Diarrhea during the Conditioning Regimen Is Correlated with the Occurrence of Severe Acute Graft-versus-Host Disease through Systemic Release of Inflammatory Cytokines

Abstract

Graft-versus-host disease (GVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although many indicators have been used to predict GVHD, the prediction of GVHD remains very difficult. Determining how to predict the occurrence of acute GVHD (aGVHD) as exactly as possible has been a huge challenge so far. Systemic release of inflammatory cytokines during the conditioning regimen and early-phase post-HSCT plays a crucial role in the generation of aGVHD; additionally, the conditioning regimen causes the damage to the intestinal tract. Diarrhea is a common symptom of intestinal tract damage during the conditioning regimen. We therefore performed a prospective study to investigate the relationship between diarrhea related to the conditioning regimen, systemic release of inflammatory cytokines during the conditioning regimen and the early-phase post-HSCT, and the development of aGVHD. This study demonstrated that duration of diarrhea was >5.5 days, with a maximal volume >8.72 mL/kg and a mean volume of diarrhea for days -3 to 0 >7.94 mL/kg were risk factors of grade II to IV aGVHD. Diarrhea with any 1 risk factor was defined as severe diarrhea. Furthermore, this study first confirmed that the correlation between diarrhea and aGVHD was related to the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 during the conditioning regimen and during the early phase after transplantation. Our study demonstrated that diarrhea related to the conditioning regimen could be used as a marker for the prediction of aGVHD and further explain the possible mechanism underlying the linkage described here. Therefore, for the patients with severe diarrhea related to the conditioning regimen, low-dose glucocorticoid may be used to reduce the levels of inflammatory cytokine release by a damaged intestinal tract, and possibly further reduce the occurrence of aGVHD. For these patients, prophylaxis of aGVHD may be need to be adjusted individually.

Severe Hyperglycemia Immediately After Allogeneic Hematopoietic Stem-Cell Transplantation is Predictive of Acute Graft-Versus-Host Disease

“…Another limitation of our study is that data were unavailable on diarrhea related to conditioning, a GVHD risk factor independent of mucositis [4, 5]. In addition, our study was uninformative about hyperacute GVHD, because our eligibility criteria excluded from the cohort those patients who developed GVHD before Day 11 after allogeneic HSCT.…”

Early post-transplant contrast-enhanced abdominopelvic CT scan predicts the risk of subsequent acute GvHD

“…11 Liu et al showed that a mean volume of conditioning-related diarrhea for Days −3 to 0 larger than 7.94 mL/kg was an independent risk factor for the development of grade II-IV aGVHD. 12 Johansson et al showed that higher intestinal absorption of 51 Cr-EDTA in the first two weeks following transplant predicted the development of grade II-IV aGvHD. 13 We hypothesize that the early post-transplant period, when intestinal barrier damage is maximal and before aGvHD has developed, is a critical window during which high-risk features on abdominopelvic imaging are associated with the risk of subsequent aGvHD development.…”

Possible Implication of Bacterial Infection in Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

“…It is worthy to test whether the manipulation of intestinal microbiome is able to reduce the risk of acute GVHD. Considering the considerable difference of conditioning regimen or GVHD prophylaxis in the regimen-related toxicity of oral mucosa and gastrointestinal tract, importance of gut bacterial manipulation might be more important in patients with a myeloablative conditioning regimen than those with a reduced-intensity conditioning regimen, or in patients with short-term methotrexate than those with mycophenolate mofetil (35–40). …”