Small boweltransplantation e the latestdevelopmentsAlan Wiles

Simon Gabe

Stephen Middleton

agents such as alemtuzumab (Campath-1H) in the 1990s,11,12 and

as reported by the international registry,10 (which receives

details of >90% of all cases world wide) is lower (Table 1) but

this survival gap is continuing to close. In the better performing

centres,17,18 survival figures approximate to those on HPN,

particularly for patients given lymphocyte-depleting induction

therapy, whose survival at 1 and 5 years has been reported to be

as high as 90% and 70% respectively.17 Patient survival at the

largest UK adult transplantation centre in Cambridge has also

improved, with 2-year non-oncological survival pre- and post-

2007 of 50% and 100% respectively, associated with a 10-fold

increase in procedures undertaken per year. The larger of the UK

paediatric transplantation centres, in Birmingham, also has

improved results, reporting 69% 3-year survival since 1998 and

31% before this.19 If these improved survival rates are repro-

duced in other centres and prove a match for those of HPN at

10 years, intestinal transplantation may become the preferred

primary treatment for irreversible intestinal failure, rather than

being largely reserved for those who respond poorly to HPN. It

TRANSPLANTATIONAlan Wiles BA DPhil BMBCh MRCP is a Senior Transplantation Fellow at

Addenbrookes Hospital, Cambridge University NHS Trust and has

recently been appointed as a Consultant Gastroenterologist at Queen

Elizabeth Hospital, Kings Lynn, UK. Competing interests: none declared.

Simon Gabe BSc MD MSc FRCP is a Consultant Gastroenterologist at St

Marks Hospital in Harrow, UK. Competing interests: none declared.

Stephen Middleton MA MD FRCP FAHE is a Consultant Physician and

Gastroenterologist at Addenbrookes NHS Trust, Cambridge University

Teaching Hospital, UK. Competing interests: none declared.AbstractIntestinal transplantation has become a routine clinical procedure for

selected patients. Over the last 10 years patient survival figures have

improved considerably and are now approaching those receiving organs

such as liver, lungandheart. Patient selectionhas improvedand immunosup-

pression has been enhanced by the introduction of lymphocyte modulating

antibody therapy combined with less potent maintenance immunosuppres-

sion. The indications for intestinal transplantation remain conservative at

present and largely reserve this procedure for patients who have life threat-

ening complications of parenteral nutrition or require surgical procedures

that make simultaneous or subsequent transplantation advantageous.

However, as survival figures improve the indications are beginning to

broaden to include consideration of quality of life. Survival after transplanta-

tion is approaching that associated with uncomplicated parenteral nutrition

and if this trend continues it may replace parenteral nutrition as the treat-

ment of choice for patients with irreversible intestinal failure. This article

describes the current indications for intestinal transplantation and the

current results of the procedure. Guidelines for referring patients for trans-

plantationassessment and for themanagementof the sick transplant patient

are given. The need to consider referral of patients at an early stage to allow

timely assessment for transplantation is also discussed.

Keywords infections; intestinal; multivisceral; NASIT; nutrition;

transplantation

A brief history of intestinal transplantation

The earliest significant innovations in the technical aspects of

intestinal transplantation are considered to be the canine models

developed by Richard Lillehei in the 1950s1 and 60s,2 and the

vascular anastomotic techniques ofCarrel.3Graft rejection impededMEDICINE 39:3 183the appreciation that thorough preoperative preparation, patient

selection and scrupulous postoperativemanagement are of critical

importance (Figure 1).13 Now, intestinal transplantation can be

considered as a routine component of the management of adult

and paediatric patients with intestinal failure, and is beginning to

replace parenteral nutrition in the long-termmanagement strategy

for many of these patients. Currently, children tend to have better

survival than adults after 5 years (Figure 2).

The current role of transplantation in the management of

intestinal failure

The survival rates of patients requiring home parenteral nutrition

(HPN) range between 86e97% at 1 year, 57e83% at 5 years and

43e71% at 10 years.14e16 Survival following intestinal trans-

plantation (any combination of organs including small intestine),progress but following the introduction of a series of powerful anti-

rejection agents in the late 1980s,4,5 a cluster of reports appeared

describing transplantation of part or all the intestine both in

combination with other organs and as isolated grafts.6e9

However, long-term survival remained modest at best10 until

the introduction of lymphocyte-depleting induction therapy with

Whats new?

C Improved survival figures: 1 year 85%; 5 years 70%

C Survival gap between home parenteral nutrition (HPN) and

transplantation is closing

C Quality of life on home parenteral nutrition HPN can be

improved by transplantation

C National Adult Intestinal Transplantation (NASIT) Forum e UK

forum to discuss all patients before transplantation

C CaMi (Cambridge-Miami) score: first preoperative scoring

system to estimate postoperative survival following intestinal

transplantation

C It is now a requirement that all suitable patients should be

referred (or discussed) for assessment at an appropriate stage

before they lose the opportunity of transplantation 2010 Elsevier Ltd. All rights reserved.

Su

rviv

al

pro

ba

bil

ity

Years

Logrank p < 0.001 1: 19851989

2: 19901994

3: 19952000

4: 20002004

5: 20052009

0.0 1

2

3

4

5

23

131

409

757

856

4

39

146

196

0

1

25

68

0

1

10

0

0

0

0 20

0.6

0.8

1.0

0.4

0.2

5 10 15

Patient survival following intestinal transplantation in different eras

between 1985 and 2009

Figure 1

Su

rviv

al

pro

ba

bil

ity

Years

Logrank p < 0.584 1: 02

2: 36

3: 717

4: 18-50

5: 51+

0.0 1

2

3

4

5

360

123

116

392

125

100

39

35

100

34

0

0

0

0

0

0 6

0.6

0.8

1.0

0.4

0.2

2 1 3

21

14

8

18

4

4 5

Patient survival following intestinal transplantation according to age

of patient

Figure 2

TRANSPLANTATION

MEDICINE 39:3 184 2010 Elsevier Ltd. All rights reserved.

C Severe liver disease or progressive disease despite all reme-

dial actions.

(b) Recurrent septic episodes

C IF patients who have severe septic complications (i.e. life-

threatening line infection needing admission to ITU, or

recurrent yeast or candidal infections).

(c) Lack of central venous access

C For isolated intestine: venous access limited to three major

sites.

C For intestine as part of a cluster graft: venous access limited to

four major sites.

2. Very poor quality of life thought to be correctable by

transplantation.

3. Patients with indications for extensive surgery involving partial

or complete evisceration:

Adults

(a) Surgery to remove a large proportion of the abdominal viscera

that is considered untenable without associated multi-visceral

transplantation (e.g. extensive desmoid disease, extensive

severe mesenteric arterial disease requiring intervention).

(b) Localized malignancy considered to be amenable to curative

resection that would necessitate extensive evisceration (e.g.

localized neuroendocrine tumours and cholangiocarcinoma e

particular caution should be exercised with this group).

Children

(a) Surgery that will lead to:

C Terminal gastrostomy

C Terminal duodenostomy

C Ultra short bowel: In children

isolated intestine liver and intestine multivisceral (liver, intestine, stomach, pancreas) modified multi-visceral (intestine, stomach, pancreas).In addition, patients may undergo renal transplantation and some

centres favour splenic transplantation for immunological reasons.

Patients invariably have an ileostomy, at least initially, to provide

access for ileoscopic surveillance biopsies to detect rejection. A

few centres transplant the large intestine and abdominal wall.

Following surgery it is usual for an ITU stay of 2 or 3 days,

then HDU for 2 or 3 weeks, and finally a less intensive ward stay

for a further 4e6 weeks to establish full enteral nutrition, satis-

factory immunosuppression and resolution of any postoperative

problems such as infection.

Infection is the commonest postoperative complication (Table

3). Rejection is now less of a problem since the introduction of

lymphocyte-depleting agents, but early detection and treatment

remain a pivotal part of the process and surveillance biopsies via

the stoma are undertaken at least three times a week in the first

month. Fluid and electrolyte balance are also frequently chal-

lenging but of critical importance, to prevent the downward

spiral triggered by a confluence of salt and water imbalance,

impaired renal function and sepsis, which may result in multi-

organ failure. At this point, other pre-existing co-morbidities and

the lack of venous access for treatments such as dialysis can

result in inexorable deterioration. The postoperative manage-

ment of these patients is complex and requires a fully integrated

team of consultants from a broad range of specialties who are

well motivated and able to provide prompt consultant-led

expertise. The combination of inducing profound immunosup-

pression and transplanting an organ with very high antigenicity

that also contains a host of potential pathogens produces

Common infections following intestinal transplantation (in the UK)

Location Likely pathogens Clinica l features Diagnosis Treatment

Bacterial Central line related

Superficial

surgical site:

Pneumonia

Abdominal collection/

peritonitis

Staphylococcus aureus

(incl. MRSA)

Escherichia coli

Klebsiella,

Pseudomonas.

Coagulase-negative

Staphylococci:

(IV line infections only)

Brisk deterioration/septic

shock/and organ-specific

features

(respiratory, urinary,

intra-abdominal)

Lower-grade sepsis with

coagulase-negative

Staphylococci

Cause of death in 18%

Blood cultures/pneumococcal/

Legionella urinary antigens

Organ-specific: broncho-

alveolar lavage (BAL);

sputum, urine culture, etc.

Intra-abdominal scans

Initially broad-spectrum

antibiotics then adjust

to include sensitivities

of known organisms.

Need to cover, MRSA

and other potential

hospital-acquired

infections

Fungal Aspergillosis:

Wound, pulmonary,

disseminated,

cerebral

Aspergillus fumigatus Antibiotic-resistant

pneumonia

Aspergillosis is serious,

particularly disseminated,

and intra-cerebral

is usually fatal

Chest CT scan

BAL and trans-bronchial

biopsy PCR

Aspergillosis with

amphotericin/

AmBisome, voriconazole

or caspofungin

Candidal Candidiasis:

oropharyngeal,

genitourinary,

wound related,

line infections.

Candida albicans Antibiotic-resistant

sepsis

Blood and urine culture,

line tip culture.

AmBisome/

caspofungin

Fluconazole if

mild/known to be

sensitive.

Viral CMV looks for colitis, Influenza virus Flu-like illness

ase

ken

um

fec

ase

ula

fec

fec

ase

Nose and throat swabs, Antivirals, depending

TRANSPLANTATIONhepatitis and retinitis.

EBV PTLD late:

>1 year

Respiratory syncytial

virus (RSV) or

parainfluenza

virus 3

Cytomegalovirus (CMV)

Varicella-zoster virus

(VZV)

Herpes simplex virus 1

or 2 (HSV-1/2)

EpsteinBarr virus (EBV)

Human herpes virus 6

(HHV-6)

Adenovirus

Pneumonia

Organ dise

Severe chic

zoster, pne

Systemic in

organ dise

From gland

to PTLD

Systemic in

fever

Systemic in

organ dise

Table 3MEDICINE 39:3 186pox or

onitis

tion,

r fever

tion,

tion,

nasopharyngeal aspirate,

broncho-pulmonary

lavage PCR

on circulating strains

Nebulized ribavirin

Ganciclovir

Acyclovir

Acyclovir

Discuss with virologist

and haematologist

Discuss with virologist

Cidofovir (discuss with

virologist) 2010 Elsevier Ltd. All rights reserved.

a unique clinical setting, where patients often respond in an

unusual way to infections and treatments.

Which patients should be referred to a transplant centre for

consideration?

The management of all patients with intestinal failure should now

include consideration of the potential role of transplantation. It is

important to make every attempt to treat reversible disease and

thorough intestinal rehabilitation can often restore adequate

enteral nutrition. In the UK, this process is undertaken in regional

or national intestinal failure (IF) centres. The regional (medium-

volume) centres have a nutrition team and clinical staff with

subspecialty interests in the management of intestinal failure

patients. For themore complex patients, especiallywheremultiple

surgical procedures are thought necessary, the UK has two

national IF centres. These centres have specialist medical and

surgical staff that are dedicated to intestinal failure work and have

a high enough volume of these complex patients to build up a high

level of corporate experience. This system is very efficient as it

allows appropriate escalation and concentrates experience of the

less frequent, highly complex patients, who require a very

rounded team of clinicians to manage them effectively. In most

cases, patients fulfilling the criteria for transplantation (Table 2) or

who are approaching this situation (Table 4) should be referred.

Particular attention should be given to those who are likely tomiss

the window of opportunity. These patients often have progressive

disease, which may advance to a point that contraindicates

transplantation or results in death whilst they are on the waiting

list. Examples of this include patients who are rapidly losing

venous access points and those bleeding fromportal hypertension.

Special consideration should also be given to PN-dependent

patients who require transplantation of other organs. They may

benefit from a cluster graft including intestine rather than have

a subsequent intestinal transplantation in the setting of an existing

graft and consequent immunosuppression.

Red-flag indicators for referral for transplant assessment

[In addition to the standard indications for transplantation e Table 2]

Patients with intestinal failure and one or more of the following:

C Abnormal LFTs Persistent elevation of hepatic enzymes may

indicate PN-associated hepatic fibrosis or

cirrhosis

Assessment of liver including biopsy, optimize

HPN and exclude other causes. Refer to or

discuss with national IF or transplant centre

C Frequent line sepsis Patients with three or more episodes of line

sepsis in a year or one episode of life-

threatening sepsis may be candidates for

transplantation particularly if there are other

relative indications

Refer to/discuss with national IF centre

C Ultra-short bowel syndrome Less than 40 cm of jejunum to a stoma is

associated with rapid-onset liver disease

Refer to/discuss with a National IF or

transplant centre

C Co-existing diabetes mellitus with

complication

Diabetic complications are often indications

for pancreatic transplantation and if advanced

increase the risk associated with intestinal

transplantation. Patients may benefit from

early combined transplantation

Refer to transplantation centre for

consideration of combined pancreas and small

bowel transplantation

abd

e in

ion

my

p fo

a-pe

on

nin

s. E

erab

eria

e a

TRANSPLANTATIONa The UK National Desmoid Centre is at St Marks hospital, Harrow, London.

Table 4C Pseudo-obstruction. Complicated by

severe abdominal pain

Patients with intractable

distended small and larg

benefit from transplantat

colectomy and enterecto

a relatively high-risk grou

of intestines reduces intr

subsequent transplantati

Patients without intestinal failure

C Desmoid disease Extensive disease threate

other important structure

intervention may be pref

C Mesenteric vascular disease Extensive mesenteric art

disease involving intestin

intra-abdominal organsMEDICINE 39:3 187ominal pain from

testine may

rather than

and PN. They are

r PN and removal

ritoneal space for

Refer patient to transplant centre

g or damaging

arly surgical

le

Refer to transplantation centre for assessment

or to the national desmoid centrea

l or venous

nd other essential

Refer to transplantation centre for assessment

or to the national desmoid centre 2010 Elsevier Ltd. All rights reserved.

given this opportunity at an appropriate stage.

There are certain red flag indicators for referral to a main

centre (Table 4) in addition to the standard indications for trans-

plantation (Table 2). This is not an exhaustive list of high-risk

factors but provides a guide to the type of situation that should

prompt the gastroenterologist to consider referral, to either

a national IF centre or a transplant centre, for further consideration.

Conclusion

Considerable advances over the last 20 years have taken intes-

tinal transplantation from the first procedures that provided only

short-term success to its current status as a routine therapeutic

option for selected patients. Although HPN remains the primary

treatment for most patients with intestinal failure, we approach

the threshold of a new era when intestinal transplantation will be

considered to be the primary treatment for most patients. This

promises to be cost effective and bring with it better quality of life

for patients without reducing their longevity. A key element of

success is appropriate timing of referral to a national IF or

transplantation centre. All gastroenterologists should be aware of

when and how to refer patients, and seek advice early in the

management of the more complex patients. A

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TRANSPLANTATIONWhat is the likely future demand for intestinal transplantation?

The ongoing improvement in postoperative survival brings with it

broadening of the indications for transplantation to include larger

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receiving HPN in the UK in 2007 and 2008 were 867 and 856

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nine and eight respectively. Themajority of adult patients are aged

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Practice points

C The possibility of future intestinal transplantation should be

considered in the management of all intestinal failure (IF)

patients and those with extensive benign intra-abdominal

disease.

C IF patients with significant complications of PN should be

referred for transplantation assessment (National IF or trans-

plantation centre) or at least discussed with a centre.

C Care should be taken not to allow IF patients to deteriorate

past the point when transplantation is possible.

C Sick transplant patients must be treated without delay and

advice should be sought from their transplantation centre

immediately on presentation.

C The early use of appropriate broad-spectrum antimicrobial

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after cardiac transplantation. Thorac Cardiovasc Surg 1995; 43: 352e4.

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11 Middleton SJ, Pollard S, Friend PJ, et al. Adult small intestinal

transplantation in England and Wales. Br J Surg 2003; 90: 723e7.

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combined with tacrolimus in intestinal and multivisceral trans-

plantation. Transplantation 2003; 75: 1512e7.

13 Middleton SJ, Nishida S, Tzakis A, et al. Cambridge-Miami score for

intestinal transplantation preoperative risk assessment: initial

development and validation. Transplant Proc 2010; 42: 19e21.

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nutrition dependence in adult patients with the short bowel

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17 Abu-Elmagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and

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6: 233e9.MEDICINE 39:3 189agents in sick transplantation patients is essential as they are

most likely to have infection. 2010 Elsevier Ltd. All rights reserved.

Small bowel transplantation the latest developmentsA brief history of intestinal transplantationThe current role of transplantation in the management of intestinal failureWhat does intestinal transplantation involve?Which patients should be referred to a transplant centre for consideration?What is the likely future demand for intestinal transplantation?Why do gastroenterologists need to know about intestinal transplantation?ConclusionReferences