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Intestinal Transplantation

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History Last

Review

03/04/2019

Effective: 03/27/200

Next Review:

06/27/2019

Review History

Definitions

Additional Information

Number: 0605

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Aetna considers intestinal transplantation medically necessary for persons who

have failed total parenteral nutrition (TPN) when the selection criteria below are

met.

Parenteral nutrition (see CPB 0061 - Nutritional Support (../1_99/0061.html))

entails the administration of micronutrients and macronutrients via catheters in

central or peripheral veins. In most cases, the central venous route is used. For

long-term TPN, a central catheter (e.g., Hickman, Broviac, PIC) is placed

subcutaneously in the anterior chest. Indicators of failed TPN are liver failure,

thrombosis, frequency of infection, and dehydration as demonstrated in the

following clinical situations:

Frequent episodes of severe dehydration despite intravenous fluid supplement

in addition to TPN. Under certain medical conditions such as secretory diarrhea

and non-constructible gastro-intestinal (GI) tract, the loss of the GI and

pancreatobiliary secretions exceeds the maximum intravenous infusion rates

that can be tolerated by the cardiopulmonary system. Frequent episodes of

dehydration are detrimental to all body organs, especially the kidney and the

central nervous system with the development of multiple kidney stones, renal

failure, and permanent brain damage. Proprietary

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Frequent line infection and sepsis. The development of 2 or more episodes of

systemic sepsis due to line infection per year that requires hospitalization

indicates failure of TPN therapy. A single episode of line-related fungemia,

septic shock and/or acute respiratory distress syndrome are considered

indicators of TPN failure.

Impending or overt liver failure due to TPN-induced liver injury. The clinical

signs include elevated serum bilirubin and/or liver enzymes, splenomegaly,

thrombocytopenia, gastro-esophageal varices, coagulopathy, stomal bleeding or

hepatic fibrosis/cirrhosis.

Other complications leading to loss of vascular access. TPN failure may due to

inadequate TPN access, which is an indication for intestinal transplantation.

Thrombosis of the major central venous channels, jugular, subclavian, and

femoral veins. Thrombosis of 2 or more of these vessels is considered a life-

threatening complication and failure of TPN therapy. The consequence of

central venous thrombosis is a lack of access for TPN infusion, fatal sepsis

as a result of infected thrombi, pulmonary embolism, superior vena cava

syndrome, or chronic venous insufficiency.

Selection Criteria

Aetna considers intestinal transplant medically necessary for the indications listed

above for persons who meet the transplanting institution's protocol eligibility

criteria. In the absence of a protocol, Aetna considers intestinal transplant

medically necessary for the indications listed above when all of the following

selection criteria are met:

1. Absence of acute or chronic active infections that are not effectively treated; and

2. Adequate cardiovascular function (ejection fraction greater than or equal to 40

%); and

3. Adequate liver and kidney function, defined as a bilirubin of less than 2.5 mg/dL

and a creatinine clearance of greater than 50 ml/min/kg; and

4. No active alcohol or chemical dependency that interferes with compliance to a

strict treatment regimen. Persons with a history of drug or alcohol abuse must

be abstinent for at least 3 months before being considered a transplant

candidate eligible for coverage; and

5. No uncontrolled and/or untreated psychiatric disorders that interfere with

compliance to a strict treatment regimen; and

6. Absence of inadequately controlled HIV/AIDS, defined as:

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CD4 count greater than 200 cells/mm3 for more than 6 months; and

HIV-1 RNA (viral load) undetectable; and

No other complications from AIDS, such as opportunistic infections (e.g.,

aspergillus, tuberculosis, Pneumocystis carinii pneumonia, toxoplasmosis

encephalitis, cryptococcal meningitis, disseminated coccidioidomycosis,

other resistant fungal infections) or neoplasms (Kaposi's sarcoma, non-

Hodgkin's lymphoma); and

On stable anti-viral therapy for more than 3 months.

A combined intestinal and liver transplant is considered medically necessary for

persons with advanced liver disease necessitating liver transplantation

(see CPB 0596 - Liver Transplantation (../500_599/0596.html)) who meet the

medical necessity criteria above (other than the requirement for adequate liver

function). Note: In candidates for a combined transplant, adequacy of renal

function should be assessed with a measured glomerular filtration rate (GFR), as a

calculated GFR is inaccurate in advanced liver disease.

Contraindications

Intestinal transplant is considered not medically necessary for persons with the

following contraindications:

Advanced neurological disorders (e.g., neuroaxonal dystrophy, Tay-Sachs

disease, Niemann-Pick disease and variants, neuronal ceroid lipofuscinosis,

and Huntington disease);

Congestive heart failure with refractory symptoms and ejection fraction less than

40 %;

Malignancy, other than non-melanomatous skin cancer or low-grade prostate

cancer, that is not effectively treated such that there is a substantial risk of

recurrence;

Multi-organ failure;

Presence of other GI diseases (e.g., bleeding peptic ulcer, diverticulitis, chronic

hepatitis);

Sepsis.

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Aetna considers multi-visceral transplants from deceased donors medically

necessary for adults and children who meet criteria for the combined small

bowel/liver transplant and require 1 or more abdominal visceral organs to be

transplanted due to concomitant organ failure or anatomical abnormalities that

preclude a small bowel/liver transplant.

Aetna considers multi-visceral transplants experimental and investigational for

individuals with neuroendocrine pancreatic tumors.

Aetna considers measurement of fecal calprotectin experimental and investigational

as a test for intestinal allograft rejection because its clinical value has not been

established.

See also CPB 0342 - Intestinal Rehabilitation Programs (../300_399/0342.html).

Background

Intestinal transplantation has become the treatment of choice for patients with

chronic intestinal failure whose illness can not be maintained on total parenteral

nutrition (TPN). The term "intestinal failure" refers to gastro-intestinal (GI) function

insufficient to meet body fluid and nutrient requirements; it includes short bowel

syndrome (SBS) and severe motility disorders (e.g., chronic intestinal pseudo-

obstruction syndrome in children and congenital intractable intestinal mucosa

disorders). Short bowel (also known as short gut) syndrome is a condition in which

the absorbing surface of the small intestine is inadequate as a result of extensive

disease or surgical removal of a large segment of the small intestine. Patients with

SBS are unable to obtain adequate nutrition from enteral feeding.

In infants, SBS is generally due to congenital anomalies. Common causes of a

SBS in infants and children include microvillus atrophy, intestinal atresia, midgut

volvulus, complicated gastroschisis, aganglion syndrome, and necrotizing

enterocolitis. In adults, severe SBS usually occurs following a massive small bowel

resection, which results in rapid intestinal transit and loss of absorptive function.

Common causes of SBS in adults include Crohn's disease, desmoid tumors

(familial polyposis with Gardner’s syndrome), radiation enteritis, iatrogenic jejunal-

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ileal bypass (for morbid obesity), mesenteric venous thrombosis, superior

mesenteric artery thrombosis, and traumatic mesenteric transection (blunt

abdominal trauma).

Parenteral nutrition and home parenteral nutrition are the mainstay of therapy for

children with SBS and other causes of intestinal failure. Most infants with SBS

eventually wean from parenteral nutrition, and most of those who do not wean

tolerate parenteral nutrition for an extended period of time. However, a subgroup of

patients with intestinal failure who remain dependent on parenteral nutrition will

develop life-threatening complications as a consequence of standard therapy. The

literature indicates that intestinal transplantation is recommended for this select

group. The majority of intestinal transplantation recipients are children, especially

those under the age of 5.

Indications for intestinal transplantation include parenteral nutrition-associated liver

disease, recurrent sepsis, and threatened loss of central venous access. The

literature suggests children with liver dysfunction should be considered for isolated

intestinal transplantation before irreversible, advanced bridging fibrosis or cirrhosis

supervenes, for which a combined liver and intestinal transplant is necessary.

Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3 to

4 months of age combined with features of portal hypertension such as

splenomegaly, thrombocytopenia, or prominent superficial abdominal veins.

In children, the 1- and 3-year graft survival rates for isolated small bowel and

combined small bowel and liver transplantations range from 40 to 50 %, while the

1- and 3-year patient survival rates range from 80 to 100 %, depending on the age

range of the patient. Successful transplant recipients resume unrestricted oral

diets. Despite the use of potent immunosuppressive agents, rejection rates are still

50 % or higher. Sepsis rates are also higher for patients who have had intestinal

transplantation than for those who have received other organs because of bacterial

translocation from the gut secondary to preservation injury and graft rejection.

Graft and patient survival rates after intestinal transplantation are comparable to

rates after lung transplantation.

In addition to rejection and infection (bacterial, fungal, and viral), other

complications of intestinal transplantation are graft-versus-host disease,

cytomegalovirus infection as well as post-transplant lymphoproliferative disease

associated with aggressive immunosuppression and Epstein-Barr virus.

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Multi-Visceral Transplantation

Multi-visceral transplantation entails the simultaneous transplantation of multiple

abdominal viscera including the stomach, duodenum, pancreas, and small

intestine, with (multi-visceral transplant [MVT]) or without the liver (modified MVT,

[MMVT]).

Abu-Elmgagd et al (2009) evaluated the evolution of visceral transplantation in the

milieu of surgical technical modifications, new immunosuppressive protocols, and

other management strategies. Divided into 3 eras, a total of 453 patients received

500 visceral transplants. The primary used immunosuppression was tacrolimus-

steroid-only during Era I (5/90 to 5/94), adjunct induction with multiple drug therapy

during Era II (1/95 to 6/01), and recipient pre-treatment with tacrolimus

monotherapy during Era III (7/01 to 11/08). During era II/III, donor bone marrow

was given (n = 79), intestine was ex-vivo irradiated (n = 44), and Epstein-Barr-Virus

(EBV)/cytomegalovirus (CMV) loads were monitored. Actuarial patient survival was

85 % at 1-year, 61 % at 5-years, 42 % at 10-years, and 35 % at 15-years with

respective graft survival of 80 %, 50 %, 33 %, and 29 %. With a 10 % re-

transplantation rate, second/third graft survival was 69 % at 1-year and 47 % at

5-years. The best outcome was with intestine-liver allografts. Era III rabbit anti-

thymocyte globulin or alemtuzumab pre-treatment-based strategy was associated

with significant (p < 0.0001) improvement in outcome with 1- and 5-year patient

survival of 92 % and 70 %. The authors concluded that survival has greatly

improved over time as management strategies evolved. The current results

justified elevating the procedure level to that of other abdominal organs with the

privilege to permanently reside in a respected place in the surgical

armamentarium. Meanwhile, innovative tactics are still required to conquer long-

term hazards of chronic rejection of liver-free allografts and infection of multi-

visceral recipients

Vianna et al (2012) evaluated the clinical outcomes of MVT in the setting of diffuse

thrombosis of the porto-mesenteric venous system. A database of intestinal

transplant patients was maintained with prospective analysis of outcomes. The

diagnosis of diffuse porto-mesenteric thrombosis (PMT) was established with dual-

phase abdominal computed tomography or magnetic resonance imaging with

venous reconstruction. A total of 25 patients with grade IV PMT received 25 MVT.

Eleven patients underwent simultaneous cadaveric kidney transplantation. Biopsy-

proven acute cellular rejection was noted in 5 recipients, which was treated

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successfully. With a median follow-up of 2.8 years, patient and graft survival were

80 %, 72 %, and 72 % at 1, 3, and 5 years, respectively. To date, all survivors

have good graft function without any signs of residual/recurrent features of portal

hypertension. The authors concluded that MVT can be considered as an option for

the treatment of patients with diffuse PMT. They stated that MVT is the only

procedure that completely reverses portal hypertension and addresses the primary

disease while achieving superior survival results in comparison to the alternative

options.

Trevizol et al (2013) stated that intestinal transplantation (IT)/MVT is the gold

standard treatment for patients with intestinal failure and complications related to

TPN, gastro-intestinal inoperable indolent tumors, or diffuse portal thrombosis.

Currently, the reported 1-year patient survival rate is around 80 %, similar to other

solid organ abdominal transplantations. Unfortunately, the patient survival

decreases after the first year with the 5-year rate not close to 70 % yet. Acute

cellular rejection (ACR) is the main cause of graft loss. Its early diagnosis may

make it possible to improve survival of re-transplantations. These investigators

analyzed the reported results published in the last 5 years by leading transplant

centers to evaluate IT/MVT re-transplantation results. They performed a literature

review using PubMed focusing on multi-visceral and intestinal re-transplantation in

articles published between 2006 and 2012. In relation to the first transplantation,

these researchers analyzed demographics, immunosuppression, rejection, infection

as well as graft and patient survival rates. Two centers reported results on

intestinal and multi-visceral re-transplantations. Mazariegos et al reported their

experience with 15 intestinal re-transplantations in 14 pediatric recipients. Four

patients died from post-transplant lympho-proliferative disease, severe ACR, fungal

sepsis, or bleeding from a pseudo-aneurysm at a mean time of 5.7 months post-

transplantation. Total parenteral nutrition was weaned at a median time of 32

days. Abu-Elmaged et al reported 47 cases with a 5-year survival of 47 % for all re-

transplant modalities. Re-transplantation with liver-contained visceral allograft

achieved a 5-year survival rate of 61 % compared with 16 % for liver-free visceral

grafts. The authors concluded that despite those huge improvements, some

transplanted patients develop severe ACR, culminating in graft loss and re-

transplantation. Reports on multi-visceral and intestinal re-transplantation

outcomes suggested that it is a viable procedure with appropriate patient survival

after primary graft loss.

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Mangus et al (2013) reviewed the changing indications and outcomes for this

procedure over a 7-year period. This study was a retrospective case review of

MVTs performed between 2004 and 2010 at a single center. All cases were either

MVT or MMVT and included a simultaneous kidney transplant, if indicated. Graft

failure was defined as loss of the graft or complete loss of function. Graft function

was monitored by clinical function, laboratory values, and serial endoscopy with

biopsy. During the study period, 95 patients received 100 transplants including 84

MVT and 16 MMVT. There were 19 patients who received a simultaneous kidney

graft. There were 24 pediatric and 76 adult recipients (age range of 7 months to 66

years). Indications included intestinal failure alone, intestinal failure with cirrhosis,

complete PMT, slow-growing central abdominal tumors, intestinal pseudo-

obstruction, and frozen abdomen. All patients received antibody-based induction

immunosuppression with calcineurin inhibitor-based maintenance

immunosuppression. At a median mortality adjusted follow-up of 25 months, 1- and 3-

year patient survival rates were 72 % and 57 %, respectively. There was a learning

curve with this complex procedure resulting in a 48 % patient survival during the

period from 2004 to 2007, followed by a 70 % patient survival during the period from

2008 to 2010. Post-transplant complications included rejection (50 % MMVT and 17

% MVT), infection (greater than 90 % first year), graft-versus-host disease (13 %),

and post-transplant lymphoproliferative disorder (5 %). The authors concluded that

indications for MVT and MMVT have broadened to include patients with terminal

conditions not amenable to other medical therapies such as slow-growing tumors of

the mesenteric root, complete PMT, and abdominal catastrophes/frozen abdomen.

Outcomes have improved over time with many patients returning to full functional

status and enjoying long-term survival.

Varkey et al (2013) stated that the current treatment of choice for patients with

intestinal failure is parenteral nutrition, whereas medical therapy or resection is

preferred for patients with neuroendocrine pancreatic tumors (NEPT) along with

liver metastasis. As the survival of patients undergoing IT and MVT is improving,

the discussion for expansion of treatment options has become a subject of debate.

These researchers investigated the outcome for patients referred for IT and MVT

and determined which patient group are the ones most likely to benefit the most

from transplantation. The authors included all patients evaluated for IT and MVT at

the Sahlgrenska University Hospital and The Queen Silvia Children's Hospital

center between February 1998 and November 2009. Patients were classified

according to proposed treatment strategy, and the outcome was evaluated. A total

of 43 adults and 19 children with either intestinal failure or NEPT with liver

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metastases were evaluated for transplantation. Of these patients, 15 adults and 5

children were transplanted. Transplantation was life-saving for most children -- all

the children survived after transplantation, but 70 % (4/6) died while awaiting

transplantation. Among the adult patients with intestinal failure, the survival rate for

patients considered to be stable on parenteral nutrition was higher than the

transplanted adult patients. The survival rate of patients with NEPT was similar to

the results seen among patients transplanted for intestinal failure. The authors

concluded that the results confirmed the poor prognosis of patients with intestinal

failure awaiting transplantation and indicated that different transplantation criteria

may be applied for adults and children, especially when early transplantation is the

preferred treatment. Moreover, they stated that the role of MVT in patients with

NEPT remains uncertain.

Kubal et al (2015a) stated that intestinal failure and associated parenteral nutrition-

induced liver failure cause significant morbidity, mortality, and health care burden.

Intestine transplantation is now considered to be the standard of care in patients

with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated

liver disease is an important sequela of intestinal failure, caused by parenteral

lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in

recent years, the emergence of fish oil-based lipid emulsions have been shown to

reverse parenteral nutrition-associated hyper-bilirubinemia, but not fibrosis.

Significant progress in surgical techniques and immunosuppression has led to

improved outcomes after intestine transplantation. Intestine in varying combination

with liver, stomach, and pancreas, also referred to as multi-visceral transplantation,

is performed for patients with intestinal failure along with liver disease, surgical

abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete

porto-mesenteric thrombosis with cirrhosis of the liver. Although acute and chronic

rejections are major problems, long-term survivors have excellent quality of life and

remain free of parenteral nutrition.

Measurement of Fecal Calprotectin

Sudan et al (2007) stated that protocol endoscopy with biopsy is currently the gold

standard of small bowel transplantation (SBTx) monitoring, however it is invasive,

costly, needs skilled operator, may require anesthesia and may cause

complications. These researchers investigated fecal calprotectin level (FCL) as a

candidate non-invasive marker for monitoring patients after SBTx. Ileostomy

effluents were collected at various post-operative days before endoscopy and

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biopsy. Fecal calprotectin levels were measured by enzyme-linked immunosorbent

assay and a cut-off level of 100 ng/mg was considered positive. Results were

retrospectively evaluated in combination with clinical, endoscopic, and

histopathological findings. Fecal calprotectin levels were presented as median

ng/mg. Fecal calprotectin levels were measured in 122 samples that were obtained

from 29 patients after SBTx. Only 1 of 69 positive FCL did not accompany

abnormal findings. Retrospective evaluation showed that 11 samples from 6

patients (FCL: 217) coincided with rejection episodes, 6 samples from 3 patients

(FCL: 125) coincided with viral enteritis, 51 samples from 21 patients (FCL: 207)

coincided with non-specific inflammation, 11 samples from 2 patients (FCL: 998)

coincided with chronic intestinal ulceration, and finally 50 samples from 19 patients

(FCL: 43) coincided with normal findings. No significant FCL difference was found

between rejection, infection, and inflammation. Evolution in FCL in transplant

recipients showed that FCL can predict rejection days before histopathological

diagnosis. The authors concluded that FCL is a promising clinical screening test for

intestinal allograft rejection. The major drawback of this study was that it was a

retrospective study of selected patient samples with known diagnosis. If the clinical

utility of FCL is confirmed by prospective validation studies, its use may avoid

unnecessary protocol endoscopy with biopsy.

Monitoring of Donor-Specific Anti-HLA Antibodies after Intestine/Multi- visceral Transplantation

Kaneku and Wozniak (2014) noted that early outcomes following intestinal

transplantation (ITx) have markedly improved in recent years. However, there has

been a lack of improvement in long-term outcomes. Increasing amounts of data

suggested the humoral immune system is a major contributor to rejection and late

allograft loss. These investigators summarized the available data on donor-specific

human leukocyte antigen antibodies (DSAs) in ITx, with a focus on the clinical

significance of DSAs, diagnosis of antibody-mediated rejection (AMR), and

available treatment modalities. They stated that mounting evidence showed that

pre- and/or post-transplant DSAs are associated with rejection and allograft loss

following ITx. Preformed DSAs are present in nearly 1/3 of ITx recipients, and de-

novo DSAs develop in up to 40 % of patients. Diagnosis and treatment of AMR

remains challenging, but reports indicated that when optimal induction and

maintenance immunosuppressive agents are used, the impact of DSAs may be

negligible. The authors concluded that although data are limited due to center

differences with regard to patient population, induction and maintenance

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immunosuppression protocols, and monitoring strategies, DSAs are associated with

poor outcomes following ITx. They stated that a consensus to define AMR and

optimal treatment strategies is needed.

Kubal et al (2015b) stated that presence of circulating DSA may be associated with

worse clinical outcomes after ITx/multi-visceral transplantation. In 79 ITx/multi-

visceral recipients, sera were prospectively screened for DSA by Luminex Single

antigen test at 1, 3, 6, 9, 12, 18, 24, and 36 months after transplantation. Standard

immunosuppression included thymoglobulin-rituximab induction and tacrolimus-

prednisone maintenance. C4d staining was performed retrospectively on biopsies

in patients that developed acute rejection (AR). A total of 22 (28 %) patients

developed de novo DSA at a median post-transplant period of 3 (1 to 36) months.

De novo DSA were observed in 10 of 40 liver-including and 12 of 39 liver-excluding

transplants (p = 0.57). Occurrence of AR was slightly higher in patients with de

novo DSA (45 % versus 33 %, respectively; p = 0.41). Similarly, chronic rejection

(14 % versus 5 %; p = 0.21) and graft loss due to AR (18 % versus 7 %; p = 0.14)

were numerically higher in patients with de novo DSA. Only 35 % patients

experiencing AR had circulating de novo DSA at the time of AR. Antibody-

mediated rejection was diagnosed in 6 patients based on C4d staining, of these 2

patients had circulating de novo DSA at the time of biopsy. The authors concluded

that de novo DSA formation, particularly early in the post-transplant course may be

associated with trends toward worse outcomes. However, its significance in the

pathophysiology of AR remains uncertain. They stated that studies focusing

mechanisms of DSA-related graft injury and intra-graft DSA detection might provide

further insight into this issue.

Furthermore, an UpToDate review on “Overview of intestinal and multivisceral

transplantation” (Khan and Selvaggi, 2015) does not mention monitoring of donor-

specific anti-HLA antibodies as a management tool.

Pediatric Intestinal Transplantation

Garcia and colleagues (2017) noted that pediatric patients with irreversible

intestinal failure present a significant challenge to meet the nutritional needs that

promote growth. From 2002 to 2013, a total of 13 living-related small intestinal

transplantations were performed in 10 children, with a median age of 18 months.

Grafts included isolated living-related intestinal transplantation (n = 7), and living-

related liver and small intestine (n = 6). The immunosuppression protocol

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consisted of induction with thymoglobulin and maintenance therapy with tacrolimus

and steroids.; 7 of 10 children were alive with a functioning graft and good quality of

life (QOL); 6 of the 7 children who were alive had a follow-up longer than 10 years.

The average time to initiation of oral diet was 32 days (range of 13 to 202 days).

The median day for ileostomy takedown was 77 (range of 18 to 224 days); 7

children were on an oral diet, and 1 of them was on supplements at night through a

g-tube. These investigators observed an improvement in growth during the 1st 3

years post-transplant and progressive weight gain throughout the 1st year post-

transplantation; growth catch-up and weight gain plateaued after these time

periods. The authors concluded that living donor intestinal transplantation

potentially offers a feasible, alternative strategy for long-term treatment of

irreversible intestinal failure in children.

Lee and associates (2017) noted that standard management of intra-abdominal

pediatric solid tumors requires complete resection. However, tumors with multiple

organ and vascular involvement present a unique surgical challenge. These

investigators conducted a retrospective chart review of 4 patients, aged 2 to 14

years, undergoing MVT for intra-abdominal tumors with significant involvement of

the visceral arteries and/or porto-mesenteric venous system at the authors’

institution. Indications for MVT included hepato-cellular carcinoma (HCC),

inflammatory myofibroblastic tumor, and 2 cases of hepatoblastoma. Grafts

included liver, stomach, small bowel, and pancreas in all patients, with 2 patients

also receiving spleens, and 1, a partial esophageal transplant. Median hospital

stay was 80 days. Post-operative complications included re-operation for

abdominal hematoma and bowel obstruction, steroid responsive intestinal rejection,

wound dehiscence, fungemia, seizures, and chyle leak with pleural effusion; 1

patient developed Epstein-Barr virus-associated complications that responded well

to treatment. On follow-up (range of 2.8 to 7.8 years), all patients have satisfactory

graft function and no evidence of recurrent disease. The authors concluded that

MVT is an effective means of achieving complete gross resection of intra-

abdominal malignancies in patients with multiple organ and vascular involvement.

Total Intestinal Aganglionosis

Nakamura and colleagues (2017) stated that total intestinal aganglionosis (TIA)

occurs in less than 1 % of patients with Hirschsprung disease (HD), and TIA is the

most severe form of HD. Survival has improved with the advent of PN and ITx.

The field of ITx has rapidly progressed in the past 20 years and has now become

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an established treatment for patients with intestinal failure. These researchers

examined the clinical outcome of ITx in patients with TIA. They performed a

systematic literature search for relevant articles in 4 databases using the

combinations of the following terms: "total intestinal aganglionosis", "intestinal

transplantation", and "Hirschsprung disease/Hirschsprung's disease" for studies

published between 2003 and 2016. The relevant cohorts of ITx in patients with TIA

were systematically searched for clinical outcomes. A total of 13 studies met

defined inclusion criteria, reporting a total of 63 patients who underwent ITx for TIA.

Majority of patients were males (71.0 %), and median age of ITx was 4.3 (range of

0.25 to 17.6) years. Isolated ITx was performed in 37 % patients and multi-visceral

ITx in 63 %. Mean follow-up period was 40 months (range of 1 to 154). Overall

survival (OS) rate was 66 %; the longest survivor was 12.8-year old after ITx. The

authors concluded that ITx appeared promising in the management of TIA. They

stated that ITx can be considered a feasible therapeutic option for patients with TIA

who suffered from life-threatening complications of intestinal failure.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added f or clarification purposes. Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

44132 Donor enterectomy (including cold preservation), open; from cadaver

donor

44133 partial, from living donor

44135 Intestinal allotransplantation; from cadaver donor

44136 from living donor

44137 Removal of transplanted intestinal allograft, complete

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 Backbench reconstruction of cadaver or living donor intestine allograft

prior to transplantation; venous anastamosis, each

44721 arterial anastamosis, each

CPT codes not covered for indications listed in the CPB:

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Code Code Description

83993 Calprotectin, fecal

Other CPT codes related to the CPB:

36555 - 36597 Central venous access procedures

47135 Liver allotransplantation; orthotopic; partial or whole, from cadaver or

living donor, any age

47143 Backbench standard preparation of cadaver donor whole liver graft prior

to allotransplantation, including cholecystectomy, if necessary, and

dissection and removal of surrounding soft tissues to prepare the vena

cava, portal vein, hepatic artery, and common bile duct for implantation;

without trisegment or lobe split

47144 with trisegment split of whole liver graft into two partial liver grafts (ie,

left lateral segment (segments II and III) and right trisegment (segments

I and IV through VIII))

47145 with lobe split of whole liver graft into two partial l iver grafts (ie, left

lobe (segments II, III and IV) and right lobe (segments I and V through

VIII))

47146 Backbench reconstruction of cadaver or living donor liver graft prior to

allotransplantation; venous anastomosis, each

47147 arterial anastomosis, each

99601 - 99602 Home infusion/specialty drug administration

HCPCS codes covered if selection criteria are met:

S2053 Transplantation of small i ntestine, and liver allografts

S2054 Transplantation of multivisceral organs

S2055 Harvesting of donor multivisceral organs, with preparation and

maintenance of allografts; from cadaver donor

Other HCPCS codes related to the CPB:

B4164 - B5200 Parenteral nutrition solutions and supplies

B9004, B9006 Parenteral nutrition infusion pump, portable or stationary

S9364 - S9368 Home infusion therapy, total parenteral nutrition (TPN)

ICD-10 codes covered if selection criteria are met:

A40.0 - A40.9 Streptococcal sepsis

E86.0 - E86.9 Volume depletion

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I82.811 - I82.91

K91.2

Z90.49

ICD-10 codes not covered for indications listed in the CPB:

B18.0

B18.1

B18.2

C7A.094

D3A.020 -

D3A.029

D3A.094

D48.1

I50.1 - I50.9

K57.00 - K57.93

The above policy is based on the following references:

1. United Network for Organ Sharing (UNOS). United Network for Organ Sharing

Online [website]. Richmond, VA: UNOS; 2002. Available at:

http://www.unos.org. Accessed April 17, 2002.

2. Kaufman SS, Atkinson JB, Bianchi A, et al. Indications for pediatric

intestinal transplantation: A position paper of the American Society of

Transplantation. Pediatr Transplant. 2001;5(2):80-87.

3. Ghanekar A, Grant D. Small bowel transplantation. Curr Opin Crit Care.

2001;7(2):133-137.

4. Reyes J. Intestinal transplantation for children with short bowel syndrome.

Semin Pediatr Surg. 2001;10(2):99-104.

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5. Madariaga JR, Reyes J, Mazariegos G. The long-term efficacy of

multivisceral transplantation. Transplant Proc. 2000;32(6):1219-1220.

6. Goulet O, Lacaille F, Jan D, et al. Intestinal transplantation: Indications,

results and strategy. Curr Opin Clin Nutr Metab Care. 2000;3(5):329-338.

7. Silver HJ, Castellanos VH. Nutritional complications and management of

intestinal transplant. J Am Diet Assoc. 2000;100(6):680-468, 687-689.

8. Grant D. Intestinal transplantation: 1997 report of the international

registry. Intestinal Transplant Registry. Transplantation. 1999;67(7):1061­

1064.

9. Niv Y, Mor E, Tzakis AG. Small bowel transplantation -- a clinical review. Am

J Gastroenterol. 1999;94(11):3126-3130.

10. Bueno J, Ohwada S, Kocoshis S, et al. Factors impacting the survival of

children with intestinal failure referred for intestinal transplantation. J

Pediatr Surg. 1999;34(1):27-32; discussion 32-33.

11. Goulet O. Intestinal transplantation. Curr Opin Clin Nutr Metab Care.

1999;2(4):315-321.

12. Goulet O. Complications after intestinal transplantation: Traditional and

new. Pediatr Transplant. 1999;3(2):89-91.

13. Jan D, Michel JL, Goulet O, et al. Up-to-date evolution of small bowel

transplantation in children with intestinal failure. J Pediatr Surg. 1999;34

(5):841-843; discussion 843-844.

14. Rovera GM, DiMartini A, Schoen RE, et al. Quality of life of patients after

intestinal transplantation. Transplantation. 1998;66(9):1141-1145.

15. Tesi R, Beck L, Lambiase S, et al. Living related small bowel

transplantation: Donor evaluation and outcome. Transplantation Proc.

1997;29(1-2):686-687.

16. Asfar S, Atkison P, Ghent C, et al. Small bowel transplantation. A life-saving

option for selected patients with intestinal failure. Dig Dis Sci. 1996;41

(5):875-883.

17. Langnas AN, Shaw BW Jr, Antonson DL, et al. Preliminary experience with

intestinal transplantation in infants and children. Pediatrics. 1996;97

(4):443-448.

18. Frezza EE, Tzakis A, Fung JJ, et al. Small bowel transplantation: Current

progress and clinical application. Hepatogastroenterology. 1996;43(8):363­

376.

19. Grant D. Current results of intestinal transplantation. The International

Intestinal Transplant Registry. Lancet. 1996;347(9018):1801-1803.

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20. Kelly DA, Buckels JA. The future of small bowel transplantation. Arch Dis

Child. 1995;72(5):447-451.

21. Tzakis AG, Todo S, Starzl TE. Intestinal transplantation. Annu Rev Med.

1994;45:79-91.

22. Nightingale JM, Lennard-Jones JE. The short bowel syndrome: What's new

and old? Dig Dis. 1993;11(1):12-31.

23. Ingham Clark CL, Lear PA, Wood S, et al. Potential candidates for small

bowel transplantation. Br J Surg. 1992;79(7):676-679.

24. Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel

syndrome and intestinal transplantation. Gastroenterology. 2003;124

(4):1111-1134.

25. American Gastroenterological Association. American Gastroenterological

Association medical position statement: Short bowel syndrome and

intestinal transplantation. Gastroenterology. 2003;124(4):1105-1110.

26. Ontario Ministry of Health and Long-Term Care, Medical Advisory

Secretariat. Small bowel transplant. Health Technology Scientific Literature

Review. Toronto, ON: Ontario Ministry of Health and Long-Term Care; April

2003.

27. Fishbein TM. The current state of intestinal transplantation.

Transplantation. 2004;78(2):175-178.

28. Fryer JP. Intestinal transplantation: An update. Curr Opin Gastroenterol.

2005;21(2):162-168.

29. Fishbein TM, Matsumoto CS. Intestinal replacement therapy: Timing and

indications for referral of patients to an intestinal rehabilitation and

transplant program. Gastroenterology. 2006;130(2 Suppl 1):S147-S151.

30. Selvaggi G, Tzakis AG. Intestinal and multivisceral transplantation: Future

perspectives. Front Biosci. 2007;12:4742-4754.

31. DeLegge M, Alsolaiman MM, Barbour E, et al. Short bowel syndrome:

Parenteral nutrition versus intestinal transplantation. Where are we

today? Dig Dis Sci. 2007;52(4):876-892.

32. Selvaggi G, Weppler D, Tzakis A. Liver and gastrointestinal transplantation

at the University of Miami. Clin Transpl. 2003;:255-266.

33. Renz JF, McDiarmid SV, Edelstein S, et al. Application of combined liver-

intestinal transplantation as a staged procedure. Transplant Proc. 2004;36

(2):314-315.

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34. Herlenius G, Friman S, Bäckman L, et al. Initial experience with

multivisceral, cluster, and combined liver and small bowel transplantation

in Sweden. Transplant Proc. 2002;34(3):865.

35. Muiesan P, Dhawan A, Novelli M, et al. Isolated liver transplant and

sequential small bowel transplantation for intestinal failure and related

liver disease in children. Transplantation. 2000;69(11):2323-2326.

36. Farmer DG, McDiarmid SV, Smith C, et al. Experience with combined liver-

small intestine transplantation at the University of California, Los Angeles.

Transplant Proc. 1998;30(6):2533-2534.

37. Lacaille F, Jobert-Giraud A, Colomb V, et al. Preliminary experience with

combined liver and small bowel transplantation in children. Transplant

Proc. 1998;30(6):2526-2527.

38. Sudan D, Vargas L, Sun Y, et al. Calprotectin: A novel noninvasive marker

for intestinal allograft monitoring. Ann Surg. 2007;246(2):311-315.

39. Fryer JP. The current status of intestinal transplantation. Curr Opin Organ

Transplant. 2008;13(3):266-272.

40. Vianna RM, Mangus RS, Tector AJ. Current status of small bowel and

multivisceral transplantation. Adv Surg. 2008;42:129-150.

41. Millar AJ, Gupte G, Sharif K. Intestinal transplantation for motility

disorders. Semin Pediatr Surg. 2009;18(4):258-262.

42. Fishbein TM. Intestinal transplantation. N Engl J Med. 2009;361(10):998­

1008.

43. Weimann A, Ebener Ch, Holland-Cunz S, et al; Working group for

developing the guidelines for parenteral nutrition of The German

Association for Nutritional Medicine. Surgery and transplantation ­

Guidelines on Parenteral Nutrition, Chapter 18. Ger Med Sci.

2009;7:Doc10.

44. Sudan D. Long-term outcomes and quality of life after intestine

transplantation. Curr Opin Organ Transplant. 2010;15(3):357-360.

45. Roskott AM, Nieuwenhuijs VB, Dijkstra G, et al. Small bowel preservation

for intestinal transplantation: A review. Transpl Int. 2011;24(2):107-131.

46. Pironi L, Joly F, Forbes A, et al; Home Artificial Nutrition & Chronic

Intestinal Failure Working Group of the European Society for Clinical

Nutrition and Metabolism (ESPEN). Long-term follow-up of patients on

home parenteral nutrition in Europe: Implications for intestinal

transplantation. Gut. 2011;60(1):17-25.

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47. Venick RS, Wozniak LJ, Colangelo J, et al. Long-term nutrition and

predictors of growth and weight gain following pediatric intestinal

transplantation. Transplantation. 2011;92(9):1058-1062.

48. Abu-Elmgagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and

multivisceral transplantations at a single center: Major advances with new

challenges. Ann Surg. 2009; 250(4):567-581.

49. Vianna RM, Mangus RS, Kubal C, et al. Multivisceral transplantation for

diffuse portomesenteric thrombosis. Ann Surg. 2012;255(6):1144-1150.

50. Trevizol AP, David AI, Yamashita ET, et al. Intestinal and multivisceral

retransplantation results: Literature review. Transplant Proc. 2013;45

(3):1133-1136.

51. Mangus RS, Tector AJ, Kubal CA, et al. Multivisceral transplantation:

Expanding indications and improving outcomes. J Gastrointest Surg.

2013;17(1):179-186; discussion p.186-187.

52. Varkey J, Simren M, Bosaeus I, et al. Survival of patients evaluated for

intestinal and multivisceral transplantation - the Scandinavian experience.

Scand J Gastroenterol. 2013;48(6):702-711.

53. Gerlach UA, Vrakas G, Reddy S, et al. Chronic intestinal failure after Crohn

disease: When to perform transplantation. JAMA Surg. 2014;149(10):1060­

1066.

54. Kaneku H, Wozniak LJ. Donor-specific human leukocyte antigen antibodies

in intestinal transplantation. Curr Opin Organ Transplant. 2014;19(3):261­

266.

55. Kubal CA, Mangus RS, Tector AJ. Intestine and multivisceral

transplantation: Current status and future directions. Curr Gastroenterol

Rep. 2015a;17(1):427.

56. Khan FA, Selvaggi G. Overview of intestinal and multivisceral

transplantation. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed April 2015.

57. Kubal C, Mangus R, Saxena R, et al. Prospective monitoring of donor-

specific anti-HLA antibodies after intestine/multivisceral transplantation:

Significance of de novo antibodies. Transplantation. 2015b;99(8):e49-e56.

58. Loo L, Vrakas G, Reddy S, Allan P. Intestinal transplantation: A review. Curr

Opin Gastroenterol. 2017;33(3):203-211.

59. 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. 2017;21(4).

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60. Lee E, Hodgkinson N, Fawaz R, et al. Multivisceral transplantation for

abdominal tumors in children: A single center experience and review of

the literature. Pediatr Transplant. 2017;21(5):e12904.

61. Lauro A, D'Amico F, Gondolesi G. The current therapeutic options for

Crohn's disease: From medical therapy to intestinal transplantation.

Expert Rev Gastroenterol Hepatol. 2017;11(12):1105-1117.

62. Drastich P, Oliverius M. Crohn's disease and intestinal transplantation. Dig

Dis. 2017;35(1-2):127-133. doi: 10.1159/000449093. Epub 2017 Feb 1.

63. Nakamura H, Henderson D, Puri P. A meta-analysis of clinical outcome of

intestinal transplantation in patients with total intestinal aganglionosis.

Pediatr Surg Int. 2017;33(8):837-841.

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.

http://www.aetna.com/cpb/medical/data/600_699/0605.html 09/24/2019 Proprietary

AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment toAetna Clinical Policy Bulletin Number: 0605 Intestinal

Transplantation

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania updated 03/04/2019