A Nationwide Study of Severe and Protracted Diarrhoea in Patients with Primary Immunodeficiency Diseases
Wen-I Lee1,2, Chien-Chang Chen3, Tang-Her Jaing4,5
1Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@hotmail.com.
Insights
Severe and protracted diarrhea (SD) affects primary immunodeficiency diseases (PIDs). Identifying pathogens and genetic mutations is crucial for managing SD and improving outcomes in pediatric patients.
Area of Science:
- Immunology
- Pediatric Gastroenterology
- Infectious Diseases
Background:
- Severe and protracted diarrhea (SD) is defined as diarrhea lasting over 14 days unresponsive to conventional treatment.
- Primary immunodeficiency diseases (PIDs) can manifest with gastrointestinal symptoms, including SD.
- Understanding the prevalence, causative agents, and prognosis of SD in PIDs is critical for patient management.
Purpose of the Study:
- To investigate the prevalence, causative pathogens, and prognosis of severe and protracted diarrhea (SD) in patients with primary immunodeficiency diseases (PIDs).
- To identify specific genetic mutations associated with SD in a pediatric cohort.
- To evaluate treatment responses and mortality rates in PIDs with SD.
Main Methods:
- Retrospective analysis of 246 pediatric-onset PID patients from 2003-2015.
- Identification of pathogens through microbiological testing.
- Correlation of genetic mutations (e.g., Btk, IL2RG, WASP, CD40L, XIAP, STAT1, FOXP3, STAT3) with SD and refractory diarrhea (RD).
Main Results:
- Twenty-one patients with identified mutations and five with unidentified mutations presented with SD.
- Common pathogens included Pseudomonas and Salmonella; most patients improved with antibiotics and/or IVIG.
- Mortality rate was 27.0% (7/26), with higher risk in patients with WAS, CGD, and CD40L mutations.
- Five males with specific mutations (XIAP, STAT1, FOXP3, STAT3) had refractory diarrhea (RD) leading to mortality, with some benefiting from transplantation.
Conclusions:
- SD is a significant complication in PIDs, associated with specific genetic defects and increased mortality.
- Prompt identification of pathogens and genetic mutations is essential for targeted therapy and improved outcomes.
- Refractory diarrhea in PIDs, particularly with mutations like XIAP and FOXP3, carries a high mortality risk, but transplantation may offer a cure.
Abstract:
Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003-2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn's-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient.
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