Increased Tacrolimus Exposure in Kidney Transplant Recipients With COVID-19: Inflammation-Driven Downregulation of Metabolism as a Potential Mechanism.

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued during a COVID-19 infection. However, clinical signs of calcineurin toxicity have been described in multiple COVID-19 positive KTRs. In this report we describe the course of tacrolimus exposure prior to, during, and post COVID-19 in observations from three clinical cases as well as four KTRs from a controlled trial population. We postulate inflammation driven downregulation of the CYP3A metabolism as a potential mechanism for higher tacrolimus exposure. To mitigate the risk of tacrolimus overexposure and toxicity therapeutic drug monitoring is recommended in KTRs with COVID-19 both in the in-, out-patient and home monitoring setting.

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

SARS COV-2 infection causes acute and frequently severe respiratory disease with associated multi-organ damage and systemic disturbances in many biochemical pathways. Metabolic phenotyping provides deep insights into the complex immunopathological problems that drive the resulting COVID-19 disease and is also a source of novel metrics for assessing patient recovery. A multiplatform metabolic phenotyping approach to studying the pathology and systemic metabolic sequelae of COVID-19 is considered here, together with a framework for assessing post-acute COVID-19 Syndrome (PACS) that is a major long-term health consequence for many patients. The sudden emergence of the disease presents a biological discovery challenge as we try to understand the pathological mechanisms of the disease and develop effective mitigation strategies. This requires technologies to measure objectively the extent and sub-phenotypes of the disease at the molecular level. Spectroscopic methods can reveal metabolic sub-phenotypes and new biomarkers that can be monitored during the acute disease phase and beyond. This approach is scalable and translatable to other pathologies and provides as an exemplar strategy for the investigation of other emergent zoonotic diseases with complex immunological drivers, multi-system involvements and diverse persistent symptoms.

Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses.

We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.

Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts.

Quantitative plasma lipoprotein and metabolite profiles were measured on an autonomous community of the Basque Country (Spain) cohort consisting of hospitalized COVID-19 patients (n = 72) and a matched control group (n = 75) and a Western Australian (WA) cohort consisting of (n = 17) SARS-CoV-2 positives and (n = 20) healthy controls using 600 MHz 1H nuclear magnetic resonance (NMR) spectroscopy. Spanish samples were measured in two laboratories using one-dimensional (1D) solvent-suppressed and T2-filtered methods with in vitro diagnostic quantification of lipoproteins and metabolites. SARS-CoV-2 positive patients and healthy controls from both populations were modeled and cross-projected to estimate the biological similarities and validate biomarkers. Using the top 15 most discriminatory variables enabled construction of a cross-predictive model with 100% sensitivity and specificity (within populations) and 100% sensitivity and 82% specificity (between populations). Minor differences were observed between the control metabolic variables in the two cohorts, but the lipoproteins were virtually indistinguishable. We observed highly significant infection-related reductions in high-density lipoprotein (HDL) subfraction 4 phospholipids, apolipoproteins A1 and A2,that have previously been associated with negative regulation of blood coagulation and fibrinolysis. The Spanish and Australian diagnostic SARS-CoV-2 biomarkers were mathematically and biologically equivalent, demonstrating that NMR-based technologies are suitable for the study of the comparative pathology of COVID-19 via plasma phenotyping.

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

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 (χ2p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.