Prospective Metabolomic Studies in Precision Medicine: The AKRIBEA Project.

For a long time, conventional medicine has analysed biomolecules to diagnose diseases. Yet, this approach has proven valid only for a limited number of metabolites and often through a bijective relationship with the disease (i.e. glucose relationship with diabetes), ultimately offering incomplete diagnostic value. Nowadays, precision medicine emerges as an option to improve the prevention and/or treatment of numerous pathologies, focusing on the molecular mechanisms, acting in a patient-specific dimension, and leveraging multiple contributing factors such as genetic, environmental, or lifestyle. Metabolomics grasps the required subcellular complexity while being sensitive to all these factors, which results in a most suitable technique for precision medicine. The aim of this chapter is to describe how NMR-based metabolomics can be integrated in the design of a precision medicine strategy, using the Precision Medicine Initiative of the Basque Country (the AKRIBEA project) as a case study. To that end, we will illustrate the procedures to be followed when conducting an NMR-based metabolomics study with a large cohort of individuals, emphasizing the critical points. The chapter will conclude with the discussion of some relevant biomedical applications.

An NMR-Based Model to Investigate the Metabolic Phenoreversion of COVID-19 Patients throughout a Longitudinal Study.

After SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We have here investigated the natural history of COVID-19 disease at the molecular level, characterizing the metabolic and immunological phenoreversion over time in large cohorts of hospitalized severe patients (n = 886) and non-hospitalized recovered patients that self-reported having passed the disease (n = 513). Non-hospitalized recovered patients do not show any metabolic fingerprint associated with the disease or immune alterations. Acute patients are characterized by the metabolic and lipidomic dysregulation that accompanies the exacerbated immunological response, resulting in a slow recovery time with a maximum probability of around 62 days. As a manifestation of the heterogeneity in the metabolic phenoreversion, age and severity become factors that modulate their normalization time which, in turn, correlates with changes in the atherogenesis-associated chemokine MCP-1. Our results are consistent with a model where the slow metabolic normalization in acute patients results in enhanced atherosclerotic risk, in line with the recent observation of an elevated number of cardiovascular episodes found in post-COVID-19 cohorts.

Uneven metabolic and lipidomic profiles in recovered COVID-19 patients as investigated by plasma NMR metabolomics.

COVID-19 is a systemic infectious disease that may affect many organs, accompanied by a measurable metabolic dysregulation. The disease is also associated with significant mortality, particularly among the elderly, patients with comorbidities, and solid organ transplant recipients. Yet, the largest segment of the patient population is asymptomatic, and most other patients develop mild to moderate symptoms after SARS-CoV-2 infection. Here, we have used NMR metabolomics to characterize plasma samples from a cohort of the abovementioned group of COVID-19 patients (n = 69), between 3 and 10 months after diagnosis, and compared them with a set of reference samples from individuals never infected by the virus (n = 71). Our results indicate that half of the patient population show abnormal metabolism including porphyrin levels and altered lipoprotein profiles six months after the infection, while the other half show little molecular record of the disease. Remarkably, most of these patients are asymptomatic or mild COVID-19 patients, and we hypothesize that this is due to a metabolic reflection of the immune response stress.

SARS-CoV-2 Infection Dysregulates the Metabolomic and Lipidomic Profiles of Serum.

COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing for SARS-CoV-2 infection. We also established the profiles of 280 persons collected before the coronavirus pandemic started. Principal-component analysis discriminated both cohorts, highlighting the impact that the infection has on overall metabolism. The lipidomic analysis unraveled a pathogenic redistribution of the lipoprotein particle size and composition to increase the atherosclerotic risk. In turn, metabolomic analysis reveals abnormally high levels of ketone bodies (acetoacetic acid, 3-hydroxybutyric acid, and acetone) and 2-hydroxybutyric acid, a readout of hepatic glutathione synthesis and marker of oxidative stress. Our results are consistent with a model in which SARS-CoV-2 infection induces liver damage associated with dyslipidemia and oxidative stress.

Thoracoscopic Bullectomy for Persistent Air Leak in a 14-Year-Old Child with COVID-19 Bilateral Pulmonary Disease.

Introduction: Thoracic surgery in children with coronavirus disease-19 (COVID-19) pulmonary disease is rare, as very limited virus-related lung lesions require intervention. However, some patients may suffer from other pulmonary abnormalities that can be worsened by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they may consequently require lung surgery. COVID-19 affects the indications, surgical procedure, and postsurgical care of these patients. Background: We present a case of a 14-year-old girl with COVID-19 pulmonary disease and persistent air leak due to right apical bullae that required resection. Clinical, surgical, and safety implications are discussed. The role of thoracic minimally invasive surgery under COVID-19 conditions is also analyzed. Materials and Methods: The thoracoscopic procedure was scheduled earlier than normally expected. The surgery was performed in a COVID-19 reserved theatre with neutral pressure and only the necessary personnel was allowed inside. The use of the required personal protective equipment was supervised by an expert nurse before and after the intervention. Results: The surgeons used a three-port technique to resect the bullae with an endostapler and no mechanical pleural abrasion was added to the procedure. Electrocautery and CO2 insufflation were avoided, and a chest drain with a closed-circuit aspiration system was installed before removing the ports. The child was discharged home 3 days later after the removal of the chest drain. Conclusions: COVID-19 has an impact on the standard indications, surgical strategies and postoperative care of some conditions requiring intervention. Extra safety measures are needed in the operating room to limit the chance of transmission. Minimally invasive surgery for thoracic surgery remains safe if the current safety guidelines are followed closely.