Postoperative Care

Management of the small bowel transplant recipient is a complex and formidable task, particularly during the first 6 months posttransplantation. These patients are vulnerable to a wide range of complications related to rejection, infection, and technical problems. The biggest challenge is achieving a balance between an adequate level of immunosuppression to prevent rejection while avoiding a heavy-handed approach that may result in infectious complications. It is imperative that medical management includes surveillance studies with a preventative approach to early detection and treatment. Foremost, a multidisciplinary approach is required for an optimal outcome through the teamwork of transplant surgeons, GI specialists, infectious disease specialists, nursing staff, psychologists, and social workers as well as an array of other consultants such as child development specialists and occupational and physical therapists. Intestine transplant recipients are labor-intensive, requiring meticulous medical management with consistent long-term follow-up care.

Immunosuppression

Inadequate immunosuppression was the primary reason for the early failures of intestine transplantation. Although interest was renewed with the advent of CsA, this immunosuppressant failed to improve survival in intestine transplantation.

Since 1990, TAC has been the primary immunosuppressant used in intestine transplantation, contributing to improved survival.[11] Immunosuppression is similar for all types of intestine transplant procedures.

TAC-based immunosuppression. TAC is combined with corticosteroids as induction immunosuppression and with adjunctive immunosuppressants in a variety of protocols that are center-specific.

Immunosuppression with TAC is begun intraoperatively at a dose of 0.15-0.2 mg/kg/day through a continuous infusion. Oral TAC is usually begun at 3-4 times the IV dose of 0.2 mg/kg/day divided into 2 doses when GI motility resumes. It is often necessary to overlap dosing when changing from the IV route to the oral route, since GI absorption is unreliable during the early postoperative period. Trough levels of TAC are targeted at 20-25 ng/mL in whole blood during the early postoperative period and maintained at that range for up to 6 months; levels are decreased to 10-15 ng/mL within 6-12 months posttransplantation. Stable patients at 2 or more years posttransplantation often have levels below 10 ng/mL. It is important to note that levels vary according to length of time posttransplantation, renal function, and the presence of infection or rejection. TAC is usually well tolerated once oral dosage with stable levels is established and particularly when levels are 15 ng/mL or lower. The most common side effects are neurotoxicity, nephrotoxicity, and increased risk of infection.

Corticosteroids. IV methylprednisolone is given as an intraoperative bolus (10 mg/kg; maximum dose 1 g) followed by a taper over 5 days from 5 mg/kg/day to 1 mg/kg day in children or 200 mg/day to 20 mg/day in adults. Long-term immunosuppressive therapy has involved the use of TAC and steroids as well as a third agent in some patients. However, it is feasible that stable patients who demonstrate organ tolerance with minimal rejection may tolerate a reduction or even cessation of steroid therapy.

Adjunctive agents. Azathioprine, mycophenolate mofetil (MMF), and sirolimus are used as adjunctive agents to treat rejection when additional immunosuppression is required or to mitigate the side effects and toxicities of TAC. Some centers have used induction therapy with OKT3, cyclophosphamide, MMF, or daclizumab with varying results.[14,53]

Maintaining Fluid and Electrolyte Homeostasis

In the early postoperative period, most patients have increased interstitial accumulation of fluid into the peripheral tissues, transplanted bowel, and lungs, which peaks at 48-72 hours.[38] However, leakage from the lymphatics of the mesentery can cause increased ascites, leading to intravascular volume depletion within the setting of fluid retention. Rigid attentiveness to renal function, electrolyte imbalances, and strict measurement of intake and output followed by precise adjustments in IV fluids is imperative to maintain fluid and electrolyte balance in the early postoperative period. Management includes fluid restriction at two thirds the maintenance amount provided as dextrose or saline with colloids to maintain a central venous pressure of 6-10 cm H2O and a urine output of 0.5-1.5 mL/kg/hour.[38]

As intestine transplant recipients stabilize following the early postoperative fluid shifts, fluid imbalances are related to a loss of water, sodium, magnesium, and bicarbonate secondary to increased stool output from the ileostomy. This also may occur in patients without an ileocecal valve and colon. Dehydration, metabolic acidosis, and hyponatremia are common and usually correctable with IV replacement fluids (5% dextrose, 0.5% normal saline, or lactated Ringer's solution) containing sodium bicarbonate, sodium acetate, and/or magnesium gluconate.

Stomal losses as well as serum electrolytes are assessed to determine electrolyte content of replacement fluids. The stomal output ranges from 40-60 cc/kg/day in children and from 1-2 liters/day in adults. Fluid replacement is initially administered cc per cc for 24 hours then slowly tapered over time as the absorptive capacity and motility of the graft improves and the patient is able to tolerate enteral feeding. A majority of patients require IV fluids until the time of ileostomy reversal. Although the timing of ostomy closure varies due to the presence of infection or rejection as well as center-specific protocols, this is usually accomplished within 3-6 months posttransplantation. Ostomy reversal may not be possible in some patients with motility disorders affecting the entire GI tract, such as long-segment Hirschsprung disease, chronic intestinal pseudo-obstruction, or in patients without a colon.

Nutritional Support

Patients receive TPN in the early postoperative period to provide full nutritional support. After completion of a gastrografin swallow study to evaluate the integrity of the small bowel anastomoses and following recovery of GI motility, TPN is weaned as enteral feedings are initiated. Patients with functional grafts are able to be completely weaned from TPN within 4-6 weeks postoperatively,[17] although patients may require partial TPN during episodes of rejection and infection. In a series of 61 surviving intestine transplant recipients, 95% were completely off TPN and 5% were receiving partial support while recovering from a recent episode of rejection or infection.[12] The International Intestine Registry reported that 77% of patients do not have any TPN requirements, while 14% required partial TPN support.[11]

Feeding protocols. Although feeding protocols vary by center and postoperative complications may delay the introduction of feedings, most patients are started on enteral feeding via a jejunosotomy tube (JT) within 2 weeks posttransplantation.[59,64,65] The most suitable formula for intestine transplant recipients is a low-osmolality isotonic dipeptide solution that is age-appropriate and contains medium-chain triglycerides and glutamine to prevent hyperosmolar diarrhea, while allowing for maximal nitrogen absorption, nitrogen use, and direct absorption of fat.[59,64] Enteral feedings are given at half strength continuously over 24 hours at a low rate (usually 2 cc/hr in infants to 10 cc/hr in adults), then gradually increased to the goal rate. Once the goal rate has been attained, the concentration of the formula is increased to three quarters strength, then full strength as tolerated. Patients may also have a clear liquid diet by mouth during this time.

Absorption and tolerance. Feeding absorption and tolerance are evaluated by assessing daily stomal outputs, serum electrolytes, stool pH, and the presence of blood or reducing substances (a marker for carbohydrate absorption) in the stool. A low stool output and the absence of reducing substances are associated with feeding tolerance. In the absence of rejection, patients with high stomal output are treated with antidiarrheal medications such as loperamide, opiates, and clonidine hydrochloride as well as somatostatin. Intestinal motility may also be decreased and stomal output thickened by using pectin as a source of fiber. Pectin is added in a ratio of 3-5 tablespoons/liter of formula daily. After formula volume and tolerance to jejunostomy feedings has been established, the enteral route is transitioned to feeding via the gastrostomy tube (GT), providing additional absorption from the stomach to duodenum. This is usually accomplished within 3 months posttransplantation. Patients, particularly children, who have previously received full calories from TPN with minimal or no oral feedings may have initial difficulties with GT feedings since they are not used to a large volume of gastric contents. Partial GT and JT feedings infusing simultaneously are recommended as the patient gradually accommodates to increased feeding via the gastric route.

Caloric requirements. Caloric requirements are based on age, then adjusted according to pretransplant nutritional status as well as posttransplant complications such as fever, cardiac failure, surgery, sepsis and/or long-term growth failure.[65] The duration of enteral feedings is decreased as oral intake improves with the goal of meeting full nutritional requirements solely through oral intake. Feedings are cycled to nighttime hours to optimize oral intake while awake. Postoperative complications including rejection, pancreatitis, hyperglycemia, and renal insufficiency may alter the ability to provide optimal calories.[65]

Nutrient requirements. Intestine transplant recipients require routine monitoring of vitamin, mineral, and trace element levels that may be affected by malabsorption in the first few months posttransplantation. Zinc was most commonly found to be low in patients at 1 year posttransplantation, possibly due to high stomal outputs.[65,66] Oral zinc supplements of 1.5-3.0 times the Recommended Daily Allowance are suggested with monthly monitoring of zinc and albumin levels.[66] Patients usually do not require zinc supplementation following ostomy closure. After TPN is discontinued, a daily multivitamin containing the fat-soluble vitamins A, D, E, and K is also recommended since fat malabsorption is common. Deficiencies in red blood cell folate and copper levels have also been reported.[53,63] Free glutamine is also recommended by some centers. Food allergies, primarily to lactose and gluten agents, are common.[53] Radioallergosorbent testing, commonly referred to as RAST, is completed on patients presenting with eosinophilia on graft biopsy. Results range from 0 (no allergy) to class 4 (high allergy). Specific food restrictions are implemented in patients diagnosed with class 3 or 4 allergies. Administration of oral or IV glutamine has demonstrated efficacy in increasing villous height, villous surface area, mucosal weight, and brush border enzyme activity.[67,68] The suggested pediatric dose is 0.6 g/kg daily or 30 g daily in adults.[64,65] The powdered form of L-glutamine is added to enteral feedings.

Oral aversion. Although many patients may have difficulty meeting caloric needs by oral diet alone, oral aversion is most frequently observed in pediatric recipients -- primarily due to the fact that medical management prior to evaluation for transplantation may have established that the patient take nothing by mouth or only a restricted amount and type of fluid or food, consequently limiting their feeding experiences.[69]

Other factors that affect oral intake may include pretransplant medical and nutritional status, conditions that preclude oral feedings (severe gastroesophageal reflux with aspiration), age at onset of SGS with initiation of TPN and/or limited oral feedings, a hypergag reflex, hospital environment, parenting factors, behavioral issues, and/or limited access to or experience with food tastes, textures, and aromas. A multidisciplinary team approach is essential to provide therapy within a unified treatment plan for patients who are orally aversive. Occupational and speech therapy should be initiated in the pretransplant period and continued throughout the transplant process to mediate and resolve oral aversion. In many cases, consultation with Child Development or Psychiatry may also be helpful. Inpatient feeding programs in rehabilitation centers are able to provide continuity with behavior modification in severe cases of oral aversion, not only by working intensively with the child, but also by teaching parents how to respond to their child's eating cues, to initiate and maintain appropriate eating patterns, and to follow through with a reward system for desired behaviors. This is a challenging task for parents who often find it easier to maintain their child's nutritional status through several hours of nightly tube feedings. Parental counseling stresses the importance of achieving and maintaining normal oral feeding routines as the child and family reintegrate into home and community life.

Assessment of Graft Function

Graft function is monitored via several criteria. Adequate absorption is a good indicator of satisfactory function of the transplanted intestine and is determined by serial monitoring of carbohydrate and fat absorption. Carbohydrate absorption is assessed through D-xylose testing and the presence of reducing substances. Most patients develop satisfactory carbohydrate absorption within 1 month posttransplantation with continued improvement over time. If D-xylose testing is abnormal, rejection should be suspected. Fat malabsorption is common in intestine transplant recipients since the lymphatic channels are severed during the operative procedure. Absorption of fats is also affected by pancreatitis, which may occur postoperatively. Fat absorption is determined through a 24-hour fecal fat collection, which is compared to the dietary intake of fat during the same period. Normal parameters are 0% to 8.5%, with intestine transplant recipients having fat malabsorption of 50% to 100% of normal.[43] Fat-soluble vitamin levels can also be obtained to evaluate absorption of fats. A low-fat diet is instituted in patients with fat malabsorption, and IV intralipids may be required. Pancreatic enzymes have been reported to be effective in some cases, resulting in decreased fecal fat excretion from nearly 60% to 14.5% in 1 month, a nearly 50% decrease in overall daily stoma output and a body weight increase of 2 kg.[65]

The ability to maintain a stable and satisfactory TAC level can also be an indicator of adequate absorption. In the absence of adjusting levels for rejection or infection, an appropriate TAC level is usually achieved within 1 month posttransplantation.[38]

Graft function is also assessed by routine surveillance for rejection through frequent endoscopy and tissue biopsy. Stomal output is evaluated daily for volume, consistency, and the presence of blood and reducing substances. Radiologic evaluation is done routinely through barium studies to assess the mucosal pattern of the graft and motility. Intestinal transit time should be approximately 2 hours and a normal mucosal pattern should be seen. Increased transit time with mucosal edema and a tubular intestine with strictures indicate rejection.[38]

Incidence and Diagnosis of Allograft Rejection

Acute allograft rejection is commonly seen in small bowel transplantation; the overall incidence is 90% or greater.[23,51,53] In a series of 71 pediatric and adult small bowel recipients, a mean of 3.7 episodes of rejection per patient was reported;[51] while in a series of 55 pediatric recipients, there was an average of 2.9 +/- 2.7 episodes of rejection per patient.[53] Rejection is seen most frequently and is most severe in isolated small bowel recipients (88%) as compared with combined small bowel-liver grafts (66%) and multivisceral grafts (75%).[17] The incidence of rejection of the liver in patients with a composite graft including the liver was only 43%, suggesting a protective role of the liver.

Acute rejection. Rejection is diagnosed through clinical presentation, the endoscopic appearance of the bowel, and definitively histologic findings. Unlike liver and kidney transplantation, there are no serum markers to suggest rejection. However, abnormal TAC levels may be associated with rejection. The presentation of rejection of the small bowel is variable, ranging from a mild clinical course with minimal histologic changes to severe intractable rejection that can result in graft enterectomy or death.

Although rejection may occur at any time, it is most common in the early postoperative period, with 48% of episodes presenting within 30 days and 66% presenting within the first 100 days posttransplantation.[23] Acute rejection has appeared as early as a median of 14 days posttransplantation (range 3-42 days).[53] Rejection is rarely asymptomatic. On the contrary, it may present as a combination of symptoms including fever, malaise, abdominal pain and distention, nausea and vomiting, acute increase in stomal output or diarrhea, and/or a dusky discoloration of the stoma. Stomal output is most commonly affected. GI bleeding secondary to ulceration and mucosal sloughing is observed in severe rejection. Severe rejection may also present as an ileus, septic shock syndrome, and/or respiratory distress syndrome. Septicemia is often correlated with rejection since the mucosal barrier of the intestine is disrupted during episodes of rejection resulting in bacterial or fungal translocation.

Since there are no serum markers that denote rejection in the transplanted intestine, surveillance endoscopies are usually performed twice weekly through the graft ileostomy for the first 4-6 weeks posttransplantation.[70] Frequency is decreased over the next 6 months from weekly to as clinically indicated, depending on the patient's clinical presentation, history, and risk factors. In stable patients 3 or more years posttransplantation, endoscopy may be performed as infrequently as once a year.

On endoscopy, the intestinal mucosa may lose its normal velvety appearance, becoming nodular, edematous, dusky, or erythematous during episodes of acute rejection (Figure 5). Peristalsis may be absent or reduced. In more advanced rejection, the mucosa may also be friable with diffuse ulcerations. Severe rejection may present with broad-based ulcers, aperistalsis, and denuded mucosa with pseudomembranes.[71,72]

Acute severe rejection of the small intestine allograft.

Although rejection may be diagnosed by the endoscopic appearance, endoscopy has been reported to diagnose rejection in only 63% of rejection episodes.[72] Histology remains the definitive tool for diagnosing rejection in the transplanted bowel. Histologic criteria for acute rejection of the intestine include edema of the lamina propria with mononuclear cell infiltrates, villous blunting, cryptitis, and crypt cell apoptosis (Figure 6).[23,38,71] Varying degrees of epithelial cell necrosis and regeneration may be seen. In severe rejection, there is crypt destruction and complete sloughing of the endothelium, resulting in pseudomembranous enteritis.[38,71] The ileum is most commonly affected, although there are unevenly distributed morphologic changes throughout the intestinal graft.[23]

Acute cellular rejection.[38]A. Endoscopic biopsy 14 days after transplantation showed widening of the lamina propria and increased mononuclear cells which were often cuffed around small vessels and infiltrating the crypt epithelium (arrow).B. The reaction was more intense in biopsy specimens that contained lymphoid nodules and where blastogenesis, focal ulcerations, congestion, and neutrophil plugging of capillaries were also seen (moderate acute cellular rejection).C. Uncontrolled acute rejection eventually resulted in widespread mucosal destruction; the mucosa was replaced by granulation tissue. Note the overlying pseudomembrane (arrow).Source: Reyes J, Selby R, Abu-Elmagd K, et al. Intestinal and multiple organ transplantation. In: Shoemaker WC, Ayers SM, Grenvik NA, Holbrook PR (eds). Textbook of Critical Care, 4th ed. Philadelphia Pa: WB Saunders Co; 1999:1685.

An analysis of 3074 histologic specimens from the GI tract of 62 intestine transplant recipients established that acute rejection can be reliably identified and correlated with clinical observations.[23] Acute rejection was characterized by crypt epithelial injury and mononuclear inflammatory infiltrates with lymphocytes or increased crypt cell apoptosis. Late rejection was found to have less cellular infiltration and greater apoptosis than early rejection.

Chronic rejection. Chronic rejection presents as a consequence of persistent episodes of refractory acute rejection. Patients present with chronic diarrhea, progressive weight loss, intermittent fever, abdominal pain, and GI bleeding. On endoscopy, the mucosa may appear normal or reveal a tubular intestine with thickened mucosal folds, pseudomembrane formation, and/or chronic ulcers (Figure 7).[30,51] Mucosal histology displays villous blunting, focal ulcerations, and epithelial metaplasia with scant cellular infiltrates.[38] Full-thickness intestinal biopsies from resected grafts have shown mucosal ulceration and obliterative thickening of the arterioles with myointimal hyperplasia and subendothelial accumulation of macrophages and lymphocytes.[23,51] The incidence of chronic rejection was reported to be 8% in 1 series, although it was suggested that chronic rejection is underestimated since the diagnosis can only be made through a full-thickness biopsy from an enterectomy sample.[58]

Chronic rejection of the allograft ileum. Note the deep ulcers (B, D) associated with chronic rejection.

Treatment of Rejection

Mild-to-moderate rejection is controlled by optimizing TAC levels (20-25 ng/mL) and administering IV methylprednisolone. Patients receive a bolus dose of methylprednisolone (10 mg/kg IV; maximum dose 1 g). This bolus dose is usually followed by cycled decreasing doses over 5 days. If significant improvement is not seen on the following biopsy, a second corticosteroid bolus with or without a recycle may be administered.

Adjunctive agents such as azathioprine, MMF, or sirolimus may also be added to the baseline regimen. Patients are monitored closely with follow-up endoscopy and biopsy every 5 days or weekly until resolution of rejection is evident (Figure 8). In cases of refractory or severe acute rejection, OKT3 is given. OKT3 may be given for a maximum of 14 days, but the duration of treatment depends on biopsy results. In a series of 55 pediatric intestine transplant patients, OKT3 administration was required more often in isolated small bowel recipients (76%) than in small bowel-liver recipients (21%) or multivisceral graft recipients (50%).[53] Rabbit antithymocyte globulin (thymoglobulin) has also been used in a small number of intestine transplant recipients as an alternative treatment to OKT3 in steroid-resistant acute rejection and in OKT3-resistant rejection. Findings are inconclusive at this time based on the small sample size.

Granulating regenerating allograft ileum mucosa after aggressive treatment of rejection.

If rejection is refractory to treatment, graft enterectomy with retransplantation may be the only option. However, the survival rate after retransplantation is worse for primary transplantation. If enterectomy is performed while the patient is waiting for retransplantation, nutritional support with TPN is required. In addition, the psychological and psychosocial impact of a second transplant may be overwhelming to the patient and family.

Infection

Infection is the leading cause of morbidity and mortality in the intestine transplant recipient, accounting for up to 70% of deaths.[11,53,73] Therefore, a thorough preventative approach to infection control is essential to care of this patient population. Although preventive strategies are common, specific protocols are center-specific. Fatal septic infections are often polymicrobial and associated with multisystem organ failure. In a postmortem evaluation of 29 intestine transplant recipients, sepsis was the cause of death in 69%.[73,74,75,76] However, 94% of patients in this series had a coexisting infection at the time of death. Higher levels of immunosuppression are required in these patients, which predispose them to infection. Other contributing factors for infection include a prolonged operative time with a technically difficult surgery, the severity of preoperative liver disease, sepsis prior to transplantation, transfusions, re-explorations due to surgical complications, the inability to close the abdominal wall immediately after surgery, and multiple invasive lines, catheters, and drains that alter skin integrity. Postoperative infections are frequent, with reports of a median of 4 episodes of infection per patient.[51]

Bacterial infections. Bacterial infections are the most prevalent infections, with an incidence of 80%.[51] Staphylococci and enterococci are the most common bacterial pathogens, and gram-negative rods are usually seen with polymicrobial infections.[77] Abdominal wound infection, deep abdominal abscess, peritonitis, and pneumonia are often positive for enteric organisms.[17] Patients may have simultaneous infections from multiple sources that require polymicrobial therapy as well as repeat infections. Of particular concern is the development of resistant organisms such as vancomycin-resistant enterococci.

Translocation is the passage of bacteria or fungus through the mucosal barrier into the lamina propria and subsequently into the mesenteric lymphatics, where the organisms are transported by macrophages to the mesenteric lymph nodes for immunologic treatment.[30,74] Although translocation is limited in the native intestine because of the mucosal barrier, in the transplanted intestine the mucosal barrier may be disrupted or impaired as a result of preservation injury, rejection, high immunosuppressive levels, bacterial overgrowth, altered function of the mucosal barrier, or disruption of the lymphatics.[75,76] In an analysis of bacteremia in pediatric intestine transplant recipients, when bacteremia presented without an obvious cause, it was found to be associated with intestinal rejection and intestinal PTLD.[76] Examination of the intestine via endoscopy is recommended when an apparent source of bacteremia is not evident.[76]

Broad-spectrum IV antibiotics may be administered prophylactically for up to 5 days postoperatively. Selective bacterial bowel decontamination with nonabsorbable agents (enteral administration of tobramycin, colymycin, and amphotericin B) is generally administered every 6 hours for up to 2 weeks to prevent bacterial translocation.[77] Stool cultures are monitored routinely and if cultures show greater than 108 organisms in the presence of clinical signs of sepsis or rejection, IV antibiotics are initiated. Long-term prophylaxis for at-risk patients includes a cyclic course of bowel decontaminant agents. Although bowel decontaminants vary depending on the type of bacterial overgrowth, the most commonly prescribed regimen is tobramycin, amphotericin, and colistimethate sodium on a twice-daily dosing schedule via an enteral route. This combination of medications is alternated 2 weeks on/2 weeks off to avoid resistant organisms.

Fungal infections. Fungal infections may be associated with translocation or develop as a consequence of IV line contamination, intense use of immunosuppressants to treat rejection, intestinal leaks, repeated surgical exploration, or extensive use of antibiotics. Prophylaxis with low-dose IV amphotericin B is indicated in patients with these risk factors. IV prophylactic antifungal therapy is recommended if a fungal infection was present prior to surgery or if the patient had additional exploratory surgeries or surgical complications. Oral nystatin is prescribed 4 times daily to prevent noninvasive candidiasis while immunosuppression is high, particularly in the first 3-6 months posttransplantation. Extensive Candida that is refractory to oral therapy may be treated with IV amphotericin B or fluconazole.

Confirmed fungal infections are treated with an extended course of full-dose IV amphotericin B, Abelcet, or fluconazole. Aspergillosis is infrequent, but carries a high mortality. Since Candida esophagitis is the most frequent fungal infection,[75] patients receive routine prophylaxis with oral nystatin until the level of immunosuppression is lowered.

Viral infections. Antiviral treatment for prevention of CMV includes a 2-week course of IV ganciclovir (10 mg/kg/day) or acyclovir and CMV-specific hyperimmunoglobulin (Cytogam).[25] CMV-seronegative recipients who received a graft from a CMV-seropositive donor are administered oral acyclovir following 2-3 weeks of IV ganciclovir for a total treatment period of 3 months. Hyperimmunoglobulin is also continued once every 2 weeks for 2 months, then monthly for 2 months in this group of patients.

CMV. CMV is the most common viral pathogen following intestine transplantation, with an overall incidence of 34%[51] CMV frequently involves the allograft intestine (65%).[38] The principal determinants for development of CMV disease are donor-recipient serology mismatch and immunosuppression.[38,78,79]

Primary disease occurs in patients who were seronegative prior to transplantation and became infected with a latent virus from a CMV-seropositive donor. A seropositive/donor seronegative recipient pair represents a significant risk factor for disease in intestine transplantation.[52,53,80] Seronegative recipients of seropositive organs experience more aggressive disease with a higher incidence of recurrence, disease persistence, and organ or system involvement beyond the allograft.[17] The decreased incidence of CMV disease reported in children (24%)[80] as compared with adults (46%)[52] in the same center is attributed to the predominance of seronegative donor/seronegative recipient pairs in this series. Following protocol modifications that included CMV matching in isolated intestine transplants, the overall incidence of CMV in adult and pediatric intestine transplant recipients has been decreased from 40% to 29%.[81]

Specific immunosuppressive protocols and high levels of immunosuppression are also risk factors for acquiring CMV. By intensifying immunosuppression for treatment of rejection, cytotoxic T lymphocytes and natural killer cells may be decreased, thus interfering with the body's normal immunologic response to this pathogen.[79,82,83] The cumulative amount of corticosteroids (boluses and recycles) has been associated with an increased incidence of CMV in pediatric intestine transplant recipients.[80]

Presenting symptoms of CMV infection include gastroenteritis of varying severity, fever, myalgia, arthralgia, malaise, anorexia, hematologic abnormalities (leukopenia, thrombocytopenia, and atypical lymphocytosis), and focal ulcerations of the intestine with bleeding.[78,80,84]

An association between CMV and rejection has been suggested.[10,78,85] Although a history of rejection did not demonstrate significance as a risk factor for CMV disease in pediatric intestine transplantation, rejection was diagnosed by histology prior to the diagnosis of CMV disease in over 80% of CMV disease episodes.[80] This may be due to the high incidence of rejection in these patients during the time when they are also at the greatest risk for developing CMV. In addition, an increased incidence of rejection was not observed in this series of patients following CMV disease.

Diagnosis is made by clinical symptoms and findings as well as endoscopic and histologic results. Blood, urine, stool, and sputum specimens are cultured as part of the routine work-up for fever. Prophylaxis and management strategies are also guided by the serologic status of the donor and recipient, which are obtained pretransplantation. Endoscopy is performed routinely as well as in the setting of fever and diarrhea and may reveal protruding flat ulcers, aphthoid lesions with a white center, or ulcerations in the setting of normal mucosa.[80] Histologic findings include numerous CMV-inclusion bodies with associated inflammatory changes that may include cryptitis, gland damage, prominent inflammation, and/or variable chronic inflammation.[80] Although CMV usually presents in the allograft intestine (90%), it may also cause native gastroduodenitis and colitis as well as pneumonitis, central nervous system disease, retinitis, and hepatitis.[53,80]

Patients at risk for CMV are monitored routinely by measuring CMV-pp65 levels, a rapid diagnostic method that uses a mixture of monoclonal antibodies to detect CMV-specific antigens in peripheral polymorphonuclear cells.[86] Prophylactic therapy with IV ganciclovir has been attempted, but has not been effective in preventing CMV infection.[38] In 1 series, over 30% of pediatric recipients receiving prophylaxis developed CMV disease.[80] Current treatment strategies are center-specific and usually include avoidance of CMV-seropositive grafts in CMV-seronegative recipients, administration of IV ganciclovir and/or CMV-specific hyperimmunoglobulin, and routine monitoring of CMV-pp65 levels until the infection resolves. Therapeutic baseline immunosuppression is continued and only decreased if the patient's clinical status deteriorates.[80]

Although CMV disease is a common cause of morbidity following intestine transplantation, it has been successfully managed and treated in up to 90% of cases.[53,80] In fact, no difference in patient and graft survival is seen in patients with CMV disease as compared with those who acquired CMV disease.

EBV and PTLD. Since intestine transplant recipients require high levels of immunosuppression in view of the large amount of lymphoid tissue in the graft, they are particularly vulnerable to EBV infection and PTLD. Infection with EBV remains one of the most serious consequences of immunosuppressive management in transplantation. EBV-associated PTLD comprises a range of disorders, from nonspecific viral illness or self-limiting mononucleosis to more serious PTLDs with polyclonal or monoclonal disease, and, ultimately, lymphoma. The delicate balance required to manage rejection with augmented immunosuppression while controlling infection with decreased immunosuppression is critical for patient and graft survival.

PTLD is a significant cause of morbidity and mortality in intestine transplantation, with an overall incidence of about 20%,[87,88] higher than that observed in other types of solid organ transplantation. The incidence of PTLD is highest in pediatric recipients of multivisceral grafts (40%) compared with combined small bowel-liver grafts (20%) and isolated intestinal grafts (11%).[59,87,88]

Children are more frequently affected than adults (30% vs 9%).[87,88] Children acquire primary EBV infections more frequently than adults since they are usually seronegative for EBV at the time of transplantation. If they receive organs seropositive for EBV, a primary infection results that progresses to lymphoproliferative disease, which accounts for the higher incidence of PTLD.[89] However, contrary evidence has been reported. Sixty-seven percent of children who developed PTLD were seropositive prior to transplantation.[90] In another study, there was no significant difference in the incidence of PTLD based on EBV seronegativity or seropositivity.[87] Reactivation of virus or reinfection related to heavy immunosuppression or multiple infusions of blood products may be related to development of PTLD in this population.[90]

The median time of presentation of PTLD is 9 months (range, 1 month to 5 years).[58] Risk factors include a young age, type of intestinal graft, high levels of immunosuppression, administration of OKT3, recipient splenectomy, and EBV seropositive donor-EBV seronegative recipient pair.[17,58,59] Diagnosis is based on clinical presentation, endoscopic and histologic findings, EBV quantitation, and other laboratory studies and radiologic findings. Presenting symptoms may include fever, lethargy, malaise, nonspecific GI complaints, diarrhea, bloody stools, pain, and lymphadenopathy. Patients may also have anemia, leukopenia, or atypical lymphocytosis.[91,92] Tumors or masses may be detected on physical examination or revealed through abdominal imaging. Computed tomography scans of the chest and abdomen are obtained to evaluate for enlarged lymph nodes or disseminated disease. The most common site of involvement is the intestinal graft, but the native GI tract may also be involved.[88]

On endoscopy, early PTLD lesions usually present as nonspecific, nonulcerated submucosal nodules and can progress to 2-cm ulcers with heaped-up margins and a necrotic base (Figure 9).[72] Mature PTLD lesions can be distinguished from rejection since the surrounding mucosa is normal. On histology, the tissue has lymphocytic infiltrates with a monomorphic and/or polymorphic appearance (Figure 10).[72] The most reliable stain to confirm the diagnosis of EBV disease is in situ hybridization with the EBER-1 probe, which labels EBV-encoded RNA in infected cells (Figure 11).[93]

A. Normal allograft ileum. B-D. Nodular PTLD lesions of the allograft ileum.

Cytomegalovirus of the allograft intestine. Note the CMV-inclusion bodies.

EBV Infection/PTLD. A considerable number of lymphocytes stain with the EBER-1 Probe.

Quantification of the EBV viral load has become an additional diagnostic tool for EBV disease. The EBV-polymerase chain reaction (PCR) assay is a serologic test that identifies increased levels of circulating EBV-infected lymphocytes through measurement of peripheral blood lymphocytes.[94,95] A quantitative competitive EBV-PCR has been developed to provide an accurate quantitative measure of the viral load of EBV.[94]

Pediatric transplant recipients with PTLD had viral loads ranging from 500 to greater than 25,000 genome copies per 105 peripheral blood lymphocytes while patients with viral loads ranging from nondetectable to 200 genome copies per 105 PBL did not have clinical or histologic evidence of PTLD.[96] However, findings are inconsistent. EBV-PCR results have been found to be comparable in patients with EBV-associated viral syndromes and PTLD,[92] although some patients with elevated viral loads are asymptomatic.[97] Consequently, although the EBV-PCR is a useful diagnostic tool to monitor high-risk patients and direct treatment or preemptive therapy, histologic confirmation is necessary.

The most widely-accepted treatment for PTLD is reduction or discontinuation of immunosuppression. This strategy restores natural immune surveillance so that the proliferation of EBV-infected cells is contained. However, this approach is not always feasible in intestine transplantation due to the high immunosuppression requirement of these patients. Additional treatment for EBV disease includes antiviral therapy with IV ganciclovir, acyclovir, and/or hyperimmunoglobulin, cytokines (interferon-alpha), and/or chemotherapy.[53,59,88] Rituximab, an anti-CD20 monoclonal antibody, has recently been approved for treatment of certain CD20-positive B-cell lymphomas. Although experience with this drug is limited, it may be effective in treating PTLD that is CD20 positive.[97]

While a reduction in immunosuppression is the mainstay of therapy for PTLD, this strategy restores T lymphocytes responsible for rejection. The management dilemma of intensified immunosuppression for rejection and decreased immunosuppression for PTLD leads to significant morbidity and mortality.

In this situation, immunosuppression is increased back to the patient's baseline level while more severe rejection is treated with increased corticosteroids or the addition or resumption of other adjunctive immunosuppressive agents.

PTLD is a major cause of death in intestine transplantation; the mortality rate is 45% to 50%.[58,88] PTLD was the cause of death or was present at the time of death in nearly 70% of pediatric recipients with EBV disease.[36] Preventative strategies and early detection and treatment of PTLD are essential to decrease the morbidity and mortality of this complication of immunosuppression.

Other infections. Respiratory syncytial virus, adenovirus, and parainfluenza are community-acquired viruses seen in this population that can lead to severe morbidity and mortality, depending on the age of the recipient, timing of the infection, level of immunosuppression, and concurrent rejection. Pneumocystis carinii pneumonia (PCP) is a threat as well. Oral trimethoprim-sulfamethoxazole (TMP-SMX) is given for prophylaxis against PCP. Because immunosuppressed patients are always at risk for PCP, prophylaxis should continue indefinitely.[98,99] Suggested prophylaxis is a single daily dose of TMP-SMX 3 times/week. If sulfa drugs are contraindicated, patients may receive dapsone twice daily or pentamidine aerosol treatment monthly.

Graft-vs-Host Disease (GVHD)

GVHD is a complex immunologic reaction that occurs when mature donor T cells react against recipient antigens, resulting in destruction of recipient tissue -- essentially the reverse of acute cellular rejection. Although it was initially believed that intestine transplantation would carry a high risk for GVHD due to the abundant lymphoid tissue in the intestine, the incidence is 0% to 14% in the most active intestine transplant centers.[14,38,59] This low incidence is theorized to be the result of bidirectional migration of donor and recipient leukocytes, leading to the recipient becoming a genetic composite of cells of the donor and self.[100] Therefore, since the recipient and graft are not leukocyte-depleted, intestine transplantation can be performed with only a minimal risk of GVHD.

The most common clinical presentation of GVHD is an erythematous, maculopapular rash that usually affects the palms, soles, ears, and trunk. Fever, diarrhea, and pancytopenia may also be present. Histologic criteria include keratinocyte necrosis, epithelial apoptosis of the native GI tract, or epithelial necrosis of the oral mucosa.[17] Although GVHD has been fatal in a very few cases, the majority have been self-limiting with spontaneous resolution.

Graft Loss and Retransplantation

The most common causes of graft loss as a result of death or enterectomy are infection (43%), rejection (29%), and technical or clinical complications (29%).[17] However, the cause of death or enterectomy is usually multifactorial. Graft enterectomy should be performed if the patient has significant graft dysfunction with severe rejection that is refractory to increased immunosuppression. Enterectomy must be completed in a timely manner before GI complications and sepsis from possible perforation occurs or before infectious complications develop; these complications may persist following graft removal and consequently will affect survival. Isolated intestine transplant patients requiring graft enterectomy will resume TPN and will be relisted as transplant candidates if criteria for listing are met and the patient and family desires retransplantation. Survival is significantly decreased in patients who are retransplanted due to the surgical risk factors and complications related to liver disease and line sepsis encountered while waiting for an organ.

Retransplantation of the liver in composite grafts is usually indicated for graft loss due to primary nonfunction and surgical complications, primarily hepatic artery thrombosis. This is an extremely precarious situation due to the patient's clinical status (ie, hepatic failure) and the limited availability of donor organs. In a series of 55 pediatric recipients, 4 patients underwent retransplantation (3 combined small bowel-liver and 1 isolated intestine). The 3 patients with composite grafts died within 2 months following retransplantation of infection (n = 2) and rejection (n = 1).[53] At the time of publication, the isolated intestinal recipient survived retransplantation and was doing well, but subsequently lost the second graft to severe rejection approximately 2 years later.

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