Objective: Intestinal graft-versus-host disease (GVHD) represents one of the most serious complications of allogeneic stem cell transplantation (allo-SCT). Endoscopic and histological proof is required due to the number of differential diagnoses manifesting as diarrhea. We investigated the safety of endoscopic biopsies, and the role of conducting biopsies and inspections of the terminalileum. Patients: Thirty two colonoscopic examinations and 29 biopsies were performed for 19 patients after allo-SCT in our institute between October 2011 and May 2015. Results: Endoscopic examinations and biopsies were performed safely under the policy of transfusing platelets for thrombocytopenia (<30 × 10 3/μL). For biopsied cases, the diagnostic consistency rate with endoscopic findings was 60%, with a tendency toward negative correlations with early examinations after diarrhea onset (25% for 0 - 1 days; 62.5% for later) or low-grade GVHD according to Freiburg criteria (41.2% for grade 1, 66.7% for grade 2, 100% for higher). The terminal ileum was inspected with colonoscopy in 13 cases. Endoscopic diagnoses of the ileum were provided in 11 cases and histological diagnoses in 9 cases. Diagnostic consistency for diagnosis of the terminal ileum between endoscopy and histology was 77.8%. Conclusion: Because endoscopic and histopathological findings do not always match, caution is required when focusing on endoscopic findings alone, as there is a risk of misdiagnosis. Extensive inspection of the terminal ileum with biopsy appears useful to identify otherwise undetected lesions. Our data thus support invasive endoscopic examinations for gastrointestinal complications, including ileac inspection and biopsies under appropriate management.
Allogeneic stem cell transplantation (allo-SCT) has become an essential modality for intractable hematological diseases. Common complications of allo-SCT include infections, conditioning regimen-related toxicities, and graft-versus-host disease (GVHD). Acute GVHD mainly affects the skin, liver and gastrointestinal (GI) tract [
Diarrhea is a common and complicating symptom after allo-SCT. This symptom can result from an extremely wide range of etiologies, including preparative regimen-related toxicity, infection, and GVHD [
Among the 46 patients who received allo-SCT in our institute between October 2011 and May 2015, 32 colonoscopic examinations were performed for 19 patients. This was a retrospective study that was approved by the Institutional Review Board at Gifu University Hospital and informed consent was obtained from each patient. Myeloablative conditioning (MAC) regimens comprised cyclophosphamide (CY, 120 mg/kg) in combination with either 12 Gy of total body irradiation (TBI) or busulfan (BU, 12.8 mg/kg for intravenous form) with or without cytarabine (Ara-C). Reduced-intensity conditioning (RIC) regimens consisted of CY (60 mg/kg), fludarabine (Flu, 150 mg/kg) and 2 - 4 Gy of TBI with or without Ara-C (n = 6). Microbiological analyses of stools, including bacterial cultures and the Clostridium difficile toxin assay, were also performed in parallel with colonoscopy. Cytomegalovirus (CMV) infection was monitored using a pp 65 antigenemia assay once weekly. CMV antigenemia was described in terms of the number of positive cells per slide using the C10/11 method (150,000 cells applied) [
All colonoscopies were performed using an Olympus colonoscope (CF-H260I, CF-Q260I, PCF-Q260AI, CF-HQ-290I, CF-H290I, or PCF-290I; Olympus Optical, Tokyo, Japan). Colonoscopic procedures were performed with conscious sedation using diazepam or midazolam. Biopsies were obtained using standard endoscopic forceps. Platelet transfusions were administered before colonoscopies at the discretion of the hematologist when platelet counts were below 30,000/μL. Endoscopists determined the preparation for colonoscopy, route of intubation and indications for biopsy. Endoscopic findings were graded using the Freiburg criteria, summarized as: Grade 1, no findings compatible with upper grades; Grade 2, spotted erythema, initial aphthous lesions; Grade 3, aphthous lesions (Crohn-like) or focal erosions; or Grade 4, confluent defects, ulcerations, complete denudation of the mucosa [
Characteristics of patients and allo-SCT procedures are summarized in
Thirty colonoscopic examinations were performed for 19 patients in search of etiologies for diarrhea after allo-SCT. Seven patients received two or more colonoscopic examinations. The reasons of repeated examinations were sustained diarrhea in 5 and relapse of diarrhea in 2. Volume of diarrhea before colonoscopy was <500 mlL/day in 10 cases, 500 - 999 mL/day in 13, 1000 to 1499 mL/day in 3, 1500 to 1999 mL/day in 3, and ≥2000 mL/day in 3. Polyethylene glycol and glycerin enema were used for bowel preparations in 10 and 3 cases, respectively, and in 19 case no preparation was done. Colonoscopic biopsy was performed in 29 examinations for 19 patients. Median duration from transplantation to first colonoscopy was 36 days (range, 15 - 79 days), showing no significant difference
n | % | |
---|---|---|
Age median (range) | ||
39 | (16 - 65) | |
Sex | ||
Male/female | 11/8 | |
Diagnosis | ||
AML | 6 | 31.6 |
ALL | 3 | 15.8 |
MDS | 3 | 15.8 |
CML | 1 | 5.3 |
AA | 1 | 5.3 |
ML | 5 | 26.3 |
Stem cell source | ||
PBSC | 5 | 26.3 |
BM | 7 | 36.8 |
CB | 7 | 36.8 |
Conditioning regimen | ||
MAC | 11 | 57.9 |
RIC | 8 | 42.1 |
GVHD prophylaxis | ||
CsA + MTX | 9 | 47.4 |
TAC + MTX | 10 | 52.6 |
GI stage of acute GVHD at colonoscopy (n = 32) | ||
0 | 12 | 37.5 |
1 | 13 | 40.6 |
2 | 1 | 3.1 |
3 | 3 | 9.4 |
4 | 3 | 9.4 |
AML: acute myelogenous leukemia; ALL: acute lymphoid leukemia; MDS: myelodysplasitc syndromes; CML: chronic myelogenous leukemia; AA: aplastic anemia; ML: malignant lymphoma; BM: bone marrow; PBSC: peripheral blood stem cell; CB: cord blood; MAC: myeloablative conditioning regimen; RIC: reduced-intensity conditioning regimen; CsA: cyclosporine; MTX: methotrexate; TAC: tacrolimus; GI: gastrointestinal; GVHD: graft-versus-host disease.
from the MAC and RIC groups (41 days; p = 0.77). Median duration from onset of diarrhea to colonoscopy was 2 days (range, 0 - 9 days). Median platelet count at biopsy was 40 × 103/μL (range, 10 × 103/μL - 309 × 103/μL). Platelet transfusion was performed in 11 cases before colonoscopy, with median platelet counts of 26 × 103/μL (range, 10 × 103/μL - 40 × 103/μL) at the time of biopsy and 27 × 103/μL (range, 14 × 103/μL - 65 × 103/μL)the next day. No major bleeding events were observed after these procedures.
Endoscopic diagnoses were GVHD, CMV, and thrombotic microangiopathy (TMA) in 25, 4, and 1 cases, respectively. Endoscopic grade of GVHD was 1, 2, 3, or 4 in 11, 8, 4, and 2 cases, respectively. The cases diagnosed as having Grade 1 presented edematous or tortoise-shell pattern only. Abnormal colonic mucosa was observed in 30 cases, and biopsy was performed in 29 cases. For those 29 cases, we compared colonoscopic diagnosis and pathological findings (
The terminal ileum was inspected with colonoscopy in 13 cases (
Endoscopic diagnosis | Performed biopsy | Histological finding | n | % | |
---|---|---|---|---|---|
GVHD | 25 | 21 | GVHD | 10 | 47.6 |
GVHD + CMV | 3 | 14.3 | |||
CMV | 1 | 4.8 | |||
colitis/proctitis | 7 | 33.3 | |||
CMV | 4 | 4 | CMV | 3 | 75.0 |
GVHD | 1 | 25.0 | |||
TMA | 1 | 1 | TMA | 1 | 100 |
colitis/proctitis | 2 | 2 | colitis/proctitis | 2 | 100 |
GVHD: graft-versus-host disease; CMV: Cytomegalovirus; TMA: thrombotic microangiopathy.
Endoscopic grade | (n) | Histological GVHD diagnosis (n) | Consistency rate (%) |
---|---|---|---|
1 | 12 | 5 | 41.2 |
2 | 6 | 4 | 66.7 |
3 | 3 | 3 | 100 |
4 | 1 | 1 | 100 |
after onset of diarrhea | (n) | ||
day 0, 1 | 4 | 1 | 25 |
day 2, 3 | 4 | 4 | 100 |
≥day 4 | 13 | 8 | 61.5 |
GVHD: graft-versus-host disease.
Ileoscopic finding | Colonoscopic finding | |||
---|---|---|---|---|
Ileoscopic diagnosis | Histological diagnosis | Colonoscopic diagnosis | Histological diagnosis | |
1 | GVHD | GVHD | GVHD | GVHD |
2 | CMV | CMV | CMV | CMV |
3 | CMV | CMV | CMV | CMV |
4 | No finding | None | GVHD | GVHD |
5 | GVHD | CMV | GVHD | GVHD |
6 | CMV | GVHD | No finding | None |
7 | GVHD | None | GVHD | None |
8 | No finding | None | CMV | GVHD |
9 | GVHD | GVHD | GVHD | GVHD |
10 | TMA | TMA | No finding | No finding |
11 | GVHD | None | GVHD | colitis |
GVHD: graft-versus-host disease; CMV: Cytomegalovirus; TMA: thrombotic microangiopathy.
Intestinal GVHD represents one of the most serious complications of allo-SCT, and endoscopic and, where possible, histological proof of GVHD is desirable due to the number of differential diagnoses after allo-SCT that can manifest as diarrhea. In particular, distinguishing GVHD from infectious etiologies is essential because of the reciprocal indication of immunosuppression. However, low platelet counts just after engraftment often cause concerns about the safety of endoscopic procedures, especially when selecting specimens for removal from the fragile mucosa. At our institute, we provided the platelet transfusion before endoscopic procedures when the platelet count was below 30 × 103/μL and no hemorrhagic complications were observed. Our policy might be overly cautious, because Inamoto et al. reported that no complications developed with platelet transfusion for 30 patients, although platelet count at biopsy was less than 20 × 103/μL in 12 patients [
The endoscopic findings for intestinal GVHD range from almost normal to extensive edema and mucosal sloughing. Whether these findings can predict the histological diagnosis and endoscopic grade of GVHD remains controversial. Kreisel et al. evaluated 175 consecutive patients with intestinal GVHD examined both endoscopically and histologically, and reported high diagnostic accuracy. Setting a cutoff between endoscopic grades 1 and 2, endoscopy offered 89.2% sensitivity, 79.4% specificity, a positive-predictive value of 79.6% and a negative-predictive value of 89.0% [
The fact that endoscopic findings of GVHD are similar to those of infections is important [
We showed topical diversity in GI tract lesions after allo-SCT by demonstrating different diagnoses between ileoscopic and colonoscopic examinations in some cases. Ross et al. reported higher accuracy of biopsies in the rectosigmoid colon than in the upper GI tract. Their study analyzed 112 patients who underwent simultaneous endoscopic biopsies of the stomach, duodenum and rectosigmoid colon within the first 100 days after allo-SCT. Rectosigmoid biopsies showed the highest sensitivity (95.6%) and specificity (100%) [
Our data suggest colonoscopy as a safe, effective method to examine for lower GI complications after allo-SCT. Early definitive diagnosis is needed, because GVHD, CMV and TMA each require different therapeutic approaches. Hematologists and endoscopists should not hesitate to perform colonoscopy, if possible, ileal intubation, and biopsy when lower GI complications arise.
We have no conflicts of interest to declare.
Kitagawa, J., Matsumoto, T., Shibata, Y., Nakamura, N., Nakamura, H., Ninomiya, S., Nannya, Y., Shimizu, M., Hara, T., Araki, H. and Tsurumi, H. (2017) Endoscopic Examination for Patients with Diarrhea after Allogeneic Stem Cell Transplantation. Open Journal of Internal Medicine, 7, 105-114. https://doi.org/10.4236/ojim.2017.74011