Ileostomy for steroid-resistant acute graft-versus-host disease of the gastrointestinal tract

Abstract

Steroid-resistant acute graft-versus-host disease (GVHD) of the gastrointestinal tract associates with important morbidity and mortality. While high-dose steroids are the established first-line therapy in GVHD, no second-line therapy is generally accepted. In this analysis of 65 consecutive patients with severe, steroid-resistant, intestinal GVHD (92% stage 4), additional ileostomy surgery significantly reduced overall mortality (hazard ratio 0.54; 95% confidence interval, 0.36-0.81; p = 0.003) compared to conventional GVHD therapy. Median overall survival was 16 months in the ileostomy cohort compared to 4 months in the conventional therapy cohort. In the ileostomy cohort, both infectious- and GVHD-associated mortality were reduced (40% versus 77%). Significantly declined fecal volumes (p = 0.001) after surgery provide evidence of intestinal adaptation following ileostomy. Correlative studies indicated ileostomy-induced immune-modulation with a > 50% decrease of activated T cells (p = 0.04) and an increase in regulatory T cells. The observed alterations of the patients' gut microbiota may also contribute to ileostomy's therapeutic effect. These data show that ileostomy induced significant clinical responses in patients with steroid-resistant GVHD along with a reduction of pro-inflammatory immune cells and changes of the intestinal microbiota. Ileostomy is a treatment option for steroid-resistant acute GVHD of the gastrointestinal tract that needs further validation in a prospective clinical trial.

Keywords: Graft-versus-host disease; Hematopoietic stem cell transplantation; Ileostomy-induced immune modulation; Intestinal adaptation; Intestinal microbiota; Refractory GVHD.

Fig. 1

Significant decline of fecal volumes after ileostomy. Change of fecal volumes per day was evaluated at days 14 and 7 before (n = 9) and after ileostomy (n = 8) and at discharge (n = 7). The significance of the fecal volume changes was evaluated within the paired sample t test. Fecal volumes after ileostomy were significantly lower as compared to volumes before ileostomy. Significance levels of fecal volume change between 14 days prior to ileostomy and 7 days after ileostomy were *p = 0.02 and **p < 0.01.

Fig. 2

Comparison of overall survival of GI-aGVHD patients with additional ileostomy and conventional therapy alone. Survival from day of allogeneic stem cell transplantation until death of any cause. Data were censored after 60 months. Patients with GI-aGVHD were categorized into ileostomy (n = 10, hatched) and conventional therapy cohorts (n = 55, solid). Graphs were plotted with the Kaplan-Meier survival analysis. Cohorts were compared using the log-rank test. **p = 0.002

Fig. 3

Ileostomy reduced activated T cells and increased regulatory T cells. Lymphocyte subsets in the peripheral blood were measured by flow cytometry before and after ileostomy. Specific cell subsets within the CD45⁺ lymphocyte gate were characterized as follows: T cells, CD3⁺ (n = 7); T helper cells, CD3⁺/CD4⁺ (n = 6); activated T cells, CD3⁺/HLA-DR⁺ (n = 7); regulatory T cells, CD3⁺/CD4⁺/CD25⁺/CD127⁻ (n = 7); naïve CD4⁺ T cells, CD3⁺/CD4⁺/CD45RA⁺ (n = 5); memory CD4⁺ T cells, CD3⁺/CD4⁺/CD45RO⁺ (n = 6); B cells, CD19⁺ (n = 6). Fold change of T cells is expressed as a percentage of absolute cell numbers after ileostomy relative to that observed before ileostomy, and analyzed by the paired sample t test. p values are detailed in the figure. p < 0.05 was considered statistically significant. Data represents normalized mean values and the error bars represent the standard error of the mean

Fig. 4

Ileostomy altered the fecal microbiota. Quantitative evaluation of cultured aerobic, anaerobic bacteria, and fungi from fecal samples. Patients were evaluated pre-transplantation (n_pre = 8), during GVHD (n_GVHD = 9), and post-ileostomy (n_post = 9). Microbiota are categorized into low, medium, and high categories according to culture plate counts. The proportion of categories at these time points are shown. a Quantitative evaluation of cultured aerobic bacteria pre-transplantation (n_pre = 8), during GVHD (n_GVHD = 9), and post-ileostomy (n_post = 9). b Quantitative evaluation of cultured anaerobic bacteria (n_pre = 8, n_GVHD = 9, n_post = 9). c Quantitative evaluation of cultured fungi (n_pre = 8, n_GVHD = 8, n_post = 9). d Quantitative evaluation of all cultured microorganisms (n_pre = 24, n_GVHD = 26, n_post = 27)