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Utility of Endoscopic Examination in the Diagnosis of Acute Graft-versus-Host Disease in the Lower Gastrointestinal Tract.

1. Introduction

Early diagnosis and treatment are essential for graft-versushost disease (GVHD), which is a serious complication that influences the prognosis of patients after allogeneic transplantation [1]. However, because GVHD is frequently accompanied by various infections that developed after hematopoietic stem cell transplantation as well as by disorders induced by nonimmunological mechanisms, it is difficult to identify GVHD based solely on clinical symptoms [2].

Therefore, when making a diagnosis of GVHD in the gastrointestinal (GI) tract, it is important to perform endoscopy and diagnostic histopathological examination of biopsy specimens [3], but only a few studies have reported the endoscopic feature of GVHD in detail.

In this study, we therefore retrospectively investigated the incidence and endoscopic features of GI GVHD that had occurred within 100 days of hematopoietic stem cell transplantation and analyzed the association between the endoscopic features and histopathological GVHD.

2. Patients and Methods

2.1. Patients. Of 1231 patients who underwent allogeneic hematopoietic stem cell transplantation between January 2005 and December 2014, 523 developed GI symptoms indicative of GVHD such as diarrhea and poor appetite and 222 subsequently underwent colonoscopy. After excluding 35 patients with cytomegalovirus (CMV) infection, 186 patients who had also undergone biopsy for histopathological assessment were enrolled in this study (Figure 1). Some patients underwent identical endoscopic examinations more than twice within 100 days of transplantation. In those patients, the results from the first examination were analyzed in this study.

2.2. Methods. In each case, various endoscopic findings (edema, redness, erosion, ulcer, villous atrophy, atrophy of the ileocecal valve, and mucosal exfoliation in the terminal ileum and edema, redness, erosion, ulcer, low vascular permeability, tortoise shell-like mucosae, and mucosal exfoliation in the colon) were extracted retrospectively (Figure 2), and their association with histopathological GVHD was investigated by calculating sensitivity, specificity, and positive predictive values. A similar analysis of grade 3/4 GVHD was performed. Histopathological diagnosis of GVHD was performed according to the grading criteria developed by Sale et al. [4] (Table 1). In addition, when patients underwent multiple biopsies, the highest histopathological grade was used in this study. It should be noted here that biopsy was performed only when the number of platelets was [greater than or equal to] 50,000 cells/[mm.sup.3].

3. Results

3.1. Incidence. Based on histopathological findings in the lower GI tract, GVHD was diagnosed in 171 patients, accounting for 91.9% of the patients who had undergone endoscopy and 16.4% of all transplant recipients. Sixty patients had GVHD only in the lower GI tract and not in other organs.

3.2. Patient Background. Endoscopy was performed in 122 men and 64 women (average age, 50.6 years; range, 19-82 years) within approximately 41.3 (13-100) days after transplantation. The primary disease was acute leukemia in 120 patients, malignant lymphoma in 38, myelodysplastic syndrome in 16, chronic myelogenous leukemia in 5, and other in 7. The source of stem cells for transplantation was umbilical cord blood in 125 patients, bone marrow in 36, and peripheral blood from a relative in 25. All patients underwent additional treatment to prevent GVHD, such as combination therapy with tacrolimus (FK506) and mycophenolate mofetil (MMF) in 72 patients; combination therapy with methotrexate (MTX), MMF, and FK506 or cyclosporin A (CyA) in 57; and monotherapy with CyA in 57. Biopsies were conducted at 4.9 sites on average (Table 2). In addition, a colonoscope was inserted up to the terminal ileum in 154 (82.8%) patients, to the right-side colon in 17 (9.1%), and to the left-side colon in 15 (8.0%).

3.3. Histopathological Staging of GVHD. Histopathological severity of GVHD was grade 1 in 52 (28.0%) patients, grade 2 in 36 (19.4%), grade 3 in 45 (24.2%), and grade 4 in 38 (20.4%).

3.4. Positive Biopsy Rate. The rate of positive biopsy by a GI region was 90.4% for the terminal ileum and 94.4% for the colon (Table 3). More specifically, the left- and right-side colon and terminal ileum all had similar rates (around 90%), with no significant difference between the anatomical regions. Reanalysis of actual GVHD cases revealed that 97.3% of the patients were diagnosed with GVHD based on colonoscopy of the left side of the colon alone, whereas the remaining 2.7% were diagnosed based on colonoscopy up to the right side of the colon or terminal ileum, and GVHD was negative in the left side of the colon. In the analysis of anatomical sites with the highest grade in each patient, the most severe form of GHVD was found frequently in the following order: left side of the colon < right side of the colon < terminal ileum. This shows that the severity of GVHD tended to increase as it gets deeper.

3.5. Terminal Ileum. GVHD was present in the terminal ileum of 122 patients, one of whom was diagnosed based on the assessment of the terminal ileum alone. Frequent endoscopic findings were atrophy of the ileocecal valve (68.0%) and villous atrophy (49.6%). No abnormal findings were observed in 30 (22.2%) patients. Sensitivity toward GVHD was low for every endoscopic feature, but specificity and positive predictive value were 100% for villous atrophy, ulcer, and mucosal exfoliation and [greater than or equal to] 80% for edema, redness, and erosion. In addition, GVHD was diagnosed in 80% of the patients with no abnormal findings. Reanalysis of grade 3/4 GVHD cases showed a high positive predictive value of approximately 90% for mucosal exfoliation (Table 4).

3.6. Colon. GVHD was detected in the colon of 170 patients. Frequent endoscopic findings were low vascular permeability (80.0%), edema (73.3%), and tortoise shell-like mucosae (67.6%). Specificity was 100% for ulcer and mucosal exfoliation and 93.3% for erosion, and positive predictive value was [greater than or equal to] 90% for all endoscopic findings, showing high diagnostic performance. GVHD was diagnosed in 75% of 12 patients with no abnormal findings. Analysis of grade 3/4 GVHD cases revealed a high positive predictive value of 93.3% for mucosal exfoliation and 81.3% for ulcer (Table 4).

3.7. Treatment Efficacy. Treatment efficacy was observed in 75.4% of all patients. Potent therapy with, for example, antithymocyte globulin (ATG) or infliximab tended to be indicated for histopathologically severe GVHD, showing a correlation with actual clinical practice. A comparison by a disease stage showed that treatment efficacy was as high as 92.3% in grade 1 GVHD but decreased gradually to 86.1% in grade 2, 80.0% in grade 3, and markedly to 36.8% in grade 4 (Table 5). Comparative analyses with endoscopic findings revealed that treatment efficacy was clearly low at 50.0% in 26 patients with mucosal exfoliation.

4. Discussion

GVHD is a disease caused by donor lymphocytes recognizing host histocompatibility antigens as foreign and attacking them immunologically. In definition, GVHD occurs within 100 days of transplantation [5]. Primary target organs are the skin, liver, and GI tract, and characteristic clinical symptoms include maculopapular rash, nausea, vomiting, diarrhea, and jaundice. The pathogenesis of GI GVHD is thought to be direct mucosal damage in the GI tract made directly by donor cytotoxic T cells and tissue damage made by cytokines secreted by the T cells [1].

The incidence of acute GI GVHD is estimated to be 30-60% of all transplant recipients [6]. In general, various GI symptoms such as watery diarrhea, nausea, vomiting, and poor appetite start 1-2 weeks after the appearance of skin lesions. Abdominal pain and melena also develop as the disease progresses, and paralytic ileus is observed in severe GVHD cases. In more severe cases, sepsis may trigger endo-toxin shock, potentially causing death. Even though GVHD is a life-threatening complication, diagnostic specificity based solely on clinical symptoms was reported to be 50% or even below in patients with GVHD [7].

Biopsy is essential in making a diagnosis of GVHD, and specimens are taken from organs such as the skin, liver, and GI tract. The rate of positive biopsy was 46% for the skin but was as high as 58% for the upper and lower GI tract, indicating the validity of GI endoscopy in diagnostic biopsy [6]. In this study, histopathological diagnosis of lower GI GVHD was made in 91.9% of the patients suspected of having GVHD. At our hospital, endoscopic examination through the GI tract is performed for the definitive diagnosis of GVHD as soon as the disease is suspected, which apparently contributed to the high diagnostic rate in this study.

GVHD is histopathologically characterized by the apoptosis of crypt epithelial cells accompanied by the infiltration of lymphocytes [8]. The epithelial cells in the crypt base region, from where the intestinal epithelium proliferates, appear to be the target of GVHD [9]. The clinical course of GVHD involves the development of crypt abscess due to neutrophil infiltration, crypt loss, and eventually mucosal exfoliation. Apoptosis of crypt epithelial cells is observed occasionally in the biopsy specimens of the mucosa that appear normal, providing useful information for the early diagnosis of GVHD [4].

The differential diagnosis includes regimen-related toxicity, CMV and other viral infections, TMA (thrombotic microangiopathy), bacterial enteritis such as pseudomembranous enterocolitis, and Candida and other fungal enteritis [10]. Before making a diagnosis of GVHD, it is important to remember that CMV infection and the effect of pretransplantation chemotherapy or radiotherapy, which lasts for about 20 days after transplantation, can induce apoptosis [11]. After allogeneic transplantation, agranulocytosis triggered by pretreatments lasts for 2-3 weeks, and cellular immunodeficiency induced by immunosuppressants continues even after engraftment, increasing the risk of infection and the resulting mortality rate. These complications are closely associated with the recurrence risk of leukemia, often making their management difficult. While the risk of mortality from GVHD increases when immunosuppressants are not potent enough, superpotent immunosuppressants increase the risks of recurrent leukemia and infection. It is essential to balance the risks of GVHD and infections to improve treatment efficacy after allogeneic transplantation.

In this study, 16.4% of the 1231 transplant recipients developed GVHD in the lower GI tract. The known common sites of lower GI GVHD are the terminal ileus, cecum, and ascending colon [12]. However, no significant difference was observed between the left- and right-side colon and the terminal ileum in this study (Table 3).

The known characteristic endoscopic features of GVHD in the terminal ileum are villous atrophy, redness, edema, erosion, and shallow and wide ulcer-like lesions [12], but these features vary extensively and lack specificity. In this study, atrophy of the ileocecal valve and villous atrophy were frequent endoscopic findings with high specificity and positive predictive value. In particular, atrophy of the ileocecal valve has not been reported previously, and the high incidence rate (approximately 70%) and positive predictive value (approximately 90%) in this study suggest that atrophy of the ileocecal valve can be a useful diagnostic marker for lower GI GVHD.

The known characteristic endoscopic findings of GVHD in the colon are orange peel appearance and tortoise shelllike mucosae [13], the latter of which is a regularly mesh pattern appearing in the mucosa of the colon and can be visualized clearly by indigo carmine dye spraying. It represents highly advanced diffuse edematous changes in the mucosa and is histologically associated with edema in the lamina propria. The enlargement of the lamina propria due to edema makes cryptic density sparse in the colon and emphasizes innominate grooves and the opening of crypts, leading to the appearance of the tortoise shell-like mucosae. In this study, the incidence and positive predictive value of the tortoise shell-like mucosae were both high, suggesting that it is a characteristic endoscopic finding of lower GI GVHD. The incidence rate and positive predictive value were also high for low vascular permeability and mucosal edema.

Also in this study, 26 patients had mucosal exfoliation (18 in the terminal ileum and 15 in the colon). Despite the relatively low incidence rate, the positive predictive value of mucosal exfoliation was as high as 92.3% for grade 3/4 GVHD, indicating that this endoscopic feature is an extremely important predictor of severe GVHD. Indeed, only about 50% of the patients with mucosal exfoliation responded to treatment in this study. Therefore, when endoscopic findings include mucosal exfoliation, early intervention should be initiated even before obtaining biopsy results.

In addition, attention must be paid to patients with no abnormal endoscopic findings because in a previous study, GVHD was histopathologically diagnosed in the areas appearing virtually normal in endoscopy [2]. Also in this study, GVHD was histopathologically diagnosed in 78.9% of the terminal ileum and 75.0% of the colon where no abnormal endoscopic features were observed. Therefore, even when patients present with seemingly normal gastrointestinal mucosa, biopsy should be performed whenever possible.

In this study, we also investigated whether the deep insertion of a colonoscope is necessary. In clinical practice, it is often difficult to insert a colonoscope all the way to the terminal ileum in transplant recipients because of poor general conditions and insufficient bowel preparation. In this study, lower GI GVHD was diagnosed at a rate of 91.2% based solely on biopsy assessment of the left-side colon, suggesting that colonoscopy should be performed regardless of patient performance status. However, because the terminal ileum is often most severely affected by GVHD, colonoscopy should include the terminal ileum if possible.

This study has several limitations. First, this is a retrospective single-institution study with a limited number of patients. Secondly, the interpretation of endoscopic findings was performed by one examiner. Thirdly, GI endoscopy was not performed in all transplant recipients, generating sampling bias. Therefore, we plan to perform a prospective study with a large number of patients in the future.

In summary, lower GI GVHD was diagnosed histopathologically in 91.9% of the patients who had undergone endoscopy and 13.9% of all transplant recipients. Useful endoscopic findings for the diagnosis of GVHD were atrophy of the ileocecal valve and villous atrophy in the terminal ileum and tortoise shell-like mucosae, edema, and low vascular permeability in the colon. In addition, although rare, mucosal exfoliation was highly correlated with grade 3/4 GVHD, necessitating the initiation of early intervention even before obtaining biopsy results.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


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Kosuke Nomura, (1) Toshiro Iizuka, (1) Daisuke Kaji, (2) Hisashi Yamamoto, (2) Yasutaka Kuribayashi, (1) Masami Tanaka, (1) Tsukasa Furuhata, (1) Satoshi Yamashita, (1) Daisuke Kikuchi, (1) Akira Matsui, (1) Toshifumi Mitani, (1) Yasunori Ota, (3) Shuichi Taniguchi, (2) and Shu Hoteya (1)

(1) Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan

(2) Department of Hematology, Toranomon Hospital, Tokyo, Japan

(3) Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Correspondence should be addressed to Kosuke Nomura;

Received 20 April 2017; Accepted 28 June 2017; Published 2 October 2017

Academic Editor: Piero Chirletti

Caption: FIGURE 1: Study flow diagram. HHSCT: homologous hematopoietic stem cell transplantation; GI: gastrointestinal; CMV: cytomegalovirus.

Caption: FIGURE 2: Examples for endoscopic findings of lower GI: (a) edema, (b) redness, (c) erosion, (d) ulcer, (e) villous atrophy, (f) atrophy of the ileocecal valve, and (g) mucosal exfoliation in the terminal ileum and (h) edema, (i) redness, (j) erosion, (k) ulcer, (l) low vascular permeability, (m) tortoise shell-like mucosae, and (n) mucosal exfoliation in the colon.
TABLE 1: Definition and the histological grading system for acute

Grade                    Histological feature

I       Single-cell necrosis (apoptosis) noted on medium power

II         Evidence of epithelial damage by crypt/grandular
            abscesses, epithelial flattening, or glandular/
                            crypt dilation

III              Dropout of one or more crypts/grands

IV                    Total epithelial denudation

TABLE 2: Patient characteristics.

Number                                                   186
Average age, year (range)                           50.6 (19-82)
  Male                                                   122
  Female                                                 64
Average inspection days after transplantation
CS                                                  41.3 (13-100)
Average number of biopsy specimens                       4.9
Primary disease
  Acute leukemia                                         120
  Malignant lymphoma                                     38
  Myelodysplastic syndrome                               16
  Chronic myelogenous leukemia                            5
  Others                                                  7
Stem cell source
  Cord blood stem cell transplantation                   125
  Bone marrow transplantation                            36
  Alloperipheral blood stem cell transplantation         25
Previous treatment
  FLU-based regimen                                      161
  CY/TBI or CY/BU                                        25
Preservation of GVHD
  FK + MMF                                               72
  MTX + CyA/FK/MMF                                       57
  CyA or FK                                              57
Extent of endoscopic insertion
  Up to the left-side colon                              15
  Until the right-side colon                             17
  Terminal ileum                                         154

FLU: fludarabine; CY: cyclophosphamide; TBI: total body irradiation;
BU: busulfan; CyA: cyclosporin A; MTX: methotrexate; MMF:
mycophenolate mofetil.

TABLE 3: The rate of positive biopsy.

Terminal ileum     90.4%
Colon              94.4%
Right-side colon   91.5%
Left-side colon    91.7%
Rectum only        87.7%

TABLE 4: Summary of outcomes of lower GI.

                                    Accuracy (%)   Sensitivity (%)

Terminal ileum
  Edema                                 36.3            40.0
  Redness                               40.0            44.0
  Erosion                               28.9            31.2
  Ulcer                                 5.2              5.6
  Villous atrophy                       49.6            54.4
  Atrophy of the ileocecal valve        69.2            71.3
  Mucosal exfoliation                   12.3            14.4
  No remarkable findings                22.2            24.0
  Edema                                 73.0            75.4
  Redness                               52.2            53.2
  Erosion                               38.2            40.9
  Ulcer                                 8.6              9.4
  Low vascular permeability             80.0            81.3
  Tortoise shell-like mucosae           67.6            49.7
  Mucosal exfoliation                   8.1              8.8
  No remarkable findings                6.5              7.1

                                    Specificity (%)   PPV (%)

Terminal ileum
  Edema                                  81.8          96.2
  Redness                                81.8          96.5
  Erosion                                90.9          97.5
  Ulcer                                   100           100
  Villous atrophy                         100           100
  Atrophy of the ileocecal valve         55.6          87.7
  Mucosal exfoliation                     100           100
  No remarkable findings                 27.3          78.9
  Edema                                  53.3          94.9
  Redness                                60.0          93.8
  Erosion                                93.3          98.6
  Ulcer                                   100           100
  Low vascular permeability              33.3          93.3
  Tortoise shell-like mucosae            53.3          94.4
  Mucosal exfoliation                     100           100
  No remarkable findings                 80.0          75.0

                                         PPV (%)
                                    (Grade III or IV)

Terminal ileum
  Edema                                   65.4
  Redness                                 66.7
  Erosion                                 70.0
  Ulcer                                   71.4
  Villous atrophy                         67.6
  Atrophy of the ileocecal valve          50.6
  Mucosal exfoliation                     88.9
  No remarkable findings                   7.9
  Edema                                   50.7
  Redness                                 59.8
  Erosion                                 74.6
  Ulcer                                   81.3
  Low vascular permeability               50.3
  Tortoise shell-like mucosae             48.4
  Mucosal exfoliation                     93.3
  No remarkable findings                   0.0

PPV: positive predictive value.

TABLE 5: Histological grade and effectiveness of treatment in patients
with acute GI GVHD.

GVHD grade   No treatment or BDP   +FK, PSL, and mPSL

Grade I         100% (19/19)         87.0% (20/23)
Grade II         100% (9/9)          88.2% (15/17)
Grade III        87.5% (7/8)         90.5% (19/21)
Grade IV        100.0% (3/3)          44.4% (8/18)
Total           97.4% (38/39)        78.5% (62/79)

GVHD grade   +ATG and infliximab        Total

Grade I         90.0% (9/10)        92.3% (48/52)
Grade II        70.0% (7/10)        86.1% (31/36)
Grade III       62.5% (10/16)       80.0% (36/45)
Grade IV        17.6% (3/17)        36.8% (14/38)
Total           54.7% (29/53)      75.4% (129/171)

BDP: beclometasone dipropionate; PSL: prednisolone; mPSL:
methylprednisolone; ATG: antithymocyte globulin.
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Title Annotation:Research Article
Author:Nomura, Kosuke; Iizuka, Toshiro; Kaji, Daisuke; Yamamoto, Hisashi; Kuribayashi, Yasutaka; Tanaka, Ma
Publication:Gastroenterology Research and Practice
Article Type:Report
Date:Jan 1, 2017
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