Research
Original Investigation
Chronic Intestinal Failure After Crohn Disease When to Perform Transplantation Undine A. Gerlach, MD; Georgios Vrakas, MD; Srikanth Reddy, MD, PhD, MBBS, FRCS; Daniel C. Baumgart, MD, PhD; Peter Neuhaus, MD, PhD; Peter J. Friend, MD, MA, MB, BChir, FRCS; Andreas Pascher, MD, PhD, MBA; Anil Vaidya, MD
IMPORTANCE 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.
Invited Commentary page 1067
OBJECTIVES 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. INTERVENTIONS 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. RESULTS 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.
JAMA Surg. 2014;149(10):1060-1066. doi:10.1001/jamasurg.2014.1072 Published online August 27, 2014. 1060
Author Affiliations: Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany (Gerlach, Neuhaus, Pascher); Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom (Vrakas, Reddy, Friend, Vaidya); Division of Gastroenterology and Hepatology, Department of Medicine, CharitéUniversitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany (Baumgart). Corresponding Author: Anil Vaidya, MD, Oxford Transplant Centre, Churchill Hospital, 1 Roosevelt Dr, Headington, Oxford OX3 7LJ, United Kingdom ([email protected]). jamasurgery.com
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Crohn Disease and Intestinal Transplantation
T
he 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 CDspecific 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.
Methods 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.
Original Investigation Research
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.
Results 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.
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Table 1. Scoring System Adapted to the American Gastroenterology Association Guidelines
Table 2. Karnofsky Performance Status Score Score, %
State of Health
100
Healthy, no symptoms or signs of disease
90
Capable of normal activity, few symptoms or signs of disease
80
Normal activity with some difficulty, some symptoms or signs
500
70
Caring for self, not capable of normal activity or work
5000
60
Requiring some help, can take care of most personal requirements
>1 Life-threatening catheter infection in 12 months
5000
50
Requires help often, requires frequent medical care
1 fungal infection
5000
40
Disabled, requires special care and help
Impending or overt liver failure due to HPN
5000
30
Severely disabled, hospital admission indicated but no risk of death
Frequent dehydration leading to a decrease in eGFR by 20 mL/min at each episode
1000
20
Very ill, urgently requiring admission, requires supportive measures or treatment
10
Moribund, rapidly progressive fatal disease processes
0
Death
Criteria
Points
HPN for irreversible intestinal failure
1000
Loss of catheter access Loss of 1 supracardiac catheter Loss of ≥2 supracardiac catheters Catheter infection
Overt renal failure requiring renal replacement therapy
5000
No ECF or stoma but 100 cm of poor-quality distal bowel (strictured, matted, and obstructed and/or dilated)
5000
Persistence or recurrence of ECF after conservative management or attempted conventional surgical excision despite having optimal nutrition
5000
Prolonged hospital stay with organ dysfunction after last attempt at closure of ECF or any conventional surgical procedure to treat CD
5000
Presence of active CD
1000
Karnofsky performance status score >70%
1000
Sensitization status Unsensitized
1000
Sensitized
2500
Score analysis ITx not yet indicated: conventional surgical and medical management until score increases ITx indicated: patient referral pathway should be considered and initiated
5000 >30 000
Abbreviations: CD, Crohn disease; ECF, enterocutaneous fistula; eGFR, estimated glomerular filtration rate; HPN, home parenteral nutrition; ITx, intestinal transplantation.
Patient Characteristics Information About CD 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. Characteristics of Transplant Recipients Of the 10 patients who underwent transplantation, 6 had isolated ITx and 4 had MVTx. Three ITx recipients underwent ad1062
ditional AWT; 2 of the MVTx recipients received an additional kidney graft and 3 received the right hemicolon. Immunosuppressive Regimen 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 Abdominal Closure Management 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.
Scoring System 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.
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jamasurgery.com
Crohn Disease and Intestinal Transplantation
Original Investigation Research
Figure. Description of the Study Cohort 20 Patients with Crohn disease (19 350 [8397])
10 Patients undergoing transplantation (18 400 [7527])
6 Oxford patients (16 167 [8942])
3 ITx patients (10 833 [7767])
10 Patients not undergoing transplantation (17 550 [9733])
4 Berlin patients (21 750 [3428])
3 ITx and AWT patients (21 500 [7365])
2 MVTx patients (20 500 [4950])
4 Lost to follow-up (3 ITx and 1 MVTx patients) (14 375 [9196])
2 MVTx and KTx patients (23 000 [2121])
1 Taken off waiting list (MVTx) (33 000)
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
1 Undergoing conventional surgery (2500)
4 On waiting list (2 MVTx and 2 ITx, KTx, and AWT patients) (20 625 [4308])
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.
Rejection 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.
Outcome 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.
Karnofsky Performance Status Scores 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).
Discussion 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 upto-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
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Table 3. Characteristics of Patients With CD and IF Undergoing Transplantation Value (N = 20)a
Characteristic Medical history before referral Corticosteroids
20 (100)
Azathioprine
3 (15)
Mesalazine
4 (20)
Methotrexate
1 (5)
Infliximab and adalimumab
7 (35)
Surgical characteristics Bowel continuity
3 (14)
Stoma or ECF
17 (85)
History of ECF
11 (55)
Patients who underwent surgical attempts of closure of ECF
11 (55)
Persisting ECF
7 (35)
No. of abdominal operations before referral, mean (SD); median [range]
10.4 (7.1); 8 [2-28]
Total length of residual small bowel, mean (SD); median [range], cm
71.5 (38.0); 60 [15-180]
Small bowel proximal stoma or ECF, mean (SD); median [range], cm
66.8 (39.8); 60 [10-180]
Good-quality bowel distal to stoma or ECF, mean (SD); median [range], cm
20.8 (28.5); 10 [0-90]
Remaining colon, mean (SD); median [range], cm
31.3 (40.0); 10 [0-150]
History of catheter infections No. of catheter infections per patient, mean (SD); median [range], y
7.5 (7.7); 5 [0-22]
Patients with life-threatening catheter infections
16 (80)
Septic shock
6 (30)
Septic thrombosis
4 (20)
Endocarditis
3 (15)
Fungal infections
3 (15)
Loss of vascular access
11 (55)
>2 Central veins occluded
7 (35)
Complete superior vena cava occlusion
2 (10)
Secondary organ failure Decrease in the eGFR by 20 mL/min at each episode of dehydration (eGFR
Original Investigation
Chronic Intestinal Failure After Crohn Disease When to Perform Transplantation Undine A. Gerlach, MD; Georgios Vrakas, MD; Srikanth Reddy, MD, PhD, MBBS, FRCS; Daniel C. Baumgart, MD, PhD; Peter Neuhaus, MD, PhD; Peter J. Friend, MD, MA, MB, BChir, FRCS; Andreas Pascher, MD, PhD, MBA; Anil Vaidya, MD
IMPORTANCE 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.
Invited Commentary page 1067
OBJECTIVES 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. INTERVENTIONS 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. RESULTS 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.
JAMA Surg. 2014;149(10):1060-1066. doi:10.1001/jamasurg.2014.1072 Published online August 27, 2014. 1060
Author Affiliations: Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany (Gerlach, Neuhaus, Pascher); Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom (Vrakas, Reddy, Friend, Vaidya); Division of Gastroenterology and Hepatology, Department of Medicine, CharitéUniversitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany (Baumgart). Corresponding Author: Anil Vaidya, MD, Oxford Transplant Centre, Churchill Hospital, 1 Roosevelt Dr, Headington, Oxford OX3 7LJ, United Kingdom ([email protected]). jamasurgery.com
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Crohn Disease and Intestinal Transplantation
T
he 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 CDspecific 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.
Methods 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.
Original Investigation Research
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.
Results 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.
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Crohn Disease and Intestinal Transplantation
Table 1. Scoring System Adapted to the American Gastroenterology Association Guidelines
Table 2. Karnofsky Performance Status Score Score, %
State of Health
100
Healthy, no symptoms or signs of disease
90
Capable of normal activity, few symptoms or signs of disease
80
Normal activity with some difficulty, some symptoms or signs
500
70
Caring for self, not capable of normal activity or work
5000
60
Requiring some help, can take care of most personal requirements
>1 Life-threatening catheter infection in 12 months
5000
50
Requires help often, requires frequent medical care
1 fungal infection
5000
40
Disabled, requires special care and help
Impending or overt liver failure due to HPN
5000
30
Severely disabled, hospital admission indicated but no risk of death
Frequent dehydration leading to a decrease in eGFR by 20 mL/min at each episode
1000
20
Very ill, urgently requiring admission, requires supportive measures or treatment
10
Moribund, rapidly progressive fatal disease processes
0
Death
Criteria
Points
HPN for irreversible intestinal failure
1000
Loss of catheter access Loss of 1 supracardiac catheter Loss of ≥2 supracardiac catheters Catheter infection
Overt renal failure requiring renal replacement therapy
5000
No ECF or stoma but 100 cm of poor-quality distal bowel (strictured, matted, and obstructed and/or dilated)
5000
Persistence or recurrence of ECF after conservative management or attempted conventional surgical excision despite having optimal nutrition
5000
Prolonged hospital stay with organ dysfunction after last attempt at closure of ECF or any conventional surgical procedure to treat CD
5000
Presence of active CD
1000
Karnofsky performance status score >70%
1000
Sensitization status Unsensitized
1000
Sensitized
2500
Score analysis ITx not yet indicated: conventional surgical and medical management until score increases ITx indicated: patient referral pathway should be considered and initiated
5000 >30 000
Abbreviations: CD, Crohn disease; ECF, enterocutaneous fistula; eGFR, estimated glomerular filtration rate; HPN, home parenteral nutrition; ITx, intestinal transplantation.
Patient Characteristics Information About CD 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. Characteristics of Transplant Recipients Of the 10 patients who underwent transplantation, 6 had isolated ITx and 4 had MVTx. Three ITx recipients underwent ad1062
ditional AWT; 2 of the MVTx recipients received an additional kidney graft and 3 received the right hemicolon. Immunosuppressive Regimen 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 Abdominal Closure Management 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.
Scoring System 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.
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Crohn Disease and Intestinal Transplantation
Original Investigation Research
Figure. Description of the Study Cohort 20 Patients with Crohn disease (19 350 [8397])
10 Patients undergoing transplantation (18 400 [7527])
6 Oxford patients (16 167 [8942])
3 ITx patients (10 833 [7767])
10 Patients not undergoing transplantation (17 550 [9733])
4 Berlin patients (21 750 [3428])
3 ITx and AWT patients (21 500 [7365])
2 MVTx patients (20 500 [4950])
4 Lost to follow-up (3 ITx and 1 MVTx patients) (14 375 [9196])
2 MVTx and KTx patients (23 000 [2121])
1 Taken off waiting list (MVTx) (33 000)
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
1 Undergoing conventional surgery (2500)
4 On waiting list (2 MVTx and 2 ITx, KTx, and AWT patients) (20 625 [4308])
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.
Rejection 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.
Outcome 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.
Karnofsky Performance Status Scores 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).
Discussion 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 upto-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
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Research Original Investigation
Crohn Disease and Intestinal Transplantation
Table 3. Characteristics of Patients With CD and IF Undergoing Transplantation Value (N = 20)a
Characteristic Medical history before referral Corticosteroids
20 (100)
Azathioprine
3 (15)
Mesalazine
4 (20)
Methotrexate
1 (5)
Infliximab and adalimumab
7 (35)
Surgical characteristics Bowel continuity
3 (14)
Stoma or ECF
17 (85)
History of ECF
11 (55)
Patients who underwent surgical attempts of closure of ECF
11 (55)
Persisting ECF
7 (35)
No. of abdominal operations before referral, mean (SD); median [range]
10.4 (7.1); 8 [2-28]
Total length of residual small bowel, mean (SD); median [range], cm
71.5 (38.0); 60 [15-180]
Small bowel proximal stoma or ECF, mean (SD); median [range], cm
66.8 (39.8); 60 [10-180]
Good-quality bowel distal to stoma or ECF, mean (SD); median [range], cm
20.8 (28.5); 10 [0-90]
Remaining colon, mean (SD); median [range], cm
31.3 (40.0); 10 [0-150]
History of catheter infections No. of catheter infections per patient, mean (SD); median [range], y
7.5 (7.7); 5 [0-22]
Patients with life-threatening catheter infections
16 (80)
Septic shock
6 (30)
Septic thrombosis
4 (20)
Endocarditis
3 (15)
Fungal infections
3 (15)
Loss of vascular access
11 (55)
>2 Central veins occluded
7 (35)
Complete superior vena cava occlusion
2 (10)
Secondary organ failure Decrease in the eGFR by 20 mL/min at each episode of dehydration (eGFR
