Neuroendocrine and multisystem imaging perspectives of post-COVID-19 recovery

Abstract Introduction Post-COVID-19 syndromes remain a medical enigma. A disconnect between objective clinical markers and subjective symptoms complicates diagnosis and management for these patients in clinical practice. Catecholamines mediate the host stress response to illness. Purpose We hypothesised that dysregulation of catecholamine pathways influences the illness trajectory of Long-COVID. Methods This was a prospective, multicentre cohort study involving post-COVID-19 patients enrolled either during their hospitalisation or shortly after discharge. Participants underwent serial assessments, including the index admission and again 28–60 days after discharge. We conducted a plasma proteomics analysis using the SOMAscan® assay v4.1, measuring 7288 proteins in a cohort of 155 participants who had undergone prospective, multisystem phenotyping (MRI, Siemens 3.0T PRISMA; CT chest and pulmonary angiography, Canon Aquilion ONE), incorporating clinical data gathered during the original study period. Proteomic analysis used the Searchlight2 bioinformatics workflow. Results Among the participants (mean age: 55 years; 43% female), 72 (47%) had a history of cardiovascular disease, and 57 (37%) belonged to the highest quintile of social deprivation. Principal component analysis of the measured proteome identified a distinct cluster (n=25, Figure 1A) characterised by protein expression indicative of heightened catecholamine activity, oxidative stress (Hallmark, Reactive Oxygen Species, p.adj=0.03) and mitochondrial dysfunction (Reactome, Mitochondrial Protein Degradation, p.adj0.001) independent of disease severity, social deprivation and body mass index. This cluster had two distinct proteomic signatures Figure 1B. These participants had heightened illness perception and reduced cardiorespiratory function at follow-up, as measured by validated patient reported outcome measures Table 1, despite the absence of objective evidence of more severe disease on multisystem, cardio-renal and respiratory imaging in comparison to the remaining cohort (n=130). Conclusion The upregulation of several proteins associated with vascular dysfunction and oxidative stress are noteworthy including SOD1, ARG1 and ACE2. The lack of association between proteomic signatures and cardiovascular imaging parameters implies that global structural or functional cardiac muscle abnormalities are unlikely to be the primary drivers of differences between these participant groups. This participant cluster suggests complex interplay of oxidative stress, inflammation, and metabolic dysregulation, contributing to a pro-inflammatory, pro-oxidative environment and decreased energetic efficiency. Reducing oxidative stress and addressing mitochondrial dysfunction within the vasculature could be areas warranting further attention in Long-COVID. These findings provide novel insights of physiological and psychological factors influencing post-COVID recovery.Figure 1