X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare genetic disorder caused by pathogenic variants in the XIAP gene. It disrupts TNF-receptor signaling and NLRP3 inflammasome function, leading to chronically elevated interleukin-18 (IL-18). Patients present with diverse phenotypes and are predisposed to inflammatory complications such as hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). A threshold for symptomatology based on IL-18 levels is unknown.
We retrospectively analyzed confirmed XIAP-deficient patients to evaluate the relationship between serum IL-18 levels and clinical status. IL-18 measurements were paired with contemporaneous clinical presentations, categorized as either clinically well (no active disease), as having systemic inflammation characterized by fever and/or cytopenia with or without other symptoms of HLH or infection, or as having active IBD. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of IL-18 for systemic inflammation and IBD.
Figure 1 presents the ROC curves derived from 26 XIAP-deficient patients (n = 122 samples). IL-18 levels demonstrated poor correlation with IBD. ROC analysis demonstrated that an IL-18 cutoff of 5,000 pg/mL yielded 100% sensitivity and 95% specificity for identifying patients with systemic inflammation.
Serum IL-18 levels greater than 5,000 pg/mL strongly correlate with systemic inflammation in XIAP-deficient patients, suggesting IL-18 as a robust biomarker for risk of systemic inflammatory disease. Incorporating IL-18 measurements into clinical evaluation may improve early detection and prevention of complications of systemic inflammation in this population.
