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      Neutralizing Autoantibodies to Type I IFNs in >10% of Patients with Severe COVID-19 Pneumonia Hospitalized in Madrid, Spain

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          Abstract

          Background

          In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta.

          Objectives

          We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.

          Methods

          We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain.

          Results

          The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%), while they were not found in any of the 118 asymptomatic controls ( p = 0.0016). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels ( p = 5.10e −03) and lower lymphocyte counts ( p = 1.80e −02). No significant association with response to IFN-beta-1b therapy ( p = 0.34) was found. Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%).

          Conclusion

          Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s10875-021-01036-0.

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          Most cited references26

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          Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.

          Paul A. Harris, Robert Taylor, Robert Thielke … (2009)
          Research electronic data capture (REDCap) is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data capture tools to support clinical and translational research. We present: (1) a brief description of the REDCap metadata-driven software toolset; (2) detail concerning the capture and use of study-related metadata from scientific research teams; (3) measures of impact for REDCap; (4) details concerning a consortium network of domestic and international institutions collaborating on the project; and (5) strengths and limitations of the REDCap system. REDCap is currently supporting 286 translational research projects in a growing collaborative network including 27 active partner institutions.
          Article 0 comments Cited 10991 times – based on 0 reviews     Review now
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            COVID-19: consider cytokine storm syndromes and immunosuppression

            Puja Mehta, Daniel McAuley, Michael Brown … (2020)
            As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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              Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study

              Christopher Petrilli, Simon A. Jones, Jie Yang … (2020)
              Abstract Objective To describe outcomes of people admitted to hospital with coronavirus disease 2019 (covid-19) in the United States, and the clinical and laboratory characteristics associated with severity of illness. Design Prospective cohort study. Setting Single academic medical center in New York City and Long Island. Participants 5279 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection between 1 March 2020 and 8 April 2020. The final date of follow up was 5 May 2020. Main outcome measures Outcomes were admission to hospital, critical illness (intensive care, mechanical ventilation, discharge to hospice care, or death), and discharge to hospice care or death. Predictors included patient characteristics, medical history, vital signs, and laboratory results. Multivariable logistic regression was conducted to identify risk factors for adverse outcomes, and competing risk survival analysis for mortality. Results Of 11 544 people tested for SARS-Cov-2, 5566 (48.2%) were positive. After exclusions, 5279 were included. 2741 of these 5279 (51.9%) were admitted to hospital, of whom 1904 (69.5%) were discharged alive without hospice care and 665 (24.3%) were discharged to hospice care or died. Of 647 (23.6%) patients requiring mechanical ventilation, 391 (60.4%) died and 170 (26.2%) were extubated or discharged. The strongest risk for hospital admission was associated with age, with an odds ratio of >2 for all age groups older than 44 years and 37.9 (95% confidence interval 26.1 to 56.0) for ages 75 years and older. Other risks were heart failure (4.4, 2.6 to 8.0), male sex (2.8, 2.4 to 3.2), chronic kidney disease (2.6, 1.9 to 3.6), and any increase in body mass index (BMI) (eg, for BMI >40: 2.5, 1.8 to 3.4). The strongest risks for critical illness besides age were associated with heart failure (1.9, 1.4 to 2.5), BMI >40 (1.5, 1.0 to 2.2), and male sex (1.5, 1.3 to 1.8). Admission oxygen saturation of 1 (4.8, 2.1 to 10.9), C reactive protein level >200 (5.1, 2.8 to 9.2), and D-dimer level >2500 (3.9, 2.6 to 6.0) were, however, more strongly associated with critical illness than age or comorbidities. Risk of critical illness decreased significantly over the study period. Similar associations were found for mortality alone. Conclusions Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.
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                Author and article information

                Contributors
                Jesús Troya:
                ORCID: http://orcid.org/0000-0001-7323-114X
                jestrogar@hotmail.com
                Journal
                Journal ID (nlm-ta): J Clin Immunol
                Journal ID (iso-abbrev): J Clin Immunol
                Title: Journal of Clinical Immunology
                Publisher: Springer US (New York )
                ISSN (Print): 0271-9142
                ISSN (Electronic): 1573-2592
                Publication date (Electronic): 13 April 2021
                Pages: 1-9
                Affiliations
                [1 ]GRID grid.411171.3, ISNI 0000 0004 0425 3881, Department of Internal Medicine, , Infanta Leonor University Hospital, ; Madrid, Spain
                [2 ]GRID grid.412134.1, ISNI 0000 0004 0593 9113, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, , Necker Hospital for Sick Children, ; Paris, France
                [3 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Imagine Institute, , University of Paris, ; Paris, France
                [4 ]GRID grid.134907.8, ISNI 0000 0001 2166 1519, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, , Rockefeller University, ; New York, NY USA
                [5 ]GRID grid.417656.7, Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), , L’Hospitalet de Llobregat, ; Barcelona, Spain
                [6 ]GRID grid.411171.3, ISNI 0000 0004 0425 3881, Intensive Care Unit, , Infanta Leonor University Hospital, ; Madrid, Spain
                [7 ]GRID grid.413575.1, ISNI 0000 0001 2167 1581, Howard Hughes Medical Institute, ; New York, NY USA
                [8 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Centre for Biomedical Research in Network on Rare Diseases (CIBERER), , Instituto de Salud Carlos III, ; 28029 Madrid, Spain
                [9 ]GRID grid.425902.8, ISNI 0000 0000 9601 989X, Catalan Institution of Research and Advanced Studies (ICREA), ; Barcelona, Catalonia Spain
                Author information
                http://orcid.org/0000-0001-7323-114X
                https://orcid.org/0000-0002-5926-8437
                https://orcid.org/0000-0002-2586-0897
                https://orcid.org/0000-0002-4212-7419
                https://orcid.org/0000-0003-0466-2653
                https://orcid.org/0000-0002-0803-5350
                https://orcid.org/0000-0002-8860-6837
                https://orcid.org/0000-0001-7016-6493
                https://orcid.org/0000-0002-7782-4169
                https://orcid.org/0000-0002-9606-0600
                Article
                Publisher ID: 1036
                DOI: 10.1007/s10875-021-01036-0
                PMC ID: 8043439
                PubMed ID: 33851338
                SO-VID: 1d131867-5692-47ff-810b-6bee1c9a3dfa
                Copyright © © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 1 March 2021
                Date accepted : 5 April 2021
                Funding
                Funded by: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (CN)
                Award ID: ANR-10-LABX-62-IBEID
                Funded by: Institut Français de Recherche pour l'Exploitation de la Mer (FR)
                Award ID: EQU201903007798
                Funded by: The FRM and ANR GENCOVID project
                Award ID: ANRS-COV05
                Funded by: Fondation Bettencourt-Schueller
                Funded by: Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH)
                Award ID: R01AI088364
                Funded by: Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston (US)
                Award ID: UL1 TR001866
                Funded by: Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (MX)
                Award ID: UM1HG006504
                Funded by: French National Research Agency (ANR)
                Award ID: ANR-10-IAHU-01
                Funded by: Horizon 2020 Programme
                Award ID: 824110
                Award Recipient :
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Immunology
                Keywords: covid-19,subcutaneous interferon-beta 1b,type i ifn neutralizing autoantibodies,severity biomarkers
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: covid-19, subcutaneous interferon-beta 1b, type i ifn neutralizing autoantibodies, severity biomarkers

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