Dear Editor,
Neutralizing autoantibodies (auto-Abs) against type I interferons (IFN-I) have been identified as risk factor for life-threatening coronavirus disease 2019 (COVID-19) and were described in 101 of 987 (10%) patients with life-threatening pneumonia of whom 37 (37%) died [1]. In contrast, these antibodies were not found in patients with asymptomatic or mild disease and 0.33% of healthy individuals.
Auto-Abs against cytokines can cause severe or recurrent infections by neutralizing their target cytokine [2]. Auto-Abs to IFN-I without neutralizing ability in vitro have been identified in COVID-19 patients, but their clinical significance is unclear. Here we describe clinical characteristics of COVID-19 patients with auto-Abs neutralizing IFN-I, a subset of patients described by Bastard et al. [1]. In addition, we investigate the role of auto-Abs against IFN-I that were not neutralizing in vitro in COVID-19 and non-COVID-19 patients.
From 16 March 2020 to 8 June, 2020, 210 of 473 (43%) SARS-CoV-2 positive patients diagnosed by specific real time polymerase chain reaction (RT-PCR), hospitalized in Amsterdam UMC were selected based on sample availability and evaluated. As controls, 37 intensive care unit (ICU) patients were included who were admitted for other reasons than respiratory viral illness including COVID-19 (Supplemental Information). Clinical data were collected prospectively and blood samples were tested for auto-Abs against IFN- α2 and IFN-ω with a multiplex particle-based assay and ELISA. Blocking activity of auto-Abs was measured with a STAT1 phosphorylation assay.
Auto-Abs against IFN-I were found in 35 of 210 (17%) COVID-19 patients of whom 6 of 35 (17%) had neutralizing auto-Abs (Table 1). Neutralizing auto-Abs were only found in patients with severe COVID-19, all of whom required ICU admission compared to 83 of 204 (41%) of patients without neutralizing auto-Abs (p = 0.005). Disease course was complicated by thromboembolic events in 3 of 6 patients (50%), acute kidney injury in 4 of 6 patients (67%) and superinfections in 4 of 6 patients (67%). Five of 6 patients (83%) died compared to 52 of 204 (26%) patients without neutralizing auto-Abs (p = 0.006) including 35 of 83 (42%) in the ICU (p = 0.086). All five patients with neutralizing auto-Abs died of COVID-19-induced multi-organ failure.
Table 1.
Baseline characteristics and clinical course of COVID-19 patients with neutralizing auto-Abs against IFN-I, with auto-Abs not neutralizing in vitro and without auto-Abs
| Patients with auto-Abs neutralizing in vitro (N = 6) | Patients with auto-Abs not neutralizing in vitro (N = 26) | Patients without auto-Abs (N = 175) | |
|---|---|---|---|
| Age, years, median—IQR | 69 (60–74) | 61 (50–75) | 64 (56–71) |
| Gender, male | 6/6 (100%) | 16/26 (62%) | 111/175 (63%) |
| Comorbidities | |||
| Hypertension | 2/6 (33%) | 14/26 (54%) | 87/175 (50%) |
| Diabetes | 1/6 (17%) | 10/26 (39%) | 51/175 (29%) |
| Obesity | 1/6 (17%) | 13/25 (50%) | 61/169 (36%) |
| Complications | |||
| Acute renal injury | 4/6 (67%) | 5/26 (19%) | 15/175 (9%) |
| Bacterial pneumonia | 2/6 (33%) | 4/26 (15%) | 20/175 (11%) |
| Thromboembolic event | 4/6 67%) | 4/26 (15%) | 36/175 (21%) |
| Clinical course | |||
| ICU admission | 6/6 (100%) | 12/26 (46%) | 70/175 (40%) |
| Mortality | 5/6 (83%) | 8/26 (31%) | 44/175 (25%) |
Auto-Abs without neutralizing ability in vitro were detected in 26 of 210 COVID-19 patients (12%). Presence of these auto-Abs had no effect on clinical course (Table 1; Supplementary Table 3). Auto-abs without neutralizing ability were present in 6 of 37 (16%) non-COVID-19 patients. The proportion of ICU patients with these auto-Abs was similar between COVID-19 and non-COVID-19 (12 of 89 [13%] vs. 6 of 37 [16%]; p = 0.78).
Our study shows that auto-Abs against IFN-I that are not neutralizing in vitro occur frequently in ICU patients (16%), irrespective of COVID-19 infection. Auto-Abs that neutralize IFN-I were only found in severe COVID-19 patients and are associated with mortality. The cause of death was COVID-19-induced multi-organ failure in all, presumably attributed in part to inadequate IFN-I responses [3]. The antiviral immune response might be improved by therapies targeting neutralizing auto-Abs. As patients with non-neutralizing auto-Abs are not expected to benefit from such therapy, adequate patient selection is vital for future trials exploring auto-Abs targeted treatment.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The Amsterdam U.M.C. COVID-19 Biobank Investigators
Michiel van Agtmael2, Anne Geke Algera1, Brent Appelman2, Frank van Baarle1, Diane Bax3, Martijn Beudel4, Harm Jan Bogaard5, Marije Bomers2 Peter Bonta5, Lieuwe Bos1, Michela Botta1, Justin de Brabander2 Godelieve Bree2 Sanne de Bruin1, Marianna Bugiani5, Esther Bulle1, Nora Chekrouni4, Osoul Chouchane2 Alex Cloherty3, Dave A. Dongelmans1, Romein W.G. Dujardin1, Paul Elbers1, Lucas Fleuren1, Suzanne Geerlings2 Theo Geijtenbeek3, Armand Girbes1, Bram Goorhuis2 Martin P. Grobusch2 Florianne Hafkamp3, Laura Hagens1, Jorg Hamann7, Vanessa Harris2 Robert Hemke8, Sabine M. Hermans2 Leo Heunks1, Markus Hollmann6, Janneke Horn1, Joppe W. Hovius2 Menno D. de Jong9, Rutger Koning4, Endry H.T. Lim1, Niels van Mourik1, Jeaninne Nellen2 Esther J. Nossent5, Sabine Olie4, Frederique Paulus1, Edgar Peters2, Tom van der Poll2, Bennedikt Preckel6, Jan M. Prins2, Jorinde Raasveld1, Tom Reijnders2, Michiel Schinkel2, Marcus J. Schultz1, Alex Schuurmans10, Jaap Schuurmans1, Kim Sigaloff1, Marleen A. Slim1,2, Marry Smit1, Cornelis S. Stijnis2, Willemke Stilma1, Charlotte Teunissen11, Patrick Thoral1, Anissa M Tsonas1, Marc van der Valk2, Denise Veelo6, Heder de Vries1, Lonneke A. Vught1,2, Michèle van Vugt2, Dorien Wouters12, A. H (Koos) Zwinderman13, Matthijs C. Brouwer4, W. Joost Wiersinga2, Alexander P.J. Vlaar1, Diederik van de Beek4.
1Department of Intensive Care, Amsterdam UMC, Amsterdam, The Netherlands; 2Department of Infectious Diseases, Amsterdam UMC, Amsterdam, The Netherlands; 3Experimental Immunology, Amsterdam UMC, Amsterdam, The Netherlands; 4Department of Neurology, Amsterdam UMC, Amsterdam, The Netherlands; 5Department of Pulmonology, Amsterdam UMC, Amsterdam, The Netherlands; 6Department of Anesthesiology, Amsterdam UMC, Amsterdam, The Netherlands; 7Amsterdam UMC Biobank Core Facility, Amsterdam UMC, Amsterdam, The Netherlands; 8Department of Radiology, Amsterdam UMC, Amsterdam, The Netherlands; 9Department of Medical Microbiology, Amsterdam UMC, Amsterdam, The Netherlands; 10Department of Internal Medicine, Amsterdam UMC, Amsterdam, The Netherlands; 11Neurochemical Laboratory , Amsterdam UMC, Amsterdam, The Netherlands; 12Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, The Netherlands; 13Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, The Netherlands.
Authors contribution
The study was designed by JC, MB and DB. PB performed laboratory analysis. RK performed statistical analysis. The first draft of the manuscript was written by Rutger Koning and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding source
Corona Research Fund Amsterdam UMC, Dr. C. J. Vaillant Fonds, ZonMw (Vici 91819627).
Availability of data and material
Additional data are available upon request.
Code availability
Statistical code is available upon request.
Declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
Approval was obtained from the Medical Ethics Committees from the Academic Medical Center and VU University Medical Center.
Consent to participate/publication
All participants provided written informed consent, if applicable.
Footnotes
Members of "The Amsterdam U.M.C. COVID-19 Biobank Investigators" are listed in Acknowledgement section.
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Contributor Information
Diederik van de Beek, Email: d.vandebeek@amsterdamumc.nl.
with the Amsterdam U.M.C. COVID-19 Biobank Investigators:
Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Harm Jan Bogaard, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve Bree, Sanne de Bruin, Marianna Bugiani, Esther Bulle, Nora Chekrouni, Osoul Chouchane, Alex Cloherty, Dave A. Dongelmans, Romein W. G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H. T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Sabine Olie, Frederique Paulus, Edgar Peters, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Michiel Schinkel, Marcus J. Schultz, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Marc van der Valk, Denise Veelo, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, A. H.(Koos) Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P. J. Vlaar, and Diederik van de Beek
References
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Supplementary Materials
Data Availability Statement
Additional data are available upon request.
Statistical code is available upon request.