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Hematopoietic stem cell Transplantation in Children with very Early Onset Inflammatory Bowel Disease Secondary to Monogenic Disorders of immune-dysregulation

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Abstract

Background: Very early-onset inflammatory bowel disease (VEOIBD) is defined as IBD in children under six years of age. We present outcome data of hematopoietic stem cell transplantation (HSCT) in the above children. Patients and methods: We performed a retrospective study in children under six years of age who underwent HSCT for VEOIBD with an identified monogenic disorder from December 2012 to December 2020. Results: Of the 25 children included, the underlying diagnosis was IL10R deficiency (n = 4), Wiskott-Aldrich syndrome (n = 4), Leukocyte adhesion defect (n = 4), Hyper IgM syndrome (n = 3), Chronic granulomatous disease (n = 2), and one each with XIAP deficiency, severe congenital neutropenia, Omenn syndrome, Hyper IgE syndrome, Griscelli syndrome, MHC Class II deficiency, LRBA deficiency, and IPEX syndrome. Donors included a matched family donor in 10(40%); a matched unrelated donor in 8 (32%), haploidentical in 7 (28%) (T depleted 16%, T replete with post-transplant cyclophosphamide12%). Conditioning was myeloablative in 84% ofHSCTs. We documented engraftment in 22 (88%) children, primary graft failure in 2 children (8%), mixed chimerism in 6 (24%) children with mortality in 4/6 children. Children with a sustained chimerism of > 95% did not have recurrence of any features of IBD. Overall survival was 64%, with a median follow-up of 55 months. Mixed chimerism was associated with a significantly increased risk of mortality (p-value = 0.001). Conclusions: VEOIBD caused by monogenic disorders can be offered HSCT. Early recognition, optimal supportive care, and complete chimerism are essential components to achieving survival.

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Abbreviations

VEOIBD:

Very early onset inflammatory bowel disease

HSCT:

Hematopoietic stem cell transplantation

GVHD:

Graft versus host disease

MUD:

Matched unrelated donor

MFD:

Matched family donor

MAC:

Myeloablative conditioning

RIC:

Reduced intensity conditioning

CMV:

Cytomegalovirus

EBV:

Epstein Barr virus

ATG:

Anti thymocyte globulin

IEI:

Inborn errors of immunity

References

  1. Snapper SB (2015 Aug) Very Early-Onset Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 11:554–556 PMID: 27118953; PMCID: PMC4843045. 8

  2. Kelsen JR, Russo P, Sullivan KE (2019 Feb) Early-Onset Inflammatory Bowel Disease. Immunol Allergy Clin North Am. 39:63–79. https://doi.org/10.1016/j.iac.2018.08.008. PMID: 30466773; PMCID: PMC6954002 1

  3. Almana Y, Mohammed R (2019 Mar) Current concepts in pediatric inflammatory bowel disease; IL10/IL10R colitis as a model disease. Int J Pediatr Adolesc Med 6(1):1–5. DOI: https://doi.org/10.1016/j.ijpam.2019.02.002 Epub 2019 Mar 12. PMID: 31304220; PMCID: PMC6603158

  4. Nameirakpam J, Rikhi R, Rawat SS et al (2019) Genetics on early onset inflammatory bowel disease: An update. Genes Dis. Oct 15;7(1):93–106. doi: https://doi.org/10.1016/j.gendis.2019.10.003. PMID: 32181280; PMCID: PMC7063406

  5. Srivastava A, Sathiyasekharan M, Jagadisan B et al (2020) Oct;32(10):1305–1311 Pediatric inflammatory bowel disease in India: a prospective multicentre study. Eur J Gastroenterol Hepatol. DOI: https://doi.org/10.1097/MEG.0000000000001859. PMID: 32796356

  6. Kelsen JR, Sullivan KE, Rabizadeh S et al (2020) Mar;70(3):389–403 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Evaluation and Management for Patients With Very Early-onset Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. DOI: https://doi.org/10.1097/MPG.0000000000002567. PMID: 32079889

  7. Uhlig HH, Schwerd T, Koletzko S, COLORS in IBD Study Group and NEOPICS et al (2014 Nov) The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147(5):990–1007e3. DOI: https://doi.org/10.1053/j.gastro.2014.07.023 Epub 2014 Jul 21. PMID: 25058236; PMCID: PMC5376484

  8. Jagasia MH, Greinix HT, Arora M et al (2015 Mar) National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 21(3):389–401e1 Epub 2014 Dec 18. PMID: 25529383; PMCID: PMC4329079

  9. Zheng HB, de la Morena MT, Suskind DL The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease.Front Immunol. 2021 May26;12:675186. DOI: https://doi.org/10.3389/fimmu.2021.675186. PMID: 34122435; PMCID: PMC8187749.

  10. Tang Z, Zhang P, Ji M et al (2021) Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases. BMC Gastroenterol. Apr 13;21(1):167. DOI: https://doi.org/10.1186/s12876-021-01756-y. PMID: 33849446; PMCID: PMC8045347

  11. Cifaldi C, Chiriaco M, Di Matteo G et al Novel X-linked Inhibitor of Apoptosis Mutation in Very Early-Onset Inflammatory Bowel Disease Child Successfully Treated with HLA-Haploidentical Hematopoietic Stem Cells Transplant after Removal of αβ + T and B Cells.Front Immunol. 2017 Dec22;8:1893. DOI: https://doi.org/10.3389/fimmu.2017.01893. PMID: 29312354; PMCID: PMC5743702.

  12. Murugan D, Albert MH, Langemeier J et al (2014 Apr) Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. J Clin Immunol 34(3):331–339. doi: https://doi.org/10.1007/s10875-014-9992-8 Epub 2014 Feb 12. PMID: 24519095

  13. Kotlarz D, Beier R, Murugan D et al (2012 Aug) Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143(2):347–355. doi: https://doi.org/10.1053/j.gastro.2012.04.045 Epub 2012 Apr 28. PMID: 22549091

  14. Zhu L, Shi T, Zhong C et al IL-10 and IL-10 Receptor Mutations in Very Early Onset Inflammatory Bowel Disease. Gastroenterology Res. 2017 Apr;10(2):65–69. DOI: 10.14740/gr740w. Epub 2017 Apr 19. PMID: 28496525; PMCID: PMC5412537

  15. Karaca NE, Aksu G, Ulusoy E et al (2016) Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases. Case Rep Immunol 2016:5459029. DOI: https://doi.org/10.1155/2016/5459029 Epub 2016 Sep 6. PMID: 27699073; PMCID: PMC5028855

    Article  Google Scholar 

  16. Worth A, Nademi Z, Kammermeier J et al (2014) vol. 20 2 (pg. S89-S90)

  17. Rao A, Kamani N, Filipovich A et al Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1;109(1):383-5. DOI: https://doi.org/10.1182/blood-2006-05-025072. Epub 2006 Sep 21. PMID: 16990602

  18. Lekbua A, Ouahed J, O’Connell AE et al (2019 Jul) Risk-factors Associated With Poor Outcomes in VEO-IBD Secondary to XIAP Deficiency: A Case Report and Literature Review. J Pediatr Gastroenterol Nutr 69(1):e13–e18. DOI: https://doi.org/10.1097/MPG.0000000000002297 PMID: 31232887; PMCID: PMC6607918

  19. Marsh RA, Rao K, Satwant P et al (2013) Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes. Blood. Feb 7;121(6):877 – 83. DOI: 10.1182/blood-2012-06-432500. Epub 2012 Nov 6. PMID: 23131490; PMCID: PMC5162550

  20. Muller N, Fischer JC, Yabal M et al (2019) XIAP deficiency in hematopoietic recipient cells drives donor T-cell activation and GvHD in mice. Eur J Immunol 49:504–507. DOI: https://doi.org/10.1002/eji.201847818

    Article  CAS  PubMed  Google Scholar 

  21. Ouched J, Spencer E, Kotlarz D et al (2020) Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis. May 12;26(6):820–842. DOI: https://doi.org/10.1093/ibd/izz259. PMID: 31833544; PMCID: PMC7216773

  22. Arai K (2020 Sep) Very Early-Onset Inflammatory Bowel Disease: A Challenging Field for Pediatric Gastroenterologists. Pediatr Gastroenterol Hepatol Nutr. 23:411–422. https://doi.org/10.5223/pghn.2020.23.5.411. Epub 2020 Aug 27. PMID: 32953636; PMCID: PMC7481055 5

  23. Bakhtiar S, Fekadu J, Seidel MG et al Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Immune Dysregulatory Disorders.Front Pediatr. 2019 Nov13;7:461. doi: https://doi.org/10.3389/fped.2019.00461. PMID: 31799221; PMCID: PMC6865355.

  24. Lo B, Zhang K, Lu W et al (2015) AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. Jul 24;349(6246):436 – 40. DOI: https://doi.org/10.1126/science.aaa1663. PMID: 26206937

  25. Shouval DS, Biswas A, Kang YH et al (2016 Dec) Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. Gastroenterology 151(6):1100–1104. DOI: 10.10

  26. Begue B, Verdier J, Rieux-Laucat F et al (2011 Aug) Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol 106(8):1544–1555. doi: https://doi.org/10.1038/ajg.2011.112 Epub 2011 Apr 26. PMID: 21519361

  27. Kerur B, Benchimol EI, Fiedler K et al Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study. Inflamm Bowel Dis. 2021 Feb 16;27(3):295–302. DOI: https://doi.org/10.1093/ibd/izaa080. PMID: 32386060; PMCID: PMC8177809

  28. Maxwell EC, Dawany N, Baldassano RN et al (2017 Sep) Diverting Ileostomy for the Treatment of Severe, Refractory, Pediatric Inflammatory Bowel Disease. 65:299–305 DOI: 10.1097/MPG.0000000000001498. PMID: 28045769.53/j.gastro.2016.08.055. Epub 2016 Sep 28. PMID: 27693323; PMCID: PMC5124405. J Pediatr Gastroenterol Nutr3

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Acknowledgements

We would like to acknowledge the immense contribution of the pediatric critical care team, stem cell pheresis, infectious disease specialists, and pediatric gastroenterologists in the management of these children.

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Authors and Affiliations

  1. Department of PediatricHematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, 320, Padma complex, Anna Salai, 600035, Teynampet, Chennai, Tamil Nadu, India

    SATISHKUMAR MEENA, HARIKA VARLA, VENKATESWARAN VELLAICHAMY SWAMINATHAN, RUMESH CHANDAR, RAMYA UPPULURI & REVATHI RAJ

  2. Department of Pediatric Critical Care Hospitals, Apollo Hospitals, 320, Padma complex, Anna Salai, 600035, Teynampet, Chennai, Tamil Nadu, India

    INDIRA JAYAKUMAR

  3. Department of Biostatistics, Apollo Hospitals, 320, Padma complex, Anna Salai, 600035, Teynampet, Chennai, Tamil Nadu, India

    BALASUBRAMANIAM RAMAKRISHNAN

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  1. SATISHKUMAR MEENA
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Contributions

SKM, RU, RR conceptualized the design of the study and wrote the manuscript; VVS, RC, HV helped with data collection and data entry; IJ helped with proof reading; BR did the statistical analysis.

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Correspondence to RAMYA UPPULURI.

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MEENA, S., VARLA, H., SWAMINATHAN, V.V. et al. Hematopoietic stem cell Transplantation in Children with very Early Onset Inflammatory Bowel Disease Secondary to Monogenic Disorders of immune-dysregulation. Indian J Hematol Blood Transfus 39, 183–190 (2023). https://doi.org/10.1007/s12288-022-01586-2

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