Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute Phase Non-Hospitalized COVID-19 Patients: Implications for Assessment of Post Acute COVID-19 Syndrome

We present a multivariate metabotyping approach to assess the functional recovery of non-hospitalized COVID-19 patients and the possible biochemical sequelae of “Post Acute COVID-19 Syndrome”, colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months post-acute COVID-19 infection who were also assessed symptomatically at 6 months. Some 57% of patients had one or more persistent symptoms including respiratory-related symptoms cough, dyspnoea and rhinorrhea or other non-respiratory symptoms including chronic fatigue, anosmia, myalgia, joint pain. Plasma samples were quantitatively analysed for lipoproteins, glycoproteins, amino acids, biogenic amines and tryptophan pathway intermediates using NMR spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n=27) were compared with controls (n=41) and hospitalized SARS CoV-2 positive patients (n=18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently pathophysiological, e.g. elevated taurine (p= 3.6 x 10-3 vs controls) and reduced glutamine/glutamate ratio (p = 6.95 x 10-8 vs controls) indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near complete normalization, e.g. the plasma apolipoprotein B100/A1 ratio was similar to healthy controls, but significantly lower (p= 4.2 x 10-3) than acute COVID-19 patients, reflecting partial phenoreversion towards the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients indicative of reduction in adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, PCA and OPLS-DA showed that the follow-up patients were as a group metabolically distinct from controls and partially co-mapping with the acute phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than non-symptomatic patients for multiple parameters (Chi-squared P=0.014). Thus, asymptomatic follow-up patients including those with “Post-COVID Syndrome” display a spectrum of multiple persistent biochemical pathophysiology suggesting that the metabolic phenotyping approach may be deployed for multi-system functional assessment of individual post-COVID-19 patients.