Lipoprotein remodelling and elevated serum apolipoprotein B distinguish adults with haemophagocytic lymphohistiocytosis from sepsis

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterised by uncontrolled immune activation. Patients present with a sepsis-like syndrome, but management requires immune suppression. Reduced high- and low-density lipoprotein cholesterol and hypertriglyceridaemia are reported in HLH, suggesting lipid metabolism disturbances, although in-depth serum metabolomic analysis is lacking. Here, a lipid-focused NMR spectroscopy platform was used to define the serum metabolomic landscape of adults hospitalised with HLH compared to those with sepsis (a key clinical mimic), rheumatic disease (potential HLH drivers/triggers), patients following surgical resection of solid organ cancer (non-infectious acute inflammation controls) and healthy controls (HCs). An HLH-associated metabolomic profile was identified and found to be significantly enriched in lipid metabolism-associated pathways including: 'Plasma lipoprotein remodelling', 'Lipid particles composition', 'Glucose homeostasis' and 'Amino acid metabolism'. Metabolomic results were validated using matched whole blood RNA-sequencing and the generation of a gene-metabolite interaction network which identified differentially expressed genes enriched in metabolic modules associated with lipid, amino acid, and glucose metabolism, supporting a coordinated metabolic dysregulation in HLH from a transcriptomic to metabolomic level. Compared to all control groups, adults with HLH were defined by elevated apolipoprotein-B (ApoB)-containing triglyceride-rich lipoproteins and saturated fatty acids (area under receiver operator curve >0.70). Validation of a potential HLH-specific lipid signature using ELISA technology identified ApoB (p=0.007) and ApoB:ApoA1 (p=0.0002) as significantly different between HLH and HLH-mimics, including sepsis, supporting their utility as clinically translational biomarkers to distinguish HLH from a key mimic.