OP0255 MICROBIOTA TRANSPLANT TO CONTROL INFLAMMATION IN A NLRC4-RELATED DISEASE PATIENT WITH RECURRENT HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)

Background The NLRC4 inflammasome activation is essential in host defence, particularly against enteric pathogens. Gain-of-function mutations in NLRC4 are associated with a distinct autoinflammatory syndrome characterized by enterocolitis and recurrent HLH. Objectives To report safety and efficacy of faecal microbiota transplantation (FMT) in a patient carrying a de novo missense mutations in NLRC4, with gut inflammation and gut colonization by multi-drug resistant (MDR) pathogens. Methods Subject and donors were screened for potential FMT according to Cammarota et al. (1) with modifications introduced by Ospedale Pediatrico Bambino Gesu Committee for paediatric FMT procedures. Culture-based and NGS-based microbiota profiling were performed to address MDR persistence and microbial associated communities coupled to inflammatory profiling. After wide donor screening, a universal adult donor was selected and infusion performed twice by colonoscopy from fresh and frozen faeces, respectively. A one year FMT follow up was ensured to address clinical outcomes. Results A Caucasian 16 months old boy presented, from 1 month of life, with recurrent HLH, diarrhoea and vasculitic skin lesions, secondary to a de novo missense mutation in NLRC4 (I343N). His disease was not controlled despite treatment with repeated high dose of intravenous methylprednisolone pulses and chronic daily glucocorticoid therapy, cyclosporine-A (5 mg/kg) and anakinra (ranging from 5 to 25 mg/kg/day). Because of recurrent HLH episodes, the patient was treated with emapalumab (anti-IFNgamma antibody) for three months, with HLH control. However, the patient presented persistent diarrhoea with gut inflammation and colonization by MDR pathogens (Enterobacter cloacae and Enterococcus faecalis), leading by translocation to systemic infections and, hence, HLH reactivation. Moreover, he developed severe intestinal meteorism with subsequent paralytic-ileus that required ileostomy. Based on the hypothesis that his intestinal dysbiosis concurred in the persistent gut inflammation related to his underlying disease, he received a first FMT with initial clinical improvement. Therefore, ileal anastomosis was performed with recanalization, and a second FMT was performed a month later. The patient did not develop any complication. The stool cultures no longer showed the presence of enteropathogenic germs and since the last FMT (12 months of follow-up) he did not present any symptom of gut inflammation or HLH reactivations. Conclusion NLRC4-related disease is typically characterized by enterocolitis and NLRC4, highly expressed in intestinal macrophages, is critical for pathogen restriction by phagocytes in the gut lamina propria. The chronic gut inflammation of NLRC4-patients is a stimulus for systemic inflammation. Moreover, pathogens present in the gut can trigger HLH episodes. A presence of a selected microbiota from appropriate donor can decrease gut inflammation. FMT may represent a valid and safe therapeutic option in NLRC4-patients in order to reduce chronic inflammatory stimuli. Reference [1] Cammarota G. et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017 Apr;66(4):569-580. Disclosure of Interests Claudia Bracaglia: None declared, Giulia Marucci: None declared, Federica Del Chierico: None declared, Alessandra Russo: None declared, Manuela Pardeo: None declared, Antonella Insalaco: None declared, Giusi Prencipe: None declared, Ivan Caiello: None declared, Pavla Dolezalova: None declared, Sarka Fingerhutova: None declared, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Lorenza Putignani: None declared