REVIEW URRENT C OPINION

Gastrointestinal infections after transplantation Lara Danziger-Isakov

Purpose of review Recipients of both solid organ transplant and hematopoietic stem cell transplantation are at increased risk for infectious morbidity and mortality after transplantation due to on-going immunosuppression. Gastrointestinal infections have been increasingly reported in these populations. Recent findings Increased reports of gastrointestinal infections including bacterial infection with Clostridium difficile, viral infection with norovirus and parasitic pathogens like cryptosporidium are emerging. Risk factors identified have focused on type of transplant, transplant immunosuppression regimens and exposures. Although many events are self-limiting, significant morbidity and rare mortality are reported. Summary Improved diagnostic techniques have increased the reporting of several gastrointestinal infections after transplantation, affording improved understanding of the epidemiology of these diseases. Armed with this emerging data, prevention, recognition of infection and treatment strategies can be more thoroughly assessed in these at-risk populations. Keywords Clostridium difficile, gastrointestinal infection, norovirus, transplant infectious disease, transplantation

INTRODUCTION Gastrointestinal infections occur commonly after both solid organ (SOT) and hematopoietic stem cell transplantation (HSCT), effecting morbidity and mortality to variable degrees depending on the pathogens involved. Furthermore, development of newer diagnostic techniques has increased the understanding of several gastrointestinal pathogens and their impact in the transplant population. This review will report the current literature regarding recent epidemiology, risk factors and emerging therapies for various gastrointestinal infections after transplantation, exposing the areas for further investigation in these at-risk populations.

BACTERIAL INFECTIONS Bacterial pathogens are increasingly recognized with improvements in diagnostics including multiplex PCR. For example, detection of bacterial pathogens such as enteropathogenic Escherichia coli, Campylobacter, Shiga-toxin producing E. coli and Clostridium difficile increased from 18.5% with conventional methods to 50% with PCR assays. These results included new detection of co-pathogens that were previously undetected with conventional bacterial cultures [1 ]. Improved diagnostics will continue

to increase the ability to identify infection in transplant recipients.

Clostridium difficile infection As prevalence of C. difficile infection (CDI) in the general community has increased, expanded data regarding the impact and risk for C. difficile diarrhea in transplantation has emerged predominantly in adult patients. In pediatrics, case reports of severe presentation, such as toxic megacolon requiring colectomy after pediatric heart transplantation, exist [2], but extensive epidemiologic reports have not been published in pediatrics to date. Epidemiology in adult SOT recipients varies widely depending on the population evaluated. In a multicenter Spanish cohort of nearly 4500 SOT recipients, the incidence of CDI was only 0.94%, with 48% presenting within 30 days and 90% within Cincinnati Children’s Hospital Medical Center Correspondence to Lara Danziger-Isakov, MD, MPH, Cincinnati Children’s Hospital Medical Center, ML 7017, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Tel: +1 513 636 9101; e-mail: Lara. [email protected] Curr Opin Gastroenterol 2014, 30:40–46

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Gastrointestinal infections after transplantation Danziger-Isakov

KEY POINTS

of whom 73% developed CDI during the first month posttransplant [7 ]. In a nationwide cross-sectional evaluation using NIS data from 2004 to 2008, CDI prevalence was only 2.7% in hospitalized liver transplant recipients [8]. Liver transplant recipients with CDI had increased in-hospital mortality (5.5%) compared with those without CDI (3.2%). Risk factors for CDI reported in the kidney recipients included pretransplant colonization with vancomycin-resistant Enterococcus, receipt of an organ from Centers for Disease Control high-risk donor, and administration of high-risk antibiotics (antipseudomonal penicillins, third-generation cephalosporins, carbapenems) within 30 days posttransplant. Clearly, CDI is a growing issue in SOT and requires further investigation. In HSCT cohorts from France and Maryland, reported incidence rates have been 9–13% with increased rates in allogeneic compared with autologous transplant recipients [9 ,10 ]. Risks for infection included acute graft-versus-host disease (GVHD) [9 ,10 ,11], cord blood as the source of stem cells [10 ], receipt of chemotherapy prior to conditioning for HSCT [9 ] and broad-spectrum antimicrobial use [9 ]. GVHD was associated with the increased risk of CDI recurrence, and CDI was associated with the development of subsequent gastrointestinal GVHD in the year following allogeneic HSCT [9 ]. The interaction between CDI, acute and chronic GVHD requires additional exploration, specially if the events can be modified to prevent morbidity related to HSCT. In addition to CDI, common bacterial gastrointestinal pathogens continue to be reported in the literature. Three kidney transplant recipients in the United Kingdom acquired Salmonella typhimurium from an index case with chronic carriage [12]. Additionally, 18 patients after HSCT with nontyphoidal Salmonella were described in a 15-year single-center retrospective review. The majority presented with bacteremia; one-third notably lacked diarrhea at presentation [13]. One patient died of septic shock, and only one patient had a recurrence of infection. Tuberculosis (TB) and nontubercular mycobacteria (NTM) have also been recently reported. NTM segregated to the small bowel was recovered 80 days after HSCT in an adult patient [14], while TB colitis diagnosed by biopsy and TB-PCR appeared 18 months after kidney transplantation in a Mexican native [15]. Treatment of TB was complicated by liver toxicity and nonadherence. Therefore, evaluation for bacteria including uncommon pathogens and utilizing advanced diagnostics should be considered in SOT and HSCT recipients with diarrhea and fever. &

 Gastrointestinal infections are increasingly reported after SOT and HSCT.  Improved molecular diagnostics have increased the ability to identify pathogens effectively during symptomatic episodes.  After hematopoietic stem cell transplantation, differentiation between gastrointestinal infection and GVHD requires thorough evaluation.  In SOT, donor-derived infection must be considered for gastrointestinal pathogens, specially parasitic infections.

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6 months of transplant [3 ]. Only one patient required a colectomy, and 17% experienced a relapse. An increased risk of CDI was associated with cephalosporin use, ganciclovir prophylaxis and recent corticosteroids, but CDI was not associated with increased 1-year mortality. In a Canadian cohort, the incidence ranged from 4.5% in 1999 to a peak 21.1% in 2005. The most recent incidence reported was 9.5% in 2010 [4]. Risk factors for CDI included age more than 55 years, antithymocyte globulin use and any transplant other than kidney. Predictors for progression to severe disease included elevated white blood cell count and pancolitis on computed tomography scan. Surgical treatment of severe disease resulted in an 83% survival compared with 35% with medical treatment alone. Using the US Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project from the Agency for Healthcare Research and Quality 2009 database, one group reported CDI prevalence of 2.7% in hospitalized SOT recipients [5 ]. As with the Canadian cohort, kidney recipients were at the lowest risk for CDI. Multivariable logistic regression comparing SOT with and without CDI showed independent association with 2.5-fold increase in mortality, longer hospitalization, higher charges, more complications of the transplanted organ, and three-fold increase in colectomy. In organ specific analyses from the United States, CDI appears most frequently after lung transplantation. Single-center adult cohorts reported CDI during a recent era ranging from 22.5% (34 of 151) in adult lung transplant recipients [6 ] to 6.1% (37 of 603) in kidney transplant recipients [7 ]. Similarly to the Canadian cohort, these kidney recipients showed an increasing rate of CDI, from 3.7% in 2008 to 9.4% in 2010. Only 21% of lung transplant recipients had CDI during their initial transplant hospitalization, unlike kidney transplant recipients, &&

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Gastrointestinal infections

VIRAL INFECTIONS Viral infections occur frequently after both SOT and HSCT, with coinfections of two or more viral pathogens occurring frequently after HSCT. For example, a single pediatric HSCT recipient developed infection with rotavirus diarrhea, respiratory syncytial virus pneumonia and HHV [6 ] encephalitis simultaneously [16]. Data regarding specific viral gastrointestinal infections continues to emerge. &

Norovirus Chronic norovirus was described in 2009 in both kidney [17] and HSCT [18] and, as discussed with bacterial pathogens, molecular diagnostics has afforded detection of norovirus in which it was previously undetected [1 ]. In pediatric HSCT [19 ], 49 of 55 recipients with diarrhea tested from 2007 to 2011 revealed eight patients positive for norovirus. Risk factors for norovirus infection included the use of peripheral blood or cord blood as the stem cell source, and administration of fludarabine and alemtuzumab. Data from other HSCT cohorts correlated immunosuppression with diarrheal symptoms [19 ] or associated recovery of donor T-cells and norovirus clearance [20]. Prolonged shedding has been shown in both pediatric and adult HSCT cohorts. Thirteen pediatric patients in the United Kingdom excreted norovirus for 60–380 days [20], and the median time to viral clearance was 145 days (range, 13–263 days) in eight pediatric HSCT patients discussed previously [19 ]. In 2010, a Swiss group described prolonged shedding (from 97 to 898 days) [21] but without nosocomial transmission based on molecular genotype sequencing. However, nosocomial spread of norovirus continues to be reported, specially with the appreciation of prolonged shedding and the development of novel diagnostics. Whole genome deep &&

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sequencing to determine transmission patterns for infection control have been used with phylogenetic mapping to distinguish related viruses [22 ]. At least two outbreaks have been reported after HSCT with increased rates in the HSCT unit (26%) compared with the non-HSCT patients (0.16%) [23]. Common features in these outbreaks included symptomatic caregivers, with 10% of staff affected in one study [24]. In addition, symptoms in HSCT patients were prolonged compared with caregivers. Adequate treatment of norovirus remains elusive, but recent literature reports several emerging options (Table 1). A 43-year-old HSCT recipient had symptomatic resolution within 4 days of nitazoxanide [25] but continued to shed asymptomatically. Florescu et al. [26] administered eight doses of oral human immunoglobulin (OHIG) to each of 12 transplant recipients, predominantly pediatric small bowel recipients, and compared them with controls who were treated supportively. They hypothesized that OHIG would decrease intraluminal viral adherence and viral entry. Decreased stools at 7 days and resolution of diarrhea were reported, although the trend was not statistically significant. Finally, the use of mammalian target of rapamicin (mTOR) inhibitors (everolimus and sirolimus, respectively) has been associated with clearance of the chronic norovirus carrier state in separate case reports of a heart transplant recipient [27] and combined lung/HSCT recipient [28]. Additional information regarding the epidemiology, risk factors, diagnosis and treatment of norovirus after SOT and HSCT is needed. &

Rotavirus Rotavirus is less frequently reported in the recent literature, perhaps related to the introduction of rotavirus vaccination. In a Japanese cohort of pediatric HSCT, rotavirus antigenemia in blood

Table 1. Potential emerging therapeutics for select viruses Virus

Potential emerging therapeutics

Norovirus

Nitazoxanide Oral human immunoglobulin mTOR inhibitor inclusion in immunosuppressive regimen

Adenovirus

CMX-001 (Chimerix, USA)

Cytomegalovirus

Novel antivirals: CMX-001 (Chimerix, USA), Maribavir (ViroPharma, USA), RG7667 (Genetech, USA), Letermovir (AiCuris, Germany & Merck, USA) CMV vaccines

CMV, cytomegalovirus; mTOR, mammalian target of rapamycin.

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was present in 8 of 62 recipients and correlated with diarrhea in 50% [29]. Rotavirus infection was associated with mismatched human leukocyte antigen, and antigenemia persisted longer but at lower levels in HSCT than in immunocompetent controls [29]. Self-limited diarrhea (ranging from 6 to 13 days) occurred in 23 small bowel transplant recipients, of whom the majority were more than 6 months posttransplant [30]. Acute rejection occurred frequently in the cohort, including six patients diagnosed with concurrent rejection at the time of rotavirus infection. Two patients subsequently lost their grafts with refractory rejection that was not directly related to the rotavirus infection.

enteritis [36]. As in prior literature, CMV donor– recipient mismatch was a risk factor, and CMV disease was associated with 11-fold increase in risk of death. Monitoring is the focus of many prevention strategies; however, reports of isolated CMV enteritis with low or absent viral loads in the peripheral blood have been recently noted [37,38]. A liver and a kidney transplant recipient both developed ileal obstruction several months after an episode of CMV enteritis [39,40], and in both cases surgical resection was required. Therefore, CMV must be considered a potential pathogen for gastrointestinal disease even in the absence of circulating virus in the blood.

Adenovirus Adenovirus occurs commonly after pediatric transplantation, but after HSCT it is primarily associated with hemorrhagic cystitis and disseminated infection with multiorgan involvement. Gastrointestinal-specific adenoviral illness has been reported, with 4 of 17 kidney transplant recipients with adenovirus infection presenting with diarrhea [31]. Two of seven pediatric HSCT recipients with adenovirus presented with diarrhea [32]. In HSCT, T-cell depletion for conditioning increased the risk of adenovirus viremia but did not affect the recovery of adenovirus from stool (10.8% conventional HSCT, 12.7% T-cell depleted HSCT) by 1-year posttransplant [33]. Therefore, diarrhea and gastrointestinal disease represent only a fraction of the disease associated with adenoviral infection. To combat disseminated adenovirus infection, emerging therapy has included directed antiviral T-cells such as the trivirus T-cell infusions directed against adenovirus, cytomegalovirus (CMV) and Epstein– Barr Virus (EBV) under investigation for allogeneic HSCT [34]. In addition, a lipid-formulation of cidofovir (CMX-001: Chimerix, Durham, North Carolina, USA) is in clinical trials for the treatment of adenovirus. Clinical trials to focus specifically on gastrointestinal adenovirus are not likely to occur in the near future, given the limited burden of this manifestation of infection.

Cytomegalovirus Cytomegalovirus continues to be associated with significant morbidity and mortality despite aggressive monitoring and preventive therapies. Two of 72 HSCT cord blood recipients in a recent report developed CMV enteritis, both within 60 days of transplant [35]. Furthermore, in 98 small bowel transplant recipients, seven developed CMV disease, of whom five presented with

PARASITIC INFECTIONS Parasitic infections affect the gastrointestinal tract frequently, and transplant recipients are not spared these infections once they are exposed. In fact, a cohort study from Iran revealed that kidney transplant recipients had higher prevalence rates of intestinal parasites compared with matched controls. In particular, prevalence rates for kidney transplant recipients were higher for Entamoeba coli (10.6 vs. 7.6%), Giardia lamblia (7.4 vs. 1.8%) and Blastocystis infections (4.7 vs. 2.2%) [41]. Strongyloides infection has prevalence rates up to 4% in the Southeastern United States [42] and remains a risk for transplant recipients, particularly after SOT. A Brazilian cohort of nearly 1800 kidney and liver recipients reported only two cases of diarrhea associated with Strongyloides stercoralis infection [43]. However, several recent reports of recipient-derived reactivation including hyperinfection episodes or disseminated disease support the need for pretransplant screening of at-risk populations [40,44]. Donor-derived infection with confirmatory testing from archived donor specimens is being recognized and reported more frequently in SOT. Donor risk is often only realized after identification of a recipient’s infection. For example, a Taiwanese adolescent received an intestinal graft from a Filipino donor with baseline eosinophilia. At 30 days after transplantation, Strongyloides larvae were recovered from the graft stoma with concurrent eosinophilia [45]. Several additional donor-derived infections have been recently reported in kidney transplant recipients [46,47]. In 2012, a single donor from an endemic area infected three of four solid organ transplant recipients (kidney/ pancreas, kidney and heart) between 7 and 10 weeks posttransplant [48,49 ]. Diagnosis was confirmed by positive serology from the donor with negative

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recipient serologies. All recipients were treated with ivermectin and albendazole, but the heart recipient expired secondary to the infection. Therefore, Strongyloides risk needs to be considered in both the pretransplant candidate as well as the donor to prevent this potentially life-threatening complication after SOT. Cystoisospora belli (formerly Isospora belli) gastrointestinal infection has also been reported after intestinal [50] and liver [51] transplantation. Both cases were diagnosed by microscopic detection of stool samples and treated with trimethoprim–sulfamethoxazole; the patient with the liver transplant experienced a relapse or reinfection with the organism 2 months after the completion of initial therapy. Cryptosporidium infections have been recently reported in pediatric SOT, adult SOT and HSCT recipients. Five of 44 pediatric liver transplant recipients in Iran presenting with diarrhea were infected with Cryptosporidium species [52]. Presentation can include severe diarrhea with dehydration, as in the case of a pediatric kidney transplant recipient who was diagnosed based on stool antigen and microscopic evaluation of stool [53]. In adult SOT, cryptosporidium enteritis has been associated with elevated creatinine and tacrolimus levels in a series of 10 recipients (eight kidney, one liver, one lung); five of the cases involved recent travel exposure, indicating that interval history of travel could increase the clinical suspicion for this pathogen [54 ]. Furthermore, transplant recipients may be receiving other medications that confound the diagnosis of enteritis; discrimination between parasitic infection and mycophenolateassociated colitis has been problematic in at least one reported case [55]. In HSCT, diarrhea secondary to cryptosporidium enteritis can mimic chronic intestinal GVHD [56]. Five of 52 HSCT recipients with diarrhea in a serial cohort were positive for Cryptosporidium parvum despite environmental precautions to limit exposure. Therefore, parasitic pathogens must be explored in SOT and HSCT recipients who present with gastrointestinal symptoms, specially in the context of positive exposures elicited by an informed history. &&

FUNGAL INFECTIONS Although fungal infections, including surgical site infections, occur frequently in transplant recipients, isolated gastrointestinal infection secondary to fungal pathogens is less common after transplantation. Recent literature reports a significant proportion of posttransplant peritonitis secondary to Candida species in both pediatric small intestinal 44

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transplant recipients and adult liver and/or pancreas transplant recipients. In 98 pediatric small bowel transplant recipients, 25 developed 59 episodes of infection with Candida species, including 17 with intra-abdominal abscesses or peritoneal infection [57]. More than three-quarters of the episodes occurred within 6 months of transplant, and 41% developed within 1 month posttransplant. Candida albicans was the predominant organism in the series. Furthermore, in a cohort of liver and/or pancreas transplant recipients from Spain, the authors reported only five cases of Candida peritonitis among 717 transplants. However, Candida species (C. albicans 3, C. krusei 1, C. tropicalis 1) accounted for 10% of postoperative peritonitis events (5/48 episodes) [58]. Although invasive fungal infections are common after HSCT, isolated gastrointestinal fungal infections are rare, such as the recent case report of angioinvasive Candida kefyr enteritis that required ileostomy in an adult after HSCT [59]. Isolated gastrointestinal infections secondary to fungal pathogens are less commonly reported in nonabdominal SOT and HSCT recipients.

CONCLUSION In conclusion, gastrointestinal infections continue to emerge as significant pathogens after both SOT and HSCT. Improved diagnostics for both bacterial and viral pathogens has increased our understanding of the epidemiology and risk factors in SOT and HSCT recipients; however, significant progress in the prevention and treatment of gastrointestinal infections is needed to improve outcomes after transplantation. Acknowledgements None. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Coste JF, Vuiblet V, Moustapha B, et al. Microbiological diagnosis of severe diarrhea in kidney transplant recipients by use of multiplex PCR assays. J Clin Microbiol 2013; 51:1841–1849. Use of enhanced molecular diagnostics in a population of kidney transplant recipients with diarrhea. Improved identification of potential pathogens achieved, including demonstration of coinfections with two or more pathogens simultaneously. 2. Castillo A, Lopez J, Panadero E, et al. Conservative surgical treatment for toxic megacolon due to Clostridium difficile infection in a transplanted pediatric patient. Transpl Infect Dis 2012; 14:E34–E37.

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Gastrointestinal infections after transplantation Danziger-Isakov 3. Len O, Rodriguez-Pardo D, Gavalda J, et al. Outcome of Clostridium difficileassociated disease in solid organ transplant recipients: a prospective and multicentre cohort study. Transpl Int 2012; 25:1275–1281. Large-scale Spanish cohort evaluating the epidemiology, risk factor and outcomes for over 4500 organ transplant recipients. 4. Boutros M, Al-Shaibi M, Chan G, et al. Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. Transplantation 2012; 93:1051–1057. 5. Pant C, Anderson MP, O’Connor JA, et al. Association of Clostridium difficile && infection with outcomes of hospitalized solid organ transplant recipients: results from the 2009 Nationwide Inpatient Sample database. Transpl Infect Dis 2012; 14:540–547. Evaluation of hospitalized solid organ transplant recipients using a national database. Although only data from hospitalized patients, data provides insight into impact and outcome of CDI in this context. 6. Lee JT, Hertz MI, Dunitz JM, et al. The rise of Clostridium difficile infection in & lung transplant recipients in the modern era. Clin Transpl 2013; 27:303–310. Single-center review showing significant CDI rates after lung transplantation. 7. Neofytos D, Kobayashi K, Alonso CD, et al. Epidemiology, risk factors, and & outcomes of Clostridium difficile infection in kidney transplant recipients. Transpl Infect Dis 2013; 15:134–141. Kidney transplant recipients at a single institution developed increasing rates of CDI over the past several years. 8. Ali M, Ananthakrishnan AN, Ahmad S, et al. Clostridium difficile infection in hospitalized liver transplant patients: a nationwide analysis. Liver Transpl 2012; 18:972–978. 9. Alonso CD, Treadway SB, Hanna DB, et al. Epidemiology and outcomes of && Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2012; 54:1053–1063. Single-center retrospective review of CDI after HSCT. The association between GVHD and CDI warrants further discussion and investigation. 10. Willems L, Porcher R, Lafaurie M, et al. Clostridium difficile infection after & allogeneic hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Biol Blood Marrow Transpl 2012; 18:1295–1301. A French cohort after HSCT with CDI that introduced total body irradiation and stem cell source from cord blood as potential risk factors. 11. Collini PJ, Bauer M, Kuijper E, Dockrell DH. Clostridium difficile infection in HIV-seropositive individuals and transplant recipients. J Infect 2012; 64:131–147. 12. Tan SH, Lawler J, Foster K, et al. Nosocomial transmission of Salmonella typhimurium in renal transplant recipients. J Hosp Infect 2010; 75:241– 242. 13. Dadwal SS, Tegtmeier B, Nakamura R, et al. Nontyphoidal Salmonella infection among recipients of hematopoietic SCT. Bone Marrow Transpl 2011; 46:880–883. 14. Yamazaki R, Mori T, Nakazato T, et al. Nontuberculous mycobacterial infection localized in small intestine developing after allogeneic bone marrow transplantation. Intern Med 2010; 49:1191–1193. 15. Jarrett O, Grim SA, Benedetti E, Clark NM. Gastrointestinal tuberculosis in renal transplant recipients: case report and review of the literature. Transpl Infect Dis 2011; 13:52–57. 16. Ernst J, Sauerbrei A, Krumbholz A, et al. Multiple viral infections after haploidentical hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia. Transpl Infect Dis 2012; 14:E82–E88. 17. Westhoff TH, Vergoulidou M, Loddenkemper C, et al. Chronic norovirus infection in renal transplant recipients. Nephrol Dial Transpl 2009; 24:1051– 1053. 18. Roddie C, Paul JP, Benjamin R, et al. Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity. Clin Infect Dis 2009; 49:1061–1068. 19. Robles JD, Cheuk DK, Ha SY, et al. Norovirus infection in pediatric hema& topoietic stem cell transplantation recipients: incidence, risk factors, and outcome. Biol Blood Marrow Transpl 2012; 18:1883–1889. Single-center retrospective evaluation of norovirus infections on a pediatric HSCT unit in Hong Kong over a 4-year period. 20. Saif MA, Bonney DK, Bigger B, et al. Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support. Pediatr Transpl 2011; 15:505– 509. 21. Schorn R, Hohne M, Meerbach A, et al. Chronic norovirus infection after kidney transplantation: molecular evidence for immune-driven viral evolution. Clin Infect Dis 2010; 51:307–314. 22. Kundu S, Lockwood J, Depledge DP, et al. Next-generation whole genome & sequencing identifies the direction of norovirus transmission in linked patients. Clin Infect Dis 2013; 57:407–414. The authors explore a novel methodology to identify nosocomial norovirus transmission and discuss its potential use in infection control and prevention. 23. Doshi M, Woodwell S, Kelleher K, et al. An outbreak of norovirus infection in a bone marrow transplant unit. Am J Infect Control 2013; 41:820–823. 24. Schwartz S, Vergoulidou M, Schreier E, et al. Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation. Blood 2011; 117:5850–5856. 25. Siddiq DM, Koo HL, Adachi JA, Viola GM. Norovirus gastroenteritis successfully treated with nitazoxanide. J Infect 2011; 63:394–397. &&

26. Florescu DF, Hermsen ED, Kwon JY, et al. Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients? Pediatr Transpl 2011; 15:718–721. 27. Engelen MA, Gunia S, Stypmann J. Elimination of norovirus in a chronic carrier under immunosuppression after heart transplantation – effect of everolimus. Transpl Int 2011; 24:e102–e103. 28. Boillat Blanco N, Kuonen R, Bellini C, et al. Chronic norovirus gastroenteritis in a double hematopoietic stem cell and lung transplant recipient. Transpl Infect Dis 2011; 13:213–215. 29. Sugata K, Taniguchi K, Yui A, et al. Analysis of rotavirus antigenemia in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2012; 14:49–56. 30. Adeyi OA, Costa G, Abu-Elmagd KM, Wu T. Rotavirus infection in adult small intestine allografts: a clinicopathological study of a cohort of 23 patients. Am J Transpl 2010; 10:2683–2689. 31. Watcharananan SP, Avery R, Ingsathit A, et al. Adenovirus disease after kidney transplantation: course of infection and outcome in relation to blood viral load and immune recovery. Am J Transpl 2011; 11:1308–1314. 32. Watson T, MacDonald D, Song X, et al. Risk factors for molecular detection of adenovirus in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transpl 2012; 18:1227–1234. 33. Lee YJ, Chung D, Xiao K, et al. Adenovirus viremia and disease: comparison of T cell-depleted and conventional hematopoietic stem cell transplantation recipients from a single institution. Biol Blood Marrow Transpl 2013; 19:387–392. 34. Gerdemann U, Katari UL, Papadopoulou A, et al. Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV and CMV infections after allogeneic hematopoietic stem cell transplant. Mol Ther 2013. [Epub ahead of print] 35. Sauter C, Abboud M, Jia X, et al. Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin. Biol Blood Marrow Transpl 2011; 17:1460–1471. 36. Florescu DF, Langnas AN, Grant W, et al. Incidence, risk factors, and outcomes associated with cytomegalovirus disease in small bowel transplant recipients. Pediatr Transpl 2012; 16:294–301. 37. Papadimitriou G, Koukoulaki M, Vardas K, et al. Small bowel obstruction caused by inflammatory cytomegalovirus tumor in a renal transplant recipient: report of a rare case and review of the literature. Transpl Infect Dis 2012; 14:E111–E115. 38. Navaneethan U, Venkatesh PG, Wang J. Cytomegalovirus ileitis in a patient after liver transplantation-differentiating from de novo IBD. J Crohns Colitis 2011; 5:354–359. 39. Talmon GA. Histologic features of cytomegalovirus enteritis in small bowel allografts. Transpl Proc 2010; 42:2671–2675. 40. Grover IS, Davila R, Subramony C, Daram SR. Strongyloides infection in a cardiac transplant recipient: making a case for pretransplantation screening and treatment. Gastroenterol Hepatol 2011; 7:763–766. 41. Azami M, Sharifi M, Hejazi SH, Tazhibi M. Intestinal parasitic infections in renal transplant recipients. Braz J Infect Dis 2010; 14:15–18. 42. Genta RM. Global prevalence of strongyloidiasis: critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 1989; 11:755–767. 43. Batista MV, Pierrotti LC, Abdala E, et al. Endemic and opportunistic infections in Brazilian solid organ transplant recipients. Trop Med Int Health 2011; 16:1134–1142. 44. Issa H, Aljama MA, Al-Salem AH. Strongyloides stercoralis hyperinfection in a postrenal transplant patient. Clin Exp Gastroenterol 2011; 4:269–271. 45. Hsu CN, Tseng SH, Chang SW, Chen Y. Strongyloides stercoralis infection in an intestinal transplant recipient. Transpl Infect Dis 2013; 15:E139–E143. 46. Hamilton KW, Abt PL, Rosenbach MA, et al. Donor-derived Strongyloides stercoralis infections in renal transplant recipients. Transplantation 2011; 91:1019–1024. 47. Weiser JA, Scully BE, Bulman WA, et al. Periumbilical parasitic thumbprint purpura: strongyloides hyperinfection syndrome acquired from a cadaveric renal transplant. Transpl Infect Dis 2011; 13:58–62. 48. Chokkalingam Mani B, Mathur M, Clauss H, et al. Strongyloides stercoralis and organ transplantation. Case Rep Transpl 2013; 2013:549038. 49. Centers for Disease Control and Prevention (CDC). Transmission of Stron&& gyloides stercoralis through transplantation of solid organs – Pennsylvania. MMWR Morb Mortal Wkly Rep 2013; 62:264–266. Coordinated report of a donor who transmitted Strongyloides stercoralis to several organ recipients. The importance of donor assessment for unusual infections is reported. 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Gastrointestinal infections 54. Bonatti H, Barroso LF 2nd, Sawyer RG, et al. Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations. Transpl Infect Dis 2012; 14:635–648. Retrospective case series of an uncommon but potentially serious infection after SOT. The associations with elevated tacrolimus levels and acute kidney injury emphasize the importance of evaluating diarrhea in this population. 55. Frei P, Weber A, Geier A, et al. Lessons from a transplant patient with diarrhea, cryptosporidial infection, and possible mycophenolate mofetil-associated colitis. Transpl Infect Dis 2011; 13:416–418.

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56. Legrand F, Grenouillet F, Larosa F, et al. Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single centre study. Bone Marrow Transpl 2011; 46:858–862. 57. Florescu DF, Islam KM, Grant W, et al. Incidence and outcome of fungal infections in pediatric small bowel transplant recipients. Transpl Infect Dis 2010; 12:497–504. 58. Bartoletti M, Cervera C, Hoyo I, et al. Incidence and outcome of early Candida peritonitis after liver and pancreas transplantation. Mycoses 2013; 56:162– 167. 59. Direkze S, Mansour M, Rodriguez-Justo M, et al. Candida kefyr fungal enteritis following autologous BMT. Bone Marrow Transpl 2012; 47:465–466.

Volume 30  Number 1  January 2014

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Gastrointestinal infections after transplantation.

Recipients of both solid organ transplant and hematopoietic stem cell transplantation are at increased risk for infectious morbidity and mortality aft...
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