Immune-metabolic Recovery and Post-exertional Malaise (BioSig-PEM study)

Prof. Dr. Christian Puta presented BioSig-PEM, a collaborative research project which aims to improve the understanding of the biological mechanisms underlying post-exertional malaise (PEM) in people living with ME/CFS or Long COVID. The project integrates multiple research areas, including immune and metabolic profiling, microbiome and tryptophan metabolism, endothelial function, cognitive and neurological changes, with the goal of improving clinical phenotyping and patient classification. The project’s underlying conceptual framework proposes that PEM results from interactions between exercise-induced and infection-induced immune and metabolic responses. A key objective is to identify practical biomarkers for clinical use, with blood lactate emerging as a promising candidate. As part of the ongoing research, patients first underwent a comprehensive outpatient assessment involving multidisciplinary medical evaluations, functional testing and neurocognitive assessments. Of 251 patients screened, only 27 met diagnostic criteria for ME/CFS, highlighting the importance of rigorous case definition. Selected patients went on to complete an inpatient assessment involving continuous physiological monitoring, blood sampling, repeated one-minute sit-to-stand tests, brain magnetic resonance imaging (MRI) as well as a follow-up after twelve weeks, all with relation to PEM. Analysis of eligible patients of lactate responses before and after the sit-to-stand test identified three distinct metabolic phenotypes: efficient lactate clearance, impaired clearance and excessive lactate production with partial clearance. These metabolic patterns were combined with measures of cardiac recovery, symptom burden and patient-reported outcomes to define three recovery phenotypes, ranging from physiologically recovered to globally impaired recovery. Findings to-date suggest that impaired recovery, rather than simple physical deconditioning, is a defining feature of PEM and may help guide more personalised therapeutic strategies. Additional studies using Raman spectroscopy identified distinctive immune-metabolic signatures that became more pronounced after exertion, including alterations in lipid metabolism, amino acid depletion and nucleotide-related signals. Finally, comparisons with elite athletes recovering from SARS-CoV-2 infection showed similar immune alterations to those observed in Long COVID and ME/CFS, particularly involving T-helper and natural killer (NK) cells. These findings, again, suggest that persistent symptoms reflect dysregulated immune recovery rather than loss of fitness, providing further evidence that altered immune regulation contributes to PEM across different post-infectious conditions.