OP0255 MICROBIOTA TRANSPLANT TO CONTROL INFLAMMATION IN A NLRC4-RELATED DISEASE PATIENT WITH RECURRENT HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)
Authors: Claudia Bracaglia, Giulia Marucci, Federica Del Chierico, Alessandra Russo, Manuela Pardeo, Antonella Insalaco, Giusi Prencipe, Ivan Caiello, Pavla Dolezalova, Sarka Fingerhutova, Fabrizio De Benedetti, Lorenza Putignani
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The NLRC4 inflammasome activation is essential in host defence, particularly against enteric pathogens. Gain-of-function mutations in <i>NLRC4</i> are associated with a distinct autoinflammatory syndrome characterized by enterocolitis and recurrent HLH. <h3>Objectives</h3> To report safety and efficacy of faecal microbiota transplantation (FMT) in a patient carrying a <i>de novo</i> missense mutations in <i>NLRC4</i>, with gut inflammation and gut colonization by multi-drug resistant (MDR) pathogens. <h3>Methods</h3> Subject and donors were screened for potential FMT according to Cammarota <i>et al</i>. (1) with modifications introduced by Ospedale Pediatrico Bambino Gesù 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. <h3>Results</h3> 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 <i>NLRC4</i> (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 (<i>Enterobacter cloacae</i> and <i>Enterococcus faecalis</i>), 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. <h3>Conclusion</h3> <i>NLRC4</i>-related disease is typically characterized by enterocolitis and <i>NLRC4</i>, highly expressed in intestinal macrophages, is critical for pathogen restriction by phagocytes in the gut lamina propria. The chronic gut inflammation of <i>NLRC4</i>-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 <i>NLRC4</i>-patients in order to reduce chronic inflammatory <i>stimuli</i>. <h3>Reference</h3> [1] Cammarota G. et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017 Apr;66(4):569-580. <h3>Disclosure of Interests</h3> 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