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

Abstract

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized 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 after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients ( n = 27) were compared with controls ( n = 41) and hospitalized severe acute respiratory syndrome 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 perturbed, e.g., elevated taurine ( p = 3.6 × 10 –3 versus controls) and reduced glutamine/glutamate ratio ( p = 6.95 × 10 –8 versus 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 that of healthy controls but significantly lower ( p = 4.2 × 10 –3 ) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the 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, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped 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 that of nonsymptomatic patients for multiple parameters (χ 2 p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a ...

Molecular Phenomic Approaches to Deconvolving the Systemic Effects of SARS-CoV-2 Infection and Post-acute COVID-19 Syndrome

“…An individual can only be thought of as "fully recovered "when their biochemical profiles are substantially normalized with respect to the earlier systemic perturbations seen in the acute phase. This process of normalization is effectively the opposite of disease phenoconversion (Kimhofer et al 2020) and we refer to this process as Phenoreversion and this can be measured metabolically (Holmes et al 2021). Phenoreversion appears to be highly variable between individuals ranging between complete or full recovery, to partial recovery or no recovery, with residual immunologically driven long-term biochemical effects (Holmes et al 2021).…”

“…This process of normalization is effectively the opposite of disease phenoconversion (Kimhofer et al 2020) and we refer to this process as Phenoreversion and this can be measured metabolically (Holmes et al 2021). Phenoreversion appears to be highly variable between individuals ranging between complete or full recovery, to partial recovery or no recovery, with residual immunologically driven long-term biochemical effects (Holmes et al 2021). It was also notable that the non-hospitalised mildly affected patients at 3-month follow-up also included some new phenotypic changes not observed in the controls or the acute phase patients.…”

“…Phenoreversion appears to be a complex and variable process. Thus, the individual metabolic parameters used as Phenoreversion metrics can be substantially reversed or not reversed within the whole postacute phase population cohort, and it is inevitable that some of these changes will impact on long-term disease risks for the affected individuals (Holmes et al 2021). Even mildly symptomatic, non-hospitalized patients can show multiple symptoms months after the acute phase of the disease including chronic fatigue, joint pain anosmia and a multitude of neurological symptoms (Nalbandian et al 2021).…”

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

“…289 Indeed, it has been shown that the kynurenine/tryptophan ratio remained elevated in some postacute Covid 19 patients and the question was raised if this may be a marker for the development of PASC. 305 Summary: plausibly, the "metabolic trap" hypothesis may support a central role of the astroglial compartment in the pathophysiology of ME/CFS.…”

“…425  There may be microbiome changes in some PASC cases as supported by the observation of increased levels of 3-indole acetic acid which implies a microbiome functionality shift. 305  It seems that the activation of the innate immune system may play a central role in PASC. For one, elevated IL-1beta seems to be a consistent signal in studies of PASC.…”