Top

Published in:

19-05-2023 | Primary Immunodeficiency | Original Article

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

Authors: Wen-I. Lee, Chien-Chang Chen, Shih-Hsiang Chen, Wan-Tz Lai, Tang-Her Jaing, Liang-Shiou Ou, Chi-Jou Liang, Chen-Chen Kang, Jing-Long Huang

Published in: Journal of Clinical Immunology | Issue 6/2023

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.

Available only for authorised users

Agarwal S, Cunningham-Rundles C. Gastrointestinal manifestations and complications of primary immunodeficiency disorders. Immunol Allergy Clin North Am. 2019;39(1):81–94. https://doi.org/10.1016/j.iac.2018.08.006.CrossRefPubMedPubMedCentral

Agarwal S, Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16(4):703–11. https://doi.org/10.1002/ibd.21040.CrossRefPubMed

Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124(4):658–64. https://doi.org/10.1016/j.jaci.2009.06.018.CrossRefPubMed

Velounias RL, Tull TJ. Human B-cell subset identification and changes in inflammatory diseases. Clin Exp Immunol. 2022;210(3):201–16. https://doi.org/10.1093/cei/uxac104.CrossRefPubMed

Catassi C, Fabiani E, Spagnuolo MI, Barera G, Guarino A. Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. Working Group of the Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP). J Pediatr Gastroenterol Nutr. 1999;29(1):63–8. https://doi.org/10.1097/00005176-199907000-00016.CrossRefPubMed

Guarino A, Spagnuolo MI, Russo S, Albano F, Guandalini S, Capano G, et al. Etiology and risk factors of severe and protracted diarrhea. J Pediatr Gastroenterol Nutr. 1995;20(2):173–8. https://doi.org/10.1097/00005176-199502000-00006.CrossRefPubMed

Li Y, de Haar C, Peppelenbosch MP, van der Woude CJ. New insights into the role of STAT3 in IBD. Inflamm Bowel Dis. 2012;18(6):1177–83. https://doi.org/10.1002/ibd.21884.CrossRefPubMed

Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60(12):1739–53. https://doi.org/10.1136/gut.2009.199679.CrossRefPubMed

Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011;140(6):1704–12. https://doi.org/10.1053/j.gastro.2011.02.046.CrossRefPubMed

10.

Brand S. Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut. 2009;58(8):1152–67. https://doi.org/10.1136/gut.2008.163667.CrossRefPubMed

11.

Schmitt H, Neurath MF, Atreya R. Role of the IL23/IL17 Pathway in Crohn’s disease. Front Immunol. 2021;12:622934. https://doi.org/10.3389/fimmu.2021.622934.CrossRefPubMedPubMedCentral

12.

Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S. The IL23-IL17 immune axis in the treatment of ulcerative colitis: successes, defeats, and ongoing challenges. Front Immunol. 2021;12:611256. https://doi.org/10.3389/fimmu.2021.611256.CrossRefPubMedPubMedCentral

13.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461–3. https://doi.org/10.1126/science.1135245.CrossRefPubMedPubMedCentral

14.

Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033–45. https://doi.org/10.1056/NEJMoa0907206.CrossRefPubMedPubMedCentral

15.

Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N, et al. Infant colitis—it’s in the genes. Lancet. 2010;376(9748):1272. https://doi.org/10.1016/S0140-6736(10)61008-2.CrossRefPubMed

16.

Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012;143(2):347–55. https://doi.org/10.1053/j.gastro.2012.04.045.CrossRefPubMed

17.

Mao H, Yang W, Lee PP, Ho MH, Yang J, Zeng S, et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease. Genes Immun. 2012;13(5):437–42. https://doi.org/10.1038/gene.2012.8.CrossRefPubMed

18.

Engelhardt KR, Shah N, Faizura-Yeop I, KocacikUygun DF, Frede N, et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;131(3):825–30. https://doi.org/10.1016/j.jaci.2012.09.025.CrossRefPubMed

19.

Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130(2):481-8.e2. https://doi.org/10.1016/j.jaci.2012.05.043.CrossRefPubMedPubMedCentral

20.

Cannioto Z, Berti I, Martelossi S, Bruno I, Giurici N, Crovella S, et al. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr. 2009;168(2):149–55. https://doi.org/10.1007/s00431-008-0721-2.CrossRefPubMed

21.

Ozgür TT, Asal GT, Cetinkaya D, Orhan D, Kiliç SS, Usta Y, et al. Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory bowel disease. Pediatr Transplant. 2008;12(8):910–3. https://doi.org/10.1111/j.1399-3046.2008.00957.x.CrossRefPubMed

22.

Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–50. https://doi.org/10.1016/j.jaci.2007.08.044. (quiz 751-2).CrossRefPubMed

23.

Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol. 2012;31(3):211. https://doi.org/10.3389/fimmu.2012.00211.CrossRef

24.

Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209. https://doi.org/10.3389/fimmu.2012.00209.CrossRefPubMedPubMedCentral

25.

Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111(5 Pt 1):e622–7. https://doi.org/10.1542/peds.111.5.e622.CrossRefPubMed

26.

Marks DJ, Miyagi K, Rahman FZ, Novelli M, Bloom SL, Segal AW. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol. 2009;104(1):117–24. https://doi.org/10.1038/ajg.2008.72.CrossRefPubMed

27.

Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R, et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut. 2012;61(7):1028–35. https://doi.org/10.1136/gutjnl-2011-300078.CrossRefPubMed

28.

Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010;116(7):1079–82. https://doi.org/10.1182/blood-2010-01-256099.CrossRefPubMedPubMedCentral

29.

PachlopnikSchmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522–9. https://doi.org/10.1182/blood-2010-07-298372.CrossRef

30.

Yang X, Kanegane H, Nishida N, Imamura T, Hamamoto K, Miyashita R, et al. Clinical and genetic characteristics of XIAP deficiency in Japan. J Clin Immunol. 2012;32(3):411–20. https://doi.org/10.1007/s10875-011-9638-z.CrossRefPubMed

31.

Speckmann C, Lehmberg K, Albert MH, Damgaard RB, Fritsch M, Gyrd-Hansen M, et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol. 2013;149(1):133–41. https://doi.org/10.1016/j.clim.2013.07.004.CrossRefPubMed

32.

Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009;132(1):124–31. https://doi.org/10.1016/j.clim.2009.03.514.CrossRefPubMedPubMedCentral

33.

Lee WI, Huang JL, Jaing TH, Shyur SD, Yang KD, Chien YH, et al. Distribution, clinical features and treatment in Taiwanese patients with symptomatic primary immunodeficiency diseases (PIDs) in a nationwide population-based study during 1985–2010. Immunobiology. 2011;216(12):1286–94. https://doi.org/10.1016/j.imbio.2011.06.002.CrossRefPubMed

34.

Lien R, Lin YF, Lai MW, Weng HY, Wu RC, Jaing TH, et al. Novel mutations of the tetratricopeptide repeat domain 7A gene and phenotype/genotype comparison. Front Immunol. 2017;8:1066. https://doi.org/10.3389/fimmu.2017.01066.CrossRefPubMedPubMedCentral

35.

Lee WI, Chen CC, Jaing TH, Ou LS, Hsueh C, Huang JL. A nationwide study of severe and protracted diarrhoea in patients with primary immunodeficiency diseases. Sci Rep. 2017;7(1):3669. https://doi.org/10.1038/s41598-017-03967-4.CrossRefPubMedPubMedCentral

36.

RAPID: Resource of primary immunodeficiency diseases. http://rapid.rcai.riken.jp/ website

37.

Lee WI, Kuo ML, Huang JL, Lin SJ, Wu CJ. Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period. J Clin Immunol. 2005;25(2):162–73. https://doi.org/10.1007/s10875-005-2822-2.CrossRefPubMed

38.

Lee WI, Jaing TH, Hsieh MY, Kuo ML, Lin SJ, Huang JL. Distribution, infections, treatments and molecular analysis in a large cohort of patients with primary immunodeficiency diseases (PIDs) in Taiwan. J Clin Immunol. 2006;26(3):274–83. https://doi.org/10.1007/s10875-006-9013-7.CrossRefPubMed

39.

Chuang CH, Wang YH, Chang HJ, Chen HL, Huang YC, Lin TY, et al. Shanghai fever: a distinct Pseudomonas aeruginosa enteric disease. Gut. 2014;63(5):736–43. https://doi.org/10.1136/gutjnl-2013-304786.CrossRefPubMed

40.

Lee WI, Huang JL, Chen CC, Lin JL, Wu RC, Jaing TH, et al. Identifying mutations of the tetratricopeptide repeat domain 37 (TTC37) gene in infants with intractable diarrhea and a comparison of Asian and non-Asian phenotype and genotype: a global case-report study of a well-defined syndrome with immunodeficiency. Medicine (Baltimore). 2016;95(9):e2918. https://doi.org/10.1097/MD.0000000000002918.CrossRefPubMed

41.

Chen HM, Wang Y, Su LH, Chiu CH. Nontyphoid salmonella infection: microbiology, clinical features, and antimicrobial therapy. Pediatr Neonatol. 2013;54(3):147–52. https://doi.org/10.1016/j.pedneo.2013.01.010.CrossRefPubMed

42.

Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131(6):1611–23. https://doi.org/10.1016/j.jaci.2012.11.054.CrossRefPubMedPubMedCentral

43.

Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34. https://doi.org/10.1016/j.jaci.2013.01.052.CrossRefPubMedPubMedCentral

44.

Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, COLORS in IBD Study Group and NEOPICS, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990-1007.e3. https://doi.org/10.1053/j.gastro.2014.07.023.CrossRefPubMed

45.

Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut. 2013;62(12):1795–805. https://doi.org/10.1136/gutjnl-2012-303956.CrossRefPubMed

46.

Slatter MA, Gennery AR. Advances in hematopoietic stem cell transplantation for primary immunodeficiency. Expert Rev Clin Immunol. 2013;9(10):991–9. https://doi.org/10.1586/1744666X.2013.836061.CrossRefPubMed

47.

Kammermeier J, Lucchini G, Pai SY, Worth A, Rampling D, Amrolia P, et al. Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up. Blood. 2016;128(9):1306–8. https://doi.org/10.1182/blood-2016-01-696385.CrossRefPubMed

48.

Klemann C, Pannicke U, Morris-Rosendahl DJ, Vlantis K, Rizzi M, Uhlig H, et al. Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency. Clin Immunol. 2016;164:52–6. https://doi.org/10.1016/j.clim.2016.01.010.CrossRefPubMedPubMedCentral

49.

Notarangelo LD. Multiple intestinal atresia with combined immune deficiency. Curr Opin Pediatr. 2014;26(6):690–6. https://doi.org/10.1097/MOP.0000000000000159.CrossRefPubMed

Title: Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease
Authors: Wen-I. Lee
Chien-Chang Chen
Shih-Hsiang Chen
Wan-Tz Lai
Tang-Her Jaing
Liang-Shiou Ou
Chi-Jou Liang
Chen-Chen Kang
Jing-Long Huang
Publication date: 19-05-2023
Publisher: Springer US
Keywords: Primary Immunodeficiency
Chronic Inflammatory Bowel Disease
Septicemia
Septicemia
Antibiotic
Diarrhea
Diarrhea
Pseudomonas
Published in: Journal of Clinical Immunology / Issue 6/2023
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-023-01503-w

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2023

Steroid-Responsive Pulmonary Hypertension in a Pediatric Patient with Chronic Granulomatous Disease and Histoplasmosis

Autoantibodies Neutralizing Type I IFNs in the Bronchoalveolar Lavage of at Least 10% of Patients During Life-Threatening COVID-19 Pneumonia

“The Regimental Pediatrician”: My Training and Debut in Boden

Inborn Errors of Immunity in Hidradenitis Suppurativa Pathogenesis and Disease Burden

Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine

SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Show Markedly Reduced Cross-reactivities Against Omicron Variants

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage