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Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease

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Abstract

Purpose

Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD).

Methods

The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea 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 pediatric-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, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (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 treatments. 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 diarrhea 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 responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

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Data Availability

All have been in the text and supplemental data.

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Acknowledgements

The authors would like to thank all of the patients and their families for their kind cooperation and their physicians for the referrals.

Funding

This study received grants from the Chang-Gung Medical Research Progress (Grant CMRPG3M0351, CIRPG3M0081, and CMRPG 4B0051-53), the National Science Council (Grants MOST 110–2314-B-182A-033-, 111–2314-B-182A-110-, NMRPG3L0241, and NMRPG3M0321) and the Taiwan Foundation for Rare Disorders (TFRD, PMRPG3M0061 and PMRPG3N0031).

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Authors and Affiliations

  1. Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan

    Wen-I. Lee, Tang-Her Jaing, Chi-Jou Liang, Chen-Chen Kang & Jing-Long Huang

  2. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Wen-I. Lee, Liang-Shiou Ou, Chi-Jou Liang, Chen-Chen Kang & Jing-Long Huang

  3. Division of Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chien-Chang Chen

  4. Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Shih-Hsiang Chen & Tang-Her Jaing

  5. Division of Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    Wan-Tz Lai

  6. Department of Pediatrics, New Taipei Municipal TuChen Hospital, New Taipei, Taiwan

    Jing-Long Huang

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  1. Wen-I. Lee
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Contributions

LWI, CCC, and HJL designed the study and organized the team; LWI, LCG, and KCC performed the immunological assessments and genetic analysis; and LWI, CCC, LWT, JTH, and CSH took care of the patients. All of the authors participated in this work and approved the submitted version of the manuscript for publication.

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Correspondence to Wen-I. Lee or Jing-Long Huang.

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Lee, WI., Chen, CC., Chen, SH. et al. Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease. J Clin Immunol 43, 1455–1467 (2023). https://doi.org/10.1007/s10875-023-01503-w

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