Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona

Abstract

Background It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. Objectives We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. Methods Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. Results A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. Conclusion Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01136-x.

TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

“…We observed a very rapid and robust induction of the Type I IFN pathway at 1-2dpi, characterized by elevated pDCs in the airway and blood, IFNA and IFNB transcripts and protein, upregulated ISGs, and increased granzyme B in NK cells. The Type I IFN response in SARS-CoV-2 infection has been intensely studied: in vitro infection of airway epithelial cells have consistently resulted in a muted ISG response 43 , and patients developing severe COVID-19 have been reported to have higher incidence of mutations in IFN response genes, or elevated levels of autoantibodies against IFN-response genes (reviewed in 6,[44][45][46][47][48][49][50][51] ). Our data, in which the IFN response peaked at 2dpi and had largely abated by 10/11dpi, provides well defined kinetics of the ISG response, and similar observations have been reported in other NHP studies 21,22 .…”

Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern

“…This article is a US Government work. It is not subject to copyright under 17 105 and is also made available for use under a CC0 license.…”

“…Pre-existing antibody populations may also contribute to disease severity such as autoantibodies to type I interferons (17). As SARS-CoV-2 mutates, changes to the sensitivity of pre-exisitng neutralizing antibody populations may be effected (18).…”

“…This article is a US Government work. It is not subject to copyright under17 USC The copyright holder for this preprint this version posted November 12, 2021. ; https://doi.org/10.1101/2021.11.10.468174 doi: bioRxiv preprint…”

Complexity of immune responses in COVID-19

“…Zhang et al found enrichment in loss-of-function mutations at loci involved in type I IFN production in patients with life-threatening SARS-CoV-2 infection compared to healthy controls [ 50 ]; such susceptibility mutations are rare, but do contribute to the low interferon levels seen in severe disease. Neutralising autoantibodies to type I IFNs have been identified in ∼10% of patients with severe SARS-CoV-2 infection [ 51 , 53 , 54 ]. The presence of type 1 IFN autoantibodies appear to be a poor prognostic sign [ 53 ] and have been implicated in approximately one fifth of deaths from SARS-CoV-2 [ 55 ].…”