REVIEW URRENT C OPINION
Fungal infections in intestinal and multivisceral transplant recipients Diana F. Florescu a,b and Uriel Sandkovsky a
Purpose of review Patients who undergo intestinal and multivisceral transplantation are at increased risk for infectious complications. Fungal infections are major causes of morbidity and mortality in these patients. The current review highlights key diagnostic and management issues in this population. Recent findings Invasive infections caused by Candida spp. remain the most common invasive fungal infections in intestinal and multivisceral transplant recipients. Aspergillus is an emerging pathogen but data are limited to case reports or case series. Other fungi including the mucorales, Cryptococcus and endemic mycoses are emerging pathogens but data regarding incidence and timing of disease in intestinal and multivisceral transplant recipients are lacking. Summary Invasive candidiasis is the most common fungal infection in patients with intestinal and multivisceral transplants. Experience for diagnosis and management comes from case series and single centers. Diagnosis and management of infections caused by other pathogens such as Aspergillus, Cryptococcus, Mucor, and endemic mycoses is usually extrapolated from other solid organ transplant recipients. Keywords aspergillosis, candidiasis, fungal infections, intestinal transplantation, multivisceral transplantation
INTRODUCTION The incidence, timing, and type of fungal infection after transplantation depends on the type of allograft, and is related to the surgical procedure, the degree of immunosuppression, and prophylactic strategies implemented [1]. Results from Transplant-Associated Infection Surveillance Network (TRANSNET) showed that invasive candidiasis is the most common invasive fungal infection (IFI) among organ transplant recipients (53%), followed by invasive aspergillosis (19%), non-Aspergillus molds (8%), cryptococcosis (8%), endemic fungi (5%), and zygomycosis (2%) [2 ]. Candida infections are the most common IFIs in all solid organ transplant (SOT) allografts except lung transplant recipients wherein invasive aspergillosis is the most common [1,3 ,4 ]. The epidemiology of IFIs in SOT has changed over the last 2 decades, with nonalbicans Candida spp., Fusarium spp., and Zygomycetes being increasingly recognized [2 ,5 ,6,7]. AbuElmagd et al. [8] showed that after rejection, infection was the second common cause of graft failure. In this study, 31% of the patients with fatal infection had a fungal infection, (64.7% aspergillosis, 17.6% &&
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Scedosporium infection, and 17.6% Candida infection); even more, the rate of fatal infections decreased with changes in immunosuppression over time and availability of new antifungal agents (liposomal amphotericin B, caspofungin, and voriconazole) [8]. In this review, we focus on the available data regarding fungal infections in intestinal transplantation.
CANDIDA INFECTIONS IFIs have been reported in 25.5–59% of the intestinal transplantation recipients, with Candida spp. accounting for the majority of the infections (80– 100%) [9–11]. Invasive candidiasis is in most of the a Transplant Infectious Diseases Program, Division of Infectious Diseases and bTransplant Surgery Division, University of Nebraska Medical Center, Omaha, Nebraska, USA
Correspondence to Diana F. Florescu, MD, Transplant Infectious Diseases Program, University of Nebraska Medical Center, Omaha, NE 68198–5400, USA. Tel: +1 402 559 8650; fax: +1 402 559 5581; e-mail: [email protected] Curr Opin Organ Transplant 2015, 20:295–302 DOI:10.1097/MOT.0000000000000188
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Small bowel transplantation
KEY POINTS Fungal infections cause significant morbidity and mortality in intestinal and multivisceral transplant recipients. Invasive candidiasis remains the most common infection and is usually related to disruptions in the intestinal barrier, the surgical procedure, use of central venous catheters, or prolonged use of broad spectrum antibiotics.
Table 1. Comparison of Candida spp. isolated in an intestinal transplant study and two global surveillance studies: TRANSNET and PATH Alliance Candida spp.
Florescu et al. (2010) (%)
TRANSNET (2010) (%)
PATH Alliance (2012) (%)
C. albicans
37.3
46.2
42.1
C. glabrata
25.4
24.8
26.7
C. parapsilosis
13.6
8.6
15.9
C. tropicalis
5.1
4.4
8.7
Because no randomized studies have been performed, management of invasive candidiasis is supported by data from single centers, case series, and clinical experience.
C. krusei
6.8
2.0
3.4
C. lambica
1.7
–
–
C. lusitaniae
–
0.8
–
Aspergillus, other filamentous molds, Cryptococcus, and endemic mycoses are emerging fungal pathogens in solid organ transplant recipients but data in intestinal and multivisceral transplant recipients are limited or lacking, thus management of these infections is usually extrapolated from other transplant recipients.
C. dubliniensis
–
–
–
C. guilliermondii
–
–
–
10.1
8.8
–
–
3.9
–
&&
cases a nosocomial infection [4 ,12]. The majority of intra-abdominal fungal infections (40%) are diagnosed in the first month after transplantation, most likely due to the associated disease leading to transplantation, potentially contaminated nature of the surgical procedure, and loss of the intestine mucosal integrity during recovery, preservation, and transplantation [9]. Candidemia tends to be a late-onset process (80% of the cases 6 months after transplantation), probably in the setting of prolonged central venous access, multiple courses of antibiotics, need for hemodialysis, or total parenteral nutrition (TPN) [9]. In a study published by our group, we found that the rate of Candida infection is lower in multivisceral transplant recipients than in isolated intestinal transplantation recipients, possibly related to the immunomodulatory effect of the transplanted liver [9]. From the same study [9], we can see the comparison of different Candida spp. with the data from TRANSNET and Prospective Antifungal Therapy (PATH) Alliance global surveillance programmes (Table 1) [2 ,13 ]. The distribution of Candida spp. in intestinal transplantation recipients was similar to that reported from the global surveillance, C. albicans, and C. glabrata being the dominant species. Overall, nonalbicans Candida spp. were more frequently isolated than C. albicans, possible reflecting posttransplant prophylactic azole use. During the 3-year surveillance period, TRANSNET showed an increase in the incidence of IFI, mainly by the increase in invasive candidiasis [2 ]. The source of infection is mainly related to central line infections (skin colonization), &&
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Multiple spp. Unspecified spp. Adapted from [2
&&
,9,13
&&
].
intraabdominal infection, or translocation from the intestine microbiota. During the first year posttransplantation, patients are at higher risk for Candida infections due to repeated surgical procedures including technical difficulties that would extend the operating time, high intraoperative blood product requirements, and complicated intraoperative or postoperative courses, anastomotic disruption, retransplantation, higher degree of immunosuppression, selective pressure after multiple or prolonged courses of antibiotics, hyperglycemia, renal dysfunction sometimes requiring dialysis, use of central venous catheters, need for mechanical ventilation, administration of total parenteral nutrition, and cytomegalovirus disease [4 ,10,14–16] The most common clinical presentation is oral candidiasis manifested by odynophagia, sometimes concomitant with esophagitis presenting with dysphagia, odynophagia, reflux, or chest pain. Peritonitis and intraabdominal abscesses are usually diagnosed after surgical procedures that disrupt the integrity of the mucosal barrier. Urinary tract infections are mainly associated with the presence of catheters and after antibiotic treatment. Candidemia should be suspected in patients with central lines, recent procedures, TPN, and recent antibiotic treatments. Definite diagnosis of invasive candidiasis requires isolation of the organism from a sterile site. The sensitivity of blood cultures is relatively low, approximately 70% [17], and it is reduced by administration of antifungal medication [18]. In patients with negative cultures, but suspected Candida infections, 1–3-b-glucan (BDG) assay is a useful &&
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Fungal infections in intestinal transplantation Florescu and Sandkovsky
adjunctive diagnostic tool. Currently, there are at three main BDG detection assays available, with different performances, reference standards, and cut offs: Fungitell (Associates of Cape Code, Inc., East Falmouth, MA, USA), Wako (Wako Pure Chemical Industries, Ltd., Tokyo, Japan), and Fungitec-G test (Seikagaku, Kogyo, Tokyo, Japan). The cut-off values for the best diagnostic accuracy varies for each test: 60 pg/mL for Fungitell assay, 20 pg/mL for Fungitec G-test assay, and 11 pg/mL for Wako assay [19]. A recent meta-analysis showed that the pooled sensitivity and specificity of these three tests were 78 and 81% [19]. Identification and susceptibility of the Candida spp. can take from 48 h to 5–6 days, hampering the clinical management of the patients. Several DNA-based methods have been developed in an attempt to early detect positive yeast culture, in particular in blood cultures [20]. Although these methods are more expensive, the results are accurate, reproducible, and available in few hours after a positive blood culture, allowing timely intervention and antifungal therapy. In a study including SOT recipients, the sensitivity and specificity of BDG assay (with a cutoff at 80 pmol/ ml) was 56 and 73%, whereas for PCR sensitivity and specificity were higher at 80 and 70% [21]. In this study, PCR and BDG were similar in diagnosing candidemia (59 vs. 68%; P ¼ 0.77), but PCR was more sensitive for deep-seated candidiasis (89 vs. 53%; P ¼ 0.004) [21]. PCR and BDG were more sensitive than blood cultures among patients with deep-seated candidiasis (88 and 62 vs. 17%; P ¼ 0.0005 and P ¼ 0.003) [21]. Both the Infectious Diseases Society of America (IDSA) and the American Society of Transplantation (AST) have outlined management guidelines for different syndromes caused by Candida spp. and these are summarized in Table 2 [4 ,22]. Candida infections are considered to have a negative impact on morbidity and mortality [23]. However, our study that included 98 intestinal transplantation recipients showed that with the exception of C. glabrata, fungal infections did not have any significant impact on long-term survival [9]. Survival was not impacted by the choice of empiric or subsequent antifungal therapy, length of therapy, removal of central venous catheter, and recurrence of infection [9]. Possible prevention strategies are: antifungal prophylaxis in the immediate posttransplant period, special care of the central line, and use of alcohol lock therapy when necessary. Without supportive evidence from clinical trials, posttransplant antifungal prophylaxis is frequently administered for a minimum of 4 weeks or until anastomosis is healed [4 ]. A more tailored approach would be &&
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warranted, taking in consideration individual-risk factors (for Candida and other molds) that would dictate the selection of the antifungal agent and the duration of prophylaxis. High-risk recipients are defined transplant recipients who had two or more risk factors (Collins criteria): preoperative colonization with Candida, choledochojejunostomy anastomosis, retransplantation, early reintervention after transplantation for bleeding or graft dysfunction, preoperative renal insufficiency, and administration of at least 40 units of blood products [24]. IDSA guidelines recommend targeted prophylaxis with fluconazole (3–6 mg/kg per day) or liposomal amphotericin B (1–2 mg/kg per day) for 7–14 days after transplantation in high-risk recipients [22]. The last AST guidelines recommends the administration of fluconazole (400 mg/day) or liposomal amphotericin B (3–5 mg/kg per day) for 4 weeks or until healing of the anastomosis, in the absence of rejection in the presence of risk factors (enhanced immunosuppression, anastomotic disruption, abdominal reoperation, and multivisceral transplantation); liposomal amphotericin B is recommended when there is high suspicion for nonalbicans Candida spp. [4 ]. Bowel decontamination to reduce invasive candidiasis is not clearly defined [25–27], mainly because early infections are related to the surgical procedures, whereas late infections to the presence of central venous catheters [10] &&
ASPERGILLUS INFECTIONS Aspergillus represents only a minority of the fungal infections in intestinal transplantation recipients [28,29 ,30 ]. Cases of Aspergillus have been reported at different transplant centers [9,11,31–34]. PATH Alliance registry reported 280 SOT with invasive aspergillosis; among those 13 (4.6%) cases occurred in intestinal transplantation recipients with Aspergillus fumigatus being the most common isolate [35 ]. The most important risk factors for invasive aspergillosis are the net state of immunosuppression related to induction therapy with T-celldepleting antibodies, CMV infection, neutropenia [24,29 ,30 ,36], renal failure, prolonged ICU stay, and retransplantation [24,29 ]. Calcineurin inhibitors have activity against Aspergillus and may impair fungal growth or proliferation [37]. The most common site of infection is the lung, with angioinvasion and the possibility of dissemination to virtually any organ, especially invasion of the central nervous system (CNS) [29 ,35 ,38,39]. Diagnostic criteria have been developed and should be applied whenever possible [40,41]. Imaging studies may show infiltrates, nodules, or cavitation; computed tomography scans have higher &
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Small bowel transplantation Table 2. Recommendations for the management of different syndromes caused by Candida spp. Clinical syndrome
Antifungal therapy
Additional recommendations
Candidemia in nonneutropenic recipients
Fluconazole 12 mg/kg loading followed by 6 mg/kg per day with adjustment for renal function
Removal of intravascular catheters is recommended
Echinocandin for patients with moderate-to-severe illness or recent azole exposure
Treatment: 14 days after the first negative blood culture and resolution of signs and symptoms
Candidemia in neutropenic recipients
Alternative: Liposomal amphotericin B (3–5 mg/day) or amphotericin B deoxycholate (0.5–1 mg/kg per day) An echinocandin Liposomal amphotericin B (3–5vmg/kg per day) Alternative treatments in patients without recent azole exposure and who are not critically ill: fluconazole (12 mg/kg loading dose followed by 6 mg/kg per day with adjustment for renal function) or voriconazole (6mg/kg twice daily for two doses then 3 mg/kg twice daily).
Suppurative thrombophlebitis
Endocarditis
Liposomal amphotericin B (3–5 mg/kg per daily)
Surgical incision and drainage or resection of the vein is recommended
Fluconazole (6–12 mg/kg) adjusted for renal function an echinocandin
Treatment for at least 2 weeks after candidemia has cleared
Liposomal amphotericin B (3–5 mg/kg per day) flucytosine (25 mg/kg four times daily adjusted for renal function)
Valve replacement is strongly recommended. For those who are unable to undergo surgical removal of the valve or prosthetic valves, chronic suppression with fluconazole 400–800 mg (6–12 mg/kg per day) is recommended.
Amphotericin deoxycholate (0.6–1 mg/kg per day) flucytosine (25 mg/kg four times daily) an echinocandin Step-down therapy to fluconazole (6–12 mg/kg per day adjusted for renal function) for susceptible organism in stable patient with negative blood culture results Asymptomatic urinary tract infection
Therapy not indicated
Symptomatic cystitis
For fluconazole-susceptible organisms, fluconazole (3 mg/kg per day) should be administered for 2 weeks
Patients undergoing urologic procedures should receive treatment several days before and after the procedure with fluconazole (3–6 mg/kg per day adjusted for renal function) or amphotericin B deoxycholate (0.3–0.6 mg/kg per day).
For fluconazole-resistant organisms: amphotericin B deocycholate (0.3–0.6 mg/kg per day) flucytosine (25 mg/kg four times daily adjusted for renal function) Pyelonephritis
Should be treated as candidemia, if there is suspected disseminated candidiasis For fluconazole-susceptible organisms, fluconazole (3–6 mg/kg/day)
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Fungal infections in intestinal transplantation Florescu and Sandkovsky For fluconazole-resistant organisms: amphotericin B deoxycholate (0.5–0.7mg/kg/day) flucytosine (25mg/kg 4 times daily adjusted for renal function) Local irrigation with amphotericin B deoxycholate is adjunctive therapy to systemic therapy
Urinary fungus ball
Oropharyngeal candidiasis
Surgical removal is recommended
Fluconazole (3–6mg/kg/day adjusted for renal function) Amphotericin B deoxycholate (0.5–0.7mg/kg/day) flucytosine (25mg/kg 4 times daily adjusted for renal function) Clotrimazole troches (10 mg 5 times/day or nystatin suspension are recommended for mild disease (7–14 days) fluconazole (100–200 mg/daily) is recommended for moderate-to-severe disease (7–14 days)
Esophageal candidiasis
Fluconazole (3–6 mg/kg/day adjusted for renal function) is the preferred treatment
Respiratory candidiasis should not be treated; it is mainly colonization of the airways.
An echinocandin is the alternative treatment amphotericin B deoxycholate (0.3–0.7 mg/kg/day) for patients with refractory disease Echinocandins Systemic disease Micafungin 100 mg/day or Caspofungin 70 mg loading followed by 50 mg/day maintenance (up to 70 mg/day in neutropenic patients) or Anidulafungin 200 mg loading followed by 100 mg/day. Esophageal Candidiasis Micafungin 150 mg/day, Caspofungin 50 mg/day or && Anidulafungin 100 mg/day. Adapted from [4 ,22].
sensitivity than chest radiograph but the classic halo sign is not specific for invasive aspergillosis [30 ,41]. Serum galactomannan has acceptable specificity (84%), but low sensitivity (22%). Using a cut-off index value more than 1 in BAL specimens improved the sensitivity of galactomannan to 67% and specificity to 98% [42]. The utility of BDG assay in SOT has not been fully defined [30 ]. Isolation of Aspergillus from a BAL specimen does not equal invasive disease, but it does indicate risk for development of invasive aspergillosis [30 ,41]. Isolation from a sterile site such as blood, CNS, tissue, or histopathologic evidence of hyphal invasion with or without angioinvasion establish definitive diagnosis [40,41]. Voriconazole is the drug of choice to treat any form of Aspergillus disease, with amphotericin B, Posaconazole, and the echinocandins regarded as alternative agents; surgical management should be used as adjunctive therapy whenever necessary [30 ,41]. There is no evidence to recommend antifungal prophylaxis for Aspergillus in intestinal transplantation recipients. The 12-week postdiagnosis mortality was reported to be 22.1% in the PATH alliance [35 ]. Invasive aspergillosis was associated with shorter &
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time-to-death when compared with invasive candidiasis in our study [9].
CRYPTOCOCCUS Cryptococcus, the third most common IFI in SOT recipients, has an incidence of 0.2–5% [43,44] with almost no data published in intestinal transplantation. The risk appears to increase 6 months posttransplantation [37], with a median onset at 16–21 months [43,45,46]. Risk factors include use of T-celldepleting antibodies and corticosteroids [43,47]. Between 50 and 75% of patients have CNS disease [43], one-third present with fungemia [45,48], and one-third may only have pulmonary disease [45]. Serum cryptococcal antigen is helpful in most forms of cryptococcal disease, but it may be negative with isolated pulmonary involvement [43,49]. A lumbar puncture, urine, and blood cultures are needed to diagnose patients with disseminated or CNS disease [43]. For management, readers are referred to the treatment guidelines outlined by IDSA and AST [43,50]. The overall mortality is about 14% and is as high as 50% for SOT recipients with cryptococcal meningitis [43,45,51].
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Small bowel transplantation
MUCORMYCOSIS
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Mucormycosis is a rare complication among SOT recipients, usually associated with high levels of immunosuppression, especially with the use of T-cell-depleting antibodies [52,53], renal failure, diabetes mellitus, and prior use of voriconazole, or an echinocandin [54,55]. Timing for infection is usually 3 months posttransplantation. There are no reports of Mucormycosis among intestinal transplantation recipients in the TRANSNET or the PATH Alliance [5 ,56]. &
ENDEMIC FUNGAL INFECTIONS
experience [68 ]. Cryptococcal disease can be transmitted from any donated organ and should be suspected in any SOT recipient who presents with cryptococcal disease within 30 days [43,68 ]. Transmission of histoplasmosis has been documented in SOT, active disease may be suspected whether granulomas or organ lesions are found at the time of harvesting, but routine donor testing is not recommended [68 ,69]. Coccidioidomycosis can be readily transmitted by transplantation and donors from endemic areas should be screened with serology, complement fixation, and immunodiffusion; recipients from donors who have resided or traveled to endemic areas should undergo pretransplant screening [68 ]. Donor-derived Aspergillus, mucor, and other filamentous fungi are possible, although there are no reports of any donor-derived fungal infections among intestinal transplantation recipients. &
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The TRANSNET identified 64 cases of endemic mycoses: 48 histoplasmosis, seven coccidioidomycosis, and nine blastomycosis in SOT recipients, although none of these occurred in intestinal transplantation recipients [57 ]. Histoplasmosis is the most common endemic mycosis among SOT recipients with an incidence of one case per 1000 personyears [58–61]. Clinical manifestations range from pulmonary involvement to disseminated disease [58]. In a multicenter analysis of 152 cases of histoplasmosis among SOT recipients, 81% presented with disseminated disease and 34% were diagnosed in the first year posttransplantation, only one was an intestinal transplantation recipient [62 ]. The most common diagnostic method is detection of the Histoplasma antigen in urine, blood, BAL, or other body fluid samples. Histopathology is useful for tissue diagnosis [63]. Preferred treatment of severe, disseminated, or pulmonary disease is with liposomal amphotericin B, whereas less severe cases can be treated with itraconazole or voriconazole [64 ,65]. Mortality was reported to be 15% in TRANSNET [57 ]. The highest risk for coccidioidomycosis is during the first year post-SOT, and 50% of cases occur during the first 3 months but no data exists in intestinal transplantation [60]. The most common clinical manifestations are severe pneumonia and disseminated disease, including meningoencephalitis [64 ]. Culture and tissue histopathology are the main diagnostic modalities [64 ]. Fluconazole or itraconazole can be used to treat mild-to-moderate cases but amphotericin B should be used in cases of disseminated disease [62 ,63,65,66,67 ]. &&
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CONCLUSION It is difficult to understand the burden of fungal infections in intestinal transplantation recipients as most of the data comes from single-center experiences, case reports, or case series. Not surprisingly, invasive candidiasis is the most common IFI. However, more robust information regarding clinical presentation and treatment of invasive aspergillosis, cryptococcosis and histoplasmosis is not available and usually extrapolated from other allografts. Acknowledgements None. Financial support and sponsorship None.
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Conflicts of interest D.F.: grant from Chimerix Inc.; grant from CLS Behring; consulting for Chimerix Inc. and CLS Behring. U.S.: research grants from CLS Behring, ViiV healthcare, GSK, Pfizer. Consultation work for Rib-X pharmaceuticals. No funding was received for this work.
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DONOR-DERIVED INFECTIONS Donor-derived fungal infections are rare in SOT recipients, but may cause significant complications. Evidence of recommendations is limited as we rely on case reports, descriptive studies, and clinical 300
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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. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am 2003; 17:113–134; viii. 2. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among && organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50:1101–1111. Prospective 5-year surveillance of invasive fungal infections in transplant recipients performed at 23 selected centers in the United States. It describes current approaches to diagnosis, management, and outcomes of these infections.
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Fungal infections in intestinal transplantation Florescu and Sandkovsky 3. Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis 2010; 12:220–229. PATH alliance. Multicenter observational registry that describes and analyzes trends on epidemiology, diagnosis treatment, and outcomes of invasive fungal infections collected at 17 centers in the United States and Canada. 4. Silveira FP, Kusne S, Practice ASTIDCo. Candida infections in solid organ && transplantation. Am J Transplant 2013; 13 (Suppl 4):220–227. Current practice guidelines for the management of candidiasis in solid organ transplant recipients from the American Society of transplantation. 5. Kontoyiannis DP, Azie N, Franks B, et al. Prospective antifungal therapy & (PATH) alliance((R)): focus on mucormycosis. Mycoses 2014; 57:240–246. PATH alliance report on the epidemiology, treatment and outcomes of mucormycosis on patients with solid organ transplant, bone marrow transplants and hematological malignancies. 6. Kontoyiannis DP, Wessel VC, Bodey GP, et al. Zygomycosis in the 1990 s in a tertiary-care cancer center. Clin Infect Dis 2000; 30:851–856. 7. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:909–917. 8. Abu-Elmagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann Surg 2009; 250:567–581. 9. 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. 10. Florescu DF, Qiu F, Mercer DF, et al. Risk factors for systemic Candida infections in pediatric small bowel transplant recipients. 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28. Singh N. Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy. Clin Infect Dis 2000; 31:545–553. 29. Timpone JG Jr, Girlanda R, Rudolph L, et al. Infections in intestinal and & multivisceral transplant recipients. Infect Dis Clin North Am 2013; 27:359– 377. A review on infections among intestinal and multivisceral transplant recipients focusing on the different periods before, early after, and later after transplantation. 30. Singh N, Husain S, Practice ASTIDCo. Aspergillosis in solid organ trans& plantation. Am J Transplant 2013; 13 (Suppl 4):228–241. Clinical management guidelines for Aspergillosis in solid organ transplant recipients from the American Society of transplantation. 31. Nishida S, Levi D, Kato T, et al. Ninety-five cases of intestinal transplantation at the University of Miami. J Gastrointest Surg 2002; 6:233–239. 32. Reyes J, Abu-Elmagd K, Tzakis A, et al. Infectious complications after human small bowel transplantation. Transplant Proc 1992; 24:1249–1250. 33. Guaraldi G, Cocchi S, Codeluppi M, et al. Outcome, incidence, and timing of infectious complications in small bowel and multivisceral organ transplantation patients. Transplantation 2005; 80:1742–1748. 34. Kusne S, Manez R, Bonet H, et al. Infectious complications after small bowel transplantation in adults. Transplant Proc 1994; 26:1682–1683. 35. Steinbach WJ, Marr KA, Anaissie EJ, et al. Clinical epidemiology of 960 & patients with invasive aspergillosis from the PATH Alliance registry. J Infect 2012; 65:453–464. The article describes current trends in epidemiology, diagnosis, and outcomes of invasive aspergillosis from the PATH alliance registry. It adds to the current literature and recommendations for invasive aspergillosis. 36. Kohler S, Gerlach U, Guckelberger O, et al. Successful treatment of invasive sphenoidal, pulmonary and intracerebral aspergillosis after multivisceral transplantation. Transpl Int 2009; 22:589–591. 37. Gabardi S, Kubiak DW, Chandraker AK, et al. Invasive fungal infections and antifungal therapies in solid organ transplant recipients. Transpl Int 2007; 20:993–1015. 38. Gavalda J, Len O, San Juan R, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin Infect Dis 2005; 41:52–59. 39. Vianna R, Misra V, Fridell JA, et al. Survival after disseminated invasive aspergillosis in a multivisceral transplant recipient. Transplant Proc 2007; 39:305–307. 40. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–1821. 41. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of America. Clin Infect Dis 2008; 46:327–360. 42. Husain S, Paterson DL, Studer SM, et al. Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients. Transplantation 2007; 83:1330–1336. 43. Baddley JW, Forrest GN, Practice ASTIDCo. Cryptococcosis in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4):242–249. 44. Sun HY, Wagener MM, Singh N. Cryptococcosis in solid-organ, hematopoietic stem cell, and tissue transplant recipients: evidence-based evolving trends. Clin Infect Dis 2009; 48:1566–1576. 45. Singh N, Alexander BD, Lortholary O, et al. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis 2007; 195:756–764. 46. Vilchez R, Shapiro R, McCurry K, et al. Longitudinal study of cryptococcosis in adult solid-organ transplant recipients. Transpl Int 2003; 16:336–340. 47. Silveira FP, Husain S, Kwak EJ, et al. Cryptococcosis in liver and kidney transplant recipients receiving antithymocyte globulin or alemtuzumab. Transpl Infect Dis 2007; 9:22–27. 48. Wu G, Vilchez RA, Eidelman B, et al. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis 2002; 4:183–188. 49. Baddley JW, Perfect JR, Oster RA, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis 2008; 27:937–943. 50. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50:291–322. 51. Singh N, Perfect JR. Immune reconstitution syndrome associated with opportunistic mycoses. Lancet Infect Dis 2007; 7:395–401. 52. Almyroudis NG, Sutton DA, Linden P, et al. Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant 2006; 6:2365–2374. 53. Stelzmueller I, Lass-Floerl C, Geltner C, et al. Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients. Transpl Int 2008; 21:534–546. 54. Lanternier F, Sun HY, Ribaud P, et al. Mucormycosis in organ and stem cell transplant recipients. Clin Infect Dis 2012; 54:1629–1636. 55. Singh N, Aguado JM, Bonatti H, et al. Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis 2009; 200:1002–1011.
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Small bowel transplantation 56. Park BJ, Pappas PG, Wannemuehler KA, et al. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006. Emerg Infect Dis 2011; 17:1855–1864. 57. Kauffman CA, Freifeld AG, Andes DR, et al. Endemic fungal infections in solid && organ and hematopoietic cell transplant recipients enrolled in the TransplantAssociated Infection Surveillance Network (TRANSNET). Transpl Infect Dis 2014; 16:213–224. This is the most current literature on epidemiology, clinical presentation, diagnostic approaches, and management issues for endemic fungal infections among solid organ transplant recipients. 58. Freifeld AG, Iwen PC, Lesiak BL, et al. Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center. Transpl Infect Dis 2005; 7 (3–4):109–115. 59. Freifeld AG, Wheat LJ, Kaul DR. Histoplasmosis in solid organ transplant recipients: early diagnosis and treatment. Curr Opin Organ Transplant 2009; 14:601–605. 60. Martin-Davila P, Fortun J, Lopez-Velez R, et al. Transmission of tropical and geographically restricted infections during solid-organ transplantation. Clin Microbiol Rev 2008; 21:60–96. 61. Cuellar-Rodriguez J, Avery RK, Lard M, et al. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area. Clin Infect Dis 2009; 49:710–716. 62. Assi M, Martin S, Wheat LJ, et al. Histoplasmosis after solid organ transplant. & Clin Infect Dis 2013; 57:1542–1549. Multicenter study performed at 24 centers in the United States. The article adds valuable information on the epidemiology, diagnosis, management, and outcomes for histoplasmosis after solid organ transplantation.
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63. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007; 20:115–132. 64. Miller R, Assi M, Practice ASTIDCo. Endemic fungal infections in solid organ & transplantation. Am J Transplant 2013; 13 (Suppl 4):250–261. Current guidelines and recommendations for diagnosis and management of endemic fungal infections among solid organ transplant recipients from the American Society of transplantation. 65. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:807–825. 66. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005; 41:1217–1223. 67. Huprikar S, Shoham S, Practice ASTIDCo. Emerging fungal infections & in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4):262– 271. Current guidelines and recommendations for diagnosis and management of new and emerging fungal infections among solid organ transplant recipients from the American society of transplantation. 68. Singh N, Huprikar S, Burdette SD, et al. Donor-derived fungal infections in & organ transplant recipients: guidelines of the American Society of Transplantation, infectious diseases community of practice. Am J Transplant 2012; 12:2414–2428. Current recommendations for screening, diagnosis and management of donorderived infections in solid organ transplant recipients from the American Society of Transplantation. 69. Limaye AP, Connolly PA, Sagar M, et al. Transmission of Histoplasma capsulatum by organ transplantation. N Engl J Med 2000; 343:1163–1166.
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Fungal infections in intestinal and multivisceral transplant recipients Diana F. Florescu a,b and Uriel Sandkovsky a
Purpose of review Patients who undergo intestinal and multivisceral transplantation are at increased risk for infectious complications. Fungal infections are major causes of morbidity and mortality in these patients. The current review highlights key diagnostic and management issues in this population. Recent findings Invasive infections caused by Candida spp. remain the most common invasive fungal infections in intestinal and multivisceral transplant recipients. Aspergillus is an emerging pathogen but data are limited to case reports or case series. Other fungi including the mucorales, Cryptococcus and endemic mycoses are emerging pathogens but data regarding incidence and timing of disease in intestinal and multivisceral transplant recipients are lacking. Summary Invasive candidiasis is the most common fungal infection in patients with intestinal and multivisceral transplants. Experience for diagnosis and management comes from case series and single centers. Diagnosis and management of infections caused by other pathogens such as Aspergillus, Cryptococcus, Mucor, and endemic mycoses is usually extrapolated from other solid organ transplant recipients. Keywords aspergillosis, candidiasis, fungal infections, intestinal transplantation, multivisceral transplantation
INTRODUCTION The incidence, timing, and type of fungal infection after transplantation depends on the type of allograft, and is related to the surgical procedure, the degree of immunosuppression, and prophylactic strategies implemented [1]. Results from Transplant-Associated Infection Surveillance Network (TRANSNET) showed that invasive candidiasis is the most common invasive fungal infection (IFI) among organ transplant recipients (53%), followed by invasive aspergillosis (19%), non-Aspergillus molds (8%), cryptococcosis (8%), endemic fungi (5%), and zygomycosis (2%) [2 ]. Candida infections are the most common IFIs in all solid organ transplant (SOT) allografts except lung transplant recipients wherein invasive aspergillosis is the most common [1,3 ,4 ]. The epidemiology of IFIs in SOT has changed over the last 2 decades, with nonalbicans Candida spp., Fusarium spp., and Zygomycetes being increasingly recognized [2 ,5 ,6,7]. AbuElmagd et al. [8] showed that after rejection, infection was the second common cause of graft failure. In this study, 31% of the patients with fatal infection had a fungal infection, (64.7% aspergillosis, 17.6% &&
&&
&&
&&
&
Scedosporium infection, and 17.6% Candida infection); even more, the rate of fatal infections decreased with changes in immunosuppression over time and availability of new antifungal agents (liposomal amphotericin B, caspofungin, and voriconazole) [8]. In this review, we focus on the available data regarding fungal infections in intestinal transplantation.
CANDIDA INFECTIONS IFIs have been reported in 25.5–59% of the intestinal transplantation recipients, with Candida spp. accounting for the majority of the infections (80– 100%) [9–11]. Invasive candidiasis is in most of the a Transplant Infectious Diseases Program, Division of Infectious Diseases and bTransplant Surgery Division, University of Nebraska Medical Center, Omaha, Nebraska, USA
Correspondence to Diana F. Florescu, MD, Transplant Infectious Diseases Program, University of Nebraska Medical Center, Omaha, NE 68198–5400, USA. Tel: +1 402 559 8650; fax: +1 402 559 5581; e-mail: [email protected] Curr Opin Organ Transplant 2015, 20:295–302 DOI:10.1097/MOT.0000000000000188
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Small bowel transplantation
KEY POINTS Fungal infections cause significant morbidity and mortality in intestinal and multivisceral transplant recipients. Invasive candidiasis remains the most common infection and is usually related to disruptions in the intestinal barrier, the surgical procedure, use of central venous catheters, or prolonged use of broad spectrum antibiotics.
Table 1. Comparison of Candida spp. isolated in an intestinal transplant study and two global surveillance studies: TRANSNET and PATH Alliance Candida spp.
Florescu et al. (2010) (%)
TRANSNET (2010) (%)
PATH Alliance (2012) (%)
C. albicans
37.3
46.2
42.1
C. glabrata
25.4
24.8
26.7
C. parapsilosis
13.6
8.6
15.9
C. tropicalis
5.1
4.4
8.7
Because no randomized studies have been performed, management of invasive candidiasis is supported by data from single centers, case series, and clinical experience.
C. krusei
6.8
2.0
3.4
C. lambica
1.7
–
–
C. lusitaniae
–
0.8
–
Aspergillus, other filamentous molds, Cryptococcus, and endemic mycoses are emerging fungal pathogens in solid organ transplant recipients but data in intestinal and multivisceral transplant recipients are limited or lacking, thus management of these infections is usually extrapolated from other transplant recipients.
C. dubliniensis
–
–
–
C. guilliermondii
–
–
–
10.1
8.8
–
–
3.9
–
&&
cases a nosocomial infection [4 ,12]. The majority of intra-abdominal fungal infections (40%) are diagnosed in the first month after transplantation, most likely due to the associated disease leading to transplantation, potentially contaminated nature of the surgical procedure, and loss of the intestine mucosal integrity during recovery, preservation, and transplantation [9]. Candidemia tends to be a late-onset process (80% of the cases 6 months after transplantation), probably in the setting of prolonged central venous access, multiple courses of antibiotics, need for hemodialysis, or total parenteral nutrition (TPN) [9]. In a study published by our group, we found that the rate of Candida infection is lower in multivisceral transplant recipients than in isolated intestinal transplantation recipients, possibly related to the immunomodulatory effect of the transplanted liver [9]. From the same study [9], we can see the comparison of different Candida spp. with the data from TRANSNET and Prospective Antifungal Therapy (PATH) Alliance global surveillance programmes (Table 1) [2 ,13 ]. The distribution of Candida spp. in intestinal transplantation recipients was similar to that reported from the global surveillance, C. albicans, and C. glabrata being the dominant species. Overall, nonalbicans Candida spp. were more frequently isolated than C. albicans, possible reflecting posttransplant prophylactic azole use. During the 3-year surveillance period, TRANSNET showed an increase in the incidence of IFI, mainly by the increase in invasive candidiasis [2 ]. The source of infection is mainly related to central line infections (skin colonization), &&
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Multiple spp. Unspecified spp. Adapted from [2
&&
,9,13
&&
].
intraabdominal infection, or translocation from the intestine microbiota. During the first year posttransplantation, patients are at higher risk for Candida infections due to repeated surgical procedures including technical difficulties that would extend the operating time, high intraoperative blood product requirements, and complicated intraoperative or postoperative courses, anastomotic disruption, retransplantation, higher degree of immunosuppression, selective pressure after multiple or prolonged courses of antibiotics, hyperglycemia, renal dysfunction sometimes requiring dialysis, use of central venous catheters, need for mechanical ventilation, administration of total parenteral nutrition, and cytomegalovirus disease [4 ,10,14–16] The most common clinical presentation is oral candidiasis manifested by odynophagia, sometimes concomitant with esophagitis presenting with dysphagia, odynophagia, reflux, or chest pain. Peritonitis and intraabdominal abscesses are usually diagnosed after surgical procedures that disrupt the integrity of the mucosal barrier. Urinary tract infections are mainly associated with the presence of catheters and after antibiotic treatment. Candidemia should be suspected in patients with central lines, recent procedures, TPN, and recent antibiotic treatments. Definite diagnosis of invasive candidiasis requires isolation of the organism from a sterile site. The sensitivity of blood cultures is relatively low, approximately 70% [17], and it is reduced by administration of antifungal medication [18]. In patients with negative cultures, but suspected Candida infections, 1–3-b-glucan (BDG) assay is a useful &&
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Fungal infections in intestinal transplantation Florescu and Sandkovsky
adjunctive diagnostic tool. Currently, there are at three main BDG detection assays available, with different performances, reference standards, and cut offs: Fungitell (Associates of Cape Code, Inc., East Falmouth, MA, USA), Wako (Wako Pure Chemical Industries, Ltd., Tokyo, Japan), and Fungitec-G test (Seikagaku, Kogyo, Tokyo, Japan). The cut-off values for the best diagnostic accuracy varies for each test: 60 pg/mL for Fungitell assay, 20 pg/mL for Fungitec G-test assay, and 11 pg/mL for Wako assay [19]. A recent meta-analysis showed that the pooled sensitivity and specificity of these three tests were 78 and 81% [19]. Identification and susceptibility of the Candida spp. can take from 48 h to 5–6 days, hampering the clinical management of the patients. Several DNA-based methods have been developed in an attempt to early detect positive yeast culture, in particular in blood cultures [20]. Although these methods are more expensive, the results are accurate, reproducible, and available in few hours after a positive blood culture, allowing timely intervention and antifungal therapy. In a study including SOT recipients, the sensitivity and specificity of BDG assay (with a cutoff at 80 pmol/ ml) was 56 and 73%, whereas for PCR sensitivity and specificity were higher at 80 and 70% [21]. In this study, PCR and BDG were similar in diagnosing candidemia (59 vs. 68%; P ¼ 0.77), but PCR was more sensitive for deep-seated candidiasis (89 vs. 53%; P ¼ 0.004) [21]. PCR and BDG were more sensitive than blood cultures among patients with deep-seated candidiasis (88 and 62 vs. 17%; P ¼ 0.0005 and P ¼ 0.003) [21]. Both the Infectious Diseases Society of America (IDSA) and the American Society of Transplantation (AST) have outlined management guidelines for different syndromes caused by Candida spp. and these are summarized in Table 2 [4 ,22]. Candida infections are considered to have a negative impact on morbidity and mortality [23]. However, our study that included 98 intestinal transplantation recipients showed that with the exception of C. glabrata, fungal infections did not have any significant impact on long-term survival [9]. Survival was not impacted by the choice of empiric or subsequent antifungal therapy, length of therapy, removal of central venous catheter, and recurrence of infection [9]. Possible prevention strategies are: antifungal prophylaxis in the immediate posttransplant period, special care of the central line, and use of alcohol lock therapy when necessary. Without supportive evidence from clinical trials, posttransplant antifungal prophylaxis is frequently administered for a minimum of 4 weeks or until anastomosis is healed [4 ]. A more tailored approach would be &&
&&
warranted, taking in consideration individual-risk factors (for Candida and other molds) that would dictate the selection of the antifungal agent and the duration of prophylaxis. High-risk recipients are defined transplant recipients who had two or more risk factors (Collins criteria): preoperative colonization with Candida, choledochojejunostomy anastomosis, retransplantation, early reintervention after transplantation for bleeding or graft dysfunction, preoperative renal insufficiency, and administration of at least 40 units of blood products [24]. IDSA guidelines recommend targeted prophylaxis with fluconazole (3–6 mg/kg per day) or liposomal amphotericin B (1–2 mg/kg per day) for 7–14 days after transplantation in high-risk recipients [22]. The last AST guidelines recommends the administration of fluconazole (400 mg/day) or liposomal amphotericin B (3–5 mg/kg per day) for 4 weeks or until healing of the anastomosis, in the absence of rejection in the presence of risk factors (enhanced immunosuppression, anastomotic disruption, abdominal reoperation, and multivisceral transplantation); liposomal amphotericin B is recommended when there is high suspicion for nonalbicans Candida spp. [4 ]. Bowel decontamination to reduce invasive candidiasis is not clearly defined [25–27], mainly because early infections are related to the surgical procedures, whereas late infections to the presence of central venous catheters [10] &&
ASPERGILLUS INFECTIONS Aspergillus represents only a minority of the fungal infections in intestinal transplantation recipients [28,29 ,30 ]. Cases of Aspergillus have been reported at different transplant centers [9,11,31–34]. PATH Alliance registry reported 280 SOT with invasive aspergillosis; among those 13 (4.6%) cases occurred in intestinal transplantation recipients with Aspergillus fumigatus being the most common isolate [35 ]. The most important risk factors for invasive aspergillosis are the net state of immunosuppression related to induction therapy with T-celldepleting antibodies, CMV infection, neutropenia [24,29 ,30 ,36], renal failure, prolonged ICU stay, and retransplantation [24,29 ]. Calcineurin inhibitors have activity against Aspergillus and may impair fungal growth or proliferation [37]. The most common site of infection is the lung, with angioinvasion and the possibility of dissemination to virtually any organ, especially invasion of the central nervous system (CNS) [29 ,35 ,38,39]. Diagnostic criteria have been developed and should be applied whenever possible [40,41]. Imaging studies may show infiltrates, nodules, or cavitation; computed tomography scans have higher &
&
&
&
&
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&
&
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Small bowel transplantation Table 2. Recommendations for the management of different syndromes caused by Candida spp. Clinical syndrome
Antifungal therapy
Additional recommendations
Candidemia in nonneutropenic recipients
Fluconazole 12 mg/kg loading followed by 6 mg/kg per day with adjustment for renal function
Removal of intravascular catheters is recommended
Echinocandin for patients with moderate-to-severe illness or recent azole exposure
Treatment: 14 days after the first negative blood culture and resolution of signs and symptoms
Candidemia in neutropenic recipients
Alternative: Liposomal amphotericin B (3–5 mg/day) or amphotericin B deoxycholate (0.5–1 mg/kg per day) An echinocandin Liposomal amphotericin B (3–5vmg/kg per day) Alternative treatments in patients without recent azole exposure and who are not critically ill: fluconazole (12 mg/kg loading dose followed by 6 mg/kg per day with adjustment for renal function) or voriconazole (6mg/kg twice daily for two doses then 3 mg/kg twice daily).
Suppurative thrombophlebitis
Endocarditis
Liposomal amphotericin B (3–5 mg/kg per daily)
Surgical incision and drainage or resection of the vein is recommended
Fluconazole (6–12 mg/kg) adjusted for renal function an echinocandin
Treatment for at least 2 weeks after candidemia has cleared
Liposomal amphotericin B (3–5 mg/kg per day) flucytosine (25 mg/kg four times daily adjusted for renal function)
Valve replacement is strongly recommended. For those who are unable to undergo surgical removal of the valve or prosthetic valves, chronic suppression with fluconazole 400–800 mg (6–12 mg/kg per day) is recommended.
Amphotericin deoxycholate (0.6–1 mg/kg per day) flucytosine (25 mg/kg four times daily) an echinocandin Step-down therapy to fluconazole (6–12 mg/kg per day adjusted for renal function) for susceptible organism in stable patient with negative blood culture results Asymptomatic urinary tract infection
Therapy not indicated
Symptomatic cystitis
For fluconazole-susceptible organisms, fluconazole (3 mg/kg per day) should be administered for 2 weeks
Patients undergoing urologic procedures should receive treatment several days before and after the procedure with fluconazole (3–6 mg/kg per day adjusted for renal function) or amphotericin B deoxycholate (0.3–0.6 mg/kg per day).
For fluconazole-resistant organisms: amphotericin B deocycholate (0.3–0.6 mg/kg per day) flucytosine (25 mg/kg four times daily adjusted for renal function) Pyelonephritis
Should be treated as candidemia, if there is suspected disseminated candidiasis For fluconazole-susceptible organisms, fluconazole (3–6 mg/kg/day)
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Fungal infections in intestinal transplantation Florescu and Sandkovsky For fluconazole-resistant organisms: amphotericin B deoxycholate (0.5–0.7mg/kg/day) flucytosine (25mg/kg 4 times daily adjusted for renal function) Local irrigation with amphotericin B deoxycholate is adjunctive therapy to systemic therapy
Urinary fungus ball
Oropharyngeal candidiasis
Surgical removal is recommended
Fluconazole (3–6mg/kg/day adjusted for renal function) Amphotericin B deoxycholate (0.5–0.7mg/kg/day) flucytosine (25mg/kg 4 times daily adjusted for renal function) Clotrimazole troches (10 mg 5 times/day or nystatin suspension are recommended for mild disease (7–14 days) fluconazole (100–200 mg/daily) is recommended for moderate-to-severe disease (7–14 days)
Esophageal candidiasis
Fluconazole (3–6 mg/kg/day adjusted for renal function) is the preferred treatment
Respiratory candidiasis should not be treated; it is mainly colonization of the airways.
An echinocandin is the alternative treatment amphotericin B deoxycholate (0.3–0.7 mg/kg/day) for patients with refractory disease Echinocandins Systemic disease Micafungin 100 mg/day or Caspofungin 70 mg loading followed by 50 mg/day maintenance (up to 70 mg/day in neutropenic patients) or Anidulafungin 200 mg loading followed by 100 mg/day. Esophageal Candidiasis Micafungin 150 mg/day, Caspofungin 50 mg/day or && Anidulafungin 100 mg/day. Adapted from [4 ,22].
sensitivity than chest radiograph but the classic halo sign is not specific for invasive aspergillosis [30 ,41]. Serum galactomannan has acceptable specificity (84%), but low sensitivity (22%). Using a cut-off index value more than 1 in BAL specimens improved the sensitivity of galactomannan to 67% and specificity to 98% [42]. The utility of BDG assay in SOT has not been fully defined [30 ]. Isolation of Aspergillus from a BAL specimen does not equal invasive disease, but it does indicate risk for development of invasive aspergillosis [30 ,41]. Isolation from a sterile site such as blood, CNS, tissue, or histopathologic evidence of hyphal invasion with or without angioinvasion establish definitive diagnosis [40,41]. Voriconazole is the drug of choice to treat any form of Aspergillus disease, with amphotericin B, Posaconazole, and the echinocandins regarded as alternative agents; surgical management should be used as adjunctive therapy whenever necessary [30 ,41]. There is no evidence to recommend antifungal prophylaxis for Aspergillus in intestinal transplantation recipients. The 12-week postdiagnosis mortality was reported to be 22.1% in the PATH alliance [35 ]. Invasive aspergillosis was associated with shorter &
&
&
&
&
time-to-death when compared with invasive candidiasis in our study [9].
CRYPTOCOCCUS Cryptococcus, the third most common IFI in SOT recipients, has an incidence of 0.2–5% [43,44] with almost no data published in intestinal transplantation. The risk appears to increase 6 months posttransplantation [37], with a median onset at 16–21 months [43,45,46]. Risk factors include use of T-celldepleting antibodies and corticosteroids [43,47]. Between 50 and 75% of patients have CNS disease [43], one-third present with fungemia [45,48], and one-third may only have pulmonary disease [45]. Serum cryptococcal antigen is helpful in most forms of cryptococcal disease, but it may be negative with isolated pulmonary involvement [43,49]. A lumbar puncture, urine, and blood cultures are needed to diagnose patients with disseminated or CNS disease [43]. For management, readers are referred to the treatment guidelines outlined by IDSA and AST [43,50]. The overall mortality is about 14% and is as high as 50% for SOT recipients with cryptococcal meningitis [43,45,51].
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Small bowel transplantation
MUCORMYCOSIS
&
Mucormycosis is a rare complication among SOT recipients, usually associated with high levels of immunosuppression, especially with the use of T-cell-depleting antibodies [52,53], renal failure, diabetes mellitus, and prior use of voriconazole, or an echinocandin [54,55]. Timing for infection is usually 3 months posttransplantation. There are no reports of Mucormycosis among intestinal transplantation recipients in the TRANSNET or the PATH Alliance [5 ,56]. &
ENDEMIC FUNGAL INFECTIONS
experience [68 ]. Cryptococcal disease can be transmitted from any donated organ and should be suspected in any SOT recipient who presents with cryptococcal disease within 30 days [43,68 ]. Transmission of histoplasmosis has been documented in SOT, active disease may be suspected whether granulomas or organ lesions are found at the time of harvesting, but routine donor testing is not recommended [68 ,69]. Coccidioidomycosis can be readily transmitted by transplantation and donors from endemic areas should be screened with serology, complement fixation, and immunodiffusion; recipients from donors who have resided or traveled to endemic areas should undergo pretransplant screening [68 ]. Donor-derived Aspergillus, mucor, and other filamentous fungi are possible, although there are no reports of any donor-derived fungal infections among intestinal transplantation recipients. &
&
&
The TRANSNET identified 64 cases of endemic mycoses: 48 histoplasmosis, seven coccidioidomycosis, and nine blastomycosis in SOT recipients, although none of these occurred in intestinal transplantation recipients [57 ]. Histoplasmosis is the most common endemic mycosis among SOT recipients with an incidence of one case per 1000 personyears [58–61]. Clinical manifestations range from pulmonary involvement to disseminated disease [58]. In a multicenter analysis of 152 cases of histoplasmosis among SOT recipients, 81% presented with disseminated disease and 34% were diagnosed in the first year posttransplantation, only one was an intestinal transplantation recipient [62 ]. The most common diagnostic method is detection of the Histoplasma antigen in urine, blood, BAL, or other body fluid samples. Histopathology is useful for tissue diagnosis [63]. Preferred treatment of severe, disseminated, or pulmonary disease is with liposomal amphotericin B, whereas less severe cases can be treated with itraconazole or voriconazole [64 ,65]. Mortality was reported to be 15% in TRANSNET [57 ]. The highest risk for coccidioidomycosis is during the first year post-SOT, and 50% of cases occur during the first 3 months but no data exists in intestinal transplantation [60]. The most common clinical manifestations are severe pneumonia and disseminated disease, including meningoencephalitis [64 ]. Culture and tissue histopathology are the main diagnostic modalities [64 ]. Fluconazole or itraconazole can be used to treat mild-to-moderate cases but amphotericin B should be used in cases of disseminated disease [62 ,63,65,66,67 ]. &&
&
&
CONCLUSION It is difficult to understand the burden of fungal infections in intestinal transplantation recipients as most of the data comes from single-center experiences, case reports, or case series. Not surprisingly, invasive candidiasis is the most common IFI. However, more robust information regarding clinical presentation and treatment of invasive aspergillosis, cryptococcosis and histoplasmosis is not available and usually extrapolated from other allografts. Acknowledgements None. Financial support and sponsorship None.
&&
Conflicts of interest D.F.: grant from Chimerix Inc.; grant from CLS Behring; consulting for Chimerix Inc. and CLS Behring. U.S.: research grants from CLS Behring, ViiV healthcare, GSK, Pfizer. Consultation work for Rib-X pharmaceuticals. No funding was received for this work.
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DONOR-DERIVED INFECTIONS Donor-derived fungal infections are rare in SOT recipients, but may cause significant complications. Evidence of recommendations is limited as we rely on case reports, descriptive studies, and clinical 300
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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. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am 2003; 17:113–134; viii. 2. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among && organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50:1101–1111. Prospective 5-year surveillance of invasive fungal infections in transplant recipients performed at 23 selected centers in the United States. It describes current approaches to diagnosis, management, and outcomes of these infections.
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