Description of the study cohort of 2 intestinal transplantation (ITx) and rehabilitation centers: 10 patients underwent transplantation, and the other 10 were on the waiting list or elected not to undergo transplantation and were therefore unavailable for follow-up. One patient underwent conventional surgery and 1 was taken off the waiting list. The mean (SD) calculated scores of all subgroups are indicated in parentheses. AWT indicates abdominal wall transplantation; KTx, kidney transplantation; and MVTx, multivisceral transplantation.
Gerlach UA, Vrakas G, Reddy S, Baumgart DC, Neuhaus P, Friend PJ, Pascher A, Vaidya A. Chronic Intestinal Failure After Crohn DiseaseWhen to Perform Transplantation. JAMA Surg. 2014;149(10):1060-1066. doi:10.1001/jamasurg.2014.1072
Because of the severity of disease and additional surgery, Crohn disease (CD) may result in intestinal failure (IF) and dependency on home parenteral nutrition (HPN). Defining the indication and timing for intestinal transplantation (ITx) is challenging.
To determine the limitations of conventional surgery and to facilitate the decision making for transplantation.
Design, Setting, and Participants
Data were collected prospectively and obtained by retrospective review of medical records from all patients with CD who were assessed for ITx in Oxford, United Kingdom, and Berlin, Germany, from October 10, 2003, through July 31, 2013. Patients were considered suitable for ITx if a diagnosis of irreversible IF was established and life-threatening complications under HPN were unresolvable. Twenty patients with CD and IF, established on HPN, were evaluated for ITx. The mean (SD) age at CD onset was 17.8 (9.8) years. On first diagnosis, most patients had a stricturing CD. By the time of referral, most had a combination of stricturing and fistulizing disease.
New scoring system: a modification of the American Gastroenterology Association guidelines for ITx. Modifications are related to CD-specific issues that potentially lead to a poorer outcome and are based on the findings of the study to determine the expected benefit from ITx.
Main Outcomes and Measures
A scoring system that would alert the physician to the severity of the patient’s CD and trigger early referral for ITx. This system may translate into better long-term outcomes for patients with CD. In addition, the Karnofsky performance status score was used to compare pretransplantation and posttransplantation outcomes.
Ten patients underwent ITx, 4 were on the waiting list, and 4 were unavailable for follow-up. One patient was taken off the waiting list because of severe deterioration. One patient underwent conventional stricturoplasty and did not need transplantation. Among the transplant recipients, 17 (85%) had a stoma or enterocutaneous fistula, and the mean (SD) residual bowel length was 71.5 (38) cm. A total of 80% of transplant recipients had life-threatening catheter infections, and 13 (65%) had a significant decrease in the estimated glomerular filtration rate. At a mean (SD) follow-up of 27.6 (36.1) months for transplant recipients, the patient and graft survival is 80%, and their Karnofsky performance status score increased by a mean of 18.6%.
Conclusions and Relevance
Intestinal transplantation is a suitable treatment option for patients with CD and IF. It should be considered before any additional attempts at conventional surgery, which may cause eligible patients to miss this opportunity through perioperative complications. The suggested scoring system enables the physician to identify patients who may benefit from transplantation before HPN-associated secondary organ failure.
The pathway of Crohn disease (CD) from diagnosis to burnout is riddled with various treatment modalities, including surgery, immunosuppressive therapy, and biologicals.1 Depending on the age at onset and severity of symptoms, patients may go through the entire spectrum of treatment only to be worse off with a relatively quiescent disease process.
After the effects of surgery, many patients develop enterocutaneous fistulas (ECFs) and significant short bowel syndrome, resulting in frozen abdomens and irreversible intestinal failure (IF). Intestinal failure is a rare but devastating complication of CD. Only a few specialized IF and rehabilitation centers treat reasonably high numbers of patients with CD, so the data are limited. However, patients with CD account for almost 25% of patients who require home parenteral nutrition (HPN),2- 4 so it is crucial to recognize predisposing risk factors and early predictors for a deteriorating disease course. The 2 chief causes for IF in patients with CD are primary active and mainly stricturing disease and perioperative complications, resulting in inflammatory or penetrating CD with the necessity of additional surgery.3,4
Intestinal transplantation (ITx) has developed into an adequate therapy for selected patients with IF in whom HPN fails,5 and the indications for transplantation have traditionally relied on the American Gastroenterology Association (AGA) guidelines.6 Currently, CD accounts for approximately 14% of ITx indications,7,8 and there is a need to appreciate the CD-specific conditions, such as ECF formation, continuous immunosuppression, and delayed wound healing, that unduly discriminate patients with CD from other patients with IF. Strict adherence to the AGA guidelines in patients with CD yields the risk that a number of potential ITx candidates may not be referred because of their stable condition with HPN and additional attempted surgical procedures to rid them of their ECFs. Given the direct link among extensive surgical procedures, perioperative complications, and IF, these surgical attempts need to be critically appraised.4,9,10 In this report, we characterized patients with CD and IF who were assessed in 2 similarly sized ITx programs in Oxford, United Kingdom, and Berlin, Germany, for 10 years. We developed a scoring system that depends on salient features from different aspects of the CD process to delineate a pathway that helps to identify patients who may benefit from transplantation.
All data were collected prospectively and obtained for this study by a retrospective review of medical records; therefore, no informed consent was required. We identified all patients with CD and IF who were referred to the ITx and rehabilitation centers in Oxford and Berlin from October 10, 2003, through July 31, 2013. Approval was obtained by 2 individual committees: the technology advisory group (Isis Innovation Ltd) in Oxford and the institutional review board in Berlin (Charité-Universitätsmedizin Berlin). Patients were considered suitable for transplantation if a diagnosis of irreversible IF was established and life-threatening complications under HPN were unresolvable.
All patients with short bowel syndrome and significantly impaired venous access, recurrent catheter infections, and marginal signs of cholestatic liver disease were listed for isolated ITx. Patients with a frozen abdomen and/or advanced liver fibrosis (F2-F4 according to the Scheuer11 classification) who required an additional liver graft were listed for multivisceral transplantation (MVTx: stomach, duodenum, intestine, pancreas, and/or liver). Abdominal wall transplantation (AWT) was considered if there was evidence of loss of abdominal domain with loss of good skin quality due to overlying fistulas. Perioperative procedures and standards have been described elsewhere.12- 14
The following data were collected: patient characteristics, new scoring system for CD and ITx, surveillance of rejection, outcome, and Karnofsky performance status score. Patient characteristics included information about CD (patient demographics, age at diagnosis, phenotype of disease, medical and surgical history before referral, secondary organ failure, history of catheter infections, and status of active disease) and information about transplantation (type of graft, immunosuppressive regimen, and abdominal closure management). Table 1 details a new scoring system, which is a modification of the AGA guidelines for ITx. The modifications are related to CD-specific issues that potentially lead to a poorer outcome and are based on the findings of the presented study to determine the expected benefit from ITx. The number of points in each category was accredited according to their effect on morbidity. Both groups relied on endoscopic surveillance of the intestinal graft and histologic appearances on mucosal biopsy. The Berlin group performed endoscopy 3 times a week, whereas the Oxford group performed it once a week. In addition, posttransplantation HLA antibody screening was performed once a week or whenever necessary for diagnosis to detect de novo HLA antibodies and antibody-mediated rejections. The 1-year graft and patient survival applies to the study group. The actuarial 5- and 10-year survival rates are measured according to the overall outcome of both centers. The Karnofsky performance status scale15 was initially developed to evaluate a patient's ability to survive chemotherapy (Table 2). Because of the paucity of accurate tools to capture meaningful outcomes, it has been used in a modified version to determine the quality of life after ITx.16 The Karnofsky performance status scale was used in this study as a measure to compare pretransplantation and posttransplantation outcomes.
From October 10, 2003, through July 31, 2013, a total of 20 patients with CD and IF, established on HPN, were evaluated for ITx. Ten patients underwent transplantation, 4 were on the waiting list, and 4 were unavailable for follow-up after declining transplantation (Figure). One patient was taken off the waiting list because of severe deterioration and persisting wound infections after long-term therapy with methotrexate. One patient underwent conventional stricturoplasty and did not need transplantation.
Mean (SD) age at onset of CD was 17.8 (9.8) years. On first diagnosis, most patients presented with the phenotype of a stricturing CD. By the time of referral, most patients had a combined form of stricturing and fistulizing disease. Sixteen patients had no active signs of CD or disease recurrence until the end of the study period. One patient had an ongoing active form of stricturing CD and was treated with a conventional surgical approach that involved stricturoplasty in the proximal jejunum with 65 cm of normal distal bowel. The characteristics of the medical and surgical course of disease before referral are listed in Table 3, including all complications associated with CD, IF, and HPN.
Of the 10 patients who underwent transplantation, 6 had isolated ITx and 4 had MVTx. Three ITx recipients underwent additional AWT; 2 of the MVTx recipients received an additional kidney graft and 3 received the right hemicolon.
In Oxford, tacrolimus monotherapy was used (trough levels, 8-12 ng/mL). In Berlin, the initial immunosuppression was tacrolimus (trough levels, 8-12 ng/mL) and corticosteroids (tapered by postoperative day 80). For long-term immunosuppression, a double regimen was used with tacrolimus (trough levels, 4-6 ng/mL) and either mycophenolate mofetil (Cellcept, F. Hoffmann-La Roche Ltd, 500 or 1000 mg every 12 hours) or sirolimus (Rapamune, Wyeth Ayerst Pharmaceuticals; trough levels, 2-3 ng/mL).
The induction regimen differed in the centers: the Oxford center used 500 mg of intravenous methylprednisolone and 30 mg of alemtuzumab (Campath, Genzyme Corporation). This dose was repeated 24 hours later. The Berlin center used 30 mg of intravenous alemtuzumab on postoperative day 5 in the first MVTx recipient. The following 3 patients received thymoglobulin (Thymoglobulin, Genzyme Corporation; total dose, 7.5 mg/kg) and 1 dose of infliximab (Remicade, Centocor Biotech Inc; total dose, 5 mg/kg). Infliximab was used to mitigate ischemia and reperfusion injury and to deplete effector memory CD8+ T cells.17,18
The 6 patients who underwent ITx from the Oxford cohort were managed with primary closure, including 3 AWTs. The 4 patients who underwent MVTx from the Berlin cohort were managed with staged abdominal closure that consisted of allofascia augmented with Vicryl mesh or a free muscular flap taken from the latissimus dorsi muscle. Lack of skin layer was covered with split-thickness skin grafts.
We retrospectively classified all patients according to the newly developed score (Table 1) to analyze the severity of disease and to facilitate the indication for ITx. The mean (SD) score for transplantation recipients was 18 400 (7527). The scores of the other patients are given in the Figure.
The overall 1-year incidence of acute cellular rejection was 30%: one patient developed abdominal wall graft rejection without evidence of intestinal graft rejection or dysfunction. Furthermore, 2 MVTx recipients developed 1 episode of mild acute cellular rejection of their intestinal grafts. Antirejection therapy for all 3 patients consisted of corticosteroid pulse therapy (500 mg/d) for 5 days in Berlin and 3 days in Oxford; baseline immunosuppression was increased.
The 1-year graft and patient survival rate was 80%. The actuarial 5- and 10-year graft and patient survival rates were 71% and 68%, respectively. Two patients died in the first year after transplantation in the perioperative period of iatrogenic bowel perforation that led to uncontrolled sepsis. At a mean (SD) follow-up of 27.6 (36.1) months after transplantation, 8 of the 10 transplant recipients are alive and established on autonomous enteral nutrition.
The mean (SD) Karnofsky performance status score for all patients was 55.5% (8.9%). The patients who underwent transplantation reported a mean (SD) Karnofsky performance status score of 55.6% (7.3%) at the time of referral and 74.4% (46.0%) after transplantation. On the basis of the t test, the difference between the pretransplantation and posttransplantation Karnofsky performance status score was significant (P < .001). The same significance was achieved when comparing those who underwent transplantation with those who did not (P < .001).
Despite advances in pharmacologic therapy, at least 50% of patients with CD require surgery within the first 10 years after diagnosis.19 Unfortunately, this occurrence is often associated with additional surgical intervention and may result in irreversible IF as a direct consequence of perioperative complications related to extensive bowel resections.3 Driven by improved survival rates, ITx has become an adequate treatment option for IF.
However, HPN as the mainstay of treatment for patients with CD is widely acknowledged.4 A reasonable doubt in ITx as a treatment strategy is the immune nature of CD, especially with the emerging concept of NOD2 (GenBank AJ303140, AF178930, and NT_030834) mutation imposing an even higher risk of rejection or disease recurrence after ITx. Only a few studies7,19,20 have addressed ITx in patients with CD, and most of them are of retrospective nature and small sample size. The United Network for Organ Sharing database is the largest up-to-date study on 86 patients with CD who underwent ITx.7 The authors reported a similar outcome for CD to the overall outcome of ITx. However, they commented that, because of insufficient documentation, the reported long-term rejections may have been unrecognized episodes of CD recurrence. In a smaller study20 of 6 patients with CD, 2 cases of granulomatous enteritis of the intestinal allograft were observed, which did not occur in patients without CD undergoing ITx. The authors concluded that histologic CD recurrence may take place despite the absence of endoscopic manifestations but may not necessarily indicate clinical recurrence or require aggressive therapy. In contrast, the Berlin cohort described the phenomenon of allograft enteropathy, a late-developing ulcerative inflammation of the distal ileal graft, that was refractory to standard antirejection therapy but resolved under tumor necrosis factor inhibition in a cohort of patients without CD.21 The underlying mechanisms have been attributed to immunologic processes similar to CD and its associated polymorphisms in the NOD2 gene.22- 24 The anti-inflammatory and antichemotactic effects of tumor necrosis factor inhibition highlight the overlap between the high immune activity of the intestinal graft and CD.25,26 Whether the use of infliximab as an induction regimen may prevent CD recurrence remains to be investigated.
The salient features used to consider a patient for ITx over conventional surgery seem to be in accordance with the AGA guidelines, including impending liver failure or dysfunction, paucity of catheter access, multiple life-threatening catheter infections, and quality of life.27 The actuarial 5- and 10-year survival rates that exceed 75% in specialized centers28 have caused the redefining of referral criteria for ITx and question the rationale for continuing to give these patients long-term HPN. Redefinitions are in evolution and are merely extensions to the established criteria but have incorporated transplantation variables, such as preoperative sensitization status29,30 and CD-specific criteria, including presence of high-output ECFs,31 absence of good-quality distal bowel,30,32 loss of abdominal domain, and poor-quality abdominal wall.33
In the consideration of ITx, eligible patients should be referred to a specialized center before further deterioration will diminish the opportunity for transplantation. Patients with CD impose special challenges on the outcome because of multiple prior abdominal operations, ECFs, extensive scarring of the abdominal musculature with previous incisions, stomas, and loss of abdominal domain. In particular, patients with a frozen abdomen or HPN-related cholestatic liver disease tend to be in poorer condition. Their comorbidities often designate them for MVTx, which needs to be assessed at an early stage in a specialized center because MVTx candidates have higher mortality rates while on waiting lists because of the increasing organ shortage and select donor criteria.34 The 4 patients from the Berlin cohort were referred at a late stage with deteriorating liver function that required an MVTx; furthermore, 2 patients required an additional kidney transplantation. Another MVTx candidate had to be taken off the waiting list because of severe deterioration, so a transplantation did not ensure a survival benefit. Although a transplantation may often be the life-saving solution, consequences of a late referral and progressive state of disease may hamper outcome. This theory is supported by the United Network for Organ Sharing data that indicate an inferior 1-year survival of patients with CD undergoing combined transplantation or MVTx (63%) with those undergoing isolated ITx (85%).7
In some cases of penetrating CD and multiple ECFs, AWT,19 which was successfully performed in Oxford, may be beneficial. Although this procedure presents yet another immunologic challenge because of the high immunogenicity of the skin, it allows for a primary abdominal closure, reducing the risk of infection, prolonged wound healing, and development of fistulas.14
One aspect in the treatment of patients with CD is the potential necessity for surgical intervention before transplantation. An argument could be made for performing an enterectomy and bringing out a proximal jejunostomy to excise the ECF and strictured distal bowel. This approach may reduce the chances of bacterial translocation from the amotile diseased bowel. However, this strategy yields the risk of increasing perioperative morbidity, multiorgan dysfunction, insufficient wound healing, and further scarring of the abdominal wall. Moreover, the potential imperative for the need of blood products during a long complex operation may result in sensitization of a previously unsensitized patient and thereby diminish the chances for a suitable graft when ITx is eventually considered. This result is mirrored in the case of a patient with more than 98% class I and II HLA antibodies who has been on the Oxford center waiting list for 4 years without an appropriate offer.
Finally, favoring conventional surgery over an early referral to ITx without the prospect of withdrawing HPN decreases the patient’s quality of life. These patients do not have an incurable disease; therefore, their Karnofsky performance status score is a powerful tool to assess their recovery after a definitive procedure that will get them back to healthy living. We found an increase of 35% in the Karnofsky performance status score in our patients who underwent transplantation.
The decisions involved are complex and require flexibility within given criteria. The options of transplantation and conventional surgery have to be discussed according to the following variables in descending order of importance: (1) sensitization status; (2) venous access; (3) nutritional status during last attempt at closure of the ECF31; (4) morbidity after previous attempts at ECF closure, including transient organ dysfunction (acute renal failure that required dialysis or prolonged ventilation because of a sepsis)35; and (5) current Karnofsky performance status score.
The new score is intended as an objective measure to remove operator-driven bias in the decision-making process by including important criteria derived from published evidence and the clinical experience of 2 specialized centers. A score less than 2000 does not warrant an immediate referral for ITx; a thorough evaluation of conventional surgical and medical options would be prudent. A score of 2000 through 5000 would trigger the process for ITx evaluation in a timely fashion to ensure a better posttransplantation outcome. A score greater than 5000 indicates an urgent referral for ITx. The intermediate outcomes from ITx in this group may be less favorable than the previous group. In this context, as seen in one of the Berlin cohort patients, an upper limit to the score of 30 000 may indicate that a transplantation would no longer represent a survival benefit.
Intestinal transplantation has acquired an increasingly important role in the management of irreversible IF and short bowel syndrome. The reason for this occurrence is the demonstration of improved outcomes in the short and intermediate terms. Along with such evolution, it is important to address various disease processes that may benefit from this procedure. We believe that patients who present with CD and ECF with poor-quality distal gut and/or threatened integrity of catheter access may be suitable candidates for early referral for ITx before any further attempts at conventional surgery may cause them to miss this opportunity through complete loss of venous access or sensitization. Thus, a scoring system that would alert the physician to the severity of the patient’s CD and trigger early referral for ITx is essential. This approach may translate into better long-term outcomes for such patients.
Accepted for Publication: January 23, 2014.
Corresponding Author: Anil Vaidya, MD, Oxford Transplant Centre, Churchill Hospital, 1 Roosevelt Dr, Headington, Oxford OX3 7LJ, United Kingdom (email@example.com).
Published Online: August 27, 2014. doi:10.1001/jamasurg.2014.1072.
Author Contributions: Drs Gerlach and Vaidya had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gerlach, Reddy, Pascher, Vaidya.
Acquisition, analysis, or interpretation of data: Gerlach, Vrakas, Baumgart, Neuhaus, Friend, Pascher, Vaidya.
Drafting of the manuscript: Gerlach, Vrakas, Vaidya.
Critical revision of the manuscript for important intellectual content: Gerlach, Reddy, Baumgart, Neuhaus, Friend, Pascher, Vaidya.
Statistical analysis: Gerlach, Vaidya.
Administrative, technical, or material support: Gerlach, Vrakas, Reddy, Neuhaus, Friend, Pascher, Vaidya.
Study supervision: Gerlach, Baumgart, Pascher, Vaidya.
Conflict of Interest Disclosures: None reported.
Correction: This article was corrected on October 22, 2014, to fix an author’s last name.