Clinical features and genetic analysis of Taiwanese primary immunodeficiency patients with prolonged diarrhoea and monogenetic inflammatory bowel disease

Abstract Purpose: Diarrhoea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhoea and might overlap with inflammatory bowel disease (IBD). Methods: The prevalence, associated pathogens and prognosis of severe and protracted diarrhoea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. Results: A total of 301 patients were enrolled between 2003 and 2022, with predominantly paediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each), CVID (two) and SCID (one) without mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients were improved after approximately two-weeks antibiotic and/or IVIG treatment. Six (25.0%) mortalities without HSCT implement were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial haemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatment. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2) and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhoea onset (1.7 vs 33.3 months, p=0.0056), a longer TPN duration (34.2 vs 7.0 months, p<0.0001), a shorter follow-up period (41.6 vs 132.6 months, p=0.007) and a higher mortality rate (58.9 vs 25.0%, p=0.012) compared with the SD group. Conclusion: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor response to empiric antibiotics, IVIG and steroids. This should be confirmed by genetic analysis or/and faecal calprotectin. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.