Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID
Benjamin A. Krishna,
Eleanor Y. Lim,
Lenette Mactavous,
Paul A. Lyons,
Rainer Doffinger,
John R. Bradley,
Kenneth G.C. Smith,
John Sinclair,
Nicholas J. Matheson,
Paul J. Lehner,
Mark R. Wills,
Nyaradzai Sithole
Affiliations
Benjamin A. Krishna
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Eleanor Y. Lim
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Lenette Mactavous
Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Paul A. Lyons
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Rainer Doffinger
Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
John R. Bradley
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK; Cambridge NIHR BioResource Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Department of Renal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Kenneth G.C. Smith
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
John Sinclair
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Nicholas J. Matheson
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; NHS Blood and Transplant, Cambridge CB2 0PT, UK
Paul J. Lehner
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Mark R. Wills
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Corresponding authors at: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Nyaradzai Sithole
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Corresponding authors at: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Summary: Background: There is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative. Methods: Given the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients. Findings: We discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/−13%) and specific (88%+/−7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42–53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses. Interpretation: Our study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID. Funding: This work was funded by the Addenbrooke's Charitable Trust (900276 to NS), NIHR award (G112259 to NS) and supported by the NIHR Cambridge Biomedical Research Centre. NJM is supported by the MRC (TSF MR/T032413/1) and NHSBT (WPA15-02). PJL is supported by the Wellcome Trust (PRF 210688/Z/18/Z, 084957/Z/08/Z), a Medical Research Council research grant MR/V011561/1 and the United Kingdom Research and a Innovation COVID Immunology Consortium grant (MR/V028448/1).
