Severe COVID-19 in an APS1 patient with interferon autoantibodies treated with plasmapheresis
Authors: Andri Lemarquis, Tessa Campbell, Maribel Aranda-Guillén, Viktoria Hennings, Petter Brodin, Olle Kämpe, Kaj Blennow, Henrik Zetterberg, Christine Wennerås, Kristina Eriksson, Nils Landegren, Yenan Bryceson, Stefan Berg, Olov Ekwall
Journal: Journal of Allergy and Clinical Immunology (2021)

Type I interferons (IFNs) are crucial in protecting against severe coronavirus disease 2019 (COVID-19), and a high percentage of patients with life-threatening COVID-19 either carry loss-of-function variants in the genes for type I IFNs or neutralizing autoantibodies (aAbs) against type I IFNs.1Bastard P. Rosen L.B. Zhang Q. Michailidis E. Hoffmann H.-H. Zhang Y. et al.Autoantibodies against type I IFNs in patients with life-threatening COVID-19.Science. 2020; 370eabd4585Crossref PubMed Scopus (1777) Google Scholar,2Zhang Q. Bastard P. Liu Z. Le Pen J. Moncada-Velez M. Chen J. et al.Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.Science. 2020; 370eabd4570Crossref PubMed Scopus (1497) Google Scholar This is in agreement with observations that the IFN response is important in limiting the early viremic phase of the disease, as well as for the subsequent resolution of inflammation.3Hadjadj J. Yatim N. Barnabei L. Corneau A. Boussier J. Smith N. et al.Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science. 2020; 369: 718-724Crossref PubMed Scopus (1939) Google Scholar Removal of aAbs through plasmapheresis has been suggested as a targeted treatment in severe COVID-19 with concomitant type I IFN aAbs.1Bastard P. Rosen L.B. Zhang Q. Michailidis E. Hoffmann H.-H. Zhang Y. et al.Autoantibodies against type I IFNs in patients with life-threatening COVID-19.Science. 2020; 370eabd4585Crossref PubMed Scopus (1777) Google Scholar,4Fernández-Zarzoso M. Gómez-Seguí I. de la Rubia J. Therapeutic plasma exchange: review of current indications.Transfus Apher Sci. 2019; 58: 247-253Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by neutralizing aAbs to type I IFNs.5Meager A. Visvalingam K. Peterson P. Möll K. Murumägi A. Krohn K. et al.Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1.PLoS Med. 2006; 3: e289Crossref PubMed Scopus (285) Google Scholar As a proof-of-concept, we present the case of a child with APS1 and aAbs to type I IFN who developed life-threatening COVID-19 and responded rapidly to treatment with plasmapheresis, intravenous immunoglobulin (IVIg), and high-dosage corticosteroids. The patient is an 8-year-old girl with APS1, verified by homozygous AIRE [c.1616C>T (p.Pro539Leu)] mutations, typical clinical presentation including Addison disease, hypoparathyroidism, and vitiligo. She carried aAbs characteristic for APS1, among them high-titer aAbs against IFN-ω and IL-22 (Fig 1, C). The patient presented with a cough, fever, and a positive PCR result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Her clinical condition deteriorated, leading to transfer to the intensive care unit where she was put on a ventilator on day 7 from the onset of symptoms. Because the patient had high concentrations of aAbs to type I IFN before infection, we hypothesized that removal of these aAbs might improve her severe clinical manifestation of COVID-19. Therefore, daily plasmapheresis, followed by IVIg, was applied for 5 consecutive days (days 7-11). After 4 days on the ventilator, the patient could be extubated on day 10, and on day 22, the patient was discharged in good condition without any sequelae (Fig 1, A). Monitoring of aAbs to a broad range of type I IFNs during the course of disease showed that the initially high concentrations decreased during plasmapheresis and returned to high levels again when plasmapheresis was discontinued (Fig 1, D and E). In parallel with the decline in aAb levels, a small surge in IFN-α was detected, which was undetectable before plasmapheresis (Fig 1, C). Furthermore, after plasmapheresis, the patient's serum was less neutralizing (Fig 1, F) and to a lower extent inhibiting IFN-α–induced signal transducer and activator of transcription 1 phosphorylation (Fig 1, G) in monocytes in in vitro assays. The patient developed adaptive immunity to SARS-CoV-2 with high titers of IgA and IgG SARS-CoV-2 antibodies as well as proliferation of CD4 and CD8 T cells and production of IFN-γ and CXCL10/IP10 after S and N protein stimulation (Fig 1, H and I). The present case underlines the importance of considering inborn errors of immunity in patients with severe COVID-19. Furthermore, although a single case cannot demonstrate causality, we hypothesize that the removal of type I IFN–specific aAbs by plasmapheresis, in addition to high-dose corticosteroids and IVIg, represents a targeted treatment with benefits for patients who have aAbs against type I IFN and severe COVID-19. Formal studies are needed to test this hypothesis. We thank the National Facility for Autoimmunity and Serology Profiling at SciLifeLab and Jennie Olofsson for excellent technical support related to the bead-based array studies. Finally, we thank the patient, family members, and healthy controls for participating in this study, without whom it would not have been possible to conduct this research.