key: cord-0754631-ccljxw2s
authors: Abers, Michael S; Rosen, Lindsey B; Delmonte, Ottavia M; Shaw, Elana; Bastard, Paul; Imberti, Luisa; Quaresima, Virginia; Biondi, Andrea; Bonfanti, Paolo; Castagnoli, Riccardo; Casanova, Jean‐Laurent; Su, Helen C; Notarangelo, Luigi D; Holland, Steven M; Lionakis, Michail S
title: Neutralizing type‐I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID‐19
date: 2021-08-08
journal: Immunol Cell Biol
DOI: 10.1111/imcb.12495
sha: 1046cb4494f27780ad04adb2d7eaf76de405e8fb
doc_id: 754631
cord_uid: ccljxw2s

Type‐I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID‐19). Several lines of evidence suggest that impaired type‐I IFN signaling may predispose to severe COVID‐19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type‐I IFNs influence outcomes in patients with COVID‐19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type‐I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID‐19 at three Italian hospitals. The presence of circulating AAbs to type‐I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type‐I IFN AAbs. Our findings provide further support for the role of type‐I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID‐19 pneumonia in severe acute respiratory syndrome coronavirus 2‐infected individuals.

Type-I interferons (IFNs) mediate antiviral immunity and exert other pleiotropic immune effects. Impaired type-I IFN responses have been identified in patients with severe coronavirus disease 19 (COVID-19), suggesting that type-I IFNs play a critical role against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1, 2 We recently reported 3 that neutralizing autoantibodies (AAbs) against IFNa and/or IFNx were identified in at least 10% of critically ill COVID-19 patients but not in mildly symptomatic patients. These AAbs abolish type-I IFN signaling, circulate prior to SARS-CoV-2 infection, as evidenced in patients with incontinentia pigmenti 4 and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy/autoimmune polyglandular syndrome type-1, 5 and persist throughout the course of illness. 3 The presence of neutralizing AAbs against type-I IFNs in a subset of patients with life-threatening COVID-19 pneumonia has been replicated by several groups. 2, 6, 7 Our original report did not examine the detailed clinical course of COVID-19 in patients harboring neutralizing AAbs against type-I IFNs beyond severity of SARS-CoV-2 infection. 3 Furthermore, that study focused on patients with life-threatening infection, excluding less severe cases of COVID-19 who nonetheless required hospitalization. In the present study, we sought to determine the influence of AAbs to type-I IFNs on clinical outcomes in patients hospitalized for COVID-19.

We included 218 patients with COVID-19 in this study. Severity of illness was classified as critical in 135 patients (61.9%), severe in 44 (17.9%) and mild/moderate in 39 (20.2%). Of note, the 135 patients with critical COVID-19 were included in our previous report. 3 Neutralizing AAbs to type-I IFNs were detected in 26 patients (11.9%), most of whom (17 patients) harbored AAbs to both IFNa and IFNx (Supplementary figure 1). AAbs to IFNb were detected in a single patient who also had AAbs to both IFNa and IFNx. Clinical characteristics were compared between AAb-positive (AAb+) and AAbnegative (AAb-) patients (Supplementary table 1) . The presence of AAbs was associated with male sex and severity of illness, whereas age and medical comorbidities did not significantly differ between the two groups in this cohort. The incidence of thrombotic complications was comparable between AAb+ and AAbÀ patients (Supplementary table 1 (2) (3) (4) , respectively, P = 0.09]. The presence of neutralizing AAbs to type-I IFNs was associated with a markedly delayed time to viral clearance of SARS-CoV-2, as modeled by Cox proportional hazards [hazard ratio, 0.24; 95% confidence interval, 0.07-0.77; log-rank P = 0.003; Figure 1a ]. The mean time to viral clearance in the overall cohort was 15 days. By contrast, the mean time to viral clearance was 24 days in AAb+ patients. This finding was particularly striking in patients admitted to the intensive care unit (ICU) (Figure 1b) , with 100% of AAb-positive ICU patients remaining PCR positive 4 weeks after hospital admission. In addition, AAb positivity was associated with more severe infection ( Figure 1c ) and an increased risk for ICU admission during the first 15 days of hospitalization ( Figure 1d ; hazard ratio, 2.59; 95% confidence interval, 1.43-4.69; P = 0.004). Notably, although ICU admission was associated with greater mortality in the entire cohort of 218 patients (Figure 1e ; hazard ratio, 2.35; 95% confidence interval, 1.14-4.85; P = 0.02), the presence of AAbs was not associated with patient survival (Figure 1f ; hazard ratio, 0.64; 95% confidence interval, 0.22-1.81; P = 0.37), a finding that was consistent regardless of patient sex or ICU status (Supplementary figure 2).

Previous studies have shown that patients with AAbs against type-I IFNs have a predilection for developing life-threatening COVID-19. 3, 6, 7 In addition, most patients with autoimmune polyendocrinopathy-candidiasisectodermal dystrophy/autoimmune polyglandular syndrome type-1, 8 who carry neutralizing AAbs against type-I IFNs, are at risk for severe hypoxemic COVID-19 pneumonia. 5, 9 Initial reports of exogenous administration of IFNb or plasma exchange in these patients, or IFNa2 in those with inborn errors of type-I IFN immunity, during the early nonhypoxemic phase of COVID-19 have provided promising results. 4, 5, 10, 11 The identification of type-I IFN AAbs in a sizable proportion of patients with severe COVID-19 in conjunction with the observation that the overwhelming majority of AAbs to type-I IFNs in patients with COVID-19 are directed against IFNa and/or IFNx but not IFNb provide a compelling rationale for the preferential investigation of IFNb over IFNa in future clinical studies. [2] [3] [4] [5] [6] [7] While prior studies have established that patients with defects in the type-I IFN signaling pathway are predisposed to severe COVID-19, 1,3 the pathophysiologic mechanisms that contribute to this enhanced illness severity remain unclear. We now show that patients with type-I IFN AAbs have delayed viral clearance contributing to the greater likelihood of developing critical COVID-19 pneumonia requiring ICU admission and mechanical ventilation. However, despite their increased morbidity, these patients surprisingly did not have an increased risk of death in our cohort. Several factors may account for the lack of association between survival and the presence of neutralizing anti-type-I IFN antibodies. In particular, coordination between humoral and cellular adaptive immune responses has been shown to play a critical role in determining COVID-19 severity and outcome. 12 Moreover, while a lack of type-I IFN signaling during early infection is clearly detrimental for SARS-CoV-2 containment, type-I IFNs may contribute to secondary inflammation during the late hyperinflammatory stage of COVID-19. Furthermore, in addition to immunologic factors, a variety of clinical and demographic characteristics, most notably patient age and the presence of comorbid conditions, play a critical role in influencing clinical outcomes. However, we did not detect differences in age or the prevalence of comorbid conditions in patients with versus without AAbs. Importantly, this does not rule out the possibility that one or more unmeasured confounding factors may explain the comparable mortality between groups. More studies will be needed to verify these results and to examine whether neutralizing AAbs against type-I IFNs are associated with a greater frequency of bacterial infections in hospitalized COVID-19 patients as observed in our cohort.

In summary, we show that type-I IFN AAbs are associated with delayed SARS-CoV-2 clearance, ICU admission, mechanical ventilation and critical COVID-19 pneumonia but do not appear to independently affect survival. Early administration of IFNb in patients harboring type-I IFN AAbs may help hasten SARS-CoV-2 clearance and avert the development of critical COVID-19 pneumonia.

All patients included in this study were adults (age ≥18 years) who were admitted with laboratoryconfirmed COVID-19 to one of three Italian hospitals (ASST Spedali Civili, Brescia; Ospedale San Gerardo, Monza and Ospedale S. Matteo, Pavia) between February and May 2020. 13 The maximum severity of COVID-19 during hospitalization was determined for each patient using a previously described scoring system. 13 Neutralizing AAb characterization was performed as previously described. 3 Patients were classified as AAb+ if neutralizing AAbs to one or more type-I IFNs (IFNa, IFNb and IFNx) were detected in peripheral blood, whereas individuals who lacked such antibodies were considered AAbÀ. Time to viral clearance was defined as the interval from hospitalization to the first date on which nasopharyngeal PCR testing was negative without a subsequent positive test. Patients whose most recent test was positive were censored on that date. All PCR tests were performed in the context of clinical care without prespecified requirements for testing frequency or the number of tests per patient. All analyses involving viral clearance were limited to patients whose medical records included the date of sample collection and results for all PCR tests. Mortality was defined as death within 10 weeks of hospital admission. Patients with unknown status at this time point were censored on the date the patient was last known to be alive. To focus on COVID-19-related indications for ICU admission rather than nosocomial factors, time to ICU admission was modeled during the first 15 days of hospitalization. Continuous variables were summarized by median and interquartile ranges and groups were compared using a Mann-Whitney U-test. Categorical variables were compared by the Fisher exact test (when the number of individuals in any group was < 5) or a Chisquared test. Patient survival, time to viral clearance and time to ICU admission since hospital admission were modeled using univariate Cox proportional hazards regression; groups were compared using the log-rank test.

For all analyses, statistical significance was defined as P < 0.05. Data were analyzed using R version 4.0.4 (R Foundation, Vienna, Austria).

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Longitudinal single-cell epitope and RNA-seq reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19

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

Interferon-b therapy in a patient with incontinentia pigmenti and autoantibodies against type I IFNs infected with SARS-CoV-2

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients

Neutralizing autoantibodies to type I IFNs in >10% of patients with severe COVID-19 pneumonia hospitalized in Madrid, Spain

Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1

IFN-a2a therapy in two patients with inborn errors of TLR3 and IRF3 infected with SARS-CoV-2

Plasma exchange to rescue patients with autoantibodies against type I interferons and life-threatening COVID-19 pneumonia

Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity

An immunebased biomarker signature is associated with mortality in COVID-19 patients

The authors have no conflicts of interest to disclose. 

Data are available upon request.

Additional supporting information may be found online in the Supporting Information section at the end of the article.ª 2021 Australian and New Zealand Society for Immunology, Inc. This article has been contributed to by US Government employees and their work is in the public domain in the USA.