W140 - Impaired STAT3 Signaling Disrupts Procalcitonin Production: Clinical Insights from Autosomal Dominant Hyper-IgE Syndrome

Abstract Text: Procalcitonin (PCT) is an established biomarker for diagnosing bacterial infections and sepsis, yet the molecular mechanisms underlying its regulation are not fully elucidated. Recent studies highlight a central role for signal transducer and activator of transcription 3 (STAT3), a transcription factor activated by inflammatory cytokines, in mediating PCT synthesis. Autosomal Dominant Hyper-IgE Syndrome (AD-HIES or Job syndrome), a rare immunodeficiency characterized by dominant-negative STAT3 mutations, provides a unique clinical model to explore STAT3's role in human PCT responses.

We describe two AD-HIES patients who developed severe bacterial infections yet exhibited paradoxically low serum PCT levels: Patient 1, a 22-year-old male, developed multifocal pneumonia with sputum cultures positive for Pseudomonas aeruginosa (PCT: 0.03 µg/L); Patient 2, a 17-year-old female, presented with methicillin-resistant Staphylococcus aureus bacteremia complicated by a hepatic abscess (PCT: 0.12 µg/L). Despite microbiological confirmation of bacterial infection and significantly elevated inflammatory markers (e.g., C-reactive protein), both patients exhibited markedly suppressed PCT responses.

Our clinical observations align with prior mechanistic studies, supporting the essential role of STAT3-dependent signaling pathways in mediating PCT synthesis in response to bacterial-induced cytokines and endotoxins. While experimental models have demonstrated that reduced STAT3 activity decreases PCT expression, our findings uniquely illustrate this relationship through naturally occurring STAT3 impairment in AD-HIES patients. These cases deepen the mechanistic understanding of PCT regulation and underscore the importance of carefully interpreting serum PCT levels in immunodeficient patients, advocating for personalized approaches in infection diagnosis and management.