Scrub typhus triggers hemophagocytic lymphohistiocytosis in children: metagenomic next-generation sequencing enables rapid diagnosis.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. Rapid identification of the underlying trigger is critical for effective clinical management. This study describes the clinical features and diagnostic approach for scrub typhus-associated HLH in children, emphasizing the role of metagenomic next-generation sequencing (mNGS). Methods: We retrospectively analyzed 12 pediatric patients diagnosed with scrub typhus-associated HLH at Shenzhen Children's Hospital between July 2023 and July 2025. Demographic, clinical, laboratory, and treatment data were analyzed. The diagnostic timeline was systematically evaluated, including patient's delay, doctor's delay, and mNGS turnaround time. Results: The median age was 7.5 years (range: 3-13.7), with a male-to-female ratio of 1:2. All patients presented with prolonged fever (median duration: 9 days). Common clinical findings included eschar (66.7%), lymphadenopathy (100%), hepatomegaly (58.3%), and splenomegaly (66.7%). Notably, four patients (33.3%) were initially misdiagnosed as having Kawasaki disease. All patients met the HLH-2004 criteria, with prominent hyperferritinemia (median: 5,355 ng/mL) and elevated sCD25 (median: 5,065 U/mL). Peripheral blood mNGS confirmed the diagnosis of scrub typhus in all patients (median sequence reads: 333). Cerebrospinal fluid (CSF) mNGS was positive for Conclusion: Scrub typhus is a significant trigger for secondary HLH in children from endemic areas. mNGS may facilitate rapid etiological diagnosis and timely targeted therapy. CSF mNGS and cytokine analysis may be considered in severe cases, though further validation is warranted. We also acknowledge that our study demonstrates feasibility rather than superiority of mNGS over conventional diagnostic methods.