Inflammatory Plasma Proteins Predict Disease Severity and Response to Therapy in Patients with LCH

Purpose: Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder with clinical manifestations ranging from single lesions to lethal multi-organ disease, and front-line therapy fails in the majority of patients. No histologic features of LCH lesions have yet been demonstrated to correlate with clinical outcomes. 
We hypothesize that function of differentiated CD207+, including interactions with recruited activated lymphocytes, results in plasma protein profiles that reflect disease burden and tissue-specific DC-lymphocyte interactions. Plasma proteins may therefore inform mechanisms of pathogenesis and serve to predict risk and follow disease burden in LCH patients.

Methods: We evaluated inflammatory proteins in the plasma of LCH patients using the Luminex platform. We compared plasma concentrations of 121 analytes in 178 patients with LCH to 90 controls with discovery and validation sets. Comparisons were made based on disease status, age, and clinical risk categories. 152 samples collected from 78 patients at serial time points were also analyzed. Comparisons were made between diagnosis and cure, as well as multiple time points in therapy.

Results: Thirty-one analytes were significantly different between all LCH and controls, including proteins mediating chemotaxis and differentiation of lymphocytes and/or dendritic cells: osteopontin, SDF1A, 6CKine, CCL19, CCL20, sIL4R, IL20, and IL23. Twenty-three analytes were significantly different when comparing adult vs pediatric LCH. When comparing LCH vs control by age groups, 5 were significantly different in adults and 23 were different in children. Eighteen were different in pediatric low risk compared to high risk patients, with the most significant differences in inflammatory proteins including sTNFRI, sTNFRII, TNFa, sIL2Ra, and IL-8. Classifier analysis was able to predict risk organ involvement with a sensitivity of 91.5% and a specificity of 87.5%. Seventeen analytes changed significantly after curative treatment.

Conclusions: Distinct Plasma protein profiles exist in LCH, suggesting pathologic myeloid cells drive the inflammatory pathology of disease. Profiles are vastly different among children and adults with LCH, and differ based on burden of disease, suggesting separate inflammatory pathology. Seven analytes reliably predicted high-risk disease, and analysis of serial samples identified normalization of inflammatory proteins after cure.