Host immunometabolic reprogramming in paediatric refractory mycoplasma pneumoniae pneumonia: cellular circuits, multi-omics signatures, and translational opportunities

Paediatric refractory Mycoplasma pneumoniae pneumonia (RMPP) is a heterogeneous syndrome in which persistent microbial stimulation, dysregulated host immunity and evolving airway injury may coexist despite macrolide treatment. This review integrates clinical, experimental and multi-omics evidence to examine RMPP through an immunometabolic framework. Mycoplasma pneumoniae reprograms airway epithelial cells, macrophages and neutrophils by altering glycolysis, mitochondrial and redox signalling, autophagy and lipid and amino-acid metabolism. These responses can support early antimicrobial defence yet become maladaptive when inflammatory output is uncoupled from bacterial clearance. Epithelial ATP-dependent signalling, macrophage inflammasome activation, neutrophil aconitate decarboxylase 1 (ACOD1; historically termed immune-responsive gene 1 [IRG1])-itaconate activity and extracellular trap accumulation illustrate this context-dependent transition. Adaptive immune remodelling, compartment-specific Th17-regulatory T-cell imbalance and incomplete mucosal antibody protection may further sustain disease. Emerging metabolomic, lipidomic, microbiome and single-cell studies support biological heterogeneity but remain predominantly cross-sectional and cannot distinguish causal drivers from consequences of severe disease or treatment. Current mechanistic evidence is strongest for epithelial glycolysis and the neutrophil ACOD1-itaconate axis in experimental M. pneumoniae systems, whereas direct cell-resolved functional validation in paediatric RMPP remains limited, and ferroptosis and several proposed therapeutic targets remain provisional. We therefore present immunometabolic states as a hypothesis-generating framework rather than as validated endotypes. Future studies should determine whether dynamic combinations of pathogen burden, cell-specific metabolic function, inflammatory activity and anatomical injury reproducibly identify biological states that precede progression and predict differential treatment response. Longitudinal, cell-resolved studies integrating metabolic flux, pathogen trajectories, treatment exposure and anatomical evolution are required before these candidate states can support mechanism-informed clinical stratification.