Bowel wall thickness with transabdominal ultrasound as a predictive tool for SR-aGvHD with gut involvement after allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for a variety of hematologic malignancies; however, acute graft-versus-host-disease (aGvHD) remains a significant complication with considerable associated mortality, particularly in patients refractory to first-line corticosteroid treatment.¹

In Crohn’s disease, research has indicated that bowel wall thickness is associated with a more aggressive disease course, so Drokov et al.¹ hypothesize that measurement of bowel wall thickness in patients with gastrointestinal aGvHD (GI-aGvHD) may identify a high-risk subgroup of patients more likely to be refractory to steroid treatment. Their findings are published in the International Journal of Hematology and are summarized below.

Study design

• This prospective study enrolled 85 patients with a hematologic malignancy after allo-HSCT with voluminous diarrhea between 2014–2020.
• The diagnosis of GI-aGvHD (n = 48) was based on clinical symptoms (voluminous diarrhea where other causes had been excluded) and was confirmed by a gastrointestinal biopsy in all but one case (97.9%; n = 47).
• Steroid refractory GI-aGvHD was diagnosed in patients who
  • failed to respond to steroid treatment within 5 days;
  • despite treatment, progressed during the first 72 hours; or
  • showed a partial response after 14 days.
• All patients received aGvHD prophylaxis:
  • Posttransplant cyclophosphamide + cyclosporine A + mycophenolate mofetil (n = 40)
  • Antithymocyte globulin (n = 35)
  • Cyclosporine A + methotrexate (n = 4)
  • Ex vivo alpha/beta T cells and CD19-depleted haplo-HSCT + rituximab + tocilizumab + abatacept (n = 6)
• Transabdominal ultrasonography was used to measure bowel wall thickness in all parts of the lower GI tract (small intestine, cecum, ascending colon, transverse colon, and descending colon) within 72 hours of diarrhea onset.

Baseline characteristics

• Baseline characteristics can be seen in Table 1.
  • Median age was 35 years, and there was a higher portion of males than females.
  • Most patients were diagnosed with AML or ALL.

Table 1. Patient, transplantation, and disease characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; CML, chronic myeloid leukemia; GI-aGvHD, gastrointestinal acute graft-versus-host disease; LPD, lymphoproliferative disorders; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; PBSC, peripheral blood stem cells. *Adapted from Drokov, et al.1
Characteristic, % unless otherwise stated	Patients with GI-aGvHD (n = 48)	Patients with diarrhea due to non-aGvHD cause (n = 37)
Median age, (range)	37 (19–64)	33 (17–61)
Sex
Male	54.2	40.5
Female	45.8	59.5
Hematologic malignancy, n
AML	19	17
ALL	12	12
CML/MPN	6	—
MDS	8	2
LPD	3	6
Donor characteristics
Match related	33.3	21.6
Match unrelated	35.4	24.3
Mismatch unrelated	18.8	21.6
Haploidentical	12.5	32.4
Conditioning regimen
Myeloablative	18.8	18.9
Reduced intensity	81.3	81.1
Transplant source
BM	37.5	45.9
PBSC	62.5	54.1
Median of diarrhea volume, mL (range)	1,000 (500–3,500)	600 (500–2,500)

Results

• Bowel wall thickness was independent of sex (p > 0.05) and not correlated with age (Pearson’s correlation coefficient <0.3).
• There was no significant correlation between bowel wall thickness and volume of diarrhea, which is used as a marker of the severity of GI-aGvHD.
• aGvHD was assessed according to Glucksberg’s criteria.
  • Stage I was diagnosed in 7.1% of patients
  • Stage II was diagnosed in 14.1% of patients
  • Stage III was diagnosed in 24.7% of patients
  • Stage IV was diagnosed in 10.6% of patients
• In the non-aGvHD group the causes of voluminous diarrhea included:
  • cytomegalovirus (CMV) colitis (n = 3)
  • human herpes virus 6 (HHV6) colitis (n = 8)
  • Clostridium difficile (n = 2)
  • chemotherapy (n = 24)
• The bowel wall was significantly thicker in patients with GI-aGvHD versus patients with diarrhea due to a non-aGvHD cause (Table 2).
• In patients with GI-aGvHD, bowel wall thickness was increased significantly in patients with steroid resistant GI-aGvHD at three measurement sites (terminal ileum, transverse colon, and descending colon; Table 3).
• Using ROC analysis, the descending colon was found to be the optimal area of bowel for evaluation: a descending colon bowel wall thickness of >4.5 mm had 64.7% sensitivity and 78.6% specificity in predicting steroid resistance in GI-aGvHD.

Table 2. Bowel wall thickness in patients with GI-aGvHD compared with patients with diarrhea due to a non-aGvHD cause*

GI-aGVHD, gastrointestinal acute graft-versus-host disease. *Adapted from Drokov, et al.1 †p values for all bowel areas, 0.0001.
	Patients with GI-aGvHD (n = 48)	Patients with diarrhea due to non-aGvHD cause (n = 37)
Median bowel wall thickness, mm (range)†
Terminal ileum	3 (1.5–11)	2 (1–6)
Cecum	4 (2–12)	2 (1.5–11)
Ascending colon	3.75 (2–20)	2 (1.4–14)
Transverse colon	4 (2–13)	2 (1.5–9)
Descending colon	5 (2–11)	2 (2–11)

Table 3: Bowel wall thickness in patients with steroid-refractory GI-aGvHD versus patients with steroid-sensitive disease*

GI-aGvHD, gastrointestinal acute graft-versus-host disease. *Data from Drokov, et al.1
	Steroid-refractory GI-aGvHD (n = 34)	Steroid-sensitive GI-aGvHD (n = 14)	p value
Median bowel wall thickness, mm (range)
Terminal ileum	4 (2–11)	2.75 (1.5–7)	0.029
Cecum	5.25 (2–12)	3 (2–10)	0.106
Ascending colon	5 (2–20)	3 (2–10)	0.184
Transverse colon	5.25 (2–13)	3 (2–8)	0.012
Descending colon	5 (2–11)	3 (2–7)	0.012

Conclusion

Increased bowel wall thickness, measured from transabdominal ultrasound, was found to be significantly associated with a diagnosis of GI-aGvHD in patients with voluminous diarrhea following allo-HSCT. Furthermore, increased bowel wall thickness had good sensitivity and specificity as a predictive marker for steroid-refractory GI-aGvHD.

Given ultrasonography is widely accessible, inexpensive, and non-invasive, this study suggests its potential role as a diagnostic tool for GI-aGvHD, as well as aiding early identification of a high-risk subset of patients with GI-aGvHD. However, further investigation in multicenter trials is needed to confirm this finding.