVID-19 has yet to be defined. Of note, the general of high-dose IVIG treatment. In light of COVIDhge findings, application of such strategy is only possible when and where administration of high-dose IVIG might have the additional a standardized, validated assay to detect neutralizing anti-type benefit of “washing out” the pathogenic anti-type I IFN auto- I IFN auto-Abs is readily available with a quick turnaround Abs [49]. High-dose IVIG are thus beneficial in immune time (<24 h). Recombinant monoclonal antibodies, targeted thrombocytopenia [50] and Guillain-Barré syndrome [51]. against SARS-CoV-2 spike protein, obviate these concerns Careful studies of the kinetics of anti-IFN-auto-Abs are nec- and are potentially safer [34–36]. Moreover, the neutralizing essary, together with longitudinal assessment of serum cyto- titers achieved with for instance REGN-COV2 (a cocktail of kines, to provide proof of principle for this approach. casirivimab plus imdevimab, two non-competing neutralizing Seven RCTs have examined the effect of low-dose ste- human IgG1 antibodies targeting the receptor binding domain roids, as a broad-acting anti-inflammatory agent, in critical of the spike protein) were more than 1000 times the titers COVID-19, and one RCT in non-critical COVID-19. The achievable with CP. A combination of bamlanivimab and largest trial, in 2104 subjects, showed a reduced 28-day mor- etesevimab (two other non-competing anti-spike neutralizing tality (22.9% vs. 25.7%) in dexamethasone versus usual care monoclonal antibodies derived from 2 patients who recovered [52]. A meta-analysis of all trials showed a significant de- from COVID-19), but not bamlanivimab alone, administered crease in day 28 mortality for dexamethasone compared to within 72 h of onset, reduced viral load and resulted in a supportive care in three trials, in patients with critical decreased hospitalization rate compared with placebo in COVID-19 [53]. A more specific approach to dampen the mild-to-moderate COVID-19 [36]. REGN-COV2 had a pro- cytokine storm in COVID-19 is by targeting IL-6, using the found and rapid effect on viral load, with most reduction oc- anti-IL6 receptor (IL6R) blocking monoclonal antibodies, curring within 48 h and with a stronger effect in individuals tocilizumab, or sarilumab. Multiple observational studies with a high viral load [35]. Studies of the impact on clinical hinted towards improved outcome using tocilizumab. outcome as a primary outcome are ongoing. However, viral Several RCTs have now been conducted in severe COVID- strains carrying mutations in the target epitopes of SARS- 19 [54–60]. The largest trial, which focused on patients with CoV-2 spike protein have already been described, clouding critical COVID-19, reported reduced days on organ support the future of monoclonal antibody treatment [37]. and a small reduction mortality in patients receiving anti-IL6R antagonists versus placebo (27% in the pooled tocilizumab or sarilumab arm vs. 36% in the placebo arm, REMAP-CAP Anti-inflammatory Drugs: Intravenous trial) [61]. Overall, the RCTs have been unimpressive in terms Immunoglobulin (IVIG), Corticosteroids, of beneficial effect on survival [62]. and Anti-IL6R Antagonists In the two-step model of critical COVID-19, the first phase of Anti-inflammatory Agents that Interfere insufficient type I IFN immunity results in deleterious pulmo- with Type I IFNs: JAK Inhibitors nary and systemic inflammation, calling for anti-inflammatory interventions. High-dose IVIG (0.8 g/kg to 2 g/kg) has immu- Several classes of drugs interfere with the type I IFN path- nomodulatory capacity, presumably via inhibition of comple- ways, including antagonists/monoclonal antibodies targeting ment system activation; decreased endothelial cell activation; IFNAR/IFN. Janus kinase (JAK) inhibitors (Jakinibs) target anti-inflammatory effects on monocytes, macrophages, and many signaling pathways, depending on their selectivity [63]. neutrophils; and stimulation of regulatory T cells [38]. High- Ruxolitinib inhibits JAK1 and JAK2 and thereby interferes dose IVIG has been used in several studies in COVID-19 as an with, respectively, the common cytokine receptor γ-chain immunomodulatory therapy to treat multisystem inflammato- (used by IL-2, IL-4, IL-7, IL-9, IL-15); the gp130 pathway ry syndrome in children and adults associated with SARS- (IL-6, IL-11, OSM, LIF); the class II cytokine receptor family CoV-2 infection, but also in severe COVID-19 pneumonia (IFN-α/β, IFN-γ, IL-10) (JAK1); and the EPO, TPO, IFNγ, J Clin Immunol and βc family (IL-3, IL-5, GM-CSF) (JAK2). Tofacitinib po- Depletion of plasmablasts can be achieved by antibodies tently inhibits JAK3 next to JAK1 and thus may also impair targeting CD38 (e.g., daratumumab); the latter has been suc- the γc receptor family. Ruxolitinib is an especially potent cessfully used to treat multiple myeloma [74], autoimmune inhibitor of type I IFN signaling. Finally, IFN-kinoid (IFN-α cytopenias [75], autoimmune organ diseases [76, 77], and coupled to the carrier protein, keyhole limpet hemocyanin) infection due to auto-Abs to cytokines [78]. These depletive induces the production of antibodies against all 13 IFNα therapies have not been studied as acute treatment for [64]. These drugs are in various phases of development and COVID-19 in the context of RCT or, to our knowledge, even clinical trials and some have been approved by the FDA to published as case reports. However, results of retrospective treat malignancies, rheumatoid arthritis, psoriasis, inflamma- studies on the outcome of COVID-19 are inconclusive in pa- tory bowel disease, and systemic lupus erythematosus. tients previously on a B cell–depleting agent for underlying In the two-phase model of severe COVID-19, use of a immune-mediated diseases, such as rheumatoid arthritis Jakinib after the initial phase could dampen inflammatory cas- [79–83]. In the context of COVIDhge, B cell/plasmablast de- cades triggered by ligand-binding to the multiple cytokine pletion can potentially be used to curb the ongoing secretion receptors as described above. However, in the early phase, of neutralizing anti-type I IFN IgG. Of note, data from patients when type I IFN signaling is crucial for antiviral defense, the with X-linked agammaglobulinemia (XLA), which is caused biological consequences of Jakinibs and IFN-kinoid resemble by mutations in Bruton’s tyrosine kinase (BTK), suggest they the phenotypes of patients with auto-Abs against type I IFNs are not untowardly susceptible to severe COVID-19 [65, 84, [4] and AR IFNAR1 or IFNAR2 deficiency [3]. Thus, patients 85]. This may suggest that absent development of protective who are already receiving these agents, and become infected neutralizing antibodies to COVID-19, as well as vaccination with SARS-CoV-2, are potentially at risk for severe COVID- responses, may not predispose to severe COVID-19 [86]. An 19. Thus, it is prudent to consider halting of these drugs in the alternative or additional explanation may relate to reduced initial phase of SARS-CoV-2 infection. However, in a retro- inflammatory cytokine release by BTK-deficient monocytes. spective study, of three patients with Aicardi-Goutières syn- In line with this are the promising results seen with the BTK drome on Jakinibs, 2 were asymptomatically infected and 1 inhibitors, acalabrutinib and ibrutinib, in patients infected with only experienced a rash upon infection [65], although their SARS-CoV-2 while on these drugs, and in an observational excessive type I IFN signaling may be incompletely downreg- trial using acalabrutinib in hospitalized patients with severe ulated by the Jakinibs [65]. Additionally, Jakinibs have been COVID-19 [87, 88], in which the benefit correlated with the or are being studied to treat patients with severe COVID-19 impairment of monocyte activation. Several clinical trials are (e.g., ARDS; “cytokine release syndrome”). The ACTT-2 under way to evaluate the potential benefit of BTK inhibitors study demonstrated that the Jakinib baricitinib (in association in COVID-19. Whether such treatment is associated with per- with the antiviral remdesivir) reduced recovery time and ac- sistent shedding of viable SARS-CoV-2 virus is unclear celerated improvement in clinical status in moderate-to-severe [89–92]. The question of prolonged shedding and temporary COVID-19 [66]. Remdesivir itself failed to show any benefi- blunting of antibody responses will need to be studied when cial effect on initiation of ventilation, duration of hospital stay, evaluating the use of B cell/plasmablast depletion during the and mortality in the recent Interim WHO Solidarity Trial management of COVID-19 in patients with auto-Abs. These Report [16, 67]. One additional RCT using ruxolitinib versus patients may be at risk of re-infection and will not likely be placebo in hospitalized patients has recently been completed able to respond to vaccines while the B cell deficiency and 20 more are recruiting [68]. The finding of beneficial persists. effects of Jakinibs in the second phase of moderate-to-severe COVID-19 disease is consistent with the two-stage disease model of COVID-19. However, as the threshold level of type Therapeutic Plasma Exchange (TPE): Past I IFN activity and the duration of type I IFN activity required and Present to mitigate COVID-19 are unknown, caution is required when using IFN-kinoid or Jakinibs. TPE refers to the removal of a large volume of plasma, typi- cally 30–40 ml/kg, necessitating replacement of fluid by a colloid solution (e.g., albumin and/or plasma) or a combina- B Cell and Plasmablast Depletion and BTK tion of crystalloid/colloid solution. In contrast, plasmapheresis Inhibition: How About COVID? (PP) is based on removing (not replacing) only 15% of plasma volume. TPE is currently used in over 60 medical conditions Depletion of B cells can be achieved with an anti-CD20 anti- according to the American Society for Apheresis [93]. The body (e.g., rituximab). In mycobacterial infections due to anti- rationale of TPE lies in the removal of a pathogenic substance IFN-γ auto-antibodies, another phenocopy of an inborn error from plasma, such as immune complexes, cryoglobulins, of immunity, rituximab has been used with success [69–73]. toxins, or lipids. More specifically, TPE has been used J Clin Immunol successfully in conditions mediated by auto-antibodies, such Type I IFN: Almost 50 Years of Therapy as vasculitis, Guillain-Barré syndrome, Goodpasture syn- with IFN-α and IFN-β in Various Diseases drome, thrombotic thrombocytopenic purpura, and autoim- mune hemolytic anemia, some of which are associated with Type I IFN production, amplification, and response contribute viral infections [93]. TPE has also been applied in patients to antiviral innate and intrinsic immunity. The first clinically with shock-like presentation in the context of respiratory viral successful use of type I IFN in humans dates back to 1973 and infection in an attempt to clear inflammatory and pertained to viral respiratory infections [113]. Type I IFNs antifibrinolytic mediators of the cytokine storm, and to replen- were thereafter proposed as treatment of several other viral ish anticoagulant proteins and to reduce viremia [94–97]. The infections, especially chronic hepatitis C (HCV) and hepatitis latter report of TPE in three critically ill children with H1N1 B (HBV) virus infections. Recombinant IFN-α2 was first used influenza–related acute respiratory distress syndrome showed in HCV treatment in 1986 [114]. Pegylated IFN-α2 (PEG- that TPE is effective even in the later stages of cytokine storm. IFN-α2), allowing sustained blood levels, was introduced in Importantly, TPE comes at the cost of eliminating protective the early 2000s and became standard treatment for chronic antibodies and drugs, an issue to consider when managing HCV infection until the appearance of direct-acting antivirals infection by TPE. [115]. At present, PEG-IFN-α2 is still a treatment option in As the risk of developing severe and even potentially mild-to-moderate chronic hepatitis B patients. IFN-α2a and fatal COVID-19 pneumonia is extremely high in patients IFN-α2b are also used as an adjuvant in cancer treatment, harboring auto-Abs against type I IFN, eliminating these such as certain leukemias (e.g., hairy cell; chronic myeloid) auto-Abs by TPE emerges as an attractive additional line and Kaposi’s sarcoma [116], based on its anti-proliferative, of treatment in hospitalized patients. So far, the use of anti-angiogenesis, and immunomodulatory actions. TPE for COVID-19 pneumonia has been limited to case Recombinant IFN-β1a and IFN-β1b, which exert effects sim- series. Another case reported the successful use of TPE in ilar to those of IFN-α2, have also been used therapeutically. a pregnant woman suffering from thrombotic thrombocy- IFN-β1a is a standard treatment for relapsing-remitting mul- topenic purpura with SARS-CoV-2 [98–105]. In these re- tiple sclerosis (MS) since the 1990s [117–119]. Short-term ports from the initial phases of the pandemic, TPE was IFN-α2 treatment is associated in 20–30% with self-limiting used empirically for management of the “cytokine storm” flu-like symptoms. Long-term IFN-α2 treatment is associated during the phase of critical illness [98, 99, 101–104, 106, with various side effects including (% affected; onset) fever 107]. In some patients, intravenous immunoglobulins or (20–30%; 4–6 h after injection; self-limited); asthenia (60– convalescent plasma from other patients was used to re- 90%; 3 months); psychiatric manifestations with depression place circulating antibodies. Although these cases provide and suicidal ideation (5–60%; 3 months); and thyroid autoim- anecdotal evidence of potential benefits in some patients munity (3–6%; median 17 weeks) [120–122]. Adverse reac- with severe COVID-19, they have also raised concern tions to IFN-β are similar to those of IFN-α [118]. In addition, about its general use as a “rescue therapy” for all such long-term treatment with either molecule may illicit neutraliz- patients [108–110]. A prospective clinical trial is required ing anti-drug antibodies that can adversely affect treatment, as to better define its use [111]. Interestingly, in one of the first reported in a patient receiving IFN-β for nasopharyngeal original reports where TPE was used, the authors demon- carcinoma [123–126]. These idiosyncratic reactions may be strate a reduction in circulating antiphospholipid antibod- polygenically driven [127]. In all, short-term IFN-α or IFN-β ies [103]. In light of the findings from COVIDhge [4], treatment appears safe with little side effects and has proven TPE can be considered specifically in those with demon- efficient in the treatment of certain viral infections. strable auto-Abs to type I IFN. Proof of concept for this mechanism-based use of TPE in severe COVID-19 has been recently reported [112]. Interestingly, the depletion IFN-α2 in Past and Current COVID Trials of anti-IFN-abs by TPE was not accompanied by a deple- tion of anti-SARS-CoV-2 IgG [112]. Given the constella- In the context of COVID-19, a NIH-issued guideline advises tion of reports to date, the optimal use of TPE in COVID- to restrict the use of IFN to clinical trials. Understandably, 19 needs to be better defined, including number of ses- based on type I IFN’s direct inhibitory effects on viral repli- sions needed and choice of volume replacement, but it cation and indirect immunomodulatory effects, and based on appears to be best aimed at hospitalized patients with its antiviral experience, IFN-α was one of the first drugs to be moderate-to-severe/critical disease who harbor anti-type repurposed during the ongoing pandemic [128]. Only a few I IFN auto-Abs. As stated above, the feasibility of this studies, and no randomized double-blind placebo-controlled approach is contingent on the availability of a certified trials (DBRCT), using IFN-α2 as a treatment have been pub- assay to detect and quantify neutralizing auto-Abs to type lished (Table 1). In a retrospective study, 242 of 446 hospital- I IFN. ized patients with severe COVID-19 received aerosolized Table 1 Observational and interventional studies using type I IFN therapy IFN Study registry Objective Controlled trial Country multi/ Route Daily dose Dosing regimen No. of single center patients IFN-α1a NA Efficacy in reducing mortality of aerosolized NA China inhaled NA NA 446 IFN-α1a nebulized IFNα-2b NA Efficacy of IFN-α2b in reducing the time to - NA China Inhaled IFN-α2b (5 IFN bid, arbidol 77 (7/24/46 PCR nebulized mU), arbidol tid per arm) (200 mg), both IFNβ-1a NCT04385095 Efficacy and safety of inhaled nebulized Randomized, UK multi-centric: 9 Inhaled 6 MIU or Daily × 14 days SNG001: 50 interferon β -1a (SNG001) for the treatment double-blind, centers nebulized placebo placebo: of patients admitted to hospital with placebo-controlled, 51 COVID-19 phase 2 pilot trial IFNβ-1a NCT04315948 Mortality trial of four repurposed antiviral drugs WHO’s Solidarity Trial International mainly s.c. s.c. IFN: 44 μg s.c. IFN: 3 doses in IFN: 2050 - remdesivir, hydroxychloroquine, lopinavir, multi-centric: or i.v. IFN: 6 days i.v. IFN: control: and interferon β-1a 405 hospitals in 10 μg daily for 6 days :2050 30 countries IFNβ-1b NCT04276688 Study benefit of adding combined IFNβ+ Randomized open-label China (Hong Kong) s.c. Combined IFN: alternate days Combined: ribavirin to standard care with LPV/r phase 2 trial multi-centric n=6 group: 8 MIU ×3 86 + ribavirin days/ribavirin: control: 41 400 mg every 12h IFNβ-1a IRCT20100228003449N28 Compare 2 arms: IFNβ vs. control Randomized Iran single center s.c. 44 μg 3 times per week × IFN: 42 2 weeks control: 39 IFNβ-1b IRTC20100228003449N27 compare 2 arms: IFNβ vs. control Randomized Iran single center s.c. 250 μg 1 dose every other 33 per arm day × 2 weeks IFNβ-1a IRCT20151227025726N12 All treated No Iran single center s.c. 44 μg 1 dose every other 20 day × 10 days IFNβ-1b - All treated no France single inhalation 300 μg (lung 12 days 4 center delivery 10%) IFNβ-1b - All treated no Korea single center N.R. N.R. 3–16 days 5 Ongoing trials COVID-19 PEG-IFN-α2b NCT04480138 Compare change in clinical status with or Multicenter open-label Mexico, s.c. 1 mcg/kg d1 and d8 40 without IFN-a2b randomized comparator Multicenter controlled IFN-α 1b NCT04320238 To compare new-onset COVID-19-related No placebo China i.n. 2–3 drops 4 t/day nr symptoms at 6w from baseline IFN-α NCT04320238 To compare new-onset COVID-19-related No placebo China i.n. 2–3 drops 4t/day nr symptoms at 6w from baseline IFN-α 2b NCT04579518 To determine safety of iv rintatolimod with or Open label USA i.v. Dose escalation d1, d3or4 44 without iv IFN-α2b IFN-α1β NCT04293887 Efficacy and safety of IFN-α compared to SOC Multicenter randomized China Nebulization 10 mcg bid, 10 days 328 for hospitalized adult patients with open-label blank COVID-19 controlled multistage clinical trial IFN-α NCT04534725 (ARM1) Compare incidence of COVID-19 in Sequential multiple arm Austrialia, i.n. nr daily 2282 cancer patients on prophylaxis with IFN-α randomized trial multicenter estimated IFN-α Sequential multiple arm Austrialia, i.n. nr daily 2282 randomized trial multicenter estimated J Clin Immunol Table 1 (continued) (ARM2) Compare incidence of COVID-19 infection in cancer patients on post-exposure prophylaxis y/n with IFN-α J Clin Immunol IFNβ-1a NCT04492475 ongoing Compare combination of IFNβ-1a + remdesivir ACTT-3 trial randomized NIAID USA s.c. 44 μg 4 doses on days 1, 1000 vs. remdesivir alone. Evaluate safet and double-blind multi-centric 3, 5, and 7 efficacy placebo-controlled n=100 while phase 3 trial hospitalized IFNβ-1a NCT02735707 universal Compare diverse immunomodulatory treatment REMAP-CAP trial International mullti- > 4000 trial no. (IFNβ among them) https://www.remapcap. centric U1111-1189-1653 org/ IFNβ-1a NCT04449380 Compare IFNb-1a+ standard care vs. standard INTERCOP trial Italy mono-centric s.c. 44 μg (12 MIU) 3 times × week at 126 care alone randomized, controlled, least 48h apart, random- open-label, phase II trial for 2 weeks ized 2:1 to IFNβ-1a IFNβ-1a NCT04521400 ongoing Compare high- vs. low-dose IFNβ Randomized open-label Iran single center Arm 1: Intention to controlled 2-arm high-dose treat: 50 parallel group; phase 2a IFN arm 2: patients trial low-dose IFN per arm Previous studies IFNβ-1a NCT02622724 Efficacy and adverse events of IFNβ in patients Randomized double-blind E.U. Multi-center i.v. 10 μg IFNb vs. Once daily × 6 IFN: 144 with moderate ARDS parallel-group trial n=74 ICU in 8 placebo days placebo: countries 152 IFNβ-1b NCT02845843 Combined treatment with recombinant IFNβ-1b Randomized adaptive Saudi Arabia s.c. IFNβ: 0.25 mg Alternate days for IFN:43 and LPV/r reduces mortality among patients double-blinded multi-centric n=9 (8 MIU) 14 days placebo:52 with MERS placebo-controlled trial sites placebo: saline IFN Sex Age (y) Other therapy Inclusion criteria Hospitalization Result Adverse events Ref (%men) mean (SD days mean or range) (range or SD) IFN-α1a 53.2 50y Umifenovir/LPV/r All admitted patients with N.R. Early IFN-α1a < 5d:reduced in N.R. [129] confirmed SARS-CoV-2 by hospital mortality PCR IFNα-2b 0-20-11% 41 Antibiotics All admitted patients with 21.1 vs. 27d vs. IFN-α2b: time to (-) PCR NR [130] (27–68)- confirmed SARS-CoV-2 by 20.3d/all IFN significantly shorter vs. 40 PCR vs. arbidol : (25–80) 20 days vs. 64 (37–73)* % IFNβ-1a SNG001: SNG001: All eligible participants had to have Patients who received SNG001 Headache: 15% [131] 62 58 (15) a confirmed SARS-CoV-2 test had greater odds of patients in SNG001 placebo: placebo: result. Exclusion criteria improvement and recovered group and 10% in 56 57 (12) included inability to use a more rapidly from placebo group. nebulizer with a mouthpiece SARS-CoV-2 infection than There were 3 deaths (e.g., ventilated patients and patients who received placebo, in the placebo group patients in intensive care); and providing a strong rationale for and none in the pregnancy further trials SNG001 group Table 1 (continued) IFNβ-1a IFN: 64 No No other trial Eligible patients were 18 years of Interim results: these drug [16] control: differ- treatments age or older, were hospitalized regimens had little or no effect 62 ence in with a diagnosis of Covid-19, on hospitalized patients with age were not known to have Covid-19, as indicated by distribu- received any trial drug, were not overall mortality, initiation of tion expected to be transferred ventilation, and duration of between elsewhere within 72 h, and, in hospital stay. IFN regimens IFN and the physician’ view, had no were discontinued for futility on control contraindication to any trial October 16,2020 groups drug IFNβ-1b Combined: Combined: All received LPV/r Treatment initiated <7 days from Combined: 9 The combination group had a No difference between [132] 52% 51 symptom onset (7–13) significantly shorter median groups con- (31–61) control: 15 time from start of treatment to trol:56% cont:52 (9–16) negative nasopharyngeal swab (34–63) than the control group IFNβ-1a IFN: 52% IFN: 57 LPV/r or atanazavir/r Severe COVID-19: hypoxemia or IFN: 15 (8) Time to clinical response was no Psychiatric problems [133] control: (47–67) & HCQ & other hypotension or renal failure or control:12 (7) different. 28-day mortality was in 4 patients of the 56% cont:61 drugs (no neurologic disorders or lower in the IFN group 19% vs. IFN group (50–70) differences thrombocytopenia, or severe control group 17%. Early between groups) gastrointestinal symptoms administration significantly reduced mortality IFNβ-1b IFN: 61% IFN: 60 LPV/r or First 48h after admission with O2 IFN:11 (9–13) Time to clinical improvement was N.R. [134] control: (47–73) atanazavir/r& sat<93% PaO2/FiO2 < 300 control: 13 shorter in the IFN group 58% cont:61 HCQ mmHg (10–17) (p=0.002). ICU admission rate (50–71) higher in the control group (p=0.04) IFNβ-1a 80 58 (13) LPV/r & HCQ RR>30 breaths/min or O2 17 (14–25) No deaths or significant adverse N.R. [135] sat<90% or PaO2/FiO2 < 300 events mmHg IFNβ-1b 75 59 (5) HCQ and/or ICU/severe ARDS (PaO2/FiO2 < 33 (22–58) 3 patients improved at day 15 N.R. [136] antibiotics & (in 100 mmHg) some patients: LPV/r & corticosteroids & vitamin C) IFNβ-1b 80 60 (14) LPV/r, HCQ, N.R. 32 (16–41) 3 patients deteriorated and were N.R. [137] corticosteroids rescued with corticoids Ongoing trials COVID-19 PEG-IFN-α2b >18y SOC Laboratory confirmed Moderate Change in clinical status by day 14 SARS-CoV-2 infection. Illness of any duration, and at least one of the following: Radiographic infiltrates by imaging (chest X-ray, CT scan, etc.), SpO2 >93% and RR< 30/min IFN-α 1b nr NA Medical staff in non-isolated Number of infections general wards or laboratories, not in direct contact with COVID-19 patients IFN-α J Clin Immunol Table 1 (continued) Thymosinα sc 1 × Medical staff in isolated wards in per week direct contact with COVID-19 patients J Clin Immunol IFN-α 2b Rintatolimod: ds Cancer and mild-to-moderate Kinetics of viral load in nasopharyngeal swabs up to 30 days post-initiation RNA designed to COVID-19 (active therapy or mimic viral within 6 months - no HSCT or infection active leukemia) - not specified within how many days from onset symptoms IFN-α1β Age > 18y, COVID-19 pneumonia, time between onset of symptoms and enrollment 7 days IFN-α >18y > 18y, any hematological or solid na Number of infections tumor, cancer therapy within the last 12 months IFN-α >18y > 18y, any hematological or solid na Number of infections tumor, cancer therapy within the last 12 months, exposed to known COVID-19 case within last 72h (15 min face to face, 2h in close space, household contact) IFNβ-1a All patients will Laboratory confirmed Primary outcome is time to https://clinicaltrials. receive SARS-CoV-2 infection. Illness recovery by day 29 remdesivir of any duration, and at least one 200 mg iv. On of the following: Radiographic day 1 & 100 mg infiltrates by imaging (chest once-daily while X-ray, CT scan, etc.), OR SpO2 hospitalized for <= 94% on room air, OR up to a 10-day Requiring supplemental O2, total course among other > 4000 The trial is Patients admitted to ICU with The trial generates estimates multifactorial acute respiratory insufficiency of superiority, inferiority, as it tests due to suspected pneumonia and equivalence between multiple regimens on the primary interventions outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection IFNβ-1a No other anti-viral Patients with positive swab The primary outcome is the time to [139] drugs will be used detection of SARS-CoV-2, negative conversion of as part of the radiological signs of SARS-CoV-2 nasopharyngeal regimens, both in pneumonia, and swabs. Secondary outcomes the control and the mild-to-moderate disease include improvement or intervention arms worsening in a clinical severity Table 1 (continued) score measured on a 7-point ordinal scale, among others IFNβ-1a All patients will SPO2<93% or RR> 24 + one of Primary outcome: time to clinical [140] receive LPV/R the following manifestations: improvement Secondary B.T<37.8 °C or cough, or outcome: (a) mortality at the end shortness of breath or nasal of the study; (b) Improvement of congestion/discharge, or SPO2 during hospitalization; (c) myalgia/arthralgia or duration of hospitalization; (d) diarrhea/vomiting or headache incidence of mechanical or fatigue on admission ventilation Previous studies IFNβ-1a IFN: 71 IFN: 58 Meeting ARDS criteria in 24h and IFN: 28 No significant difference in 21-day 28% adverse events in Ranieri et al., 2020 placebo: placebo: first dose drug administration (24–28) mortality between the IFNb the IFN group and 60 58 within 48h of ARDS diagnosis placebo: 28 group and placebo group 22% in the placebo (22–28) group IFNβ-1b IFN: 72 IIFN: 56 All received oral Hospitalized adults with Death by day 90 A combination of recombinant Serious adverse events Arabi et al., 2020 place- (43–67) LPV/r laboratory-confirmed MERS (%) IFN: 28 interferon β-1b and occurred in 4 bo:85 placebo: with evidence of acute organ placebo: 44 lopinavir-ritonavir led to lower patients (9%) in the 56 dysfunction related to MERS mortality than placebo among intervention group (44–67) patients who had been and in 10 (19%) in hospitalized with the placebo group laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset J Clin Immunol J Clin Immunol IFN-α2b. In 89%, nebulized IFN-α2b was initiated within 5 However, about 50% of these patients received corticoste- days of admission, which was associated with reduced mor- roids, which may have blunted the IFN effect [134]. tality. Late initiation of nebulized IFN-α2b therapy was asso- Importantly, the adaptive COVID-19 treatment trial 3 ciated with increased mortality [129]. A prospective explor- (ACTT3) compared remdesivir plus placebo to remdesivir atory trial in hospitalized patients compared inhaled IFN-α2b plus s.c. IFN-β1a and was halted prematurely in hospitalized with or without umifenovir, a broadly acting anti-viral, to patients receiving high-flow oxygen when interim data umifenovir alone [130]. IFN-α2b was only included as a treat- showed potential harm from subcutaneous IFN-β1a. In con- ment arm when administered within 8 days of admission. The trast, no harm was observed in patients receiving low-flow or time to negative PCR was significantly shorter in patients no oxygen, in whom the efficacy of IFN-β1a is still being receiving inhaled IFN-α2b [130]. Other trials included evaluated. On the other hand, some trials seem to show a IFN-α2 in treatment arms with multiple drugs, including benefit. A prospective, open-label, randomized single-center Chinese traditional medicine (Table 1). Overall, there has trial reported no significant difference in time to clinical re- been a trend towards shorter duration of hospitalization and sponse, but lower mortality at day 28 when s.c. IFN-β1a was shorter time to negative SARS-CoV-2 PCR in patients admit- added to treatment arms at median 10 days after onset of ted with COVID-19 pneumonia and treated with IFN-α2; symptoms in hospitalized patients (Table 1) [133]. IFN-β1b however, interpretation of the data is hampered by the lack s.c. plus lopinavir/ritonavir and ribavirin started at median 5 of a rigorously conducted DBRCT. Several protocols are cur- days in patients hospitalized with COVID-19 pneumonia re- rently recruiting hospitalized COVID-19 patients to study the sulted in shorter time to negative PCR in the triple treatment efficacy and safety of administration within 7 days of symp- arm versus the lopinavir/ritonavir alone [132]. In an open- tom onset of s.c., i.v., or nebulized IFN-α2 (Table 1). Also, label RCT including severe COVID-19 patients, time to clin- several trials will assess the efficacy of intranasal or nebulized ical improvement was shorter in the IFN-β1b s.c. group IFN-α2 to prevent COVID-19 pneumonia. For instance, an (p=0.002) and ICU admission rate higher in the control group Australian study will investigate the efficacy of IFN-α2 nose (p=0.04) [134]. Finally, in a double-blind RCT, daily inhaled drops as a pre- or post-exposure prophylaxis in cancer pa- IFNβ-1a for 14 days in admitted patients led to a faster and tients. This trial in particular will be of interest as it can impact stronger clinical improvement on the WHO Ordinal Scale for on the type I IFN deficiency in the first phase of COVID-19 Clinical Improvement compared with placebo [131]. The pa- infection, the time at which rapid induction of antiviral state is tients had a median duration of symptoms of 10 days at re- crucial. cruitment and IFN-β was given for 14 days and was well tolerated. More trials are on the way, focusing on either ven- tilated COVID-19 patients or ambulatory patients to study the IFN-β in COVID-19 impact of late and early (at home) intervention with IFN-β (Table 1). Overall, the trials are inconclusive, potentially due In the context of highly pathogenic coronaviruses, IFN-β was to the relatively late administration of IFNs. reportedly more active than IFN-α, at least in vitro, in its antiviral activity [141–143]. Moreover, most patients with auto-Abs to type I IFNs had auto-Abs to the 13 individual A Proposal: Early IFN-β in the Outpatient IFN-α, including α2, and/or IFN-ω, but only 2% of them also Setting had auto-Abs to IFN-β, IFN-κ, or IFN-ε [4]. Thus, therapeutic use of IFN-β should be a better choice than IFN-α from this The two-step pathophysiology model of severe COVID-19 viewpoint. Previous experience with another coronavirus, pneumonia suggests that early administration of IFN-β at Middle East respiratory syndrome (MERS) virus, also sup- the onset of SARS-CoV-2 infection, or even prior to infection ports this approach, with a clinical trial showing that in exposed individuals, may halt disease progression [5]. IFN-β1b reduced mortality compared with placebo in hospi- Especially at risk are individuals above age 65 years and in- talized patients [144]. More trials with IFN-β than with dividuals of any age with genetic defects of the type I IFN IFN-α2 have been reported in the context of COVID-19 response pathway or with neutralizing anti-type I IFN auto- (Table 1). Several trials failed to show a beneficial effect. Abs. Several lines of evidence point to advantages in using Oral favipiravir plus inhaled IFN-β failed to demonstrate IFN-β. First, in vitro data indicate higher efficacy of IFN-β any benefit when compared with hydroxychloroquine in terms against highly pathogenic coronaviruses. Second, the trials of mortality, ICU admission, and inflammatory markers in with IFN-β in MERS support its use, without neglecting the hospitalized patients with moderate-to-severe COVID-19 need for caution raised by the ACTT-3 trial. Third and most pneumonia in an open-label randomized trial [145]. importantly, the auto-Abs to type I IFN neutralized the 13 Similarly, the WHO Solidarity Trial failed to show a reduction IFN-α and IFN-ω but very rarely IFN-β. Among individuals in mortality in the s.c. and i.v. IFN-β1a treatment arms. at risk, either (A) a close contact of an index case (i.e., exposed J Clin Immunol but negative for SARS-CoV-2), (B) an asymptomatic infected IFN-λ or placebo (N=30 per group) [151]. Those receiving subject, or (C) an ambulatory (mildly symptomatic) patient peg-IFN-λ demonstrated faster viral clearance by day 7. may benefit from early IFN-β administration, i.e., as soon as Treatment tolerance was similar to placebo. Although the possible post-exposure or post-infection. Indeed, the peak vi- study was not powered to look at clinical evolution, 5 ral load on nasopharyngeal swab occurs at or even prior to (16.7%) in the placebo group and 1 (3.3%) in the peg-IFN-λ onset of symptoms [146]. These three groups need distinct group required visit to the emergency room by day 14. On the clinical trials to assess the efficacy of early IFN-β therapy in other hand, another study with a similar design showed that mitigating disease and viral shedding, as well as safety. peg-IFN-λ did not shorten the duration of viral shedding Individuals vaccinated adequately against the viral variant di- [152]. Differences in results between these two studies may agnosed in the contact or themselves may or may not be con- be due to differences in baseline viral loads (58% of subjects sidered. Of course, this presumes that viral strain testing can with >6.0 log copies/ml in the former vs. 75% with <5.5 log be performed with a short turnaround time. As outlined above, copies/ml in the latter) as well as differences in SARS-CoV-2 IFN-β can be administered via several routes, including i.m., antibody positivity at baseline (0% in the treatment group and s.c. (Pegylated form), nebulized, or a combination thereof. 10% in the placebo group in the former vs. 25% in the treat- Nebulized IFN-β is likely to be of benefit early pre- or post- ment group and 46.7% in the placebo group in the latter). infection, owing to its local effect, whereas s.c./i.m. acts sys- Although additional studies are needed, these studies pro- temically and is likely to be effective beyond the first days vide proof of principle that a single dose of adjunctive peg- post-infection. Thus, one could envisage having trials of post- IFN-λ can be administered early following infection, is well exposure prophylaxis by nebulized IFN-β acting locally for tolerated, and may provide enhanced virological clearance the duration of the incubation time (14 days) in group (A), especially in those with high viral load or delayed seroconver- combined with s.c./i.m. IFN-β for systemic action in groups sion. Whether this treatment impacts hospitalization or trans- (B) and (C). Alternatively, all three groups could receive a mission requires further investigation. However, several ca- single s.c. injection of peg-IFN-β. The advantage of pegylated veats are in place. First, there is currently no genetic or immu- IFN-β is that a single subcutaneous injection is sufficient and nological evidence that insufficient IFN-λ immunity can un- can easily be given in the outpatient setting. This early inter- derlie severe COVID-19 pneumonia. Second, prolonged vention with IFN-β in individuals at risk may theoretically IFN-λ signaling has been described to disrupt lung epithelial alleviate the lack of type I IFN signaling early post-exposure repair following viral infection more potently than IFN-α and or post-infection, the first phase of COVID-19 disease, by -β [153]. Third, sustained type III IFN signaling in inflamed rapid induction of an anti-viral state, and may mitigate the lungs led to increased susceptibility to bacterial infection, at natural evolution of SARS-CoV-2 infection to potentially fa- least in a mouse model [154]. Thus, the epithelial distribution tal disease. of IFN-λ receptors may be disadvantageous rather than help- ful in limiting the effects of this IFN to the epithelia. Fourth, we are still in the learning curve on IFN-λ as a treatment, both Type III IFN: IFN-λ in terms of safety and side effect profile, but also in terms of pharmacokinetics and pharmacodynamics, favoring the pref- The IFN-λ family of cytokines can be produced by a number erential use of IFN-β in future trials aimed at preventing evo- of cell types, including macrophages and plasmacytoid den- lution to severe COVID-19 in individuals at risk. dritic cells, in response to viral stimulation [147]. Like the type I IFN, they can establish an antiviral state; however, they do so through a distinct receptor complex primarily expressed on Conclusion epithelial cells, including those in the respiratory tract. Signalling by type I or type III IFN shares overlapping antivi- Insight that type I IFN defects underlie severe COVID-19 in at ral IFN-stimulated gene (ISG) expression [148], suggesting least 10% of patients challenges past, ongoing, and future that IFN-λ may potentially substitute or complement type I trials and clinical treatment strategies. Here, we discussed IFN therapy. In support of the latter, in vitro (using primary how findings from the COVIDhge provide a rationale for human airway epithelial cells) and mouse model data demon- targeted interventions during specific phases of COVID-19 strate that IFN-λ (specifically, IFN-λ1a) reduces SARS-CoV- pathogenesis. Early testing can identify individuals with de- 2 replication when used either prophylactically or therapeuti- fects in the type I IFN circuit, whether genetically or serolog- cally [149, 150]. Similar to what we propose with IFN-β, ically mediated, who stand to most benefit from IFN-β thera- early outpatient treatment of persons infected with SARS- py prior to or during the early viral replication phase. In addi- CoV-2 using peg-IFN-λ has been studied. Patients who were tion, the efficacy of IFN-β therapy would not be anticipated to either within 7 days of symptom onset or at first positive test if be affected by the infecting SARS-CoV-2 variant. Those hos- asymptomatic were treated with a single s.c. dose of peg- pitalized and found to harbor neutralizing auto-Abs to type I J Clin Immunol IFN might benefit from TPE. Ideally, trials should be designed Competing Interests The authors declare no competing interests. to specifically address these different treatment groups. Our findings also raise important questions about some of the cur- rent approaches being evaluated, e.g., the use of convalescent References plasma and the use of Jakinibs. Finally, despite the advent of 1. NIH. Clinical spectrum of SARS-CoV-2 infection December 17, efficacious vaccines in the general population, patients with 2020 [Available from: https://www.covid19treatmentguidelines. defects of type I IFN immunity may continue to remain at risk, nih.gov/overview/clinical-spectrum/. for example, due to impaired innate responses in the face of 2. Johns Hopkins University & Medicine CRC. https://coronavirus. emerging variants or to sub-optimal adaptive immunity. The jhu.edu/map.html 2021 [ 3. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, ongoing work of our consortium, in conjunction with the re- et al. Inborn errors of type I IFN immunity in patients with life- cent promising results of IFN-β in treatment of SARS-CoV-2 threatening COVID-19. Science. 2020;370(6515). infection, opens bold new avenues in the global fight against 4. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, this pandemic. Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515). 5. Zhang Q, Bastard P, Bolze A, Jouanguy E, Zhang SY, Effort CHG, et al. Life-threatening COVID-19: defective interferons un- Availability of Data and Materials Not applicable for this commentary. leash excessive inflammation. Med (N Y). 2020;1(1):14–20. 6. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Author Contribution DV, LA, PB, MC, AC, PG, FH, MC, DH, PS, AP, et al. Impaired type I interferon activity and inflammatory re- APu, LN, QZ, HS, JLC, and IM wrote the manuscript. DV, JLC, and IM sponses in severe COVID-19 patients. Science. 2020;369(6504): edited the manuscript. All authors commented and approved the final 718–24. version. 7. Trouillet-Assant S, Viel S, Gaymard A, Pons S, Richard JC, Perret M, et al. Type I IFN immunoprofiling in COVID-19 patients. The Funding D.C.V. is supported by the Fonds de la recherche en santé du Journal of Allergy and Clinical Immunology. 2020;146(1):206–8 Québec clinician-scientist scholar Junior 2 program. e2. L.D.N. and H.C.S. are supported by the Intramural Research Program 8. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, of the National Institute of Allergy and Infectious Diseases, National Moller R, et al. Imbalanced host response to SARS-CoV-2 drives Institutes of Health. development of COVID-19. Cell. 2020;181(5):1036–45 e9. The Laboratory of Human Genetics of Infectious Diseases is support- 9. Meffre E, Iwasaki A. Interferon deficiency can lead to severe ed by the Howard Hughes Medical Institute, the Rockefeller University, COVID. Nature. 2020;587(7834):374–6. the St. Giles Foundation, the National Institutes of Health (NIH) 10. Beck DB, Aksentijevich I. Susceptibility to severe COVID-19. (R01AI088364), the National Center for Advancing Translational Science. 2020;370(6515):404–5. Sciences (NCATS), NIH Clinical and Translational Science Award 11. Troya J, Bastard P, Planas-Serra L, Ryan P, Ruiz M, de Carranza (CTSA) program (UL1 TR001866), a Fast Grant from Emergent M, et al. Neutralizing autoantibodies to type I IFNs in >10% of Ventures, Mercatus Center at George Mason University, the Yale patients with severe COVID-19 pneumonia hospitalized in Center for Mendelian Genomics and the GSP Coordinating Center Madrid, Spain. J Clin Immunol. 2021. funded by the National Human Genome Research Institute (NHGRI) 12. Koning R, Bastard P, Casanova JL, Brouwer MC, van de Beek D, (UM1HG006504 and U24HG008956), the Fisher Center for with the Amsterdam UMCC-BI. Autoantibodies against type I Alzheimer’s Research Foundation, the Meyer Foundation, the French interferons are associated with multi-organ failure in COVID-19 National Research Agency (ANR) under the “Investments for the patients. Intensive Care Med. 2021. Future” program (ANR-10-IAHU-01), the Integrative Biology of 13. van der Wijst MGP, Vazquez SE, Hartoularos GC, Bastard P, Emerging Infectious Diseases Laboratory of Excellence (ANR-10- Grant T, Bueno R, et al. Longitudinal single-cell epitope and LABX-62-IBEID), the French Foundation for Medical Research (FRM) RNA-sequencing reveals the immunological impact of type 1 in- (EQU201903007798), the FRM and ANR GENCOVID project, ANRS- terferon autoantibodies in critical COVID-19. bioRxiv. 2021. COV05, the Square Foundation, Grandir - Fonds de solidarité pour 14. Goncalves D. Antibodies against type-I Interferon: detection and l’enfance, the SCOR Corporate Foundation for Science, Institut association with severe clinical outcome in COVID-19 patients. National de la Santé et de la Recherche Médicale (INSERM), and the medRxiv. 2021. University of Paris. 15. Vazquez SE, Bastard P, Kelly K et al. Neutralizing Autoantibodies PB is supported by the MD-PhD program of the Imagine Institute to Type I Interferons in COVID-19 Convalescent Donor Plasma. J (with the support of the Fondation Bettencourt-Schueller). I.M. is a Clin Immunol 2021;1–3. https://doi.org/10.1007/s10875-021- Senior Clinical Investigator at the Research Foundation – Flanders, and 01060-0. is chair of the CSL Behring Chair of Primary Immunodeficiencies at KU 16. Consortium WHOST, Pan H, Peto R, Henao-Restrepo AM, Leuven, by the KU Leuven C1 Grant C16/18/007, by a VIB GC PID Preziosi MP, Sathiyamoorthy V, et al. Repurposed antiviral drugs Grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N, and for Covid-19 - interim WHO Solidarity Trial results. N Engl J by the Jeffrey Modell Foundation. This work is supported by ERN-RITA. Med. 2021;384(6):497–511. 17. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva- Atanasova K, Danon L. Risk of mortality in patients infected with Declarations SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021;372:n579. Ethical Statement; Consent to Participate; Consent to Publish No ethi- 18. Garcia-Beltran WF, Lam EC, St Denis K, Nitido AD, Garcia ZH, cal approval required. Consent to publish not applicable. Consent to pub- Hauser BM, et al. Multiple SARS-CoV-2 variants escape neutral- lish not applicable. ization by vaccine-induced humoral immunity. Cell. 2021;184(9): 2523. J Clin Immunol 19. Le Bon A, Schiavoni G, D’Agostino G, Gresser I, Belardelli F, 38. Gelfand EW. Intravenous immune globulin in autoimmune and Tough DF. Type I interferons potently enhance humoral immunity inflammatory diseases. N Engl J Med. 2012;367(21):2015–25. and can promote isotype switching by stimulating dendritic cells 39. Cao W, Liu X, Bai T, Fan H, Hong K, Song H, et al. High-dose in vivo. Immunity. 2001;14(4):461–70. intravenous immunoglobulin as a therapeutic option for deterio- 20. Moens L, Van Eyck L, Jochmans D, Mitera T, Frans G, Bossuyt rating patients with coronavirus disease 2019. Open Forum X, et al. A novel kindred with inherited STAT2 deficiency and Infectious Diseases. 2020;7(3):ofaa102. severe viral illness. The Journal of allergy and clinical immunol- 40. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis ogy. 2017;S0091-6749(16):31440–3. of SARS-CoV-2 infection-a review of immune changes in patients 21. Meyts I, Casanova JL. Viral infections in humans and mice with with viral pneumonia. Emerging Microbes & Infections. genetic deficiencies of the type I IFN response pathway. European 2020;9(1):727–32. Journal of Immunology. 2021. 41. Mohtadi N, Ghaysouri A, Shirazi S, Sara A, Shafiee E, Bastani E, 22. Bastard P. Anti-IFN autoantibodies and YFV disease. The Journal et al. Recovery of severely ill COVID-19 patients by intravenous of Experimental Medicine. 2021. immunoglobulin (IVIG) treatment: A case series. Virology. 23. Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters 2020;548:1–5. JL, et al. Deployment of convalescent plasma for the prevention 42. Zhang J, Yang Y, Yang N, Ma Y, Zhou Q, Li W, et al. and treatment of COVID-19. J Clin Invest. 2020;130(6):2757–65. Effectiveness of intravenous immunoglobulin for children with 24. Casadevall A, Dadachova E, Pirofski LA. Passive antibody ther- severe COVID-19: a rapid review. Annals of Translational apy for infectious diseases. Nat Rev Microbiol. 2004;2(9):695– Medicine. 2020;8(10):625. 703. 43. Liu X, Cao W, Li T. High-dose intravenous immunoglobulins in 25. Pandey S, Vyas GN. Adverse effects of plasma transfusion. the treatment of severe acute viral pneumonia: the known mecha- Transfusion. 2012;52(Suppl 1):65S–79S. nisms and clinical effects. Frontiers in Immunology. 2020;11: 26. Arvin AM, Fink K, Schmid MA, Cathcart A, Spreafico R, 1660. Havenar-Daughton C, et al. A perspective on potential antibody- 44. Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan dependent enhancement of SARS-CoV-2. Nature. S, et al. Case series of multisystem inflammatory syndrome in 2020;584(7821):353–63. adults associated with SARS-CoV-2 infection - United Kingdom 27. Chai KL, Valk SJ, Piechotta V, Kimber C, Monsef I, Doree C, and United States, March-August 2020. MMWR Morbidity and et al. Convalescent plasma or hyperimmune immunoglobulin for Mortality Weekly Report. 2020;69(40):1450–6. people with COVID-19: a living systematic review. Cochrane 45. Ouldali N, Toubiana J, Antona D, Javouhey E, Madhi F, Lorrot Database Syst Rev. 2020;10:CD013600. M, et al. Association of intravenous immunoglobulins plus meth- 28. Wooding DJ, Bach H. Treatment of COVID-19 with convalescent ylprednisolone vs immunoglobulins alone with course of fever in plasma: lessons from past coronavirus outbreaks. Clin Microbiol multisystem inflammatory syndrome in children. Jama. 2021. Infect. 2020;26(10):1436–46. 46. Shao Z, Feng Y, Zhong L, Xie Q, Lei M, Liu Z, et al. Clinical 29. Vegivinti CTR, Pederson JM, Saravu K, Gupta N, Evanson KW, efficacy of intravenous immunoglobulin therapy in critical ill pa- Kamrowski S, et al. Efficacy of convalescent plasma therapy for tients with COVID-19: a multicenter retrospective cohort study. COVID-19: a systematic review and meta-analysis. J Clin Clinical & Translational Immunology. 2020;9(10):e1192. Apheresis. 2021. 47. Tabarsi P, Barati S, Jamaati H, Haseli S, Marjani M, Moniri A, 30. Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, et al. Evaluating the effects of intravenous immunoglobulin (IVIg) Vallone MG, Vazquez C, et al. A randomized trial of convalescent on the management of severe COVID-19 cases: a randomized plasma in Covid-19 severe pneumonia. N Engl J Med. controlled trial. Int Immunopharmacol. 2021;90:107205. 2021;384(7):619–29. 48. Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi SR, 31. Libster R, Perez Marc G, Wappner D, Coviello S, Bianchi A, Hajizadeh R. The use of intravenous immunoglobulin gamma for Braem V, et al. Early high-titer plasma therapy to prevent severe the treatment of severe coronavirus disease 2019: a randomized Covid-19 in older adults. N Engl J Med. 2021;384(7):610–8. placebo-controlled double-blind clinical trial. BMC Infect Dis. 32. Barone P, DeSimone RA. Convalescent plasma to treat coronavi- 2020;20(1):786. rus disease 2019 (COVID-19): considerations for clinical trial de- 49. Peter HH, Ochs HD, Cunningham-Rundles C, Vinh DC, sign. Transfusion. 2020;60(6):1123–7. Kiessling P, Greve B, et al. Targeting FcRn for 33. Subbarao K, Mordant F, Rudraraju R. Convalescent plasma treat- immunomodulation: benefits, risks, and practical considerations. ment for COVID-19: tempering expectations with the influenza The Journal of Allergy and Clinical Immunology. 2020;146(3): experience. Eur J Immunol. 2020;50(10):1447–53. 479–91.e5. 34. Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al. 50. Benesch M, Kerbl R, Lackner H, Berghold A, Schwinger W, SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients Triebl-Roth K, et al. Low-dose versus high-dose immunoglobulin with Covid-19. The New England journal of medicine. for primary treatment of acute immune thrombocytopenic purpura 2021;384(3):229–37. in children: results of a prospective, randomized single-center trial. 35. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore Journal of Pediatric Hematology/Oncology. 2003;25(10):797– R, et al. REGN-COV2, a neutralizing antibody cocktail, in outpa- 800. tients with Covid-19. The New England Journal of Medicine. 51. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, 2021;384(3):238–51. and treatment of Guillain-Barré syndrome. The Lancet Neurology. 36. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. 2008;7(10):939–50. Effect of bamlanivimab as monotherapy or in combination with 52. Group RC, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, etesevimab on viral load in patients with mild to moderate et al. Dexamethasone in hospitalized patients with Covid-19. N COVID-19: a randomized clinical trial. Jama. 2021;325(7):632– Engl J Med. 2021;384(8):693–704. 44. 53. Group WHOREAfC-TW, Sterne JAC, Murthy S, Diaz JV, 37. Starr TN, Greaney AJ, Addetia A, Hannon WW, Choudhary MC, Slutsky AS, Villar J, et al. Association between administration Dingens AS, et al. Prospective mapping of viral mutations that of systemic corticosteroids and mortality among critically ill pa- escape antibodies used to treat COVID-19. Science. tients with COVID-19: a meta-analysis. Jama. 2020;324(13): 2021;371(6531):850–4. 1330–41. J Clin Immunol 54. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey anti-interferon γ autoantibodies. Open Forum Infectious Diseases. L, Foulkes AS, et al. Efficacy of tocilizumab in patients hospital- 2019;6(4):ofz131. ized with Covid-19. N Engl J Med. 2020;383(24):2333–44. 72. Naik R, Cortes JA. Persistent Mycobacterium abscessus infection 55. Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, secondary to interferon-γ autoantibodies. Annals of Allergy, Ravaud P, et al. Effect of tocilizumab vs usual care in adults Asthma & Immunology. 2016;116(5):461–2. hospitalized with COVID-19 and moderate or severe pneumonia: 73. Pruetpongpun N, Khawcharoenporn T, Damronglerd P, a randomized clinical trial. JAMA Intern Med. 2021;181(1):32– Suthiwartnarueput W, Apisarnthanarak A, Rujanavej S, et al. 40. Disseminated Talaromyces marneffei and Mycobacterium 56. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, abscessus in a patient with anti-interferon-γ autoantibodies. et al. Effect of tocilizumab vs standard care on clinical worsening Open Forum Infectious Diseases. 2016;3(2):ofw093. in patients hospitalized with COVID-19 pneumonia: a randomized 74. Shah UA, Mailankody S. Emerging immunotherapies in multiple clinical trial. JAMA Intern Med. 2021;181(1):24–31. myeloma. BMJ (Clinical research ed). 2020;370:m3176. 57. Rosas IO, Brau N, Waters M, Go RC, Hunter BD, Bhagani S, et al. 75. Even-Or E, Naser Eddin A, Shadur B, Dinur Schejter Y, Najajreh Tocilizumab in hospitalized patients with severe Covid-19 pneu- M, Zelig O, et al. Successful treatment with daratumumab for monia. N Engl J Med. 2021. post-HSCT refractory hemolytic anemia. Pediatric Blood & 58. Klopfenstein T, Zayet S, Lohse A, Balblanc JC, Badie J, Royer Cancer. 2020;67(1):e28010. PY, et al. Tocilizumab therapy reduced intensive care unit admis- 76. Ratuszny D, Skripuletz T, Wegner F, Groß M, Falk C, Jacobs R, sions and/or mortality in COVID-19 patients. Med Mal Infect. et al. Case report: daratumumab in a patient with severe refractory 2020;50(5):397–400. anti-NMDA receptor encephalitis. Frontiers in Neurology. 59. Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. 2020;11:602102. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N 77. Bag-Ozbek A, Hui-Yuen JS. Emerging B-cell therapies in system- Engl J Med. 2021;384(1):20–30. ic lupus erythematosus. Therapeutics and Clinical Risk 60. Veiga VC, Prats J, Farias DLC, Rosa RG, Dourado LK, Zampieri Management. 2021;17:39–54. FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in 78. Ochoa S, Ding L, Kreuzburg S, Treat J, Holland SM, Zerbe CS. patients with severe or critical coronavirus disease 2019: Daratumumab (anti-CD38) for treatment of disseminated randomised controlled trial. BMJ. 2021;372:n84. nontuberculous mycobacteria in a patient with anti-IFN-γ autoan- 61. Investigators R-C, Gordon AC, Mouncey PR, Al-Beidh F, Rowan tibodies. Clin Infect Dis 2020. KM, Nichol AD, et al. Interleukin-6 receptor antagonists in criti- 79. Fallet B, Kyburz D, Walker UA. Mild course of COVID-19 and cally ill patients with Covid-19. N Engl J Med. 2021. spontaneous virus clearance in a patient with depleted peripheral blood B cells due to rituximab treatment. Arthritis & 62. Rubin EJ, Longo DL, Baden LR. Interleukin-6 receptor inhibition Rheumatology (Hoboken, NJ). 2020;72(9):1581–2. in Covid-19 - cooling the inflammatory soup. N Engl J Med. 2021. 80. Monti S, Montecucco C. Diagnostic and therapeutic challenges 63. Gadina M, Chisolm DA, Philips RL, McInness IB, Changelian for patients with ANCA-associated vasculitides at the time of PS, O’Shea JJ. Translating JAKs to Jakinibs. J Immunol. COVID-19. Response to: 'Rituximab for granulomatosis with po- 2020;204(8):2011–20. lyangiitis in the pandemic of COVID-19: lessons from a case with 64. Lauwerys BR, Hachulla E, Spertini F, Lazaro E, Jorgensen C, severe pneumonia' by Guilpain et al. Annals of the Rheumatic Mariette X, et al. Down-regulation of interferon signature in sys- Diseases. 2021;80(1):e11. temic lupus erythematosus patients by active immunization with 81. Sanchez-Piedra C, Diaz-Torne C, Manero J, Pego-Reigosa JM, interferon alpha-kinoid. Arthritis Rheum. 2013;65(2):447–56. Rúa-Figueroa Í, Gonzalez-Gay MA, et al. Clinical features and 65. Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, et al. outcomes of COVID-19 in patients with rheumatic diseases treat- Coronavirus disease 2019 in patients with inborn errors of immu- ed with biological and synthetic targeted therapies. Annals of the nity: an international study. The Journal of Allergy and Clinical Rheumatic Diseases. 2020;79(7):988–90. Immunology. 2020;147(2):520–31. 82. Loarce-Martos J, Garcia-Fernandez A, Lopez-Gutierrez F, Garcia- 66. Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Garcia V, Calvo-Sanz L, Del Bosque-Granero I, et al. High rates Ghazaryan V, et al. Baricitinib plus remdesivir for hospitalized of severe disease and death due to SARS-CoV-2 infection in rheu- adults with Covid-19. The New England Journal of Medicine. matic disease patients treated with rituximab: a descriptive study. 2020. Rheumatol Int. 2020;40(12):2015–21. 67. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, 83. Kow CS, Hasan SS. Use of rituximab and the risk of adverse Kalil AC, et al. Remdesivir for the treatment of Covid-19 - Final clinical outcomes in COVID-19 patients with systemic rheumatic Report. N Engl J Med. 2020;383(19):1813–26. disease. Rheumatol Int. 2020;40(12):2117–8. 68. Cao Y, Wei J, Zou L, Jiang T, Wang G, Chen L, et al. Ruxolitinib 84. Soresina A, Moratto D, Chiarini M, Paolillo C, Baresi G, Focà E, in treatment of severe coronavirus disease 2019 (COVID-19): a et al. Two X-linked agammaglobulinemia patients develop pneu- multicenter, single-blind, randomized controlled trial. The Journal monia as COVID-19 manifestation but recover. Pediatric Allergy of Allergy and Clinical Immunology. 2020;146(1):137–46 e3. and Immunology. 2020;31(5):565–9. 69. Browne SK, Zaman R, Sampaio EP, Jutivorakool K, Rosen LB, 85. Quinti I, Lougaris V, Milito C, Cinetto F, Pecoraro A, Mezzaroma Ding L, et al. Anti-CD20 (rituximab) therapy for anti-IFN-γ I, et al. A possible role for B cells in COVID-19? Lesson from autoantibody-associated nontuberculous mycobacterial infection. patients with agammaglobulinemia. The Journal of allergy and Blood. 2012;119(17):3933–9. clinical immunology. 2020;146(1):211–3.e4. 70. Czaja CA, Merkel PA, Chan ED, Lenz LL, Wolf ML, Alam R, 86. Papp KA, Haraoui B, Kumar D, Marshall JK, Bissonnette R, et al. Rituximab as successful adjunct treatment in a patient with Bitton A, et al. Vaccination guidelines for patients with immune- disseminated nontuberculous mycobacterial infection due to ac- mediated disorders on immunosuppressive therapies. Journal of quired anti-interferon-γ autoantibody. Clinical Infectious Cutaneous Medicine and Surgery. 2019;23(1):50–74. Diseases. 2014;58(6):e115–8. 87. Thibaud S, Tremblay D, Bhalla S, Zimmerman B, Sigel K, 71. Yerramilli A, Huang GKL, Griffin DWJ, Kong KL, Muhi S, Gabrilove J. Protective role of Bruton tyrosine kinase inhibitors Muttucumaru RS, et al. Disseminated nontuberculous mycobac- in patients with chronic lymphocytic leukaemia and COVID-19. terial infection associated with acquired immunodeficiency due to British Journal of Haematology. 2020;190(2):e73–e6. J Clin Immunol 88. Roschewski M, Lionakis MS, Sharman JP, Roswarski J, Goy A, 103. Ma J, Xia P, Zhou Y, Liu Z, Zhou X, Wang J, et al. Potential effect Monticelli MA, et al. Inhibition of Bruton tyrosine kinase in pa- of blood purification therapy in reducing cytokine storm as a late tients with severe COVID-19. Sci Immunol. 2020;5(48). complication of critically ill COVID-19. Clinical Immunology 89. Kos I, Balensiefer B, Roth S, Ahlgrimm M, Sester M, Schmidt T, (Orlando, Fla). 2020;214:108408. et al. Prolonged course of COVID-19-associated pneumonia in a 104. Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, et al. Successful B-cell depleted patient after rituximab. Frontiers in Oncology. treatment with plasma exchange followed by intravenous immu- 2020;10:1578. noglobulin in a critically ill patient with COVID-19. Int J 90. Yasuda H, Tsukune Y, Watanabe N, Sugimoto K, Uchimura A, Antimicrob Agents. 2020;56(2):105974. Tateyama M, et al. Persistent COVID-19 pneumonia and failure to 105. Aminimoghaddam S, Afrooz N, Nasiri S, Motaghi Nejad O, develop anti-SARS-CoV-2 antibodies during rituximab mainte- Mahmoudzadeh F. A COVID-19 pregnant patient with thrombot- nance therapy for follicular lymphoma. Clinical Lymphoma, ic thrombocytopenic purpura: a case report. J Med Case Rep. Myeloma & Leukemia. 2020;20(11):774–6. 2021;15(1):104. 91. Leipe J, Wilke EL, Ebert MP, Teufel A, Reindl W. Long, relaps- 106. Dogan L, Kaya D, Sarikaya T, Zengin R, Dincer A, Akinci IO, ing, and atypical symptomatic course of COVID-19 in a B-cell- et al. Plasmapheresis treatment in COVID-19-related autoimmune depleted patient after rituximab. Seminars in Arthritis and meningoencephalitis: case series. Brain, Behavior, and Immunity. Rheumatism. 2020;50(5):1087–8. 2020;87:155–8. 92. Schulze-Koops H, Krueger K, Vallbracht IV, Hasseli R, Skapenko 107. Gucyetmez B, Atalan HK, Sertdemir I, Cakir U, Telci L. A. Treatment of patients with inflammatory rheumatic diseases Therapeutic plasma exchange in patients with COVID-19 pneu- with rituximab should be carefully considered during the SARS- monia in intensive care unit: a retrospective study. Critical care CoV-2/COVID-19 pandemic. Response to: 'Persistence of rT- (London, England). 2020;24(1):492. PCR-SARS-CoV-2 infection and delayed serological response, 108. Honore PM, Mugisha A, Kugener L, Redant S, Attou R, Gallerani as a possible effect of rituximab according to the hypothesis of A, et al. Therapeutic plasma exchange as a routine therapy in Schulze-Koops et al' by Benucci et al. Annals of the rheumatic septic shock and as an experimental treatment for COVID-19: diseases. 2020. we are not sure. Crit Care. 2020;24(1):226. 93. Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, 109. Stahl K, Bode C, David S. First do no harm-beware the risk of Klingel R, Meyer E, et al. Guidelines on the use of therapeutic therapeutic plasma exchange in severe COVID-19. Crit Care. apheresis in clinical practice - evidence-based approach from the 2020;24(1):363. Writing Committee of the American Society for Apheresis: The 110. Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel Eighth Special Issue. Journal of Clinical Apheresis. 2019;34(3): treatment approach to the novel coronavirus: an argument for the 171–354. use of therapeutic plasma exchange for fulminant COVID-19. Crit 94. Ishikawa T, Abe S, Kojima Y, Sano T, Iwanaga A, Seki KI, et al. Care. 2020;24(1):128. Prediction of a sustained viral response in chronic hepatitis C 111. Faqihi F, Alharthy A, Alodat M, Asad D, Aletreby W, patients who undergo induction therapy with double filtration Kutsogiannis DJ, et al. A pilot study of therapeutic plasma ex- plasmapheresis plus interferon-beta/ribavirin. Exp Ther Med. change for serious SARS CoV-2 disease (COVID-19): a struc- 2015;9(5):1646–50. tured summary of a randomized controlled trial study protocol. 95. Jagdish K, Jacob S, Varughese S, David VG, Mohapatra A, Trials. 2020;21(1):506. Valson A, et al. Effect of double filtration plasmapheresis on var- 112. Ranganathan C, Fusinski SD, Obeid IM, Ismail KM, Ferguson ious plasma components and patient safety: a prospective obser- DT, Raminick MF, et al. Therapeutic plasma exchange for persis- vational cohort study. Indian J Nephrol. 2017;27(5):377–83. tent encephalopathy associated with Covid-19. eNeurologicalSci. 96. Liu X, Zhang Y, Xu X, Du W, Su K, Zhu C, et al. Evaluation of 2021;22:100327. plasma exchange and continuous veno-venous hemofiltration for 113. Merigan TC, Reed SE, Hall TS, Tyrrell DA. Inhibition of respira- the treatment of severe avian influenza A (H7N9): a cohort study. tory virus infection by locally applied interferon. Lancet (London, Ther Apher Dial. 2015;19(2):178–84. England). 1973;1(7803):563–7. 97. Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK. Use of 114. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 Peters M, et al. Treatment of chronic non-A,non-B hepatitis with influenza A–an associated respiratory failure and hemodynamic recombinant human alpha interferon. A preliminary report. The shock. Pediatr Crit Care Med. 2011;12(2):e87–9. New England journal of medicine. 1986;315(25):1575–8. 98. Adeli SH, Asghari A, Tabarraii R, Shajari R, Afshari S, Kalhor N, 115. Aghemo A, Rumi MG, Colombo M. Pegylated interferons et al. Therapeutic plasma exchange as a rescue therapy in patients alpha2a and alpha2b in the treatment of chronic hepatitis C. with coronavirus disease 2019: a case series. Pol Arch Intern Med. Nature Reviews Gastroenterology & Hepatology. 2010;7(9): 2020;130(5):455–8. 485–94. 99. Morath C, Weigand MA, Zeier M, Speer C, Tiwari-Heckler S, 116. Lin FC, Young HA. Interferons: success in anti-viral immunother- Merle U. Plasma exchange in critically ill COVID-19 patients. apy. Cytokine & Growth Factor Reviews. 2014;25(4):369–76. Crit Care. 2020;24(1):481. 117. Randomised double-blind placebo-controlled study of interferon 100. Tabibi S, Tabibi T, Conic RRZ, Banisaeed N, Streiff MB. beta-1a in relapsing/remitting multiple sclerosis. PRISMS Therapeutic plasma exchange: a potential management strategy (Prevention of Relapses and Disability by Interferon beta-1a for critically ill COVID-19 patients. J Intensive Care Med. Subcutaneously in Multiple Sclerosis) Study Group. Lancet 2020;35(9):827–35. (London, England). 1998;352(9139):1498-504. 101. Kesici S, Yavuz S, Bayrakci B. Get rid of the bad first: therapeutic 118. Tenembaum SN, Banwell B, Pohl D, Krupp LB, Boyko A, Meinel plasma exchange with convalescent plasma for severe COVID-19. M, et al. Subcutaneous interferon Beta-1a in pediatric multiple Proceedings of the National Academy of Sciences of the United sclerosis: a retrospective study. Journal of Child Neurology. States of America. 2020;117(23):12526–7. 2013;28(7):849–56. 102. Lin JH, Chen YC, Lu CL, Hsu YN, Wang WJ. Application of 119. Kalincik T, Spelman T, Trojano M, Duquette P, Izquierdo G, plasma exchange in association with higher dose CVVH in cyto- Grammond P, et al. Persistence on therapy and propensity kine storm complicating COVID-19. J Formos Med Assoc. matched outcome comparison of two subcutaneous interferon beta 2020;119(6):1116–8. 1a dosages for multiple sclerosis. PloS one. 2013;8(5):e63480. J Clin Immunol 120. Sulkowski MS, Cooper C, Hunyady B, Jia J, Ogurtsov P, Peck- combination therapy with lopinavir/ritonavir, Radosavljevic M, et al. Management of adverse effects of Peg-IFN hydroxychloroquine, and interferon beta-1b. Int J Antimicrob and ribavirin therapy for hepatitis C. Nature Reviews Agents. 2020;56(2):106052. Gastroenterology & Hepatology. 2011;8(4):212–23. 138. Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, 121. Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto et al. Effect of hydrocortisone on mortality and organ support in M, et al. Side effects of high-dose interferon therapy for chronic patients with severe COVID-19: the REMAP-CAP COVID-19 hepatitis C. Journal of Hepatology. 1996;25(3):283–91. Corticosteroid Domain Randomized Clinical Trial. Jama. 122. Raison CL, Demetrashvili M, Capuron L, Miller AH. 2020;324(13):1317–29. Neuropsychiatric adverse effects of interferon-alpha: recognition 139. Bosi E, Bosi C, Rovere Querini P, Mancini N, Calori G, Ruggeri and management. CNS Drugs. 2005;19(2):105–23. A, et al. Interferon beta-1a (IFNbeta-1a) in COVID-19 patients 123. Vallbracht A, Treuner J, Flehmig B, Joester KE, Niethammer D. (INTERCOP): study protocol for a randomized controlled trial. Interferon-neutralizing antibodies in a patient treated with human Trials. 2020;21(1):939. fibroblast interferon. Nature. 1981;289(5797):496–7. 140. Alavi Darazam I, Hatami F, Rabiei MM, Pourhoseingholi MA, 124. Dunn N, Fogdell-Hahn A, Hillert J, Spelman T. Long-term con- Moradi O, Shokouhi S, et al. An investigation into the beneficial sequences of high titer neutralizing antibodies to interferon-β in effects of high-dose interferon beta 1-a, compared to low-dose multiple sclerosis. Frontiers in immunology. 2020;11:583560. interferon beta 1-a (the base therapeutic regimen) in moderate to 125. Aruna LL. Anti-interferon alpha antibodies in patients with high- severe COVID-19: A structured summary of a study protocol for a risk BCR/ABL-negative myeloproliferative neoplasms treated randomized controlled l trial. Trials. 2020;21(1):880. with recombinant human interferon-α. Medical Science Monitor. 141. Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson 2018;24:2302–9. RF, et al. Interferon-beta and mycophenolic acid are potent inhib- 126. Steis RG, Smith JW 2nd, Urba WJ, Clark JW, Itri LM, Evans LM, itors of Middle East respiratory syndrome coronavirus in cell- et al. Resistance to recombinant interferon alfa-2a in hairy-cell based assays. The Journal of General Virology. 2014;95(Pt 3): leukemia associated with neutralizing anti-interferon antibodies. 571–7. The New England Journal of Medicine. 1988;318(22):1409–13. 142. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr 127. Andlauer TFM, Link J, Martin D, Ryner M, Hermanrud C, HW. Treatment of SARS with human interferons. Lancet. Grummel V, et al. Treatment- and population-specific genetic risk 2003;362(9380):293–4. factors for anti-drug antibodies against interferon-beta: a GWAS. 143. Mantlo E, Bukreyeva N, Maruyama J, Paessler S, Huang C. BMC Medicine. 2020;18(1):298. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020;179:104811. 128. Pellegrini S, Uze G. An old cytokine against a new virus? J 144. Arabi YM, Asiri AY, Assiri AM, Balkhy HH, Al Bshabshe A, Al Interferon Cytokine Res. 2020;40(8):425–8. Jeraisy M, et al. Interferon beta-1b and lopinavir-ritonavir for 129. Wang N, Zhan Y, Zhu L, Hou Z, Liu F, Song P, et al. Middle East respiratory syndrome. N Engl J Med. 2020;383(17): Retrospective multicenter cohort study shows early interferon 1645–56. therapy is associated with favorable clinical responses in 145. Khamis F, Al Naabi H, Al Lawati A, Ambusaidi Z, Al Sharji M, COVID-19 patients. Cell Host Microbe. 2020;28(3):455–64 e2. Al Barwani U, et al. Randomized controlled open label trial on the 130. Zhou Q, Chen V, Shannon CP, Wei XS, Xiang X, Wang X, et al. use of favipiravir combined with inhaled interferon beta-1b in Interferon-alpha2b treatment for COVID-19. Front Immunol. hospitalized patients with moderate to severe COVID-19 pneumo- 2020;11:1061. nia. Int J Infect Dis. 2021;102:538–43. 131. Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, 146. To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC, et al. Mankowski M, et al. Safety and efficacy of inhaled nebulised Temporal profiles of viral load in posterior oropharyngeal saliva interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infec- samples and serum antibody responses during infection by SARS- tion: a randomised, double-blind, placebo-controlled, phase 2 tri- CoV-2: an observational cohort study. Lancet Infect Dis. al. Lancet Respir Med. 2021;9(2):196–206. 2020;20(5):565–74. 132. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. 147. Hillyer P, Mane VP, Schramm LM, Puig M, Verthelyi D, Chen A, Triple combination of interferon beta-1b, lopinavir-ritonavir, and et al. Expression profiles of human interferon-alpha and ribavirin in the treatment of patients admitted to hospital with interferon-lambda subtypes are ligand- and cell-dependent. COVID-19: an open-label, randomised, phase 2 trial. Lancet. Immunology and Cell Biology. 2012;90(8):774–83. 2020;395(10238):1695–704. 148. Crotta S, Davidson S, Mahlakoiv T, Desmet CJ, Buckwalter MR, 133. Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Albert ML, et al. Type I and type III interferons drive redundant Salehi M, Abbasian L, et al. A randomized clinical trial of the amplification loops to induce a transcriptional signature in efficacy and safety of interferon beta-1a in treatment of severe influenza-infected airway epithelia. PLoS Pathogens. COVID-19. Antimicrob Agents Chemother. 2020;64(9). 2013;9(11):e1003773. 134. Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, 149. Vanderheiden A, Ralfs P, Chirkova T, Upadhyay AA, Hajizadeh N, Jalalabadi NZ, et al. Interferon beta-1b in treatment Zimmerman MG, Bedoya S, et al. Type I and type III interferons of severe COVID-19: a randomized clinical trial. Int restrict SARS-CoV-2 infection of human airway epithelial cul- Immunopharmacol. 2020;88:106903. tures. Journal of Virology. 2020;94(19). 135. Dastan F, Nadji SA, Saffaei A, Marjani M, Moniri A, Jamaati H, 150. Dinnon KH 3rd, Leist SR, Schäfer A, Edwards CE, Martinez DR, et al. Subcutaneous administration of interferon beta-1a for Montgomery SA, et al. A mouse-adapted model of SARS-CoV-2 C O V I D - 1 9 : a n o n - c o n t r o l l e d p r o s p e c t i v e t r i a l . In t to test COVID-19 countermeasures. Nature. 2020;586(7830): Immunopharmacol. 2020;85:106688. 560–6. 136. Mary A, Henaut L, Macq PY, Badoux L, Cappe A, Poree T, et al. 151. Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux Rationale for COVID-19 treatment by nebulized interferon-beta- C, et al. Peginterferon lambda for the treatment of outpatients with 1b-literature review and personal preliminary experience. Front COVID-19: a phase 2, placebo-controlled randomised trial. Pharmacol. 2020;11:592543. Lancet Respiratory Med. 137. Hong SI, Ryu BH, Chong YP, Lee S, Kim S, Kim HC, et al. Five 152. Jagannathan P, Andrews JR, Bonilla H, Hedlin H, Jacobson KB, severe COVID-19 pneumonia patients treated with triple Balasubramanian V, et al. Peginterferon lambda-1a for treatment J Clin Immunol of outpatients with uncomplicated COVID-19: a randomized 154. Broggi A, Ghosh S, Sposito B, Spreafico R, Balzarini F, Lo placebo-controlled trial. Nat Commun. 2021;12(1):1967. Cascio A, et al. Type III interferons disrupt the lung epithelial 153. Major J, Crotta S, Llorian M, McCabe TM, Gad HH, Priestnall barrier upon viral recognition. Science. 2020;369(6504):706–12. SL, et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science. 2020;369(6504): Publisher’s Note Springer Nature remains neutral with regard to jurisdic- 712–7. tional claims in published maps and institutional affiliations.