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ORIGINAL ARTICLE:

Endoscopy Following Pediatric Intestinal Transplant

Joanna Yeh, yKhiet D. Ngo, Laura J. Wozniak, Jorge H. Vargas, Elizabeth A. Marcus, Sue V. McDiarmid, zDouglas G. Farmer, and Robert S. Venick

ABSTRACT Key Words: , , ileoscopy, intestinal transplant, Objectives: remain the criterion standard in the diagnosis of pediatric intestinal transplant (ITx) rejection, and gastrointestinal endoscopy plays a pivotal role in patient management. Herein, we describe a single-center 23-year endoscopic experience in pediatric ITx recipients. (JPGN 2015;61: 636–640) Methods: A retrospective review of endoscopy and reports of all ITx recipients <18 years old transplanted between 1991 and 2013 was performed with the aim of describing the procedural indications, findings, What Is Known and complications. Results: A total of 1770 endoscopic procedures within 1014 sessions were Endoscopy with biopsies remains the criterion stan- performed. A combination of esophagogastroduodenoscopy and ileoscopy dard for diagnosis of intestinal transplant rejection. was the most common procedure (36%). Increased stool output (35%) and The rate of serious or life-threatening complications surveillance endoscopy (32%) were the most common indications. A total of in children undergoing endoscopy is estimated <1%; 162 episodes of biopsy-proven rejection were diagnosed. The first episode of the rate of serious endoscopic complications for rejection occurred at a median of 1 month after ITx. Of histology-proven pediatric intestinal transplant recipients is not well rejections, 45% had normal-appearing . The rate of procedural described. complications, including but not limited to bleeding and perforation, was 1.8%. What Is New Conclusions: Endoscopy with plays a significant role in the care of ITx recipients. Multiple procedures are required for graft surveillance, An endoscopic rate of 1.8% was diagnosis of rejection, subsequent treatment, and follow-up of therapy. observed over a 2-decade experience at a large The gross endoscopic appearance, particularly in mild to moderate acute pediatric intestinal transplant center. cellular rejection, does not correlate well with histology. Complex , Increased awareness of the higher risks and specific complication rates that are higher than patients with non-ITx pediatric nuances in the care of these patients is essential as is endoscopy, and timely histologic interpretation by experienced the need to develop a noninvasive biomarker to pathologists are reasons that these procedures should be performed at reliably detect rejection. centers accustomed to caring for ITx recipients. The field would benefit from the development of a noninvasive biomarker to reliably and efficiently detect rejection.

ntestinal transplantation (ITx) is a lifesaving operation for I children with intestinal failure who develop advanced intestinal Received October 7, 2014; accepted May 18, 2015. failure–associated disease, loss of central venous access From the Division of Pediatric Gastroenterology, Hepatology, and needed for parenteral nutrition, or life-threatening fluid and electro- Nutrition, University of California, Los Angeles, the yDivision of lyte problems (1). Advancements in allocation, surgical Pediatric Gastroenterology, Loma Linda University School of , techniques, immunosuppression, and posttransplant monitoring Loma Linda, CA, and the zDivision of Liver and Transplan- have translated into significant improvements in patients and graft tation, David Geffen School of Medicine, University of California, Los survival (2). Angeles. Timely diagnosis and treatment of graft dysfunction has Address correspondence and reprint requests to Joanna Yeh, MD, Department of Pediatrics, David Geffen School of Medicine and Mattel been an instrumental part of improved outcomes. After ITx, a Children’s Hospital, University of California, 10833 Le Conte Ave, noninvasive test to determine the etiology of allograft dysfunc- MDCC 12-383, Los Angeles, CA 90095-1752 (e-mail: JoYeh@mail. tion and to differentiate infectious enteritis from acute cellular cho.org). rejection (ACR) has yet to be developed. Therefore, serial This article has been developed as a Journal CME Activity by NASP- endoscopies with mucosal biopsies have been the standard GHAN. Visit http://www.naspghan.org/content/59/en/Continuing- invasive tests for allograft surveillance and rejection diagnosis Medical-Education-CME to view instructions, documentation, and sincetheinceptionofITx.Histologiccriteriahavebeenagreed the complete necessary steps to receive CME credit for reading this upon to grade ACR, thus solidifying the role of post-ITx endo- article. scopy (3). Creation of an at the time of ITx allows for E.A.M. is a National Institutes of Health/National Institute of Digestive and direct access to facilitate the monitoring of graft function. With Diseases grant recipient (1KO8DK100661-01). The other authors report no conflicts of interest. early recognition of graft dysfunction, immunosuppression can Copyright # 2015 by European Society for Pediatric Gastroenterology, be tailored accordingly. There are few reports on endoscopy in Hepatology, and Nutrition and North American Society for Pediatric pediatric ITx patients. The purpose of the present study is to Gastroenterology, Hepatology, and Nutrition characterize and analyze the endoscopic experience at a large DOI: 10.1097/MPG.0000000000000871 pediatric ITx center.

636 JPGN Volume 61, Number 6, December 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited. JPGN Volume 61, Number 6, December 2015 Endoscopy Following Pediatric Intestinal Transplant

METHODS In the majority of patients undergoing EGD, 2 to 3 sites each This institutional review board–approved analysis included consisting of 2 to 3 biopsies were taken every 5 to 10 cm from the all endoscopies performed by a single ITx center over a 23-year proximal graft, ideally 10 cm beyond the anastomosis of the period from 1991 to 2013. A retrospective review of a prospectively native and transplanted small bowels. For ileoscopies, 2 to 3 sites maintained database and medical record review included all ITx each consisting of 2 to 3 biopsies were also taken every 5 to 10 cm recipients <18 years of age at the time of transplant. All of the from the distal graft. Depending on the patient’s anatomy and risks, endoscopy and pathology reports were also reviewed. Surgical the distal graft was typically surveyed up to 50 to 60 cm from the techniques, immunosuppression, and outcomes have been pre- ostomy or ileocolonic anastomosis. A total of 1 to 2 sites of the viously described (4,5). native , , and/or colon were obtained to help differentiate rejection from infection because rejection should affect only transplanted bowels. Procedure Protocols and Techniques Owing to their complex medical histories and frequent significant requirements, the majority of patients typically Endoscopy of ITx recipients was performed for 2 main required the care of the pediatric team. Patients with reasons: surveillance monitoring or allograft dysfunction with delayed gastric emptying and a history of aspiration or respiratory suspected rejection. Our post-ITx surveillance protocol was weekly issues with procedures often underwent general anesthesia with for the first 4 to 6 weeks, every other week in month 2, and monthly endotracheal . Nearly all of the ileoscopies alone were in months 3 through 6. Surveillance endoscopy was also performed performed with deep sedation without intubation. before ostomy takedown and repeat establishment of gastrointes- The visual appearance of the bowel was assessed by the tinal (GI) continuity. During the first month after ITx, typically only endoscopists (a combination of gastroenterology fellow in training ileoscopy was performed to avoid intubation and manipulation of and attending physicians experienced in the care of ITx recipients). the proximal anastomosis. All of the ITx recipients had end Standard descriptors of mucosal appearance included erythematous, ileostomy (n ¼ 18, 20%), end ileostomy þ proximal ileocolostomy friable, ulcerated, denuded, or grossly unremarkable. Assessments (n ¼ 51, 56%), loop ileostomy (n ¼ 13, 14%), or proximal end for the villous appearance (normal or blunted) and the vascular ileostomy þ ileoileostomy and ileocolostomy (n ¼ 9, 10%) created pattern were also made. during the transplant procedure to facilitate surveillance and accu- All of the biopsy samples were processed within 24 hours. rate monitoring of stool output and consistency. Immunohistochemical tissue staining for adenovirus and CMV Symptomatic reasons for endoscopy included allograft dys- became our standard practice with the selective use of EBV-encoded function with increased stool output (>30 cm3 kg1 day1), GI small RNA and other hematopathology staining on a case-by-case bleeding, persistent Epstein-Barr virus (EBV) or cytomegalovirus basis if there were concerns for posttransplant lymphoproliferative (CMV) viremia, or marginal weight gain. For patients who presented disease (PTLD). Biopsies were reported to have absence of inde- acutely with an increase in stool output, our practice evolved into terminate, mild, moderate, or severe ACR per criteria established in sending a first line of stool studies (which currently includes stool 2004 (3). Enteritis was also reported. cells, Clostridium difficile, adenovirus, rotavirus, norovirus, viral Biopsy-proven mild to moderate ACR episodes were treated culture, and early viral antigen). If these stool studies were negative with high-dose intravenous methylprednisolone bolused over and stool outputs remained elevated for 72 to 96 hours, then we 7 days. Anti-thymocyte globulin was generally reserved for epi- proceeded with second line of stool studies (bacterial culture, ova and sodes of severe rejection. Infectious enteritis was treated with parasite, cryptosporidium, and giardia) and endoscopy. supportive care and in some instances with antibiotics when appro- Preparation for endoscopy varied significantly depending on priate. Following the diagnosis of either acute rejection or infection, clinical indication, age, and clinical status (ie, hydration status and treatment was initiated, and patients were observed closely for renal function) of the patient. Patients who underwent routine clinical response. Subsequent follow-up endoscopies were per- surveillance were typically placed on a clear liquid diet the day formed as frequently as biweekly to monthly to track histologic before their procedure and were made nil per os before the changes closely (Fig. 1). procedure according to their age. Patients undergoing upper endo- scopy and/or ileoscopy rarely received additional bowel pre- paration. In the patients undergoing colonoscopy, additional RESULTS bowel preparation including GoLytely (Braintree Laboratories, During this time period 74 children received 91 ITx. A total Braintree, MA) or may have been administered. of 1770 endoscopies were performed during 1014 endoscopy Given the frequency of renal insufficiency in this population, bowel sessions in 71 children (Tables 1 and 2). Their ages ranged from preparation was typically administered conservatively (6). 9 months to 18 years at the time of transplant. The mean age at the Preprocedure laboratory tests were performed to ensure a time of transplant was 4.7 4.3 years and median age was 2.8 years platelet count of 50,000/mL and international normalized ratio of (1.3, 7.7 years). After ITx, 76% of children underwent ostomy 1.5 to decrease the risk of bleeding. Biopsy forceps used were takedown at 16 months (11,24). Overall, 1- and 5-year survivals either 2.8 or 2.0 mm (Boston Scientific, Marlbor- among pediatric ITx recipients was 80% and 68% of patients, and ough, MA) depending on the age and size of the patient. Endoscopes 68% and 59% of graft survival. used were Olympus GIF 160, GIF H180, and PCF 160 AL The procedures included 708 ileoscopies, 725 EGDs (upper (Olympus America, Center Valley, PA). enteroscopies), and 337 . The most common type of Esophagogastroduodenoscopy (EGD) and ileoscopy were endoscopy session was EGD þ ileoscopy (36% of the endoscopy performed with appropriately sized endoscopes. In patients in sessions). whom the proximal anastomosis between native and transplanted The most common indications for endoscopy were small bowel was difficult to reach with shorter endoscopes (ie, increased stool output, accounting for 35% of the endoscopy >100 cm from mouth), a colonoscope was used. For colonoscopy, sessions, and surveillance (32%). The remaining indications typically a PCF 160 AL was used, but in younger recipients and in included follow-up of allograft from recent rejection episodes, patients with a shorter length of colon, a standard upper endoscope GI bleeding, obstructive symptoms, and other indications, which could be used. canbefoundinTable2.

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FIGURE 1. Endoscopic view of severe acute rejection with nodularity, loss of normal vascular pattern, and loss of normal appearance of villi (A). Endoscopic view of typical surgical anastomosis site with afferent and efferent limbs ‘‘owl’s eye’’ (B).

perforations occurred within the first 6 months after ITx; however, TABLE 1. Demographics there were 3 perforations that occurred 2 to 4 years out from ITx. Sex (male:female) 38:33 (54% male:46% female) The majority of perforations occurred during ileoscopies (9/11), Ethnicity Latino, n ¼ 41 whereas 2 were during colonoscopies. Of the 11 perforations, 8 White, n ¼ 22 underwent exploratory , and 3 were medically managed African American, n ¼ 4 with bowel rest and broad-spectrum antibiotics. Among the 8 Asian American, n ¼ 3 surgically managed perforations, 6 required resection of small Other, n ¼ 1 bowel (range 1–12 cm) and ultimately underwent primary repeat Median age at transplant 2.8 y (1.3, 7.7 y) anastomosis or placement of a diverting ostomy. The remaining 2 (25%, 75% quartiles) exploratory underwent peritoneal washout with the Mean age at transplant (SD) 4.7 y (4.3 y) inability to identify the perforation site, presumably because the site Median follow-up time 42 mo (11, 83 mo) had already sealed off. One patient did lose the entire graft because (25%, 75% quartiles) of delayed recognition of perforation. This child developed perito- nitis and subsequent with hypotension, contributing to the ischemic necrosis of the transplanted bowel. General endotracheal anesthesia was the most commonly used method for sedation, accounting for approximately two thirds of patients compared with conscious or deep sedation. DISCUSSION Among 1770 endoscopies (9%), 162 episodes of biopsy- The majority of early post-ITx care is performed at special- proven rejection were detected. Of these, 45% had a normal gross ized centers. The community gastroenterologist should be aware of appearance to the endoscopists. A total of 7 patients with PTLD the unique needs of ITx patients, however, when they return home involving the GI tract were diagnosed via endoscopy. to their local community. Potential complications from endoscopy, Thirty-two serious complications were documented comorbid medical conditions, and complex anatomy are factors that (Table 2). The most frequent complications included GI bleeding differentiate post-ITx patients from the general pediatric GI patient. (13 patients) and perforation (11 patients). The serious complication rate overall was 1.8% (32/1770). No deaths and 1 graft loss resulted Indications for Endoscopy from these complications. Among patients who sustained perforations, the age at the A significant number of post-ITx endoscopies are performed time of complication ranged from 1 to 12 years. Overall, most as surveillance. In an asymptomatic patient, particularly in the early

TABLE 2. Endoscopic and histologic results

Total no. of endoscopy procedures performed 1770 Total no. of endoscopy sessions 1014 Endoscopy types EGD þ ileoscopy ¼ 367 Ileoscopy ¼ 221 EGD þ colonoscopy ¼ 167; EGD þ ileoscopy þ colonoscopy ¼ 102 EGD ¼ 89; colonoscopy ¼ 50; ileoscopy þ colonoscopy ¼ 18 Indications Increased outputs ¼ 352; surveillance ¼ 325; follow-up rejection ¼ 106 GI bleed ¼ 97; procedure ¼ 25; obstructive symptoms ¼ 14; other ¼ 95 Sedation types General endotracheal anesthesia ¼ 680; conscious/deep sedation ¼ 334 Complications (n ¼ 32) GI bleeding ¼ 13; GI perforation ¼ 11; GI hematoma ¼ 6; gastric mucosa avulsion ¼ 1; distension from retained air ¼ 1

CMV ¼ cytomegalovirus; EBV ¼ Epstein-Barr virus; EGD ¼ esophagogastroduodenoscopy; GI ¼ gastrointestinal; PTLD ¼ posttransplant lymphoproli- ferative disease. EBV, CMV, preoperative ostomy takedown, fever, , PTLD follow-up, and adenovirus.

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posttransplant time period, surveillance endoscopy is routinely used In our experience, the most common type of procedure performed as the criterion standard at ITx centers to allow for early detection was EGD þ ileoscopy, thereby allowing for surveillance of both and effective treatment of rejection. Frequent and early endoscopies proximal (jejunal) and distal (ileal) grafts. Diagnostic yield from are performed given the high prevalence of ACR in the early endoscopy can be increased by performing 2 to 3 biopsies at posttransplant period (2). Indeed, this has been the case at our multiple locations typically separated by 5 to 10 cm. It is also institution where the median time to the first episode of ACR is important to evaluate the native bowel and to perform biopsy on it to 35 days. allow for adequate evaluation of an infectious process, PTLD, or Although stool output is closely measured and recorded daily medication’s adverse effects (ie, mycophenolate-associated enter- in the early post-ITx period, waiting for stool outputs to rise before itis). This is an extremely important point because the differential performing endoscopy early on after ITx would be synonymous diagnosis of pathology affecting the transplanted allograft alone as with waiting for a liver transplant recipient to become jaundiced compared with both the native bowel and transplanted allograft are before performing a to delineate their cause of graft unique. to visualize all of the allograft is a dysfunction. Such an approach delays early diagnosis and treatment consideration, but given the relatively young age of this cohort of and may significantly reduce the chances for successful treatment. patients, their propensity to dysmotility, and their high number of The field of ITx lacks a consistent biomarker to screen for prior abdominal , this must be approached with caution. and diagnose ACR. Unlike liver or , which rely on changes in transaminases or serum creatinine, such a marker Rejection is lacking in ITx. An acute increase in ostomy outputs often raises concern in ITx patients, but this is a nonspecific finding, which can Histology is critical in the diagnosis of ACR because gross be secondary to variation in enteral intake, infectious enteritis, or endoscopic findings can be misleading. Advancements including rejection. Stool calprotectin has been heralded as a potential zoom magnification endoscopy have not replaced histologic exam- biomarker, but it has significant interpatient variability and is ination for the diagnosis of rejection (13). Gross findings, including unable to differentiate between infection and rejection (7). Serum erythema, nodularity, pallor, and edema, are nonspecific. Even citrulline has also been considered; however, it has not been shown frank ulcerations, although suspicious for rejection, may be con- to predict asymptomatic rejection and also has significant varia- sistent with other diagnoses including infection. Sigurdsson et al bility between patients (8). Immune cell function assay (Cylex (14) reported that 37% of patients with ACR would have been ImmuKnow; Viracor-IBT Laboratories, Lee’s Summit, MO) has missed without biopsies. This was consistent with previous findings been investigated, and although it may be used as an adjunctive that mucosal visualization alone was not sensitive enough to diagnostic tool, it cannot replace endoscopy with biopsy (9). establish a diagnosis and would miss patients with mild ACR Finally, the newly Food and Drug Administration–approved Plex- (15–17). Our experience is congruent with these previous findings immune test (Plexision, Pittsburgh, PA) is designed to predict the in that nearly half of biopsy-proven rejection episodes had grossly risk of ACR after pediatric liver or intestine transplantation but is normal-appearing endoscopies. yet to be used in a large multicenter study. Although gross findings may be unreliable in patients with Beyond surveillance, other indications for endoscopy include mild or moderate ACR, in patients with severe exfoliative ACR, symptoms such as , fever, , abdominal pain, GI endoscopists will often have a strong sense of the clinical problem bleeding, and abdominal distension. In such patients, endoscopy and may even elect to initiate treatment before the biopsy results with biopsies can help in evaluating for PTLD, tissue invasive CMV being reported. Despite being the criterion standard for rejection, infection, and rejection. Endoscopy may also be indicated for there are limitations to endoscopy with biopsy. Rejection of the - tube replacement, the evaluation of the graft can be patchy in nature, and endoscopy is unable to survey the health of the graft before ostomy takedown, or surveillance follow- entire transplanted bowel. As reported by Pasternak et al (18), in ing the treatment of rejection or PTLD. patients with mild and moderate rejection, histologic findings are Infectious enteritis is a common complication in immuno- absent in 20% of tissue samples. Furthermore, although useful for suppressed ITx patients (10), and endoscopy can help to differen- diagnosing ACR, endoscopic biopsies do not yield the full thickness tiate rejection and infection, especially when initial stool studies are biopsies needed to diagnose chronic rejection. Finally, although the negative yet patients continue to have elevated stool outputs. field of knowledge of antibody-mediated rejection including C4d Infectious enteritis, in particular adenovirus, can also present con- staining has grown, this diagnostic tool has not been validated in comitantly with a rejection episode. recipients of ITx. Finally, graft-vs-host disease (GVHD) of the GI tract is an extremely rare but serious complication that can occur when donor Posttransplant Lymphoproliferative Disease immune cells in the transplanted bowel attack the native remnant bowel. Histologic evaluation is essential in diagnosing GVHD (11). PTLD is an uncommon but fatal complication of ITx. The prevalence of PTLD in our pediatric ITx population is 16%. The median time to diagnosis of PTLD following ITx is 20 months with Type of Endoscopy 31% diagnosed in the first year. Presentation and clinical symptoms associated with PTLD vary greatly but can include fever, weight Based on clinical experience and previously published work loss, hematochezia, abdominal distension, obstruction, and diar- (12), it is known that the pattern of ITx rejection may be patchy. rhea. In our experience, 7 patients >23 years developed PTLD Therefore, sampling of both suspicious and normal-appearing involving the GI tract that was diagnosed histologically via endo- bowel in multiple graft locations is necessary to identify histologic scopic biopsies. These GI presentations account for 58% of the evidence of rejection. Studies have shown that the is most PTLD, which we have observed. Grossly, most PTLD lesions were reliable in the detection of rejection, whereas jejunal sampling alone found incidentally on biopsy in that they did not stand out dramatic- may miss rejection episodes. Our ability to broadly survey the ally to the endoscopists. Five of these 7 patients had PTLD transplanted allograft is limited to the more proximal and distal involving the transplanted ileum, whereas 2 had PTLD in their portions of the graft with the majority of the middle portion of the native colon. Time to diagnosis ranged from 1.7 to 107 months graft unreachable. This represents a major limitation of endoscopy. after ITx.

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Complications REFERENCES There is a paucity of integrated, consistent data on the 1. Kaufman SS, Pehlivanova M, Fennelly EM, et al. Predicting liver failure in parenteral nutrition-dependent short bowel syndrome in infancy. incidence of complications in non-ITx pediatric endoscopy. In J Pediatrics 2010;156:580–5. non-ITx patients, the EGD complication rate is reported as 2.3%, 2. Fischbein TM. Intestinal transplantation. NEJM 2009;361:998–1008. most of which were hypoxia related (66%) and reversible (19). In 3. Ruiz P, Bagni A, Brown R, et al. Histological criteria for the identifica- this same study of EGDs, the bleeding rate was 0.3% (28 episodes of tion of acute cellular rejection in human small bowel allografts. 10,236 procedures), and there were no perforations (19). The Transplant Proc 2004;36:35–7. overall rate of serious or life-threatening complications in children 4. Farmer DG, McDiarmid SV, Edelstein S, et al. 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