ABSTRACT
After acute infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a significant proportion (0.2 – 30%) of patients experience persistent symptoms beyond 12 weeks, termed Long COVID. Understanding the mechanisms which cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic and monitoring purposes is urgently required. Persistently high levels of IFN-γ were detected from peripheral blood mononuclear cells (PBMCs) of Long COVID patients using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in Long Covid patients, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. IFN-γ release was CD8+ T cell mediated and dependent on MHC-I antigen presentation by CD14+ cells. After vaccination, a significant decrease in IFN-γ correlated with resolution of some Long COVID symptoms. Our study highlights a key mechanism underlying Long COVID, enabling the search for biomarkers and therapeutics in patients with Long COVID.
Subject(s)
Acute Disease , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
National Institute for Health and Care Excellence (NICE) guidelines define Long COVID as signs and symptoms that develop during or after an infection consistent with COVID-19, that continue for more than 12 weeks and are not explained by an alternative diagnosis. Long COVID is as yet poorly understood and difficult to diagnose. The diagnostic complexity of Long COVID is compounded in many patients who were infected with SARS-CoV-2 but not tested at acute presentation and are antibody negative. Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.Funding: This work was funded by Addenbrooke’s Charitable Trust grant awarded to N.S. and supported by the NIHR Cambridge Biomedical Research Centre.Declaration of Interest: The authors declare no competing interestsEthical Approval: The Long COVID study patients were recruited and consented under the Cambridge COVID-19 NIHR BioResource joint Consent Form (Research Ethics Committee (NRES number (REC)) no. T1gC1) study NBR87.
Subject(s)
COVID-19ABSTRACT
National Institute for Health and Care Excellence (NICE) guidelines define Long COVID as signs and symptoms that develop during or after an infection consistent with COVID-19, that continue for more than 12 weeks and are not explained by an alternative diagnosis. Long COVID is as yet poorly understood and difficult to diagnose. The diagnostic complexity of Long COVID is compounded in many patients who were infected with SARS-CoV-2 but not tested at acute presentation and are antibody negative. Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.
Subject(s)
COVID-19ABSTRACT
Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This brought to mind the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. We demonstrated the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes we also observed in B cell VHL-deficient mice. This was corroborated by hypoxia-related transcriptional changes in COVID-19 patients, and by similar B cell abnormalities in mice kept in hypoxic conditions, including reduced marginal zone and germinal center B cells. Thus hypoxia might contribute to B cell pathology in COVID-19, and in other hypoxic states. Through this mechanism it may impact on COVID-19 outcome, and be remediable through early oxygen therapy.
Subject(s)
COVID-19ABSTRACT
In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.Funding: We are grateful for the generous support of CVC Capital Partners, the Evelyn Trust (20/75), UKRI COVID Immunology Consortium, Addenbrooke’s Charitable Trust (12/20A) and the NIHR Cambridge Biomedical Research Centre for their financial support. K.G.C.S. is the recipient of a Wellcome Investigator Award (200871/Z/16/Z); M.P.W. is the recipient of Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H. was funded by a Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M. was funded by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02); I.G.G. is a Wellcome Senior Fellow and was supported by funding from the Wellcome (Ref: 207498/Z/17/Z).Conflict of Interest: The authors declare they have no competing interests.