Pediatric Small Bowel Transplantation

I. Overview

Small bowel transplantation (intestinal transplantation) is indicated for children with irreversible intestinal failure when enteral nutrition is impossible and parenteral nutrition (PN) is failing or causing life‑threatening complications. Transplant types range from isolated intestinal grafts to multivisceral grafts that include stomach, liver, pancreas, and colon when indicated.

II. Indications

A. Conditions Considered for Transplantation

1. Loss of intestinal length
   • Volvulus
   • Gastroschisis / ruptured omphalocele
   • Trauma
   • Necrotizing enterocolitis
   • Mesenteric ischemia / thrombosis
   • Intestinal atresia
   • Crohn disease (rare, only catastrophic loss or refractory disease)
2. Disorders of intestinal function
   • Microvillus inclusion disease
   • Tufting enteropathy
   • Congenital chloride diarrhea
   • Severe secretory diarrheas
   • Autoimmune enteropathy
   • Extensive radiation enteritis
3. Motility disorders
   • Chronic intestinal pseudo‑obstruction
   • Total intestinal aganglionosis
   • Long‑segment Hirschsprung disease with failure of other therapies
4. Malignant and premalignant disorders
   • Desmoid tumors involving intestine
   • Multiple polyposis syndromes with unresectable/mutilating disease

B. Clinical Indications / Referral Criteria

• Failure of enteral feeding plus failure or life‑threatening complications of PN:
  • Lack of central venous access due to thrombosis of jugular/subclavian/central veins
  • Intestinal failure–associated liver disease (IFALD) with progressive cholestasis or synthetic dysfunction
  • Recurrent central line–associated bloodstream infections (≥2 episodes of sepsis/year or persistent bacteremia)
  • Severe dehydration despite supplemental fluid therapy
• High risk of death or poor prognosis without transplant:
  • Residual small bowel length <10 cm in infants (or <20 cm in adults) with dependence on PN
  • Frequent hospitalizations, narcotic dependency, or refractory pseudo‑obstruction
  • Failure of comprehensive intestinal rehabilitation programs
  • Patient/caregiver refusal or inability to continue long‑term PN

III. Contraindications

• Contraindications similar to other solid‑organ transplants
• Active, uncontrolled infection (pneumonia, uncontrolled fungemia/sepsis)
• Uncontrolled or disseminated malignancy not eradicated prior to transplant
• Severe, irreversible cardiopulmonary disease (e.g., severe pulmonary hypertension, decompensated heart failure) unless corrected or part of combined procedure
• Significant non‑adherence risk, lack of caregiver support, or inability to comply with complex posttransplant regimen
• Severe psychiatric disease without adequate treatment/support

IV. Types of Transplantation

• Isolated small intestine (SI) transplant — bowel only, may include terminal ileum ± colon segments when indicated.
• Combined liver and intestine — indicated when IFALD is advanced or when including liver reduces rejection risk.
• Modified multivisceral transplant — stomach plus intestine (liver spared).
• Multivisceral transplant — intestine + stomach + liver ± pancreas/duodenum; pancreas and duodenum often included en bloc to facilitate biliary drainage and reduce anastomoses.
• Colonic inclusion — some centers include colonic segments to improve absorption, especially after prior colectomy.
• Living donor intestinal transplant — rare; performed in select centers with specific donor/recipient considerations.

V. Preoperative Considerations

• Nutritional optimization — maximize growth, correct micronutrient deficiencies, treat IFALD where possible, plan for early enteral advancement posttransplant.
• Vascular access evaluation — map central venous stenosis/thrombosis; consider alternative access plans.
• Infection screening — bacterial, fungal, viral screening; address active infections before listing if possible.
• Immunologic workup — blood type, HLA typing, CMV and EBV serostatus, crossmatch planning.
• Psychosocial assessment — caregiver capacity, adherence potential, family support, social resources.
• Multidisciplinary planning — transplant surgeon, pediatric gastroenterology, hepatology (if liver involved), infectious disease, nutrition, social work, pharmacy.

VI. Operative Considerations

• Graft procurement aims to preserve arterial and venous inflow and lymphatic handling to reduce postoperative chyle leak.
• Stoma creation (ileostomy) commonly used for surveillance and access for endoscopy/biopsy.
• En bloc transplantation for multivisceral grafts reduces biliary reconstruction complexity.
• Abdominal domain planning to avoid primary abdominal compartment syndrome; staged closure or biologic meshes used when space limited.

VII. Posttransplant Management

A. Immunosuppression

• Induction — monoclonal antibodies (alemtuzumab, basiliximab) or polyclonal ATG given pre/intraoperative per center protocol.
• Maintenance — tacrolimus is cornerstone (enteral when feasible). Early postoperative tacrolimus target historically 20–25 ng/mL; many centers aim for high levels initially then reduce to lower maintenance targets (often 8–12 ng/mL then lower over months) to balance rejection risk and toxicity.
• Corticosteroids used perioperatively and tapered per protocol; some centers attempt steroid‑sparing strategies.
• Mycophenolate mofetil often avoided early due to GI intolerance but may be used later if tolerated; sirolimus used by some centers in combination regimens.

B. Infection Prophylaxis and Surveillance

• Broad‑spectrum IV antibiotics commonly given for ~7 days postoperatively for surgical prophylaxis and to cover translocation risks.
• Antiviral prophylaxis: CMV prophylaxis (ganciclovir/valganciclovir) and/or CMV immunoglobulin per donor/recipient serostatus and center protocol.
• Pneumocystis jirovecii prophylaxis (trimethoprim‑sulfamethoxazole) for at least 6–12 months.
• Fungal prophylaxis may be used guided by risk and local epidemiology.
• Routine surveillance:
  • CMV DNA monitoring/antigenemia per protocol
  • EBV PCR monitoring frequently in early months (weekly to biweekly initially)
  • Bacterial surveillance cultures as indicated
  • Frequent ileostomy/ileoscopy with biopsies for early rejection detection (weekly in first month at many centers, then gradually spaced)

C. Nutritional Management and Feed Advancement

• Advance enteral feeds as GI function returns: decreasing gastrostomy output, passage of gas, enteric output into stoma.
• Start with trophic feeds then advance to enteral formula; individualized progression to oral intake.
• No‑ or low‑fat diet initially to reduce chylous ascites risk due to disrupted lymphatics; medium‑chain triglyceride formulations may be used if needed.
• Monitor fluid balance closely, replace large stoma/intestinal losses with appropriate electrolytes and volume.

D. Monitoring for Ischemia, Bleeding, and Organ Function

• Monitor serum pH and lactate for early ischemia detection.
• Frequent abdominal exams, drainage/aspirate observation, hemoglobin/hematocrit surveillance.
• When combined grafts are present, monitor respective organ markers (liver enzymes, creatinine, amylase/lipase) for rejection or dysfunction.

VIII. Complications

A. Surgical Complications

• Graft thrombosis — arterial or venous compromise requiring urgent reoperation or graft loss.
• Graft ischemia and technical failure.
• Anastomotic leak and intra‑abdominal sepsis.
• Abdominal compartment syndrome when abdominal domain insufficient; staged closure may be necessary.
• High reoperation rates in children (reported center variability, often 40–60%).

B. Rejection

• Most common within first 6–12 months.
• Acute rejection:
  • Reported ~40–60% depending on graft type and era; isolated intestinal grafts have higher rejection rates than combined liver‑intestine grafts.
  • Typical timeframe: early (within 90 days) and later acute episodes.
• Chronic rejection:
  • Occurs in ~10% and is more frequent with isolated intestinal grafts; manifests as progressive graft dysfunction, strictures, and loss of absorptive capacity.
• Diagnosis relies on three pillars:
  1. Clinical course — increasing stoma output (often >40–60 mL/kg/day), bloody output, congested or cyanotic stoma, abdominal pain/distention, decreased stoma output with obstruction, fever/leukocytosis with bandemia, metabolic acidosis.
  2. Endoscopy — ileostomal endoscopy showing patchy inflammation, ulceration; early rejection may be subtle and biopsies multiple to detect patchy involvement.
  3. Histology — mucosal necrosis, villous blunting/loss, crypt apoptosis/cryptitis/crypt loss, transmural mononuclear infiltrates, endothelitis.
• Treatment:
  • High‑dose IV methylprednisolone bolus (commonly 10 mg/kg) followed by steroid taper/cycle and optimization of calcineurin inhibitor (tacrolimus) levels.
  • For steroid‑resistant rejection: antithymocyte antibodies (ATG), OKT3 historically, or other antilymphocyte agents; plasmapheresis and augmented immunosuppression in select cases.
  • In severe refractory rejection, graft removal or retransplantation may be required.
• Note: Up to half of intestinal rejection episodes can occur without simultaneous rejection of other organs in combined grafts.

C. Infections

Bacterial

• Major infection routes:
  • Leakage of lymphatic fluid from severed graft lymphatics → peritoneal contamination/peritonitis.
  • Bacterial translocation from graft lumen to portal/systemic circulation → bacteremia and sepsis.
• Common pathogens: Escherichia coli, Klebsiella spp., Enterobacter, staphylococci, Enterococcus spp.

Viral

• Cytomegalovirus (CMV):
  • Incidence often reported 15–30% depending on prophylaxis and serostatus; highest risk when donor is CMV‑positive and recipient CMV‑negative.
  • Presentation: fever, increased stoma output, abdominal pain, GI bleeding, leukopenia; CMV enteritis commonly causes superficial ulcers with characteristic inclusion bodies on biopsy.
  • Diagnosis: quantitative CMV PCR/DNA or antigenemia; endoscopic biopsy with histologic confirmation.
  • Treatment: ganciclovir/valganciclovir ± CMV immunoglobulin; careful balancing of immunosuppression reduction to control infection without precipitating rejection.
• Epstein‑Barr virus (EBV):
  • Primary EBV infection in EBV‑negative recipients confers high PTLD risk.
  • Monitoring: EBV PCR surveillance frequently in early posttransplant period.
• Adenovirus, rotavirus, norovirus, and enterovirus can produce severe enteritis, malabsorption, and graft dysfunction in pediatric recipients.

Fungal

• Candida species and Aspergillus can cause invasive disease in highly immunosuppressed patients; prophylaxis and early treatment guided by risk.

D. Posttransplant Lymphoproliferative Disorder (PTLD)

• PTLD incidence is higher after intestinal transplantation than many other solid organ transplants and is particularly elevated in multivisceral graft recipients.
• Highest risk group: pediatric patients who are EBV‑seronegative at transplant receiving EBV‑positive grafts.
• Typical onset: 2–6 months posttransplant but may occur anytime.
• Surveillance: routine EBV PCR monitoring starting immediately after transplant — many centers perform weekly tests for initial months, then space out if stable.
• Prevention strategies:
  • Antiviral prophylaxis (ganciclovir) and/or IV immunoglobulin for variable periods (3–12 months) in high‑risk recipients.
  • Short prophylaxis with intensive surveillance and preemptive therapy on rising EBV loads is an alternative approach.
• Treatment:
  • First step: reduction of immunosuppression (commonly by ~50%) — effective in ~1/3 of cases.
  • If no response: rituximab (anti‑CD20) is commonly the first‑line biologic therapy for EBV‑associated PTLD.
  • Additional therapy for progressive disease: chemotherapy regimens, adoptive EBV‑specific cytotoxic T lymphocyte therapy, surgical/graft removal in fulminant cases.

E. Graft‑Versus‑Host Disease (GVHD)

• The intestinal graft contains donor immune cells capable of mounting GVHD against the recipient; GVHD after intestinal transplant is less common than rejection but can be severe.
• Presentation: rash, profuse diarrhea, liver dysfunction, marrow suppression; diagnosis confirmed by biopsy of affected tissues.
• Treatment: increase immunosuppression and specific GVHD therapies; balance required to minimize infection and PTLD risk.

F. Graft Dysfunction and Malabsorption

• Reported in a minority of recipients (~5% in some series), more frequent in pediatric compared with adult recipients.
• Symptoms: chronic diarrhea, weight loss, failure to thrive, nutrient deficiencies.
• Causes:
  • Rejection (acute or chronic)
  • Enteric infection (viral, bacterial, protozoal)
  • Small intestinal bacterial overgrowth (SIBO)
  • Bile acid malabsorption
  • Eosinophilic gastroenteritis related to food allergy
  • Vitamin B12 deficiency when terminal ileum not present or reduced; may also occur when adult donor grafts are reduced for pediatric recipients or distal resection is required to close abdomen
• Workup: stool studies, endoscopy with biopsy, breath tests for SIBO, serum micronutrients (fat‑soluble vitamins, B12, folate), imaging as needed.
• Treatment: address underlying cause (antibiotics for SIBO, nutritional repletion, immunosuppression adjustment for rejection, enteral/oral diet modifications).

IX. Outcomes

• Reported survival varies by era, center volume, graft type, and patient factors.
• Historical pediatric registry outcomes (post‑2000 era with broader ATG use) commonly reported:
  • Patient survival approximately 77% at 1 year, ~58% at 5 years, ~48% at 10 years in some series; other high‑volume centers report improved 1‑year survival up to 85–90% in recent eras.
  • Graft survival reported ~71% at 1 year, ~50% at 5 years, ~41% at 10 years in some cohorts; many centers report improved early graft survival with center experience and combined graft strategies.
• Retransplantation is required in a subset (~7% reported in some pediatric series).
• Combined liver‑intestine grafts historically associated with lower acute rejection rates compared with isolated intestinal grafts in multiple series.
• Quality of life and rates of enteral autonomy have improved over time; many children achieve substantial oral intake and reduced or ceased PN with successful transplant and rehabilitation.

X. Follow‑Up and Long‑Term Care

• Frequent early follow‑up with transplant center: clinical exam, stoma assessment, labs (electrolytes, LFTs, CBC, tacrolimus levels), CMV/EBV PCR.
• Regular endoscopic surveillance with biopsies through ileostomy or transanal approach per center protocol.
• Long‑term monitoring for chronic rejection, PTLD, metabolic complications of immunosuppression (renal dysfunction, hypertension, dyslipidemia, growth delay), and psychosocial adaptation.
• Vaccination planning: inactivated vaccines per schedule; live vaccines generally contraindicated while significantly immunosuppressed — coordinate with infectious disease and transplant team for timing after immunologic recovery.
• Transition planning to adult care for adolescents with chronic graft function.

XI. Key Practical Points and High‑Yield Facts

• Early referral to an intestinal transplant center is essential once PN complications, loss of access, or poor rehabilitation progress are identified.
• Isolated intestine transplants have higher rejection rates than combined liver‑intestine grafts; inclusion of liver may be protective against rejection.
• Stoma monitoring and routine ileoscopy with multiple biopsies remain gold standards for early rejection detection; histology can be patchy, so multiple samples help sensitivity.
• Balance between infection control and maintaining sufficient immunosuppression is critical — reduction of immunosuppression may control PTLD or infection but risks graft rejection.
• Multidisciplinary care (surgery, gastroenterology, hepatology, ID, nutrition, social work, pharmacy) optimizes outcomes.

XII. Suggested References for Further Reading (examples)

• International Intestinal Transplant Registry reports and center series (search for latest registry updates).
• Recent review articles in pediatric transplant and gastroenterology journals on intestinal transplantation, rejection surveillance, and PTLD management.
• Center‑specific protocols for immunosuppression and infectious prophylaxis (useful for local practice alignment).