Multi-organ structural and functional deficits in association with long COVID: a population-based case-control study

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Background: Multi-system impacts of long COVID remain unknown. We aimed to compare multi-system deficits between people with long COVID and controls. Methods: We conducted a case-control study and recruited participants from two UK population-based cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and TwinsUK. Participants provided samples for SARS-CoV-2 serology between 2020 and 2021 and were asked about duration of COVID-19 symptoms between July and December 2021. Cases had long COVID (evidence of COVID-19 infection and persistent symptoms ≥4 weeks post infection); controls comprised 3 groups: acute COVID-19 only (symptoms reported for <4 weeks) and serological evidence of infection; self-reported long COVID-like symptoms but without wild-type SARS-CoV-2 virus antibodies; no symptoms or history of COVID-19 infection. People who were severely unwell or pregnant were excluded. Participants attended a clinic follow-up visit between 2021 and 2023 and underwent multi-system MRI, (cardiac, brain, lung, kidney), measurement of blood pressure and autonomic function, spirometry, renal function, exercise tests, strength and physical capability. Severity of deficit was then scored for each system as 0 (none) to 3 (severe). Primary outcome was a single composite multi-domain score summing each of nine domains: autonomic, brain, exercise capacity, heart, lungs, physical, renal, strength and vascular, with a maximum score of 27. Findings: In total, 349 participants, 141 with long COVID (40%) and 208 (60%) controls were recruited. Overall deficit score in cases was 0.22 (95% CI -0.44, 0.88) units greater than controls, adjusted for age, sex, ethnicity, cohort membership and relatedness. This estimate was little changed (0.32 (-0.34, 0.98)) when additionally adjusted for educational status, index of multiple deprivation, physical activity, smoking and co-morbidity. Restricting cases to those reporting symptoms including fatigue (n = 46) increased the excess deficit score to 0.81 (-0.19, 1.81) units in the minimally adjusted model. A difference was only observed in the vascular domain, largely attributable to elevated blood pressure, showing a 1.76 (1.04, 2.97) multivariable adjusted odds ratio excess in cases, and 3.04 (1.36, 6.80) when restricted to cases with fatigue. Interpretation: There was no evidence of marked residual subclinical deficits in most systems in people with long-COVID, although there was evidence of persistent deficits in the vascular system, largely related to elevated blood pressure. Mechanisms unrelated to organ dysfunction may contribute to symptoms. Blood pressure measurement and control should be included in clinical follow-up. Funding: Jointly funded by the National Institute for Health and Care Research and UK Research and Innovation (CONVALESCENCE, COV-LT-0009, MC_PC_20051).

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