Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients

Rickard Lagedal; Oskar Eriksson; Anna Sörman; Joram B Huckriede; Bjarne Kristensen; Stephanie Franzén; Anders Larsson; Anders Bergqvist; Kjell Alving; Anders Forslund; Barbro Persson; Kristina N Ekdahl; Pablo Garcia de Frutos; Bo Nilsson; Gerry A F Nicolaes; Miklos Lipcsey; Michael Hultström; Robert Frithiof

doi:10.3390/jcm11123419

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients

J Clin Med. 2022 Jun 14;11(12):3419. doi: 10.3390/jcm11123419.

Authors

Rickard Lagedal¹, Oskar Eriksson^{2

3}, Anna Sörman², Joram B Huckriede⁴, Bjarne Kristensen⁵, Stephanie Franzén¹, Anders Larsson⁶, Anders Bergqvist^{7

8}, Kjell Alving⁹, Anders Forslund⁹, Barbro Persson², Kristina N Ekdahl^{2

10}, Pablo Garcia de Frutos¹¹, Bo Nilsson², Gerry A F Nicolaes⁴, Miklos Lipcsey^{1

12}, Michael Hultström^{1

13}, Robert Frithiof¹

Affiliations

¹ Department of Surgical Sciences, Anaesthesia and Intensive Care, Uppsala University, 752 36 Uppsala, Sweden.
² Department of Immunology, Genetics and Pathology, Uppsala University, 752 36 Uppsala, Sweden.
³ Department of Medical Biochemistry and Microbiology, Uppsala University, 752 36 Uppsala, Sweden.
⁴ Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6211 LK Maastricht, The Netherlands.
⁵ Thermo Fisher Scientific, 3450 Allerod, Denmark.
⁶ Department of Medical Sciences, Uppsala University, 752 36 Uppsala, Sweden.
⁷ Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University, 752 36 Uppsala, Sweden.
⁸ Clinical Microbiology and Hospital Infection Control, Uppsala University Hospital, 752 36 Uppsala, Sweden.
⁹ Department of Women's and Children's Health, Uppsala University, 752 36 Uppsala, Sweden.
¹⁰ Linneus Centre for Biomaterials Chemistry, Linneus University, 392 31 Kalmar, Sweden.
¹¹ Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS and CIBERCV, 08036 Barcelona, Spain.
¹² Hedenstierna Laboratory, Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, 752 36 Uppsala, Sweden.
¹³ Unit for Integrative Physiology, Department of Medical Cell Biology, Uppsala University, 752 36 Uppsala, Sweden.

Abstract

Purpose: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival.

Methods: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure.

Results: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively.

Conclusion: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

Keywords: COVID-19; NET; SARS-CoV-2; antibody response; critical care; histones.

Grants and funding

SciLifeLab/KAW national COVID-19 research program project grant (KAW 2020.0182 and KAW 2020.0241) and from the Swedish Heart-Lung Foundation (20210089) to MH. The Swedish Research Council (2014-02569 and 2014-07606) and The Swedish Kidney Foundation (F2020-0054) to RF. The study was supported by the Netherlands Thrombosis Foundation (2016_01) and Thrombosestichting (2016-1) to GN. OE was supported by grants from the Göran Gustafsson Foundation, the Swedish Society of Medicine (SLS-943007) and the Swedish Research Council (2015-06429).