The Silent Infection: Cytokine Blockade, Blunted Sepsis Physiology, and Soft Tissue Infection With NLRP12-Associated...

NLRP12-associated autoinflammatory syndrome is a rare monogenic autoinflammatory disease characterized by recurrent innate immune dysregulation and systemic inflammation. Distinguishing infection from hyperinflammatory disease activity in these patients is particularly challenging during cytokine-directed immunosuppressive therapy. We report a 20-year-old male with NLRP12/FCAS2-associated disease, systemic juvenile idiopathic arthritis (sJIA), and prior hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) who presented with bilateral gluteal cellulitis, recurrent fevers, and inflammatory biomarker elevation initially concerning for sepsis. Despite progressive soft tissue findings, the patient remained hemodynamically stable without leukocytosis, lactic acidosis, or positive blood cultures. Imaging demonstrated diffuse inflammatory thickening without organized abscess formation. Multidisciplinary evaluation suggested that the patient's recurrent fever pattern and sepsis-like physiology were driven predominantly by underlying cytokine dysregulation rather than uncontrolled systemic infection alone. Clinical improvement occurred following selective adjustment of immunosuppressive therapy in combination with antimicrobial treatment. This case highlights the emerging concept of "immune-modified infection," in which cytokine blockade alters the physiologic and biochemical manifestations of infection. In patients with autoinflammatory disease, inflammatory biomarker elevation may reflect immune amplification rather than microbial burden, complicating conventional sepsis assessment and management.