Background: Paediatric hyper-inflammation spans infection-associated syndromes, immune dysregulation, autoinflammation, and hemophagocytic lymphohistiocytosis (HLH). Overlapping features complicate diagnosis and therapy. In resource-limited settings, the HLH-2004 framework remains the anchor, and ferritin >10,000 µg/L strengthens suspicion [1,2]. Infections are frequent precipitants of secondary HLH, but attribution is often multifactorial [3,4].
Case: A previously healthy 12-year-old girl presented with persistent fever and MSSA UTI, then developed meningeal features and longitudinally extensive transverse myelitis confirmed by MRI/CSF. She improved after IV antibiotics, two doses of IVIG, and pulse methylprednisolone with a 6-week taper; transient urinary retention required intermittent catheterization.
Two weeks after discharge, she re-presented with daily fevers, turbid urine, a persistent erythematous facial rash with palmar/plantar involvement, and painful oral ulcers. Cultures revealed ESBL Enterobacter cloacae UTI and Salmonella Group B bacteremia, both clearing after 10 days of meropenem. An empiric trial of anakinra for suspected autoinflammation was stopped because of an immediate generalized cutaneous reaction.
Within 48 hours, she evolved a fulminant hyper-inflammatory picture consistent with secondary HLH—neutropenic leukopenia (ANC 0.65 × 10^9/L), hyperferritinemia (peak 14,142 µg/L), hypertriglyceridemia (311 mg/dL), rising LDH, and hepatocellular injury with direct hyperbilirubinemia—despite a down-trending CRP. Fibrinogen and sIL-2R were not obtained at onset; marrow was deferred (no organomegaly, no pancytopenia beyond neutropenia, repeated blood films negative). Pulse methylprednisolone (30 mg/kg/day × 3) led to stabilization, followed by a slow taper. Whole-exome sequencing identified a heterozygous STXBP2 variant; because FHL-5 is autosomal recessive, this was interpreted as a VUS without immediate therapeutic implications [3].
Discussion: Trigger attribution for HLH was unresolved, given concurrent infections, steroid taper, and biologic hypersensitivity. This complexity is common in pediatric HLH and highlights the need for a criteria-informed, physiology-first approach when advanced assays are limited [1,3].
The clinical triad of mucocutaneous inflammation, post-infectious myelitis, and HLH suggested possible monogenic disorders. TNFAIP3 haploinsufficiency (HA20) mimics Behçet disease with recurrent ulcers [5]; STAT3 gain-of-function drives autoimmunity and hyper-inflammation [6]; SAVI presents with vasculopathy and type I interferon signatures [7]; and broader type I interferonopathies (e.g., Aicardi–Goutières) usually show CNS calcifications, which were absent [8].
Though unavailable, theoretical pathway-level phenotyping could have refined therapy. The IFN-γ axis (sCD25, CXCL9) aids in HLH recognition and monitoring [3]. IL-18 elevation suggests macrophage activation syndrome and potential IL-18/IL-1–targeted strategies [9]. Type I interferon signatures (interferon-stimulated genes or SIGLEC1 expression) support interferonopathies and potential JAK inhibition [8]. Cytotoxic pathway testing (NK-cell function/degranulation) can reveal perforin/granule defects and inherited HLH [3]. Finally, JAK/STAT phospho-flow could identify pathway dysregulation relevant to targeted inhibitors [6–8].
In this case, steroid responsiveness, absence of vasculopathy, and lack of CNS calcifications argue for an IFN-γ/IL-1–skewed process, though definitive assignment awaits functional and genetic correlation.
Conclusion: When advanced immunology and biologics are limited by access or intolerance, a steroid-led, criteria-informed strategy guided by ferritin, triglycerides, cytopenias, and liver indices can stabilize paediatric hyper-inflammation while definitive evaluation proceeds. Maintaining diagnostic breadth and iterative reassessment remain essential [1–4].
