Pathogen virulence and host response: A systematic review of severe illness in childhood musculoskeletal infection

Severe forms of childhood bone and joint infection (BJI) involve multifocal sepsis, often requiring multiple surgeries and intensive care. Dysregulation of the Acute Phase Response (APR) occurs, as bacterial virulence factors disrupt protective inflammatory and coagulation mechanisms.^1,2 Many algorithms attempt to identify severe cases at diagnosis. Factors driving progression to life-threatening disease remain incompletely understood. This review summarizes risk associations for severe BJI in the context of host-pathogen interactions.

A systematic review of the literature was undertaken from 01/01/2000-1/08/2025. Studies reporting host or pathogen factors associated with BJI severity for children Kingella kingae or atypical organisms were excluded. C-reactive protein (CRP) trends in the context of severe illness were also examined. ROBINS-E was used to assess risk of bias. As it does not consider specific interventions and exposures, this review was not registered with PROSPERO.

Literature search of electronic databases returned 1171 articles, of which 38 met full criteria. These comprised 10,084 patients across multiple continents. Pathogen factors associated with severe illness included Methicillin-resistant Staphylococcus aureus (MRSA), Panton-Valentine Leukocidin (PVL), and individual bacterial virulence factors identified genomically. Notably, these virulence factors may be more important than methicillin resistance, with some MSSA strains causing equally severe disease. Very young children, specific ethnic groups, and those with congenital abnormalities were at higher risk. Early genetic studies propose variability in host inflammatory response genes. Sustained CRP elevation was a feature of worse disease, independent of pathogen subtype.

These findings indicate that severe pediatric BJI results from complex interactions between bacterial virulence factors and host response capacity. Awareness of these factors should equip clinicians to recognise potentially high-risk cases early in the course of illness. Future research should ascertain how virulence factors dysregulate the host APR, guiding therapeutic interventions targeting the underlying pathophysiology.