Invasive Fungal Infections After Kidney Transplantation: A Single-center Experience T. Santosa,*, B. Aguiara, L. Santosa, C. Romaozinhoa, R. Tomeb, F. Macarioa, R. Alvesa, M. Camposc, and A. Motaa a Kidney Transplant Unit, Urology and Kidney Transplant Department, Coimbra University Hospital, Coimbra, Portugal; bClinical Pathology Department, Coimbra University Hospital, Coimbra, Portugal; and cNephrology Department, Coimbra University Hospital, Coimbra, Portugal

ABSTRACT Introduction. Invasive fungal infections (IFI) affecting transplant recipients are associated with increased mortality and graft dysfunction. Objective. Describe the frequency, clinical features, and outcomes of IFI (except pneumocystis infection) in kidney transplant recipients. Method. Single-center descriptive study including every kidney transplant recipient with a culture-proven or probable IFI between 2003 and 2013, according to the EORTC-MSG criteria. Results. We identified 45 IFI. There were 13 cases of invasive candidiasis (C. albicans: 6 and noneC. albicans candidial spp.: 7), 11 cases of pulmonary aspergillosis (A. fumigatus: 9 and A. flavus: 2); 11 cases of subcutaneous mycosis (Alternaria spp.: 9, Paecilomyces spp.: 1, and Pseudallescheria spp.: 1); 7 cases of cryptococcosis; 2 cases of pneumonia by nonAspergillus molds (Mucor spp.: 1 and Cunninghamella spp.: 1); and 1 case of Geotrichum capitatum pneumonia. All patients were recipients from deceased donors. Six cases occurred in the first 3 months post-transplant, 15 cases between the third and twelfth months, and 21 cases after the twelfth month. Treatment options were fluconazole for Candida infections, voriconazole or caspofungin for aspergillosis, liposomal amphotericin for cryptococcosis, and itraconazole plus excision or cryotherapy for subcutaneous mycosis. Fifteen patients died (33%). Mortality rates were 15% for invasive candidiasis, 45% for aspergillosis, 71% for cryptococcosis, 100% for non-Aspergillus molds and G. capitatum pneumonia, and 0% for subcutaneous mycosis. Six patients who survived (14%) started regular hemodialysis. Conclusion. IFI still have a high mortality and morbidity in kidney transplant recipients, as verified in this report. We reinforce the need for a high index of suspicion and prompt treatment.

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NFECTIONS are one of the most concerning events after organ transplantation because of the frequent need of hospitalization, increased mortality, and graft dysfunction. According to the U.S. Renal Data System 2014 [1], infections are the second most common cause of hospitalization in the first year after kidney transplantation and the first thereafter, with admission rates of 31.8 per 100 patients in the first year and 17.8 in the second year post-transplant [1]. In the U.K., data from prevalent kidney transplant ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 47, 971e975 (2015)

patients [2] showed that their major cause of death is infection, followed by cancer and cardiovascular disease. Bacterial infections are by far more frequent than fungal infections but the latter may be challenging in terms of diagnosis and treatment. The incidence of IFI after kidney *Address correspondence to Telma Santos, Coimbra University Hospital, Praceta Mota Pinto, 3000-075 Coimbra, Portugal. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.03.040

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transplant is not well known. Available reports show variability between countries: in an American multicentric study [3], the incidence was 1.3%, while in Iran, Turkey, Kuwait, and India, it was 0.87%, 4%, 3.5%, and 14%, respectively [4]. The risk factors for IFI depend on the transplant type (it is more frequent in hematopoietic cell, intestinal, lung, and liver transplant), on underlying disease, on comorbid conditions, and on surgical techniques. Several studies have addressed this issue over the last years [3,5e7]: factors such as prolonged immunosuppression, pulses of corticosteroids, chronic graft dysfunction, previous use of broad-spectrum antibiotics, neutropenia, cytomegalovirus infection, diabetes, and advanced age have been associated to IFI. Transmission may be donorderived [8,9], sometimes associated with transplant tourism [10] or with contamination of preservation fluid [11]. IFI may result from reactivation of latent infection in the recipient (e.g. tuberculosis, pneumocystosis). IFI may be community-acquired or nosocomial (due to prolonged hospitalization and invasive procedures such as catheterization and intubation). The most commonly reported IFI among kidney transplant recipients are invasive candidiasis, cryptococcosis, and invasive mold infections, such as invasive aspergillosis [3]. A multicenter study about post-transplant IFI that included 15 transplantation centers in the U.S. with more than 16,000 transplant recipients between 2002 and 2005 [3] identified the most frequent IFI: invasive candidiasis (53% in all types of transplant and 49% in kidney transplant), aspergillosis (19% and 14%), cryptococcosis (8% and 15%), and non-Aspergillus mold infections (8% and 5%). Post-transplant time to diagnosis was 103 days for invasive candidiasis, 184 days for aspergillosis, and 575 days for cryptococcosis. The majority of studies found a greater incidence of IFI in the first 6 months post-transplantation, when immunosuppression is more intense (e.g., induction with thymoglobulin). According to recent ESCMID Study Group for Infections in Compromised Hosts recommendations [12], antifungal prophylaxis is not required for kidney transplant recipients. Symptoms of systemic fungal infections are nonspecific, particularly in early stages. Fever may be absent. Common infected organs are the urinary tract, upper airways, lungs, paranasal sinuses, and central nervous system. Skin lesions are the most frequent findings in pheohyphomycosis, fusariosis, and mucormycosis. Delay in the diagnosis or treatment can lead to complications such as perinephric abscess, fungus balls, renal arteritis with aneurysm, necrotizing pneumonia, and pulmonary cavitation. Unexplained fever despite broadspectrum antibiotic treatment or relapse of fever can indicate a fungal infection. Early diagnosis remains difficult to achieve and post-mortem diagnosis is common, in part because conventional diagnostic tests have low sensitivity and specificity. Current methods for the diagnosis include imaging procedures, biopsies, microscopic and culture techniques, serology (galactomannan-based), and the polymerase chain reactione based detection of fungal DNA. CT imaging and bronchoscopy may be of particular benefit in documenting the course of invasive pulmonary fungal infections, particularly aspergillosis.

SANTOS, AGUIAR, SANTOS ET AL Table 1. Invasive Fungal Infections in Kidney Transplant Recipients in Our Center Between 2003 and 2013 and Fungal Species Isolated in Cultures Invasive Fungal Infection

N (%)

Invasive candidiasis with candidemia C. albicans C. parapsilosis C. tropicalis C. krusei C. albicans þ C. guillermondii Pulmonary aspergillosis A. fumigatus A. flavus Non-Aspergillus molds pulmonary infections Mucor spp. Cunninghamella bertholletiae Cryptococcosis C. neoformans Subcutaneous mycosis Alternaria alternata Paecilomyces lilacinus Pseudallescheria boydii Other Geotrichum capitatum Total

13 (28.9%) 6 4 1 1 1 11 (24.4%) 9 2 2 (4.4%) 1 1 7 (15.6%) 7 11 (24.5%) 9 1 1 1 (2.2%) 1 45

EORTC diagnostic criteria [13] have been developed to maintain consistency in clinical and epidemiologic studies, but they should not preclude therapeutic decision-making. The criteria for diagnosis includes a positive culture result from normally sterile body fluids (e.g., blood, pleural effusion, cerebrospinal fluid) or from biopsy samples and the result of histologic tissue analysis. The accurate interpretation of positive fungal cultures is challenging and blood cultures may be false-negative. After fungal growth is seen, susceptibility testing to antifungal agents should follow. Newer diagnostic approaches have focused on noneculture-based methods (e.g., galactomannan assay for Aspergillus infection, metabolite detection, and the molecular detection of fungal DNA). These new techniques have the potential to detect fungal infections before the appearance of clinical signs and symptoms in immunocompromised patients. In summary, clinical experience to date has shown that each of the available diagnostic tests is of limited use in the early diagnosis of IFI. A combination of various methods and regular screening is advisable to ensure that diagnosis is reached as sooner as possible. Considering the relevance of the IFI for transplant recipients, our purpose was to evaluate the frequency, clinical features, and outcomes of IFI (except pneumocystis infection) in kidney transplant recipients in a transplant center in Portugal.

PATIENTS AND METHODS Study Design and Patients This study was conducted at the Kidney Transplantation Unit of Coimbra University Hospital. A retrospective search of the database

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Table 2. Baseline Demographic Characteristics of the Patients, Etiology of Kidney Disease, Transplant Characteristics, and Time After Kidney Transplant at Diagnosis Invasive Fungal Infections Case Patients

N Age at diagnosis Average (in years) Minimumemaximum (in years) Males, n (%) Etiology of chronic kidney disease, n (%) Indeterminate Glomerular Systemic (diabetes, hypertension) Tubulointerstitial Cystic Year of transplantation, n (%) Before 2000 2000 and after Deceased donor, n (%) Retransplantation, n (%) Induction treatment, n (%) Thymoglobulin Basiliximab No induction Maintenance immunosuppression, n (%) Tacrolimus þ antimetabolite Cyclosporine A þ antimetabolite Sirolimus þ cyclosporine A Sirolimus þ antimetabolite Time post-transplant at diagnosis of IFI, n (%) Less than 3 months 3 to 12 months More than 12 months

42 51.9 23e73 29 (69%) 13 11 9 5 4

(31%) (26%) (21%) (12%) (10%)

4 38 42 1

(10%) (90%) (100%) (2.4%)

15 (38%) 8 (19%) 19 (45%) 21 15 3 3

(50%) (36%) (7%) (7%)

6 (14%) 15 (36%) 21 (50%)

for every fungal culture in the Microbiology Department from January 2003 to December 2013 was undertaken. Fifty-five fungal cultures from transplant recipients were found, 10 being excluded due to the lack of evidence for “proven” or “probable” IFI according to the EORTC/MSG diagnosis criteria after the review of individual clinical registries. The other 45 cultures, from 42 patients, corresponded to IFI considered proven or probable and were included in the study. Case data included infection site, date of transplant, history of immunosuppressive treatment, antifungal treatment data, patient status (dead or alive), and graft status (function or loss of renal function with need of renal replacement therapy) after initial diagnosis of IFI. Among patients who died, cause of death due to IFI was determined by the investigator. Available cultures and pathologic specimens were processed at the microbiology laboratory at our center. Species identification was performed using routine methods. Antifungal susceptibility testing was not performed.

RESULTS

The authors found 45 invasive fungal infections considered “proven” or “probable” according to the EORTC/MSG diagnosis criteria between January 2003 and December 2013. In this period, a total of 2156 kidney recipients were

followed at our center (prevalent patients); therefore, the estimated frequency of IFI is 2.1%. Culture samples comprised 13 blood cultures positive for Candida spp, 7 bronchial aspirate cultures and 4 sputum cultures positive for Aspergillus spp., 5 blood cultures and 2 liquor cultures positive for Cryptococcus spp., and 3 bronchial aspirate cultures positive for Mucor spp., Cunninghamella spp., and Geotrichum spp., respectively. The other 11 cases corresponded to subcutaneous mycosis with skin cultures positive for Alternaria spp. (9), Paecilomyces spp. (1), and Pseudallescheria spp. (1). Table 1 shows the fungal species isolated in this series of kidney transplant recipients. The patients’ demographic characteristics, the etiology of the kidney disease, and transplant data are shown in Table 2. The majority of the IFI patients received their graft after 2000. All kidneys came from deceased donors. One patient was a recipient of a second kidney transplant. The median time posttransplant at diagnosis is described in Table 3. Fifteen patients died (33%): 2 patients with isolate Candida infection (15%), 5 patients with pulmonary aspergillosis (45%), 5 patients with cryptococcosis (71%), both patients with non-Aspergillus mold infections (100%), plus the patient with Geotrichum pneumonia (100%). With respect to the evolution of graft function, 2 patients died with functioning kidney (5%), 12 patients died in hemodialysis (29%), 22 patients survived with preserved graft function (52%), and 6 patients survived but started regular hemodialysis (14%). A description of each IFI follows: Candida spp. There were 13 cases of Candida infection, which presentation was fever not responding to antibiotics (n ¼ 7), pneumonia (n ¼ 5), and one case of graft mycotic aneurysm with necessity of transplantectomy. Three patients had simultaneous pulmonary aspergillosis; these patients died and death was attributed to Aspergillus infection. Median time post-transplant at diagnosis was 366 days. Patients with isolate Candida infection (n ¼ 9) were treated with intravenous fluconazole; 2 patients lost graft function and died despite initiation of antifungal treatment. Another 2 patients were cured of infection but started regular hemodialysis. Aspergillus spp. The clinical presentation of aspergillosis was pneumonia with respiratory failure in all 11 cases, with typical radiological findings in some cases. Table 3. Time After Kidney Transplant at the Diagnosis of Invasive Fungal Infections

Fungal Infections

Days From Transplantation Median (minimumemaximum)

Invasive candidiasis Invasive aspergillosis Non-Aspergillus mold pneumonia Cryptococcosis Subcutaneous mycosis Geotrichum capitatum pneumonia

366 (45e4431) 175 (8e3451) (125e1253) 1045 (125e9127) 368 (134e734) 85 (only 1 case)

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Treatment consisted of IV voriconazole in 4 cases, IV caspofungin in 2 cases, and IV itraconazole in 1 case; some patients had an initial empirical course of fluconazole. Five patients died; most before initiation of treatment due to rapid course of disease and late diagnosis (n ¼ 4), plus 1 patient treated with fluconazole and subsequent caspofungin. Non-Aspergillus Molds. The two patients with nonAspergillus mold pneumonia (Mucor spp. and Cunninghamella spp.) were treated with liposomal amphotericin plus pulmonary surgery in the case of mucormycosis. Unfortunately both patients died. Cryptococcus. The clinical presentation of the 7 cases was fever not responsive to antibacterial treatment with fungemia (n ¼ 5) and meningitis (n ¼ 3). The treatment consisted of liposomal amphotericin in 5 patients, and 2 patients were only diagnosed post-mortem and therefore did not receive appropriate treatment. Five patients died: 4 after starting hemodialysis and 1 with residual graft function. The 2 survivors maintained residual graft function. Alternaria spp. Paecilomyces spp., and Pseudallescheria spp. Subcutaneous mycosis cases evolved favorably and were treated with oral itraconazole for alternariosis and voriconazole for the other infections, plus cryotherapy or surgery in each case. Geotrichum Capitatum. The only patient with this IFI had severe pneumonia and the diagnosis was made postmortem. DISCUSSION

IFIs are opportunistic infections that affect immunocompromised patients, such as kidney transplant recipients, mainly during periods of greater immunosuppression. In this study, 2.1% of the 2156 prevalent kidney transplant patients developed an IFI between 2003 and 2013. This percentage may be underestimated because our center receives patients from all over the country and it is possible that cases of IFI could have been diagnosed in other hospitals closer to where the patients lived. There was a greater percentage of male patients (69%) and age at diagnosis was, on average, 51.9 years. The majority of patients (90%) were transplanted after 2000, probably reflecting a better consciousness about emerging IFIs, a better diagnostic workup, and eventually the use of more potent immunosuppressive therapy. In this set of patients, Candida spp. were the most common isolates (28.9%), followed by Aspergillus spp. (24.4%), Cryptococcus spp. (15.6%), and other fungi. The proportion of Candida infection was lower than reported in large studies [3]. Conversely, there were more cases of invasive aspergillosis. Median time of Candida infection diagnosis was at 366 days post-transplantation, which is later than usually reported [3]. noneC. albicans candidial spp. were slightly more frequent than C. albicans, although C. albicans remains the most common isolate in large studies [3,14].

SANTOS, AGUIAR, SANTOS ET AL

NoneC. albicans candidial spp. infection emerged in recent years [15], which is consistent with our results. A systematic review by Falagas et al [16] showed that the highest proportion of C. albicans was found in North and Central Europe and in the U.S. Although less common, noneC. albicans candidial spp. are found in a greater proportion in South America, Asia, and South Europe, including Portugal. This is important because noneC. albicans candidial spp. may show resistance to fluconazole and echinocandines in about 20% of cases [17]. Among noneC. albicans candidial spp., C. glabratta was commonly isolated in the U.S. and in North and Central Europe; C. parapsilosis in South America, South Europe, and several parts of Asia; and C. tropicalis in South America and Asia [16]. This is in accordance with our findings on Candida isolates. With respect to aspergillosis, median time at diagnosis of infection was 175 days post-transplantation, which is in line with other studies [3,18]. Clinical presentation was consistent with remarkable literature on this infection [19]. In a large series of patients (including transplant patients) from an American registry [20], overall survival was 64.4%, similar to our results. According to the literature [21,22], the most frequent clinical manifestations of cryptococcal infection are disseminated disease, involvement of the CNS, and pulmonary disease, which is consistent with our results. Time at diagnosis was 1045 days after transplantation, later than usually reported [3], and certainly due to the long surveillance period of this study. Our study did not evaluate the utilization of pulsed corticosteroids for treatment of rejection episodes in the period before diagnosis of IFI or other risk factors, such as the presence of neutropenia, previous diagnosis and treatment of bacterial or viral infections, and previous hospitalization, which could explain the late infections. Of the commonest IFI, cryptococcosis had the highest mortality, which is consistent with other reports [21]. With respect to the induction treatment, more patients received thymoglobulin when compared with basiliximab (38% vs 19%, respectively); however, the majority of cases did not receive induction therapy (45%). These findings are inconclusive. The maintenance immunosuppression consisted of a calcineurin inhibitor plus an antimetabolite in 86% of cases (50% with tacrolimus and 36% with cyclosporine); these percentages reflect an increased frequency of IFI in patients using more potent immunosuppression. The overall mortality rate was 33% and was greater for rare fungal infections such as non-Aspergillus molds (100%), cryptococcosis (74%), and aspergillosis (45%). Deaths occurred mainly due to late diagnosis or nondiagnosis, which is consistent with literature. Of the patients who were treated effectively and discharged from hospital, 14% lost graft function and started regular hemodialysis. CONCLUSION

IFI remain a clinical challenge. Considering the age of kidney transplant recipients and the presence of several

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comorbidities, we reinforce the need for a high index of suspicion for fungal infection and prompt treatment to avoid mortality. The development of new, more accurate diagnostic procedures would be useful. Frequent monitoring of the patient’s net state of immunosuppression and maintaining it at the minimum levels efficacious to prevent rejection, is recommended. Reporting IFI cases should be encouraged to better guide our clinical practice and to improve the standards of care of transplant patients. REFERENCES [1] United States Renal Data System, 2014 annual data report: An overview of the epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. [2] Pruthi R, Casula A, MacPhee I. UK Renal Registry 16th Annual Report: Chapter 3. Demographic and biochemistry profile of kidney transplant recipients in the uk in 2012: national and centre-specific analyses. Nephron Clin Pract 2013;125:55e80. [3] Pappas P. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010;50:1101e11. [4] Einollahi B. Invasive fungal infections following renal transplantation: A review of 2410 recipients. Ann Transplant 2008;13: 55e8. [5] Vilardell A, Moreno J. Infecciones oportunistas en pacientes com transplante renal. Nefrologia 1996;XVI:291e306. [6] Badiee P, Alborzi A. Invasive fungal infections in renal transplant recipients. Exp Clin Transplan 2011;9:355e62. [7] Vazquez JA. Invasive fungal infections in transplant recipients. Ther Adv Infect Dis 2013;1:85e105. [8] Gomez CA. Donor-derived filamentous fungal infections in solid organ transplant recipients. Curr Opin Infec Dis 2013;26: 309e16. [9] Singh N. Donor-derived fungal infections in organ transplant recipients: guidelines of the American Society of Transplantation. Am J Transplant 2012;12:2414e28.

975 [10] Shoam S, Hinestrosa F, Moore Jr J, et al. Invasive filamentous fungal infections associated with renal transplant tourism. Transpl Infect Dis 2010;12:371e4. [11] Albano L. Evidence that graft-site candidiasis after kidney transplantation is acquired during organ recovery: a multicenter study in France. Clin Infect Dis 2009;48:194e202. [12] Gavaldà J. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect 2014;20(Suppl 7):27e48. [13] De Pauw B. 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). Clin Infect Dis 2008;46:1813e21. [14] Lockhart SR. Comparison of in vitro susceptibility characteristics of Candida species from cases of invasive candidiasis in solid organ and stem cell transplant recipients: TransplantAssociated Infections Surveillance Network (TRANSNET), 2001 to 2006. J Clin Microbiol 2011;49:2404e10. [15] Horn DL. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009;48:1695e703. [16] Falagas ME. Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis 2010;14:e954e66. [17] Pfaller M. Epidemiology and outcomes of invasive candidiasis due to non-albicans species of candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) Registry 2004e2008. PLoS One 2014;9:e101510. [18] Neofytos D. Epidemiology, outcomes,and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transplant Infect Dis 2013;15: 233e42. [19] Lortholary O. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect 2011;17:1882e9. [20] Steinbach WJ. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect 2012;65:453e64. [21] Singh N. Cryptococcosis in solid organ transplant recipients: current state of the science. Clin Infect Dis 2008;47:1321e7. [22] Crabol Y. Invasive mold infections in solid organ transplant recipients. Scientifica (Cairo) 2014;2014:821969.

Invasive Fungal Infections After Kidney Transplantation: A Single-center Experience.

Invasive fungal infections (IFI) affecting transplant recipients are associated with increased mortality and graft dysfunction...
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