Description
This evidence review addresses transplantation and retransplantation of an intestinal allograft in combination with a liver allograft, either alone or in combination with one or more of the following organs: stomach, duodenum, jejunum, ileum, pancreas, or colon.

For individuals who have intestinal failure and evidence of impending end-stage liver failure who receive a small bowel and liver transplant alone or multivisceral transplant, the evidence includes a limited number of case series. Relevant outcomes are overall survival, morbid events, and treatment-related mortality and morbidity. These transplant procedures are infrequently performed and few reported case series exist. However, results from the available case series have revealed fairly high postprocedural survival rates. Given these results and bearing in mind the abysmal survival rates of patients who exhaust all other treatments, transplantation may prove not only to be the last option, but also a beneficial one. To be clear, transplantation is contraindicated for patients in whom the procedure is expected to be futile due to comorbid disease, or in whom posttransplantation care is expected to significantly worsen comorbid conditions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a failed small bowel and liver or multivisceral transplant without contraindications for retransplant who receive a small bowel and liver retransplant alone or multivisceral retransplant, the evidence includes case series. Relevant outcomes are overall survival, morbid events, and treatment-related mortality and morbidity. Although limited in quantity, the available post retransplantation data has suggested reasonably high survival rates. Given exceedingly poor survival rates without retransplantation of patients who have exhausted other treatments, evidence of postoperative survival from uncontrolled studies is sufficient to demonstrate that retransplantation provides a survival benefit in appropriately selected patients. Retransplantation is contraindicated for patients in whom the procedure is expected to be futile due to comorbid disease or in whom posttransplantation care is expected to significantly worsen comorbid conditions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background
Solid organ transplantation offers a treatment option for patients with different types of end-stage organ failure that can be lifesaving or provide significant improvements to a patient’s quality of life.¹ Many advances have been made in the last several decades to reduce perioperative complications. Available data supports improvement in long-term survival as well as improved quality of life particularly for liver, kidney, pancreas, heart, and lung transplants. Allograft rejection remains a key early and late complication risk for any organ transplantation. Transplant recipients require life-long immunosuppression to prevent rejection. Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by Organ Procurement and Transplantation Network and United Network of Organ Sharing.

Small Bowel/Liver and Multivisceral Transplant
In 2019, 39,719 transplants were performed in the United States procured from almost 11,900 deceased donors and 7,400 living donors. Intestinal transplants occur less frequently than other organ transplants, with 10 or fewer patients receiving liver-intestine transplant each year from 2008 to 2019.https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/# Small bowel and liver or multivisceral transplant is usually considered in adults and children who develop serious complications related to parenteral nutrition, including inaccessibility (e.g., due to thrombosis) of access sites, catheter-related sepsis, and cholestatic liver disease.

Short Bowel Syndrome
Short bowel syndrome is defined as an inadequate absorbing surface of the small intestine due to extensive disease or surgical removal of a large portion of the small intestine.² In some instances, short bowel syndrome is associated with liver failure, often due to the long-term complications of total parenteral nutrition.

Treatment
A small bowel/liver transplant or a multivisceral transplant includes the small bowel and liver with 1 or more of the following organs: stomach, duodenum, jejunum, ileum, pancreas, and/or colon. The type of transplantation depends on the underlying etiology of intestinal failure, quality of native organs, presence or severity of liver disease, and history of prior abdominal surgeries.³ A multivisceral transplant is indicated when anatomic or other medical problems preclude a small bowel/liver transplant. Complications following small bowel/liver and multivisceral transplants include acute or chronic rejection, donor-specific antibodies, infection, lymphoproliferative disorder, graft-versus-host disease, and renal dysfunction.⁴

Regulatory Status
Small bowel/liver and multivisceral transplantation are surgical procedures and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA).

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Solid organs used for transplantation are subject to these regulations.

Related Policies
70304 Isolated Small Bowel Transplant

Policy:
A small bowel/liver transplant or multivisceral transplant may be considered MEDICALLY NECESSARY for pediatric and adult patients with intestinal failure (characterized by loss of absorption and the inability to maintain protein-energy, fluid, electrolyte or micronutrient balance) who have been managed with long-term total parenteral nutrition (TPN) and who have developed evidence of impending end-stage liver failure.

A small bowel/liver retransplant or multivisceral retransplant may be considered MEDICALLY NECESSARY after a failed primary small bowel/liver transplant or multivisceral transplant.

A small/bowel/liver transplant or multivisceral transplant is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY in all other situations.

Policy Guidelines
General
Potential contraindications to solid organ transplant (subject to the judgment of the transplant center):

1. Known current malignancy, including metastatic cancer
2. Recent malignancy with high risk of recurrence
3. History of cancer with a moderate risk of recurrence
4. Systemic disease that could be exacerbated by immunosuppression
5. Untreated systemic infection making immunosuppression unsafe, including chronic infection
6. Other irreversible end-stage disease not attributed to intestinal failure
7. Psychosocial conditions or chemical dependency affecting ability to adhere to therapy

Intestinal failure results from surgical resection, congenital defect or disease-associated loss of absorption and is characterized by the inability to maintain protein-energy, fluid, electrolyte or micronutrient balance (adapted from reference 1).¹ Short bowel syndrome is one cause of intestinal failure.

Candidates should meet the following criteria:

• Adequate cardiopulmonary status
• Documentation of patient compliance with medical management.

Human immunodeficiency virus (HIV)-positive patients who meet the following criteria, as stated in the 2001 guidelines of the American Society of Transplantation, could be considered candidates for small bowel/liver or multivisceral transplantation:

• CD4 count greater than 200 cells per cubic millimeter for greater than 6 months
• HIV-1 RNA undetectable
• On stable anti-retroviral therapy > 3 months
• No other complications from acquired immune deficiency syndrome (AIDS) (e.g., opportunistic infection, including aspergillus, tuberculosis, coccidiosis mycosis, resistant fungal infections, Kaposi’s sarcoma or other neoplasm) and meeting all other criteria for transplantation.

Small Bowel/Liver Specific
Evidence of intolerance of total parenteral nutrition (TPN) includes, but is not limited to, multiple and prolonged hospitalizations to treat TPN-related complications, or the development of progressive but reversible liver failure. In the setting of progressive liver failure, small bowel transplant may be considered a technique to avoid end-stage liver failure related to chronic TPN, thus avoiding the necessity of a multivisceral transplant.

Benefit Application
BlueCard/National Account Issues
Small bowel/liver or multivisceral transplants should be considered for coverage under the transplant benefit.

What is covered under the scope of the human organ transplant (HOT) benefit needs to be considered. Typically, the following are covered under the HOT benefit:

• Hospitalization of the recipient for medically recognized transplants from a donor to a transplant recipient
• Pre-hospital workup and hospitalization of a living donor undergoing a partial hepatectomy should be considered as part of the recipient transplant costs
• Evaluation tests requiring hospitalization to determine the suitability of both potential and actual donors, when such tests cannot be safely and effectively performed on an outpatient basis
• Hospital room, board and general nursing in semi-private rooms
• Special care units, such as coronary and intensive care
• Hospital ancillary services
• Physicians’ services for surgery, technical assistance, administration of anesthetics and medical care
• Acquisition, preparation, transportation and storage of organ
• Diagnostic services
• Drugs that require a prescription by federal law

Expenses incurred in the evaluation and procurement of organs and tissues are benefits when billed by the hospital. Included in these expenses may be specific charges for participation with registries for organ procurement, operating rooms, supplies, use of hospital equipment and transportation of the tissue or organ to be evaluated.

Administration of products with a specific transplant benefit needs to be defined as to:

• When the benefit begins (at the time of admission for the transplant or once the patient is determined eligible for a transplant, which may include tests or office visits prior to transplant).
• When the benefit ends (at the time of discharge from the hospital or at the end of required follow-up, including the immunosuppressive drugs administered on an outpatient basis).

Coverage usually is not provided for:

• HOT services, for which the cost is covered/funded by governmental, foundational or charitable grants.
• Organs sold rather than donated to the recipient.
• An artificial organ.

Rationale
This evidence review was created in December 1995 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 10, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Transplantation of Small Bowel and Liver or Multivisceral Organs
Clinical Context and Therapy Purpose
The purpose of small bowel and liver transplant alone or multivisceral transplant in patients who have intestinal failure and evidence of impending end-stage liver failure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does small bowel and liver transplant alone or multivisceral transplant improve the net health outcome in individuals with intestinal failure and evidence of impending end-stage liver failure?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with intestinal failure and evidence of impending end-stage liver failure.

Interventions
The therapy being considered is small bowel and liver transplant alone or multivisceral transplant.

Comparators
The following practices are currently being used to make decisions about intestinal failure and evidence of impending end-stage liver failure: medical management and parenteral nutrition.

Outcomes
The general outcomes of interest are overall survival (OS), morbid events, and treatment-related mortality and morbidity, including short- and long-term graft survival and 1- and 5-year OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A TEC Assessment (1999) focused on multivisceral transplantation and offered the following conclusions:

"Multivisceral transplantation in patients with small bowel syndrome, liver failure, and/or other gastrointestinal problems such as pancreatic failure, thromboses of the celiac axis and the superior mesenteric artery, or pseudo-obstruction affecting the entire gastrointestinal tract is associated with poor patient and graft survival. Pediatric and adult patients have a similar 2- and 5-year survival of 33% to 50%. However, without this procedure, it is expected that these patients would face 100% mortality."⁶

Registry Studies and Case Series
The published literature consists of a registry study and case series, mainly reported by single centers in the U.S. and Europe. Tables 1 and 2 summarize the characteristics and results of these publications, respectively. Many case series have included isolated small bowel transplantations (see evidence review 7.03.04).

Reasons for transplantations were mainly short bowel syndrome. Other reasons included congenital enteropathies and motility disorders. Outcomes most commonly reported were survival rates and weaning off total parenteral nutrition (TPN). Several studies have presented survival rates by type of transplantation, while others have combined all or some types of transplants when reporting survival rates. When rates were reported by type of transplant, isolated transplantations had higher survival rates than multivisceral transplants (see Table 2).

Several investigators have reported higher survival rates in transplants conducted more recently than those conducted earlier.^7,8,9,10 Reasons for improved survival rates in more recent years have been attributed to the development of more effective immunosuppressive drugs and the learning curve for the complex procedure.

Authors of these publications, as well as related reviews, have observed that while outcomes have improved over time, recurrent and chronic rejection and complications of immunosuppression continue to be obstacles to long-term survival. A separate discussion of complications follows the evidence tables.

Table 1. Summary of Key Registry Studies and Case Series Characteristics for Transplantations

Study	Country	N	Median Age (Range), y	Interventions		Follow-Up (Range)
				Treatment	n
Raghu et al. (2019)10	International	2080	2.5 (1.1 to 6.3)	Isolated ITx Combined liver ITx Multivisceral graft (including modified [intestine and stomach without liver] and full [intestine, stomach, and liver])	725 966 389	5 y
Lacaille et al. (2017)11	France	110	5.3 (0.4 to 19)	Isolated ITx Combined liver ITx Multivisceral graft	45 60 5	Of 55 alive: 17 at < 5 y 17 at 5 to 10 y 21 at ≥ 10 y
Garcia Aroz et al. (2017)12,a	U.S.	10	1.5 (0.7 to 13)	Isolated ITx Combined liver ITx	7 3	6/7 alive at ≥ 10 y
Dore et al. (2016)13	U.S.	30	0.2 (0.1 to 18)	Isolated ITx Combined liver ITx Multivisceral graft	6 6 18	28 (4 to 175) mo
Rutter et al. (2016)14	U.K.	60	1.8 (0 to 8)	Isolated ITx Combined liver ITx Modified multivisceral	16 35 9	21.3 (0 to 95) mo
Lauro et al. (2014)15	Italy	46	34 (NR)	Isolated ITx Combined liver ITx Multivisceral graft	34 6 6	51.3 mo
Varkey et al. (2013)16	Sweden	20	Adults: 44 (20 to 67) Children: 6 (0.5 to 13)	Isolated ITx Combined liver ITx Multivisceral graft	4 1 15	NR
Mangus et al. (2013)7	U.S.	100	Adults: 48 (NR to 66) Children: 1 (0.6 to NR)	Multivisceral graft Modified multivisceral	84 16	25 mo

ITx: intestinal transplantation; NR: not reported.
^aLiving donors.

Table 2. Summary of Key Registry Studies and Case Series Results for Transplantations

Study	Interventions		Survival	Off TPN
	Treatment	n
Raghu et al. (2019)10	Isolated ITx Combined liver ITx Multivisceral graft (including modified [intestine and stomach without liver] and full [intestine, stomach, and liver])	725 966 389	All transplantations combined: Patient survival: 72.7% at 1 y; 57.2% at 5 y Graft survival: 66.1% at 1 y; 47.8% at 5 y	NR
Lacaille et al. (2017)11	Isolated ITx Combined liver ITx Multivisceral graft	60 45 5	59% at 10 y; 54% at 18 y 48% at 10 y NR	All transplantations combined: 73% at last follow-up
Garcia Aroz et al. (2017)12,a	Isolated ITx Combined liver ITx	7 3	All transplantations combined: 70%	All transplantations combined: 100% at last follow-up
Dore et al. (2016)13	Isolated ITx Combined liver ITx Multivisceral graft	66 18	83% at 9 y 33% at 10 y 67% at 2.5 y	All transplantations combined: 71% in 31 d 62% at last follow-up
Rutter et al. (2016)14	Isolated ITx Multivisceral graft Modified multivisceral	16 35 9	92% at 1 y; 37% at 5 y 71% at 1 y; 33% at 5 y 85% at 1 y; 65% at 5 y	NR
Lauro et al. (2014)15	Isolated ITx Combined liver ITx Multivisceral graft	34 6 6	All transplantations combined: 77% at 1 y 58% at 3 y 53% at 5 y 37% at 10 y	NR
Varkey et al. (2013)16	Isolated ITx Combined liver ITx Multivisceral graft	4 1 15	All transplantations combined: 78% at 1 y 50% at 5 y	NR
Mangus et al. (2013)7	Multivisceral graft Modified multivisceral	84 16	All transplantations combined: 72% at 1 y 57% at 5 y	NR

ITx: intestinal transplantation; NR: not reported; TPN: total parenteral nutrition.
^aLiving donors.

Complications
Several case series have focused on complications after small bowel and multivisceral transplantation. For example, Spence et al. (2020) performed a retrospective chart review of intra-abdominal and bloodstream infections in adults undergoing intestinal or multivisceral transplant at a single center in the U.S.¹⁷ A total of 103 adult patients (median age, 44 years) were included who received 106 intestinal or multivisceral transplants between 2003 and 2015. Intra-abdominal infection occurred in 46 (43%) patients, and concurrent bloodstream infection occurred in 6 (13%) patients. The median time to first intra-abdominal infection was 23 days (interquartile range, 10 to 48). All-cause mortality was not significantly different between patients with versus without intra-abdominal infections (p = .654).

Nagai et al. (2016) reported on cytomegalovirus (CMV) infection after intestinal or multivisceral transplantation at a single center in the U.S.¹⁸ A total of 210 patients had either an intestinal transplant, multivisceral transplant, or modified multivisceral transplant between 2003 and 2014. The median length of follow-up was 2.1 years. Thirty-four (16%) patients developed CMV infection at a median of 347 days after transplantation. Nineteen patients had tissue-invasive CMV disease. Cytomegalovirus infection was significantly associated with rejection (odds ratio, 2.6; p < .01) and adversely affected patient survival (hazard ratio, 2.7; p < .001). In a 2016 report from another U.S. center, Timpone et al. (2016) reported that 16 (19%) of 85 patients undergoing intestinal or multivisceral transplantation developed CMV infection a mean of 139 days (range, 14 to 243) postoperatively.¹⁹

Wu et al. (2016) investigated the incidence and risk factors of acute antibody-mediated rejection (ABMR) among patients undergoing intestinal transplantation (N = 175).²⁰ All patients were 25 years of age. Acute ABMR was diagnosed by clinical evidence; histologic evidence of tissue damage; focal or diffuse linear C4d deposition; and circulating anti-human leukocyte antigen antibodies. Of the 175 intestinal transplants, 58% were liver-free grafts, 36% included a liver graft, and 6.3% were retransplantations. Eighteen cases of acute ABMR were identified; 14 (14%) among the patients undergoing first liver-free transplantation, 2 (3%) among patients undergoing liver and small bowel transplantations, and 2 (18%) among the patients undergoing retransplantation. Graft failure occurred in 67% of patients with acute ABMR. The presence of a donor-specific antibody and a liver-free graft were associated with the development of acute ABMR.

In a series by Cromvik et al. (2016), 5 (19%) of 26 patients were diagnosed with graft-versus-host disease after intestinal or multivisceral transplantation.²¹ Risk factors for graft-versus-host disease were: malignancy as a cause of transplantation; neoadjuvant chemotherapy; or brachytherapy before transplantation.

In a retrospective study, Florescu et al. (2012) reported on bloodstream infections among 98 children (> 18 years) with small bowel and combined organ transplants.²² Seventy-seven (79%) underwent small bowel transplant in combination with a liver, kidney, or kidney and pancreas, and 21 had an isolated small bowel transplant. After a median follow-up of 52 months, 58 (59%) patients had survived. The 1-year survival rate was similar in patients with combined small bowel transplant (75%) and those with isolated small bowel transplant (81%). In the first year after transplantation, 68 (69.4%) patients experienced at least 1 episode of bloodstream infection. The 1-year survival rate for patients with bloodstream infections was 72% compared with 87% in patients without bloodstream infections (p = .056 for the difference in survival in patients with and without bloodstream infections).

Wu et al. (2011) reported on 241 patients who underwent intestinal transplantation.²³ Of these, 147 (61%) had multivisceral transplants, 65 (27%) had small bowel transplants, and 29 (12%) had small bowel/liver transplants. Recipients included 151 (63%) children and 90 (37%) adults. Twenty-two (9%) patients developed graft-versus-host disease. Children younger than 5 years old were more likely to develop this condition (13.2% [16/121]) than children between 5 and 18 years (6.7% [2/30]) and adults older than 18 years (4.4% [9/90]).

Human Immunodeficiency Virus-Positive Transplant Recipients
Solid-organ transplant for patients who are HIV-positive was historically controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. No studies reporting on outcomes in HIV-positive patients who received small bowel and liver or multivisceral transplants were identified in literature reviews.

Current Organ Procurement Transplantation Network policy permits HIV-positive transplant candidates.²⁴

The British HIV Association and the British Transplantation Society (2017) updated their guidelines on kidney transplantation in patients with HIV disease.²⁵ These criteria may be extrapolated to other organs:

• Adherent with treatment, particularly antiretroviral therapy
• CD4 count greater than 100 cells/mL (ideally > 200 cells/mL) for at least 3 months
• Undetectable HIV viremia (< 50 HIV-1 RNA copies/mL) for at least 6 months
• No opportunistic infections for at least 6 months
• No history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma.

Section Summary: Transplantation of Small Bowel/Liver or Multivisceral Organs
Intestinal transplantation procedures are infrequently performed and only 1 registry study and relatively small case series, generally single-center, are available. For patients experiencing significant complications from TPN, which can lead to liver failure and repeated infections, this literature has shown reasonably high posttransplant survival rates in patients who have a high probability of death without treatment. Guidelines and U.S. federal policy no longer view HIV infection as an absolute contraindication for solid organ transplantation.

Retransplantation of Small Bowel and Liver or Multivisceral Organs
Clinical Context and Therapy Purpose
The purpose of small bowel and liver retransplant alone or multivisceral retransplant in patients who have a failed small bowel and liver or multivisceral transplant without contraindications for retransplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does small bowel and liver retransplant alone or multivisceral retransplant improve the net health outcome in individuals with a failed small bowel and liver or multivisceral transplant and no contraindications to retransplant?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with a failed small bowel and liver or multivisceral transplant without contraindications for retransplant.

Interventions
The therapy being considered is small bowel and liver retransplant alone or multivisceral retransplant.

Comparators
The following practices are currently being used to make decisions about failed small bowel and liver or multivisceral transplant when there are no contraindications for retransplant: medical management and parenteral nutrition.

Outcomes
The general outcomes of interest are OS, morbid events, treatment-related mortality, and treatment-related morbidity, including short- and long-term graft survival and 1- and 5-year OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series
Evidence for the use of retransplantation to treat individuals who have failed intestinal transplantations includes several case series, mostly from single institutions. The case series by Desai et al. (2012) analyzed records from the United Network for Organ Sharing (UNOS) database.⁹ Among the case series described in Table 3, reasons for retransplantations included: acute rejection, chronic rejection, CMV, liver failure, lymphoproliferative disorder, and graft dysfunction. Survival rates for retransplantations are listed in Table 4.

Table 3. Summary of Key Case Series Characteristics for Retransplantations

Study	Country	N	Median Age (Range), y	Interventions		Follow-Up , mo
				Treatment	n
Ekser et al. (2018)26	U.S.	18b	27.0 (17.4)a (0.9 to 57)	Isolated ITx Modified multivisceral transplant Multivisceral graft	1 1 16	NR
Lacaille et al. (2017)11	France	10	13 (5 to 16)	Isolated ITx Combined liver ITx	3 7	4
Desai et al. (2012)9	U.S.	72 (adults) 77 (children)	NR	Adults: Isolated ITx Combined liver ITx Children: Isolated ITx Combined liver ITx	41 31 28 49	NR
Abu-Elmagd et al. (2009)8	U.S.	47	NR	Isolated ITx Combined liver ITx Multivisceral graft	31 7 9	NR
Mazariegos et al. (2008)27	U.S.	14	9.4 (3.2 to 22.7)	Isolated ITx Combined liver ITx Multivisceral graft	1 3 10	55.9

ITx: intestinal transplantation; NR: not reported.
^aMean (standard deviation).
^bOf a cohort of 218 transplants or retransplant procedures.

Table 4. Summary of Key Case Series Results for Retransplantations

Study	Interventions		Survival	Off TPN
	Treatment	n
Ekser et al. (2018)26	Isolated ITx Modified multivisceral transplant Multivisceral graft	1 1 16	Graft survival: 71% at 1 y; 56% at 3 y; 44% at 5 y Patient survival: 71% at 1 y; 47% at 3 y; 37% at 5 y	NR
Lacaille et al. (2017)11	Isolated ITx Combined liver ITx	3 7	All transplantations combined: 30% at last follow-up	NR
Desai et al. (2012)9	Adults: Isolated ITx Combined liver ITx Children: Isolated ITx Combined liver ITx	Adults: 41 31 Children: 28 49	Adults: 80% at 1 y; 47% at 3 y; 29% at 5 y 63% at 1 y; 56% at 3 y; 47% at 5 y Children: 81% at 1 y; 74% at 3 y; 57% at 5 y 42% at 1 y; 42% at 3 y; 42% at 5 y	NR
Abu-Elmagd et al. (2009)8	Isolated ITx Combined liver ITx Multivisceral graft	31 7 9	All transplantations combined: 69% at 1 y 47% at 5 y	NR
Mazariegos et al. (2008)27	Isolated ITx Combined liver ITx Multivisceral graft	1 3 10	All transplantations combined: 71% at last follow-up	100%

ITx: intestinal transplantation; NR: not reported; TPN: total parenteral nutrition.

Section Summary: Retransplantation of Small Bowel and Liver or Multivisceral Organs
Evidence for retransplantations derives mostly from single-center case series, though 1 series used records from the UNOS database. Although limited in quantity, the available follow-up data after retransplantation have suggested reasonably high survival rates after small bowel and liver transplants and multivisceral retransplantation in patients who continue to meet criteria for transplantation.

Summary of Evidence
For individuals who have intestinal failure and evidence of impending end-stage liver failure who receive a small bowel and liver transplant alone or multivisceral transplant, the evidence includes a registry study and a limited number of case series. Relevant outcomes are OS, morbid events, and treatment-related mortality and morbidity. These transplant procedures are infrequently performed and few reported case series exist. However, results from the available literature have revealed fairly high postprocedural survival rates. Given these results and the exceedingly poor survival rates of patients who exhaust all other treatments, transplantation may prove not only to be the last option but also a beneficial one. Transplantation is contraindicated for patients in whom the procedure is expected to be futile due to comorbid disease, or in whom posttransplantation care is expected to significantly worsen comorbid conditions. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a failed small bowel and liver or multivisceral transplant without contraindications for retransplant who receive a small bowel and liver retransplant alone or multivisceral retransplant, the evidence includes case series. Relevant outcomes are OS, morbid events, and treatment-related mortality and morbidity. Although limited in quantity, the available post retransplantation data have suggested reasonably high survival rates. Given exceedingly poor survival rates without retransplantation of patients who have exhausted other treatments, evidence of postoperative survival from uncontrolled studies is sufficient to demonstrate that retransplantation provides a survival benefit in appropriately selected patients. Retransplantation is contraindicated for patients in whom the procedure is expected to be futile due to comorbid disease or in whom posttransplantation care is expected to significantly worsen comorbid conditions. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Gastroenterological Association
In 2003, the American Gastroenterological Association published a position statement on short bowel syndrome and intestinal transplantation.²⁸ The statement noted that only patients with life-threatening complications due to intestinal failure or long-term total parenteral nutrition (TPN) have undergone intestinal transplantation. The statement recommended the following Medicare-approved indications, pending availability of additional data:

• Impending liver failure
• Thrombosis of major central venous channels
• Frequent central line-associated sepsis
• Frequent severe dehydration.

American Society of Transplantation
In 2001, the American Society of Transplantation issued a position paper on indications for pediatric intestinal transplantation.²⁹ The society listed the following disorders in children as being potentially treatable by intestinal transplantation: short bowel syndrome, defective intestinal motility, and impaired enterocyte absorptive capacity. Contraindications for intestinal transplant to treat pediatric patients with intestinal failure are similar to those of other solid organ transplants: profound neurologic disabilities, life-threatening comorbidities, severe immunologic deficiencies, nonresectable malignancies, autoimmune diseases, and insufficient vascular patency.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in July 2022 did not identify any ongoing or unpublished trials that would likely influence this review.

References:    

1. Black CK, Termanini KM, Aguirre O, et al. Solid organ transplantation in the 21st century. Ann Transl Med. Oct 2018; 6(20): 409. PMID 30498736
2. Organ Procurement and Transplantation Network (OPTN). National Data. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/. Accessed June 10, 2022.
3. Sulkowski JP, Minneci PC. Management of short bowel syndrome. Pathophysiology. Feb 2014; 21(1): 111-8. PMID 24341969
4. Bharadwaj S, Tandon P, Gohel TD, et al. Current status of intestinal and multivisceral transplantation. Gastroenterol Rep (Oxf). Feb 2017; 5(1): 20-28. PMID 28130374
5. Loo L, Vrakas G, Reddy S, et al. Intestinal transplantation: a review. Curr Opin Gastroenterol. May 2017; 33(3): 203-211. PMID 28282321
6. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Small bowel transplants in adults and multivisceral transplants in adults and children. TEC Assessments. 1999;Volume 14:Tab 9.
7. Mangus RS, Tector AJ, Kubal CA, et al. Multivisceral transplantation: expanding indications and improving outcomes. J Gastrointest Surg. Jan 2013; 17(1): 179-86; discussion p.186-7. PMID 23070622
8. Abu-Elmagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann Surg. Oct 2009; 250(4): 567-81. PMID 19730240
9. Desai CS, Khan KM, Gruessner AC, et al. Intestinal retransplantation: analysis of Organ Procurement and Transplantation Network database. Transplantation. Jan 15 2012; 93(1): 120-5. PMID 22113492
10. Raghu VK, Beaumont JL, Everly MJ, et al. Pediatric intestinal transplantation: Analysis of the intestinal transplant registry. Pediatr Transplant. Dec 2019; 23(8): e13580. PMID 31531934
11. Lacaille F, Irtan S, Dupic L, et al. Twenty-eight years of intestinal transplantation in Paris: experience of the oldest European center. Transpl Int. Feb 2017; 30(2): 178-186. PMID 27889929
12. Garcia Aroz S, Tzvetanov I, Hetterman EA, et al. Long-term outcomes of living-related small intestinal transplantation in children: A single-center experience. Pediatr Transplant. Jun 2017; 21(4). PMID 28295952
13. Dore M, Junco PT, Andres AM, et al. Surgical Rehabilitation Techniques in Children with Poor Prognosis Short Bowel Syndrome. Eur J Pediatr Surg. Feb 2016; 26(1): 112-6. PMID 26535775
14. Rutter CS, Amin I, Russell NK, et al. Adult Intestinal and Multivisceral Transplantation: Experience From a Single Center in the United Kingdom. Transplant Proc. Mar 2016; 48(2): 468-72. PMID 27109980
15. Lauro A, Zanfi C, Dazzi A, et al. Disease-related intestinal transplant in adults: results from a single center. Transplant Proc. Jan-Feb 2014; 46(1): 245-8. PMID 24507060
16. Varkey J, Simren M, Bosaeus I, et al. Survival of patients evaluated for intestinal and multivisceral transplantation - the Scandinavian experience. Scand J Gastroenterol. Jun 2013; 48(6): 702-11. PMID 23544434
17. Spence AB, Natarajan M, Fogleman S, et al. Intra-abdominal infections among adult intestinal and multivisceral transplant recipients in the 2-year post-operative period. Transpl Infect Dis. Feb 2020; 22(1): e13219. PMID 31778012
18. Nagai S, Mangus RS, Anderson E, et al. Cytomegalovirus Infection After Intestinal/Multivisceral Transplantation: A Single-Center Experience With 210 Cases. Transplantation. Feb 2016; 100(2): 451-60. PMID 26247555
19. Timpone JG, Yimen M, Cox S, et al. Resistant cytomegalovirus in intestinal and multivisceral transplant recipients. Transpl Infect Dis. Apr 2016; 18(2): 202-9. PMID 26853894
20. Wu GS, Cruz RJ, Cai JC. Acute antibody-mediated rejection after intestinal transplantation. World J Transplant. Dec 24 2016; 6(4): 719-728. PMID 28058223
21. Cromvik J, Varkey J, Herlenius G, et al. Graft-versus-host Disease After Intestinal or Multivisceral Transplantation: A Scandinavian Single-center Experience. Transplant Proc. Jan-Feb 2016; 48(1): 185-90. PMID 26915866
22. Florescu DF, Qiu F, Langnas AN, et al. Bloodstream infections during the first year after pediatric small bowel transplantation. Pediatr Infect Dis J. Jul 2012; 31(7): 700-4. PMID 22466325
23. Wu G, Selvaggi G, Nishida S, et al. Graft-versus-host disease after intestinal and multivisceral transplantation. Transplantation. Jan 27 2011; 91(2): 219-24. PMID 21076376
24. Organ Procurement and Transplantation Network (OPTN). Organ Procurement and Transplantation Network Policies. 2022; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed June 10, 2022.
25. Working Party of the British Transplantation Society. Kidney and Pancreas Transplantation in Patients with HIV. Second Edition (Revised). British Transplantation Society Guidelines. Macclesfield, UK: British Transplantation Society; 2017.
26. Ekser B, Kubal CA, Fridell JA, et al. Comparable outcomes in intestinal retransplantation: Single-center cohort study. Clin Transplant. Jul 2018; 32(7): e13290. PMID 29782661
27. Mazariegos GV, Soltys K, Bond G, et al. Pediatric intestinal retransplantation: techniques, management, and outcomes. Transplantation. Dec 27 2008; 86(12): 1777-82. PMID 19104421
28. American Gastroenterological Association. American Gastroenterological Association medical position statement: short bowel syndrome and intestinal transplantation. Gastroenterology. Apr 2003; 124(4): 1105-10. PMID 12671903
29. Kaufman SS, Atkinson JB, Bianchi A, et al. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant. Apr 2001; 5(2): 80-7. PMID 11328544
30. Center for Medicare & Medicaid Services. National Coverage Determination (NCD) for Intestinal and Multi- Visceral Transplantation (260.5). 2006; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=280&ncdver=2&CoverageSelection=National&KeyWord=intestinal&KeyWordLookUp=Title& KeyWordSearchType=And&generalError=Thank+you+for+your+interest+in+the+Medicare+Coverage+Database. +You+may+only+view+the+page+you+attempted+to+access+via+normal+usage+of+the+Medicare+Coverage+ Database.&bc=gAAAACAAAAAAAA%3d%3d&. Accessed June 10, 2022.

Coding Section

Codes	Number	Description
CPT	44120	Enterectomy, resection of small intestine; single resection and anastomosis
	44121	; each additional resection and anastomosis
	44132	Donor enterectomy (including code preservation), open; from cadaveric donor
	44133	; partial, from living donor
	44715	Backbench standard preparation of cadaver or living donor intestine allograft prior to transplantation, including mobilization and fashioning of the superior mesenteric artery and vein
	44720	Backbernch reconstruction of cadaver or living donor intestine allograft prior to transplantation, venous anastomosis, each
	44721	; arterial anastomsis, each
	44799	Unlisted procedure, intestine
	47133	Donor hepatectomy (including code preservation), from cadaver donor
	47135	Liver allotransplantion, orthotopic, partial or whole, cadaver or living donor, any age
	47136	Liver allotransplantation, heterotopic, partial or whole, cadaver or living donor, any age
	47140	Donor hepatectomy (including cold preservation), from living donor; left lateral segment only segments II and III
	47141	total left lobectomy (segments ll, lll or lV)
	47142	total right lobectomy (segments V, Vl, Vll and Vlll)
	47143	Baclbemcj stamdard preparation of cadaver donor whole liver graftprior to allotransplantation, including cholecystectomy, if necessary, and dissection and removal of surrounding tissues to prepare the vena cava, portal vein, hepatic artery, and common bile duct for implantationl without trisegment or lobe split
	47144	with trisegment split of whole liver graft into two partial liver grafts (i.e., left lobe [segments ll and lll] and right trisegment [segments l and lV through Vlll])
	47175	with lobe split of whole liver graft into two partial liver grafts (i.e., left lobe [segments l , lll and lV] and right lobe [segments l and V through Vlll])
	47146	Backbench reconstruction of cadaver or living donor liver graft prior to allotransplantationl venous anastomosis
	47147	arterial anastomosis, each
ICD-9 Procedure	45.63	Total removal of small intestine
	46.97	Transplant of intestine
	50.59	Transplant, liver
ICD-9 Diagnosis	570	Acute and subacute necrosis of liver
	572.8	Failure, liver
	579.3	Syndrome, short bowel
HCPCS	S2053	Transplantation of small intestine, and liver allografts
	S2054	Transplntation of multivisceral organs
	S2055	Harvesting of donor multivisceral organs, with preparation and maintenance of allografts; from cadaver donor
ICD-10-CM (effective 10/01/15)	K72.00-K72.01	Acute and subacute hepatic failure code range.
	K72.10-K72.11	Chronic hepatic failure code range
	K91.2	Postsurgical malabsortion, not elsewhere classified (includes shoe bowel syndrome)
ICD-10-PCS (effective 10/01/15)	0DY60Z0	Transplantation, stomach, open, allogenic
	0DY80Z0	Transplantation, small intestine, open, allogeneic
	0DYE0Z0	Tranplantation, large intestine, ope allogeneic
	0FY00Z0	Transplantation, liver, open allogeneic
	0FYG0Z0	Transplantation, pancreas, open allogeneic
Type of Service	Surgery
Place of Service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Index
Multivisceral Transplant
Small Bowel/Liver and Multivisceral Transplant
Small Bowel/Liver Transplant
Transplant, Multivisceral
Transplant, Small Bowel/Liver

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward     

12/01/2022	Annual review, no change to policy intent. Updating regulatory status, rationale and references
12/01/2021	Annual review, no change to policy intent. Updating rationale and references.
12/01/2020	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
03/03/2020	Correct typo in coding section. No other changes made.
12/02/2018	Annual review, no change to policy intent. Updating rationale and references.
12/31/2018	Annual review, no change to policy intent. Updating rationale and references.
12/19/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
12/05/2016	Annual review, no change to policy intent.
12/07/2015	Annual review,no change to policy intent. Updated background, description, rationale,and references.
12/01/2014	Annual review, updating rationale and references. Adding coding. Adding statement to policy "A small/bowel/liver transplant or multivisceral transplant is considered investigational in all other situations.
12/5/2013	Annual review. Updated rationale, references and policy statement (added " small bowel/liver transplant or multivisceral retransplant may be considered medically necessary after a failed primary small bowel/liver transplant or multivisceral transplant). Added related policies and benefit applications.