Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Non-invasive diagnosis of acute intestinal graft-versus-host disease by a new scoring system using ultrasound morphology, compound elastography, and contrast-enhanced ultrasound

Bone Marrow Transplantation volume 54, pages 1038–1048 (2019)Cite this article

Subjects

Abstract

Acute gastrointestinal (GI) graft-versus-host disease (GvHD) is a life-threating complication in patients after allogeneic stem cell transplantation (ASCT). In 60 sonographic analyses, a novel scoring system for non-invasive diagnosis of severe GI GvHD was developed. The score comprised morphological and vascular changes using B-mode and color-coded Doppler sonography, changes of mural stiffness using compound elastography, and dynamic microvascularisation using contrast-enhanced ultrasound (CEUS). Furthermore, inflammatory parameters such as CRP, Calprotectin, and regenerating islet-derived protein 3α (Reg3α) were obtained. ROC curve analysis of our novel GvHD sum score revealed an area under the curve of 1.0 (95% CI: 0.99–1.00) in diagnosing GI GvHD and 0.88 (95% CI: 0.79–0.96) for severe GI GvHD. A sum score above 5 correlated with GI GvHD with a sensitivity of 97.6% (41/42) and a specificity of 94.4% (17/18) and score values above 10 with severe GI GvHD with a sensitivity of 91.7% (11/12) and specificity of 79.2% (38/48). The additional use of inflammatory parameters did not improve the predictive power. CEUS is a promising, non-invasive tool for the diagnosis of acute GI GvHD. Together with further descriptive parameters for inflammatory processes, it gains significant diagnostic accuracy in identifying patients with severe stages of acute intestinal GvHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.

    Article  CAS  Google Scholar 

  2. Pavletic SZ, Fowler DH. Are we making progress in GVHD prophylaxis and treatment? Hematol Am Soc Hematol Educ Program. 2012;2012:251–64. https://doi.org/10.1182/asheducation-2012.1.251.

    Article  Google Scholar 

  3. Malard F, Mohty M. New insight for the diagnosis of gastrointestinal acute graft-versus-host disease. Mediat Inflamm. 2014;2014:701013 https://doi.org/10.1155/2014/701013.

    Article  Google Scholar 

  4. Khan K, Schwarzenberg SJ, Sharp H, Jessurun J, Gulbahce HE, Defor T, et al. Diagnostic endoscopy in children after hematopoietic stem cell transplantation. Gastrointest Endosc. 2006;64:379–85. https://doi.org/10.1016/j.gie.2005.08.040.

    Article  PubMed  Google Scholar 

  5. Schreyer AG, Landfried K, Zorger N, Hoffstetter P, Ammer J, Fellner C, et al. Transmural penetration of intravenously applied microbubbles during contrast-enhanced ultrasound as a new diagnostic feature in patients with GVHD of the bowel. Bone Marrow Transplant. 2011;46:1006–11. https://doi.org/10.1038/bmt.2010.232.

    Article  CAS  PubMed  Google Scholar 

  6. Schreyer AG, Landfried K, Jung EM, da Silva NP, Poschenrieder F, Dornia C, et al. Contrast-enhanced ultrasound for differential diagnosis of suspected GvHD in patients after allogeneic transplantation. Clin Hemorheol Microcirc. 2011;49:129–36. https://doi.org/10.3233/CH-2011-1463.

    Article  PubMed  Google Scholar 

  7. Wilson SR, Greenbaum LD, Goldberg BB. Contrast-enhanced ultrasound: what is the evidence and what are the obstacles? AJR. 2009;193:55–60. https://doi.org/10.2214/AJR.09.2553.

    Article  PubMed  Google Scholar 

  8. Dietrich CF, Bamber J, Berzigotti A, Bota S, Cantisani V, Castera L, et al. EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, update 2017 (long version). Ultraschall Med. 2017;38:e16–47. https://doi.org/10.1055/s-0043-103952.

    Article  PubMed  Google Scholar 

  9. Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118:6702–8. https://doi.org/10.1182/blood-2011-08-375006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Renteria AS, Levine JE, Ferrara JL. Development of a biomarker scoring system for use in graft-versus-host disease. Biomark Med. 2016;10:793–5. https://doi.org/10.2217/bmm-2016-0162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Girlich C, Schacherer D, Lamby P, Scherer MN, Schreyer AG, Jung EM. Innovations in contrast enhanced high resolution ultrasound improve sonographic imaging of the intestine. Clin Hemorheol Microcirc. 2010;45:207–15. https://doi.org/10.3233/CH-2010-1299.

    Article  CAS  PubMed  Google Scholar 

  12. Kreft A, Mottok A, Mesteri I, Cardona DM, Janin A, Kuhl AA, et al. Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility. Virchows Arch. 2015;467:255–63. https://doi.org/10.1007/s00428-015-1803-y.

    Article  PubMed  Google Scholar 

  13. Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et al. NIH consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant. 2015;21:589–603. https://doi.org/10.1016/j.bbmt.2014.12.031.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, Thomas ED. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6:367–71.

    CAS  PubMed  Google Scholar 

  15. Kucharzik T, Wittig BM, Helwig U, Borner N, Rossler A, Rath S, et al. Use of intestinal ultrasound to monitor Crohn’s disease activity. Clin Gastroenterol Hepatol. 2017;15:535–42 e532. https://doi.org/10.1016/j.cgh.2016.10.040.

    Article  PubMed  Google Scholar 

  16. Sung AD, Chao NJ. Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment. Stem Cells Transl Med. 2013;2:25–32. https://doi.org/10.5966/sctm.2012-0115.

    Article  CAS  PubMed  Google Scholar 

  17. Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296–307. https://doi.org/10.1182/blood-2011-06-364265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Castilla-Llorente C, Martin PJ, McDonald GB, Storer BE, Appelbaum FR, Deeg HJ, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49:966–71. https://doi.org/10.1038/bmt.2014.69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cruz-Correa M, Poonawala A, Abraham SC, Wu TT, Zahurak M, Vogelsang G, et al. Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy. 2002;34:808–13. https://doi.org/10.1055/s-2002-34257.

    Article  CAS  PubMed  Google Scholar 

  20. Thompson B, Salzman D, Steinhauer J, Lazenby AJ, Wilcox CM. Prospective endoscopic evaluation for gastrointestinal graft-versus-host disease: determination of the best diagnostic approach. Bone Marrow Transplant. 2006;38:371–6. https://doi.org/10.1038/sj.bmt.1705453.

    Article  CAS  PubMed  Google Scholar 

  21. Claudon M, Cosgrove D, Albrecht T, Bolondi L, Bosio M, Calliada F, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS)—update 2008. Ultraschall Med. 2008;29:28–44. https://doi.org/10.1055/s-2007-963785.

    Article  CAS  PubMed  Google Scholar 

  22. Cantisani V, Bertolotto M, Weskott HP, Romanini L, Grazhdani H, Passamonti M, et al. Growing indications for CEUS: The kidney, testis, lymph nodes, thyroid, prostate, and small bowel. Eur J Radiol. 2015;84:1675–84. https://doi.org/10.1016/j.ejrad.2015.05.008.

    Article  CAS  PubMed  Google Scholar 

  23. De Franco A, Marzo M, Felice C, Pugliese D, Veronica AD, Bonomo L, et al. Ileal Crohn’s disease: CEUS determination of activity. Abdom Imaging. 2012;37:359–68. https://doi.org/10.1007/s00261-011-9831-9.

    Article  PubMed  Google Scholar 

  24. Serafin Z, Bialecki M, Bialecka A, Sconfienza LM, Klopocka M. Contrast-enhanced ultrasound for detection of Crohn’s disease activity: systematic review and meta-analysis. J Crohns Colitis. 2016;10:354–62. https://doi.org/10.1093/ecco-jcc/jjv196.

    Article  PubMed  Google Scholar 

  25. Pescatori LC, Mauri G, Savarino E, Pastorelli L, Vecchi M, Sconfienza LM. Bowel sonoelastography in patients with Crohn’s disease: a systematic review. Ultrasound Med Biol. 2018;44:297–302. https://doi.org/10.1016/j.ultrasmedbio.2017.10.004.

    Article  PubMed  Google Scholar 

  26. Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA. Phylogenetic perspectives in innate immunity. Science. 1999;284:1313–8.

    Article  CAS  PubMed  Google Scholar 

  27. Tibble JA, Bjarnason I. Fecal calprotectin as an index of intestinal inflammation. Drugs Today. 2001;37:85–96.

    Article  CAS  Google Scholar 

  28. O’Meara A, Kapel N, Xhaard A, Sicre de Fontbrune F, Manene D, Dhedin N, et al. Fecal calprotectin and alpha1-antitrypsin dynamics in gastrointestinal GvHD. Bone Marrow Transplant. 2015;50:1105–9. https://doi.org/10.1038/bmt.2015.109.

    Article  CAS  PubMed  Google Scholar 

  29. Bastos Oreiro M, Castilla-Llorente C, de la Guia AL, de Paz R, Van Domselaar M, Nieto J, et al. Fecal calprotectin in allogeneic stem cell transplantation for the diagnosis of acute intestinal graft versus host disease. Bone Marrow Transplant. 2012;47:1241–2. https://doi.org/10.1038/bmt.2011.241.

    Article  CAS  PubMed  Google Scholar 

  30. Lorenz F, Marklund S, Werner M, Palmqvist R, Wahlin BE, Wahlin A. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation. Sci Rep. 2015;5:7920. https://doi.org/10.1038/srep07920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rodriguez-Otero P, Porcher R, Peffault de Latour R, Contreras M, Bouhnik Y, Xhaard A, et al. Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease. Blood. 2012;119:5909–17. https://doi.org/10.1182/blood-2011-12-397968.

    Article  CAS  PubMed  Google Scholar 

  32. Chiusolo P, Metafuni E, Giammarco S, Bellesi S, Piccirillo N, Fanali C, et al. Role of fecal calprotectin as biomarker of gastrointestinal GVHD after allogeneic stem cell transplantation. Blood. 2012;120:4443–4. https://doi.org/10.1182/blood-2012-08-447326.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors acknowledge the help of Heike Bremm, Constanze Winter, Tatjana Schifferstein and Yvonne Schumann in collecting and cryopreserving patient specimens as well as Heike Bremm in performing Reg3α PCR analyses.

Author contributions

D. Weber, E-MJ, and EH were involved in conception and design of the study. E-MJ and D. Weber performed ultrasound examinations including CEUS. D. Weber was responsible for collection of specimens and clinical patient data. SG was responsible for PCR-analysis of Reg3α. KH performed histopathological analysis of patient biopsies. MW contributed to statistical data analysis. D. Weber and EH collected and analyzed clinical data and wrote the manuscript. WH, D. Wolff, and E-MJ were involved in interpretation and discussion of study results according to the current literature. All authors read, revised, and approved the final draft.

Author information

Author notes

  1. These authors contributed equally: Ernst Holler, Ernst-Michael Jung

Authors and Affiliations

  1. Department of Hematology and Oncology, Internal Medicine III, University Medical Center- Regensburg, Regensburg, Germany

    Daniela Weber, Sakhila Ghimire, Daniel Wolff, Joachim Hahn, Wolfgang Herr & Ernst Holler

  2. Department of Orthopedic Surgery, University Medical Center-Regensburg, Regensburg, Germany

    Markus Weber

  3. Department of Pathology, University Medical Center-Regensburg, Regensburg, Germany

    Katrin Hippe & Matthias Evert

  4. Department of Radiology, University Medical Center-Regensburg, Regensburg, Germany

    Ernst-Michael Jung

Authors
  1. Daniela Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katrin Hippe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sakhila Ghimire
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joachim Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthias Evert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wolfgang Herr
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ernst Holler
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ernst-Michael Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniela Weber.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weber, D., Weber, M., Hippe, K. et al. Non-invasive diagnosis of acute intestinal graft-versus-host disease by a new scoring system using ultrasound morphology, compound elastography, and contrast-enhanced ultrasound. Bone Marrow Transplant 54, 1038–1048 (2019). https://doi.org/10.1038/s41409-018-0381-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0381-4

This article is cited by

Search

Advanced search

Quick links