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

Abstract

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

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“…On day 6 after symptom onset, he developed fever (Tmax 39.5°C) and became hypoxic with SpO2 of 91% ( Figures 1A, B ) and PaO2 of 63 mmHg necessitating supplemental oxygen (2 liters/min by nasal cannula). Because corticosteroids decrease COVID-19–associated hyper-inflammation and improve survival ( 27 ) and initiation of corticosteroids within 24 hours of hypoxemia onset was associated with improved outcomes in APECED patients ( 13 ), we initiated methylprednisolone (0.5 mg/Kg/day) on day 6 after symptom onset. Fever and cough resolved by day 8 after symptom onset.…”

“…In particular, patients with genetic defects in type-I IFN pathways or neutralizing autoantibodies directed against type-I IFNs, including APECED patients, are among those carrying a high risk for severe disease. A recent study describing the clinical course of 22 APECED patients with COVID-19 showed higher rates of ICU admission (68%), mechanical ventilation (50%) and death (18%) ( 13 ). The study suggested that therapeutic modalities aimed at early augmentation of viral clearance (IFN-β, remdesivir), lowering of type-I IFN autoantibody titers (plasmapheresis), and early initiation of corticosteroids upon hypoxemia onset may help improve patient outcomes ( 13 ).…”

“…Both patients were enrolled on an IRB-approved protocol (NCT01386437) ( 23 ) and admitted to the NIH Clinical Center for evaluation and management of COVID-19. The two patients were not included in our recent report ( 13 ). Median inhibitory concentration (IC50) curves representing IFN-α2– and IFN-ω–induced pSTAT1 levels were determined by assessing STAT1 phosphorylation [Alex Fluor 647 mouse anti-Stat1 (pY701), BD Biosciences cat# 612597] by flow cytometry in healthy donor CD14+ monocytes (FITC anti-human CD14, BD Biosciences, cat#555397) after 15 minutes of stimulation with 10 ng/mL of IFN-α2 (R&D, cat# 11101-2) or 10 ng/mL of IFN-ω (Peprotech, cat# 300-02J) in the presence of 10% human serum AB (Innovative Research, cat# IPLA-SERAB-OTC-HI) or patient plasma serially diluted into human serum AB.…”

“…Therefore, the US Food and Drug Administration has issued an Emergency Use Authorization for these mAbs for the treatment of non-hospitalized, non-hypoxemic patients with mild-to-moderate COVID-19 who are at high risk for progressing to severe disease ( 21 ). Although APECED patients are at high risk for progression to severe COVID-19 pneumonia ( 13 ), the use of mAbs directed to the SARS-CoV-2 spike protein has not been studied in this population to date. Here we report the use of bamlanivimab and etesevimab in two APECED patients with neutralizing type-I IFN autoantibodies and pre-existing lung disease who were infected with SARS-CoV-2.…”

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“…Furthermore, it was shown that some patients with life-threatening COVID-19 had neutralizing IgG auto-antibodies against IFN-ω, IFN-α, or both. These antibodies prevent the corresponding type I IFNs from blocking SARS-CoV-2 infection in vitro and were preferentially found in patients with severe COVID-19 [ 575 , 576 , 577 , 578 ]. Altogether, these data strongly support the notion that dysregulated type I IFN immunity underlies life-threatening COVID-19 pneumonia.…”