Integrative Plasma Metabolic and Lipidomic Modelling of SARS-CoV-2 Infection in Relation to Clinical Severity and Early Mortality Prediction

Abstract

An integrative multi-modal metabolic phenotyping model was developed to assess the systemic plasma sequelae of SARS-CoV-2 (rRT-PCR positive) induced COVID-19 disease in patients with different respiratory severity levels. Plasma samples from 306 unvaccinated COVID-19 patients were collected in 2020 and classified into four levels of severity ranging from mild symptoms to severe ventilated cases. These samples were investigated using a combination of quantitative Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS) platforms to give broad lipoprotein, lipidomic and amino acid, tryptophan-kynurenine pathway, and biogenic amine pathway coverage. All platforms revealed highly significant differences in metabolite patterns between patients and controls (n = 89) that had been collected prior to the COVID-19 pandemic. The total number of significant metabolites increased with severity with 344 out of the 1034 quantitative variables being common to all severity classes. Metabolic signatures showed a continuum of changes across the respiratory severity levels with the most significant and extensive changes being in the most severely affected patients. Even mildly affected respiratory patients showed multiple highly significant abnormal biochemical signatures reflecting serious metabolic deficiencies of the type observed in Post-acute COVID-19 syndrome patients. The most severe respiratory patients had a high mortality (56.1%) and we found that we could predict mortality in this patient sub-group with high accuracy in some cases up to 61 days prior to death, based on a separate metabolic model, which highlighted a different set of metabolites to those defining the basic disease. Specifically, hexosylceramides (HCER 16:0, HCER 20:0, HCER 24:1, HCER 26:0, HCER 26:1) were markedly elevated in the non-surviving patient group (Cliff’s delta 0.91–0.95) and two phosphoethanolamines (PE.O 18:0/18:1, Cliff’s delta = −0.98 and PE.P 16:0/18:1, Cliff’s delta = −0.93) were markedly lower in the non-survivors. These results indicate that patient morbidity to mortality trajectories is determined relatively soon after infection, opening the opportunity to select more intensive therapeutic interventions to these “high risk” patients in the early disease stages.

Nonsevere Burn Induces a Prolonged Systemic Metabolic Phenotype Indicative of a Persistent Inflammatory Response Postinjury

“…57,58 Depletions in plasma concentrations of specific subfractions including HDL-4 apolipoprotein A2 (H4A2) have also been associated with poor outcomes and mortality in patients with pulmonary arterial hypertension, 59 while lipoproteins H4A1, H4A2, and H4CH were significant markers of SARS-CoV-2 infection and severity. 33,56,60 As with GlycB, our data demonstrated lower concentrations of HDL were sustained from admission to the follow-up sampling time point, indicating a persistence of the inflammatory response to a nonsevere burn injury.…”

“…Such lipoprotein signatures have previously been associated with clinical outcomes in both acute and chronic inflammatory states, while HDL-associated apolipoprotein HDA1 has been reported to play an important anti-inflammatory role in diseased states, due to its ability to carry anti-inflammatory molecules, bioactive lipids, and cholesterol. , Depletions in plasma concentrations of specific subfractions including HDL-4 apolipoprotein A2 (H4A2) have also been associated with poor outcomes and mortality in patients with pulmonary arterial hypertension, while lipoproteins H4A1, H4A2, and H4CH were significant markers of SARS-CoV-2 infection and severity. ,, As with GlycB, our data demonstrated lower concentrations of HDL were sustained from admission to the follow-up sampling time point, indicating a persistence of the inflammatory response to a nonsevere burn injury.…”

Stratification of Sepsis Patients on Admission into the Intensive Care Unit According to Differential Plasma Metabolic Phenotypes

“…26 We have previously shown with SARS-CoV-2 infection that the relative levels of glycoproteins and SPC gives insight into the inflammatory status of a patient where the glycoproteins are increased and SPC decreased in comparison to healthy control samples. 25,28 We have also shown that the SPC regions change differently in nonsevere burns patients and remain perturbed at 6 weeks post-injury. 77 At admission into ICU, GlycA and GlycB values in sepsis and septic shock patients were significantly different from those of the healthy controls but were not elevated in the ICU patients who did not develop sepsis.…”

“…SPC signals arise from the trimethylammonium headgroups of phospholipids in lipoprotein subcompartments, where SPC 1 represents the phospholipid content of HDL4, SPC 2 is the phospholipid of HDL1–3, and SPC 3 is the phospholipid from LDL . We have previously shown with SARS-CoV-2 infection that the relative levels of glycoproteins and SPC gives insight into the inflammatory status of a patient where the glycoproteins are increased and SPC decreased in comparison to healthy control samples. , We have also shown that the SPC regions change differently in nonsevere burns patients and remain perturbed at 6 weeks post-injury …”

“…We have previously shown that preinterventional metabolic phenotyping can enable prediction of interventional outcomes such as drug toxicity, drug metabolism, and anticancer drug efficacy in animals and humans . The same principle using a training-test set model can be applied to predict disease trajectory outcomes including recovery or progression to long-COVID in SARS CoV-2 infection or even COVID-19 induced death in intensive care unit (ICU) patients . Since the biomarkers that are currently used to identify sepsis are inadequate for discriminating between sepsis and septic shock patients in ICU, we applied a multiplatform metabolic profiling approach to ascertain whether plasma profiles could be used to differentiate patients with no sepsis, sepsis, and septic shock at admission into ICU regardless of admission route or type.…”