Longitudinal Sequelae of Severe COVID-19 3-12 Months Post Omicron Infection

Background: Persistent and remitting-relapsing symptoms are frequently reported many months after SARS-CoV-2 infection. However, evidence of whether biological and clinical features of long COVID are associated with initial Omicron infection severity is lacking. Methods: A prospective observational cohort study of n=40 SARS-CoV-2 (Omicron B.1.1.529) infected individuals was performed, comprising n=20 non-hospitalised and n=20 hospitalised cases. ISARIC symptomology was collected at baseline, 3-, 6- and 12-months post infection. Total and neutralising IgG antibody and inflammatory proteome concentrations were determined in plasma at baseline and 3 months. Pairwise comparisons were made between non-hospitalised and hospitalised subgroup biological and symptom data to investigate differences over time. ClinicalTrials.gov NCT05548829. Findings: By 3 months post infection, the non-hospitalised subgroup had higher median levels of Omicron variant specific ACE2 neutralising antibodies (BA.1, BA.2, BA.3), in particular females (p=0·06 - 0·09). A notable reduction in the levels of Omicron variant neutralizing antibodies was observed at 3 months in the hospitalised subgroup (p=0·09 - 0·16). Protracted elevation of inflammatory proteins type 1 keratin, prostasin and leukocyte associated immunoglobulin receptor 1 was observed in the hospitalised subgroup between baseline and 3 months post infection (padj <0·05). Fatigue, muscle pain, headache, and cough were the predominant symptoms at baseline, in both hospitalisation subgroups. Whilst these symptoms subsided over the 12 month follow up period in non-hospitalised, significantly more hospitalised individuals continued to experience muscle pain and shortness of breath (p<0·05). Interpretation: This is the first prospective study evidence of the link between Omicron hospitalisation and long term humoral immune response, inflammatory plasma proteome, and symptom persistence. Funding: This work (primarily Cohort A) was supported by an Opportunity-Led Research Award to DSG (PI) and co-authors AJB, EM, TSR, SDZ, PS from Health and Social Care, Research and Development Division (HSC R&D), Public Health Agency (COM/5631/20) and National Core Study: Immunity (NCSi4P program) funding from United Kingdom Research and Innovation (UKRI) to DSG and PS. Cohort B recruitment was supported by a research grant to AJB (PI) and coauthors DSG, CW, SDZ, PS from the Department for the Economy Northern Ireland under its contribution to Science Foundation Ireland’s COVID-19 Rapid Response Call (Phase 2). Declaration of Interest: The authors declare no conflict of interest related to this work. Ethical Approval: Ethical approval was obtained from the Health and Care Research Wales Ethics committee (20/WA/0179; 14/07/2020). Informed consent was obtained for all participants in the study, allowing for publication of anonymised demographic, biological and clinical data.