Infectious Complications After Multivisceral Transplantation in Adults

Infectious Complications After Multivisceral Transplantation in Adults M. Oltean, G. Herlenius, M. Gäbel, V. Friman, and M. Olausson ABSTRACT It is thought that multivisceral transplantation requires high levels of immunosuppression and therefore, patients run an increased risk of infection. We retrospectively reviewed our center’s experience with clinically relevant infectious complications. Patients. Between 2000 and 2005, 10 adult patients underwent multivisceral transplantation. Two immunosuppression protocols were used: between 2000 and 2003, a high immunosupression protocol (six patients; daclizumab induction, tacrolimus trough levels ⬎20 ng/mL and steroids) and an immunomodulatory, low imunosuppression scheme from 2003 onward (four patients; ATG induction, tacrolimus levels 5 to 10 ng/mL, no steroids). Standard antimicrobial prophylaxis consisted of vancomycin, meropenem, and amphotericin B. Cytomegalovirus (CMV) prophylaxis was used in all but first two cases. Donor and recipient CMV status were D⫹/R⫹ (n ⫽ 7), D⫹/R⫺ (n ⫽ 2), D⫺/R⫹ (n ⫽ 1). Results. The median follow-up period was 627 days (range, 19 to 2207 days). A total of 47 infectious episodes were recorded in all patients (range 1 to 14 per patient). The etiology was bacterial in 32 (69%), viral in 8 (17%), and fungal in 7 (14%) cases. The most frequent were catheter related (n ⫽ 13) followed by respiratory (n ⫽ 7), intraabdominal (n ⫽ 6), and wound infections (n ⫽ 5). Symptomatic viral infection of the graft (CMV gastritis or enteritis, adenoviral enteritis) was also encountered. Epstein-Barr virus was transiently detected in the serum of nine patients, one of whom later developed posttransplant lymphoproliferative disorder (PTLD). Three deaths all among patients receiving high immunosuppression were owing to infectious complications: pulmonary PTLD at 4 months posttransplantation, ruptured mycotic aneurysm after 8 weeks, and sepsis after 3 weeks. Conclusions. Infections accounted for a high morbidity after multivisceral transplantation, representing the leading cause of mortality. Exhaustive monitoring, early antimicrobial intervention, and lower immunosuppression may improve the outcome.

B

ECAUSE OF the high immunogenicity of the intestine, transplantation, of this organ alone or in composite grafts, requires high levels of immunosuppression compared with other organs. Insufficient treatment rapidly leads to acute rejection, which in turn may promote bacterial translocation from the intestinal lumen, secondary to morphologic impairment of the graft. In contrast, overimmunosuppression renders the patient vulnerable to viral and fungal opportunistic infections.1 Furthermore, additional risk factors for infections include the presence of indwelling catheters for nutritional support, the extensive magnitude of the surgical procedure and reoperations, as well as the contaminated content of the graft. We herein have reported our current experience regarding the infec-

tious complications occurring after multivisceral transplantation in adult recipients. PATIENTS AND METHODS We performed nine adult multivisceral and one combined liver– small bowel transplantations between February 2000 and July 2005. From the Departments of Transplantation and Liver Surgery (M.Olt., G.H., M.G., M.Ola.) and Department of Infectious Diseases (V.F.), Sahlgrenska University Hospital, Göteborg, Sweden. Address reprint requests to Dr Gustaf Herlenius, Department of Transplantation and Liver Surgery, Sahlgrenska University Hospital, 41345, Göteborg, Sweden. E-mail: gustaf.herlenius@ vgregion.se

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0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.07.035

Transplantation Proceedings, 38, 2683–2685 (2006)

2683

OLTEAN, HERLENIUS, GA¨BEL ET AL

2684 Table 1. Patient Demographics Patient

Age

Gender

Diagnosis

Type of Transplant

57 44 57 38 58 27 40 67 44 37

M M F M F M F F M F

NEPT NEPT SBS, CIPO NEPT NEPT SBS SBS CIPO NEPT SBS

Multivisceral Multivisceral Combined liver–intestine Multivisceral Multivisceral Multivisceral Multivisceral Multivisceral Multivisceral Multivisceral

1 2 3 4 5 6 7 8 9 10

Abbreviations: NEPT, neuroendocrine pancreatic tumor with liver metastases; SBS, short bowel syndrome; CIPO, chronic intestinal pseudoobstruction.

The patient demographics are presented in Table 1. Postoperative management included a protocol based on tacrolimus (Prograf, Astellas, Osaka, Japan), broad-spectrum antimicrobial prophylaxis (vancomycin, meropenem, amphotericin B) and routine endoscopies for rejection surveillance. Cytomegalovirus (CMV) prophylaxis consisted of a combination of ganciclovir (Cymevene, Roche Pharmaceuticals) and CMV immune globulin for the first year. Two different immunosuppression protocols were: during 2000 and 2003 (n ⫽ 6 patients), daclizumab induction (Zenapax, Roche Pharmaceuticals) was combined with tacrolimus (target trough levels ⫽ 20 to 25 ng/mL) and steroids. In two cases, treatment was switched to sirolimus (Rapamune, Wyeth) owing to deteriorating renal function. After 2003, the immunosuppressive protocol consisted of ATG induction, tacrolimus (levels ⫽ 5 to 10 ng/mL with further tapering) and no steroids. Patient records were retrospectively reviewed for clinically relevant infectious episodes, based on clinical presentation, systemic inflammatory response, positive bacteriology, or polymerase chain reaction (PCR) in blood or tissues, immunohistochemistry as well as pertinent radiologic and endoscopic examinations.

RESULTS

The median follow-up period was 627 days (range 19 to 2207 days). A total of 47 infectious episodes were recorded in all patients (range 1 to 14 per patient). The etiology was bacterial in 32 (68%), viral in 8 (17%), and fungal in 5 (11%) cases. Mixed bacterial and fungal etiology was observed in two cases (4%). Over half of the infections (25/47) occurred within three months after transplantation. We also noted a difference in the total number of infections between both immunosuppressive protocols during the first 6 months posttransplant (24 vs. 8). Bacterial infections were most frequently seen (32/47): Enterococcus sp. was the most common pathogen, seconded by coagulase-negative Staphylococcus epidermidis, and Pseudomonas sp. Sepsis and bacteremia originating in central line infections, were the most common expression of bacterial infections (n ⫽ 13) followed by respiratory infections (n ⫽ 7), intraabdominal infections (n ⫽ 5), wound infections (n ⫽ 5), and cholangitis (n ⫽ 2). Respiratory tract infections, the second in order of frequency, were favored by prolonged mechanical ventilation and bed stay, tracheostomy, pleural effusions, and fistulae or

inefficient coughing, owing to the lack of an abdominal wall. The pleuropulmonary complications showed prolonged evolution, but ultimately resolved. The extensive abdominal surgery favored intraabdominal infections and wound infections, some requiring surgical exploration and drainage. CMV donor–recipient status was D⫹/R⫹ (n ⫽ 7), D⫹/R⫺ (n ⫽ 2), D⫺/R⫹ (n ⫽ 1). Tissue-invasive CMV disease occurred in three patients (D⫹/R⫹), with two documented episodes of gastritis and one of CMV enteritis, which resolved after antiviral therapy and tapering of immunosuppression. Two episodes of CMV disease occurred within 4 months, all bouts were within the first year after transplantation. No CMV disease was documented outside the graft: namely, hepatitis, retinitis, or pneumonia. Adenovirus was found coincidentally in various graft biopsies at three times (adenovirus DNA positive PCR), but only caused enteritis in one case. Initially, this case was mistakenly considered and treated as rejection until biopsies and PCR provided the correct diagnosis and reoriented the therapy. All viral infections with one exception were recorded in patients receiving the high tacrolimus regimen. All episodes occurred at least 2 months posttransplant. Transient, low EBV viremia was found on 17 different occasions in all but one patient. Viremia resolved after decreasing immunosuppression except in one case, in whom it eventually lead to pulmonary posttransplant lymphoproliferative disease (PTLD) and ultimately the patient’s death. Fungal or viral (herpes simplex virus type 1) stomatitis, pharyngitis, and esophagitis accounted for six infectious episodes. Fungal and bacterial sepsis lead to multiorgan failure and death in one patient. Despite ongoing antifungal prophylaxis, another patient displayed concomitant wound infection and pancreatitis, a mycotic aneurysm of the aortic conduit developed and ultimately ruptured, resulting in fulminant hemorrhage and patient death. All three deaths owing to infectious causes occurred within 4 months posttransplantation. DISCUSSION

Infection is a common occurrence after solid organ transplantation. It significantly contributes to the increased morbidity and mortality posttransplantation.1 Moreover, in intestinal transplantation, the interplay between rejection and infection is closer than in any other transplantable organ owing to the contaminated nature of the graft. The present report described the highest incidence of infections, mostly bacterial, in the early postoperative period. Despite antifungal prophylaxis, deep fungal infections may occur, favored by the presence of other intraabdominal infections and iterative surgical explorations. The current analysis showed that the frequency and distribution of infections as well as the etiologic agents were similar to those described by other centers. The majority of infections were bacterial in origin and in the blood, respiratory tract, or intraabdominal cavity, the most frequent sites of infection.2–5 In an early study, although considered un-

INFECTIOUS COMPLICATIONS

avoidable prerequisites following intestinal and multivisceral transplantation, high levels of FK506, the use of steroids and the use of OKT3 were identified as significant risk factors for the development of infections.6 The longlasting paradigm of high tacrolimus levels in intestinal transplantation has been recently challenged; excellent results were reported using an immunomodulatory approach with ATG induction, low tacrolimus levels, and no steroids.7,8 The implementation of such a protocol in our program seemed to produce a reduced rate of infectious episodes without an increment in the frequency or severity of rejection. REFERENCES 1. Fishman J, Rubin R: Infection in organ-transplant recipients. N. Engl J Med 338:1741, 1998

2685 2. Guaraldi G, Cocchi S, De Ruvo N, et al: Outcome, incidence, and timing of infections in small bowel/multivisceral transplantation. Transplant Proc 36:383, 2004 3. Tzakis A, Kato T, Levi D, et al: 100 Multivisceral transplants at a single center. Ann Surg 242:480, 2005 4. Farmer DG, McDiarmid SV, Edelstein S: Improved outcome after intestinal transplantation at a single institution over 12 years. Transplant Proc 36:303, 2004 5. Green M, Reyes J, Nour B, et al: Early infectious complications of liver-intestinal transplantation in children: preliminary analysis. Transplant Proc 26:1420, 1994 6. Todo S, Reyes J, Furukawa H, et al: Outcome analysis of 71 clinical intestinal transplantations. Ann Surg 222:270, 1995 7. Reyes J, Mazariegos G, Abu-Elmagd K, et al: Intestinal transplantation under tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti-thymocyte globulin (thymoglobulin). Am J Transplant 5:1430, 2005 8. Grant D, Abu-Elmagd K, Reyes J, et al: 2003 report of the Intestine Transplant Registry: a new era has dawned. Ann Surg 241:607, 2005