Mycopathologia DOI 10.1007/s11046-015-9875-4
Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors Sezin Zorlu Sahin • Halis Akalin • Alparslan Ersoy • Abdulmecit Yildiz • Go¨khan Ocakoglu • Ezgi Demirdo¨ven Cetinoglu • Og˘uzhan Sıtkı Dizdar • Esra Kazak • Beyza Ener
Received: 30 October 2014 / Accepted: 11 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Background Invasive fungal infections are a major cause of morbidity and mortality among renal transplant recipients. Objectives The aim of this study was to investigate the frequency and risk factors for fungal infections in renal transplant recipients. Methods We retrospectively evaluated all kidney transplant recipients at our center from December 1988 to June 2010 for the epidemiology, spectrum, risk factors, and mortality of invasive fungal infections. Results In 32 patients (10.30 %), at least one fungal infection developed after the transplantation. The most common pathogens causing fungal infections in our
patients were Candida spp. and Aspergillus spp. The independent risk factors associated with invasive fungal infection episodes were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90–64.73, p \ 0.001), cytomegalovirus infection (OR 18.54, 95 % CI 9.01–38.17, p \ 0.001), and the presence of diabetes mellitus (OR 6.01, 95 % CI 2.95–12.25, p \ 0.001). Mortality was significantly higher among patients with fungal infections than among other patients (53.10 and 17.80 %, respectively; p \ 0.001). Conclusions It is difficult to diagnose and treat fungal infections early, and it can be useful to determine independent risk factors in order to identify and treat high-risk patients.
S. Z. Sahin H. Akalin (&) E. Kazak B. Ener Department of Microbiology and Infectious Diseases, Uludag University Medical School, 16059 Gorukle, Nilufer, Bursa, Turkey e-mail: [email protected]
A. Yildiz e-mail: [email protected]
S. Z. Sahin e-mail: [email protected]
G. Ocakoglu Department of Biostatistics, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
E. Kazak e-mail: [email protected] B. Ener e-mail: [email protected] A. Ersoy A. Yildiz O. S. Dizdar Division of Nephrology, Department of Internal Medicine, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
O. S. Dizdar e-mail: [email protected]
E. D. Cetinoglu Department of Chest Diseases, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
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Keywords Kidney transplantation Fungal infection Invasive aspergillosis Candida infections
Introduction Solid organ transplant recipients comprise a growing and increasingly important group of immunocompromised hosts. Despite considerable progress in immunosuppressive and supportive treatments, a number of factors still interfere with the complete success of kidney transplantation (KT) [1]. The incidence of fungal infections varies between 1 and 14 % in renal transplant recipients [2]. Opportunistic fungi, such as Aspergillus species, species in the Mucorales order, Candida species, and Cryptococcus neoformans, cause most infections. Symptoms of systemic fungal infections are non-specific, particularly in the early stages [3]. Invasive fungal infections following KT remain a major cause of morbidity and death [1]. Many studies have investigated the epidemiology of fungal infections in renal transplant recipients [4–6]. Determining the risk factors for the development of fungal infections in this population can provide early diagnosis and treatment that may reduce mortality. Therefore, the objective of this study is to identify the epidemiology of invasive fungal infections and the risk factors affecting the development of infections and their prognosis in renal transplant recipients.
Materials and Methods This study retrospectively evaluated the medical records of 367 recipients of kidney transplants from December 1988 to June 2010 at the transplant unit of a university hospital. The study protocol was approved by our Institutional Review Board and was conducted in accordance with the Declaration of Helsinki. Ten patients who were under the age of 18 years at the time of KT, 13 patients with missing data in their charts, 14 patients with superficial Candida spp. infections, and 17 patients with possible IPA were excluded from the study. In the remaining 313 kidney transplant recipients, the following variables were assessed: age; gender; cause of end-stage renal disease; serology for cytomegalovirus (CMV),
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hepatitis B, and hepatitis C virus (HCV) prior to transplantation; dialysis type and duration; donor type (cadaveric or living); acute or chronic rejection; comorbid diseases; a history of tuberculosis; and initial immunosuppressive regimens. We identified the patients who had been diagnosed with an invasive fungal infection and who were treated at least once since the KT. Retrospective chart reviews of clinical and microbiological data were performed. Diagnosis was based on clinical, radiological, and specific laboratory (appropriate culture and/or histopathological examination) findings. Fungal infections were classified according to the site from which they originated. Invasive (hematogenous) fungal infections were included. Cutaneous and mucosal infections were considered superficial infections and were excluded. In the patients diagnosed with invasive pulmonary aspergillosis (IPA), the IPA was classified as ‘‘proven,’’ ‘‘probable,’’ or ‘‘possible’’ according to the EORTC/MSG-2008 criteria for fungal infections. ‘‘Possible’’ cases were excluded [7]. After 2003, the galactomannan antigen test (Platelia aspergillus; BioRad, France) was included for the presumptive diagnosis of IPA. Serum (cutoff = 0.5) and, if obtained, bronchoalveolar specimens (cutoff = 1) were evaluated for the presence of antigen. The definitions of CMV infection and CMV disease were followed according to Canadian Transplantation Society Guidelines [8]. For the patients diagnosed with a fungal infection, note was made of the last immunosuppressive agent combination used as maintenance therapy before the diagnosis, the amount of immunosuppressive agents administered within the previous 1 month, elevated levels of drugs, hospitalization within the last 3 months before diagnosis, a history of antibiotic treatment within the last 3 months before diagnosis, and CMV infections that had developed within the previous 6 months. In the patients who did not develop a fungal infection, determination was made of the last immunosuppressive agent combinations used during the last visit, the last level of drug measured, hospitalization at any time after KT, and the history of bacterial infection. In all patients, CMV infection occurring at any time after KT, and the treatments administered, were recorded. We decided the death whether or not due to invasive fungal infection based on clinical, laboratory, and host findings.
Mycopathologia
In all patients, total transplant time (days) was calculated from the difference between the last visit or death and the date on which KT was performed. In the patients who developed fungal infections, transplantation time at the time of diagnosis (days) was calculated from the difference between the date of fungal infection diagnosis and the date on which KT was performed. All patients received initial immunosuppressive therapy with prednisolone (KS), antimetabolites [mycophenolate mofetil (MMF), sodium-MMF, or azathioprine (AZA)] combined with calcineurin inhibitors (CNIs) [cyclosporine (CsA) or tacrolimus (TAC)] or mTOR inhibitors [sirolimus (SRL) or everolimus (EVL)] with interleukin-2 receptor antagonists (IL2ra) or antithymocyte globulin (ATG) induction, if required. All patients received intra-operative methylprednisolone (500 mg intravenously) and maintenance prednisolone (1–2 mg/kg per day orally). Surgical prophylaxis consisted of a single dose of cefazoline. Antimicrobial prophylaxis also included trimethoprim/sulfamethoxazole for the first 6–9 months after KT. Antiviral prophylaxis was with acyclovir. Isoniazid prophylaxis was administered for 9 months in recipients with a history of tuberculosis or [5 mm positivity on tuberculin skin test. Statistical Analysis Statistical analysis of the data was performed using SPSS 13.0 software (Chicago, IL). Categorical variables were given as frequency and percentage, and continuous variables were given as median (minimum–maximum). For inter-group comparison of the categorical variables, Chi-square test was used. In the inter-group comparison of the continuous variables, Mann–Whitney U test was used. In order to determine the independent risk factors for the development of fungal infection and IPA development, forward stepwise logistic regression analysis was performed, and risk factors were reported with p values, odds ratio (OR), and 95 % confidence interval (CI). In the study, p \ 0.05 was considered to be statistically significant.
Results For all patients (n = 313), median age was 33 years (18–69), and of these, 200 (63.90 %) were men and
113 (36.10 %) were women. Before KT, 220 patients had received hemodialysis, 28 patients had received peritoneal dialysis, and 32 patients had received both dialysis therapies. In 32 patients (10.30 %), at least one fungal infection developed after the transplantation. Of these 32 patients, a total of 36 (11.50 %) fungal infection episodes developed: one episode in each of 28 patients and two episodes in each of four patients. Distribution of gender, type of dialysis, donor type, and human leukocyte antigen (HLA) tissue compatibility were similar in the patients who developed fungal infections and those who did not. The patients who developed fungal infections had significantly more advanced ages, higher diabetes mellitus (DM) rates, and a fewer days post-KT compared to the patients who did not develop fungal infections (p \ 0.001, p \ 0.001, and p \ 0.001, respectively) (Table 1). All patients received at least two immunosuppressive agents. In both groups, the most commonly used regimen was the combination of KS?TAC?MMF (Table 2). The rate of immunosuppressive regimen use was similar in both groups. In 32 patients diagnosed with a fungal infection, the blood level of the immunosuppressive agent was measured within the last month before the diagnosis and eight patients (25 %) were found to have elevated levels. On the last visit of 272 patients who did not develop a fungal infection, 33 patients (12.10 %) were found to have elevated blood levels of the immunosuppressive agent (p = 0.055). Cytomegalovirus infection was detected in 10 patients who developed fungal infections (31.30 %) and in 24 patients who did not develop fungal infections (8.50 %) (p \ 0.001). CMV disease was not diagnosed in these patients. Ten of 32 patients (31.30 %) who developed a fungal infection had experienced the development of a CMV infection within the last 6 months before the fungal infection, and of these, nine (28.10 %) were treated with ganciclovir. Twelve patients who did not develop fungal infections (4.30 %) were given ganciclovir after KT (p \ 0.001). Twenty-four patients who developed fungal infections (75 %) had a history of hospitalization within the last 3 months before the diagnosis. Ninety-two patients who did not develop fungal infections (32.70 %) were hospitalized at least once after KT (p \ 0.001). Twenty-five patients who
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Mycopathologia Table 1 Characteristics of recipients with and without fungal infection Variables
Fungal infection group (n = 32)
Non-fungal infection group (n = 281)
p value
Sex (male/female)
18/14
182/99
Age (years)
36 (18–69)
32 (18–69)
Donor type (cadaveric/living) Dialysis type [n (%)]
12/20
94/186
0.805 0.402
Preemptive
3 (9.4)
30 (10.6)
Hemodialysis
21 (65.6)
199 (70.8)
Peritoneal dialysis
2 (6.2)
26 (9.3)
Both dialysis
6 (18.8)
26 (9.3)
0.449 \0.001
Hemodialysis duration (months)
36 (2–228)
24 (1–204)
Transplant duration (days)
344 (23–4237)
1141 (7–6245)
0.064
HLA matching (n)
3 (1–6)
3 (1–6)
0.227
Acute rejection [n (%)]
8 (25)a
40 (14.2)
0.121
Glomerulonephritis
2
36
Hypertension
5
30
Reflux nephropathy
3
18
Urolithiasis
1
11
\0.001
Primary disease (n)
Polycystic kidney disease
1
6
Pyelonephritis Alport syndrome
3 1
8 7
Diabetes mellitus
4
2
Amyloidosis
1
5
Acute tubular necrosis
1
4
Lupus nephritis
1
2
Vasculitis
1
2
Unknown
8
150
16 (50)
51 (18.1)
Diabetes mellitus [n (%)] a
\0.001
Acute rejection episode within last 6 month before the diagnosis of fungal infection
developed fungal infections (78.10 %) had a history of antibiotic treatment that had developed within the last 3 months before the diagnosis. Eighty patients who did not develop fungal infections (28.50 %) had experienced antibiotic treatment at any time after KT (p \ 0.001). Features of Fungal Infections We found IPA in 13 patients, intra-abdominal infection in six patients, Candida pneumonia in four patients, symptomatic urinary tract infection in four patients, candidemia in three patients, central nervous system infection in two patients, rhinocerebral mucormycosis in two patients, and osteomyelitis in two patients.
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When the fungal infections were examined according to the transplantation period during which they developed, the numbers of episodes were four (11.10 %) within the first month after KT (first period), 17 (47.20 %) within 1–6 months after KT (second period), and 15 (41.70 %) beyond 6 months after KT (third period) (Table 3). The median time to onset of the infections due to Candida species after the transplantation was 105 days, whereas the median time to onset of infections due to Aspergillus species (IPA) was 121 days. According to the EORTC/MSG fungal infection criteria, of the IPA attacks, only one (7.70 %) was proved and 12 (92.30 %) were probable. Of 13 patients diagnosed with IPA, eight patients were
Mycopathologia Table 2 Comparison of immunosuppressive regimen ratios in recipients with and without fungal infection Immunosuppressive combination [n (%)]
Fungal infection group (n = 32)
Non-fungal infection group (n = 281)
p value
KS?TAC?MMF
12 (37.5)
116 (41.3)
0.824
KS?CsA?MMF
9 (28.1)
54 (19.2)
0.338
KS?CsA?AZA KS?TAC?AZA
4 (12.5) 2 (6.3)
61 (21.7) 10 (3.6)
0.324 0.352
KS?MMF?SRL/EVL
0
KS?TAC?SRL/EVL
4 (12.5)
KS?CsA?SRL/EVL
0
KS?AZA?SRL
1 (3.1)
15 (5.3)
0.380
12 (4.3)
0.068
5 (1.8)
1.00
1 (0.4)
0.194
KS?CsA/TAC
0
6 (2.0)
1.00
KS?AZA
0
1 (0.4)
1.00
KS corticosteroid, TAC tacrolimus, CsA cyclosporin, AZA azathioprine, MMF mycophenolate mofetil or sodium, SRL sirolimus, EVL everolimus
Table 3 Distribution of 36 fungal infection episodes according to posttransplant period Fungal infection localization [n (%)]
Transplant period 1 month
1–6 months [6 months
IPA
0
8
CNS infectiona
0
0
2
Candidemia
1
1
1
Symptomatic UTI
1
1
2
Candida pneumonia
0
1
3
Osteomyelitisb
0
1
1
Rhinocerebral mucormycosis
0
1
1
Intra-abdominal infection
2
4
0
5
IPA invasive pulmonary aspergillosis, CNS central nervous system, UTI urinary tract infection a
CNS infection: Aspergillus spp. Cryptococcus neoformans in one case b
in
one
case
and
Osteomyelitis: Aspergillus fumigatus in two cases
diagnosed within the second period and five within the third period after KT. In 11 of 13 patients diagnosed with IPA, serum galactomannan (GM) antigen was investigated, and of these patients, eight (72.70 %) had positive test results. In three patients, GM antigen was investigated by bronchoalveolar lavage (BAL) and all had positive test results. Of three patients who had positive test results for BAL GM antigen, blood GM antigen was positive in one patient and negative in the other two.
Of 13 patients diagnosed with IPA, seven were treated with liposomal amphotericin-B, four were treated with caspofungin, and one was treated with voriconazole. One patient was initially treated with caspofungin and was then switched to voriconazole. In the patients diagnosed with IPA, the median of days passed with amphotericin-B was 13 (2–60). Of the patients diagnosed with IPA, eight (61.50 %) died. In all four of the patients in whom a urinary tract infection was detected, the causal microorganisms were Candida species. From the urinary cultures, Candida glabrata was isolated in one patient, Candida krusei was isolated in two patients, and Candida kefyr was isolated in one patient. In three patients, a bloodstream infection was detected. While Candida glabrata was isolated from the blood cultures of two patients, the blood culture of the third patient showed the growth of Candida parapsilosis. Among 36 fungal infection episodes, the causal microorganism was determined by culture or pathologic examination in 32 cases (89 %). Four IPA episodes were diagnosed based on galactomannan positivity in addition to the clinical and host factors. The distribution of the causal microorganisms that could be isolated is shown in Table 4. Risk Factors for Fungal Infection All of the risk factors for development of fungal infection were evaluated with logistic regression analyses. The results of the logistic regression model were found to be statistically significant (p \ 0.001).
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Mycopathologia Table 4 Distribution of the isolated fungi during 32 fungal infection episodes Causative microorganism [n (%)] Candida albicans Aspergillus spp.
Frequency 6 12
Candida glabrata
5
Candida krusei
2
Candida kefyr
2
Mucorales spp.
2
Candida parapsilosis
1
Trichosporon asahii
1
Cryptococcus neoformans
1
The variables that remained as significant independent risk factors associated with fungal infection episodes in that analysis were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90–64.73, p \ 0.001), CMV infection (OR 18.54, 95 % CI 9.01–38.17, p \ 0.001), and the presence of DM (OR 6.01, 95 % CI 2.95–12.25, p \ 0.001). Graft Function Eight patients who developed fungal infections (25 %) developed graft loss following the fungal infection due to the infection itself or other reasons. In 93 patients who did not develop infection (33.10 %), graft loss was seen following KT due to several reasons (p = 0.466). Mortality Of 32 patients who developed fungal infections, 17 (53.10 %) died due to their infection. Of 281 patients who did not develop fungal infections, 50 died due to other reasons, with a mortality rate of 17.80 % (p \ 0.001).
Discussion It is known that renal transplant recipients have the lowest rate of fungal infection among all patients who undergo solid organ transplantation. The risk of invasive fungal infection depends on variables such as underlying disease, comorbid factors, surgical technique, and the facility at which the transplantation is performed [9, 10]. In studies that retrospectively
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investigated infectious complications, the incidence of systemic or invasive fungal infection was reported to range between 0.87 and 22 % [4–7, 10]. In our study, the percentage of at least one invasive fungal infection was 10.30 %. This rate was higher compared to most of the previous studies. In our study, the most commonly isolated causal microorganisms were Candida (n = 16, of which six were Candida albicans) and Aspergillus (n = 12) species. Similar findings were reported in the literature. However, cryptococcosis is more common in the USA cohort and mucormycosis is more common in China cohort [4, 5, 10–13]. The differences in invasive fungal infection rates and fungal agents might have been due to number of patients in the study population, underlying diseases, comorbid factors, types of solid organ transplantation, definition criteria for invasive fungal infection, design of study, follow-up duration of patients after transplantation, geographical differences, time for enrollment of the patients, antifungal prophylaxis protocols, and types of immunosuppressive treatment and combinations. Some studies show that TAC is a risk factor for the development of fungal infections [11, 14]. However, some publications suggest that CNIs decrease the development of fungal infections. Calcineurin was demonstrated to play an important role in the virulence and pathogenesis of at least three important opportunistic fungi (Candida, Cryptococcus, and Aspergillus spp.) [15–18]. In a study that prospectively investigated the development of mucormycosis in patients who underwent solid organ transplantation, the use of TAC in the immunosuppressive maintenance therapy decreased the development of mucormycosis fourfold [15]. In another study, it was demonstrated that in solid organ transplant receivers who were using CNI, the dissemination and the mortality of infections due to Cryptococcus species were lower [19]. The median time to onset of infection due to Candida species after transplantation was 105 days, whereas the median time to onset of infection due to Aspergillus species (IPA) was 121 days, consistent with the literature [4, 5, 10, 12–20]. The advanced age, re-transplantation, ATG induction therapy, use of broad-spectrum antibiotics, acute rejection episodes, CMV infection, leukopenia, use of TAC or MMF in the maintenance therapy, delayed
Mycopathologia
wound-healing, the presence of DM, a prolonged hospital stay, DM-related end-stage renal disease, and having received dialysis for at least 4 years before the transplantation were reported as independent risk factors for invasive fungal infections in the literature [4, 5, 11, 13]. In our study, we determined that the presence of antibiotic treatment within the previous 3 months increased the development of fungal infections 15.88fold, the presence of DM increased them 6.01-fold, and CMV infection increased them 18.54-fold. The usage of broad-spectrum antibiotic alters the gastrointestinal tract microbiota and causes the Candida spp. colonization and invasion [21]. The usage of broad-spectrum antibiotics was reported as an independent risk factor for Candida spp. infections [22]. We know that CMV infection indirectly caused immunosuppression [23]. It was reported that reduced leukocyte response and cell-mediated immunity in DM [24]. We believe that there is no key risk factor for invasive fungal infection in KT patients. On the other hand, CMV infection, DM, usage of broad-spectrum antibiotics, TAC, and rejection are most common risk factors in the literature. However, all of the risk factors above except usage of broad-spectrum antibiotics caused increasing immunosuppression. We believe that the cumulative of risk factors-related immunosuppression is major determinant of development of invasive fungal infection in KT patients. As seen in all solid organ transplant recipients, those who undergo KT have a high mortality rate from fungal infections. Mortality rates vary by the causal factor of the infection and are reported to be 23–71 % for infections caused by Candida species and 20–100 % for infections caused by Aspergillus species [14]. Especially in IPA and central nervous system aspergillosis, mortality rates are approximately 100 % [25–27]. Rosenhagen et al. [28] retrospectively examined the medical records of 170 patients who underwent liver transplantation between 2001 and 2004. They detected proven IPA in two patients (1.20 %), probable IPA in seven patients (4.10 %), and possible IPA in five patients (2.90 %). Of these 14 patients, 13 (92 %) died within the first month after diagnosis. In another study, for IPA that developed in solid organ transplant recipients, the mortality rate was reported to be 34.40 % [29]. Pappas et al. [10] reported that 12-month survival after fungal infection was
59 % for invasive aspergillosis, 66 % for invasive candidiasis, and 73 % for cryptococcosis. In our study, in renal transplant recipients, the mortality rate from fungal infections was 53.10 % (61.5 % for IPA), consistent with the previous studies. We believe that delayed diagnosis contributes to these high mortality rates. On the other hand, it is difficult to compare the mortality rates due to differences in the time of diagnosis, treatment protocols, and follow-up duration of the patients. Especially in neutropenic patients, the investigation of GM antigen in the serum and on BAL for early diagnosis of IPA is quite promising [30, 31]. It has been reported that in solid organ transplant recipients, BAL GM levels were diagnostically more valuable than serum GM levels [32]. In our study, of 13 patients diagnosed with IPA, eight had positive serum GM testing. In all 3 patients in whom GM was investigated by BAL, the results were positive. During the last several years, an increase has been observed in cases of mucormycosis [33, 34]. While the rhinocerebral form is more commonly seen in diabetic patients, solid organ transplant recipients more commonly exhibit the pulmonary form. Mortality rates range between 52 and 92 % [15, 35]. In our study, one of the two patients who had rhinocerebral form died. The limitations of our study are that it is retrospective, single-center, and small and that it includes a long-term cohort. However, the strength of our study is that all of the KT patients were under well-organized and regular follow-up by the transplant team. Consequently, despite their low incidence, fungal infections remain an important complication in renal transplant recipients. Despite new and strong antifungal agents, the mortality of invasive fungal infections is still high in all transplant recipients. In the surviving patients, serious complications, such as graft loss, may develop. Early diagnosis and treatment of fungal infections are not always possible. Invasive fungal infection should be considered in KT patients who had CMV infection or DM or antibiotic treatment history within the 3 months. Serum and BAL GM test should be done in these patients for diagnosis of invasive aspergillosis, especially those not responding to antibiotic treatment of pneumonia. Acknowledgments The authors declare that they have no conflict of interest. The authors alone are responsible for the content and the writing of the paper.
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References 1. Ersoy A, Yıldız A. Bo¨brek Transplantasyonunda Viral Olmayan Enfeksiyo¨z Hastalıklarda Medikal Tedavi. Tu¨rkiye Klinikleri J Nephrol (Special Topics). 2010;3:55–62. 2. Singh N. Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy. Clin Infect Dis. 2000;31:545–53. 3. Badiee P, Alborzi A. Invasive fungal infections in renal transplant recipients. Exp Clin Transpl. 2011;9:355–62. 4. Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transpl. 2006;20:401–9. 5. Altiparmak MR, Apaydin S, Trablus S, et al. Systemic fungal infections after renal transplantation. Scand J Infect Dis. 2002;34:284–8. 6. Veroux M, Giuffrida G, Corona D, et al. Infective complications in renal allograft recipients: epidemiology and outcome. Transpl Proc. 2008;40:1873–6. 7. De Pauw B, Walsh TJ, Donnelly JP, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) Consensus Group. 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;46:1813–21. 8. Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian Society of Transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transpl. 2005;5:218–27. 9. Patel R. Infections in recipients of kidney transplants. Infect Dis Clin N Am. 2001;15:901–51. 10. 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;50:1101–11. 11. Abbott KC, Hypolite I, Poropatich RK, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis. 2001;3:203–11. 12. Einollahi B, Lessan-Pezeshki M, Pourfarziani V, et al. Invasive fungal infections following renal transplantation: a review of 2410 recipients. Ann Transpl. 2008;13:55–8. 13. Chen G, Zhang Z, Gu J, et al. Incidence and Risk Factors For Pulmonary Mycosis in Kidney Transplantation. Transplant Proc. 2010;42:4094–8. 14. Lecompte T, Garzoni C, Mueller N, et al. Fungal infections in solid organ transplant recipients in the Swiss Transplant Cohort Study. 52nd ICAAC, 9–12 Sep 2012, T-343, San Francisco. 15. 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;200:1002–11. 16. Blankenship JR, Wormley FL, Boyce MK, et al. Calcineurin is essential for Candida albicans survival in serum and virulence. Eukaryot Cell. 2003;2:422–30.
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17. Odom A, Muir S, Lim E, et al. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997;16:2576–89. 18. Steinbach W, Cramer RA, Perfect BZ, et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell. 2006;5:1091–103. 19. 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;195:756–64. 20. Zhang XD, HU XP, Yin H, et al. Aspergillus pneumoniae in renal transplant recipients. Chin Med J. 2008;128:791–4. 21. Mason KL, Downward JRE, Mason KD, et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun. 2012;80:3371–80. 22. Yapar N. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014;10:95–105. 23. Roman A, Manito N, Campistol JM, et al. The impact of the prevention strategies on the direct effects of CMV infection in solid organ transplant recipients. Transpl Rev. 2014;28: 84–91. 24. Rajagopalan S. Serious infections in elderly patients with diabetes mellitus. Clin Infect Dis. 2005;40:990–6. 25. Chugh KS, Sakhuja V, Jain S, et al. High mortality in systemic fungal infections following renal transplantation in third-world countries. Nephrol Dial Transpl. 1993;8:168. 26. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality: systematic review of the literature. Clin Infect Dis. 2001; 32:358. 27. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine. 1999;78:123. 28. Rosenhagen M, Feldhues R, Schmidt J, et al. A risk profile for invasive aspergillosis in liver transplant recipients. Infection. 2009;37:313–9. 29. Baddley JW, Andes DR, Marr KA, et al. Factors associated with in transplant patients with invasive aspergillosis. Clin Infect Dis. 2010;50:1559–67. 30. Maertens J, Theunissen K, Verbeken E, et al. Prospective clinical evaluation of lower cut-offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients. Br J Haematol. 2004;126:852–60. 31. Guo YL, Chen YQ, Wang K, Qin SM, Wu C, Kong JL. Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review. Chest. 2010;138:817–24. 32. Tabarsi P, Soraghi A, Marjani M, et al. Comparison of serum and bronchoalveolar lavage galactomannan in diagnosing invasive aspergillosis in solid organ transplant recipients. Exp Clin Transpl. 2012;10:278–81. 33. Bitar D, Cauteren DV, Lanternier F, et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006. Emerg Infect Dis. 2009;15(9):1395–401. 34. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. 35. Einollahi B, Lessan-Pezeshki M, Aslani J, et al. Two decades of experience in mucormycosis after kidney transplantation. Ann Transpl. 2011;16:44–8.
Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors Sezin Zorlu Sahin • Halis Akalin • Alparslan Ersoy • Abdulmecit Yildiz • Go¨khan Ocakoglu • Ezgi Demirdo¨ven Cetinoglu • Og˘uzhan Sıtkı Dizdar • Esra Kazak • Beyza Ener
Received: 30 October 2014 / Accepted: 11 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Background Invasive fungal infections are a major cause of morbidity and mortality among renal transplant recipients. Objectives The aim of this study was to investigate the frequency and risk factors for fungal infections in renal transplant recipients. Methods We retrospectively evaluated all kidney transplant recipients at our center from December 1988 to June 2010 for the epidemiology, spectrum, risk factors, and mortality of invasive fungal infections. Results In 32 patients (10.30 %), at least one fungal infection developed after the transplantation. The most common pathogens causing fungal infections in our
patients were Candida spp. and Aspergillus spp. The independent risk factors associated with invasive fungal infection episodes were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90–64.73, p \ 0.001), cytomegalovirus infection (OR 18.54, 95 % CI 9.01–38.17, p \ 0.001), and the presence of diabetes mellitus (OR 6.01, 95 % CI 2.95–12.25, p \ 0.001). Mortality was significantly higher among patients with fungal infections than among other patients (53.10 and 17.80 %, respectively; p \ 0.001). Conclusions It is difficult to diagnose and treat fungal infections early, and it can be useful to determine independent risk factors in order to identify and treat high-risk patients.
S. Z. Sahin H. Akalin (&) E. Kazak B. Ener Department of Microbiology and Infectious Diseases, Uludag University Medical School, 16059 Gorukle, Nilufer, Bursa, Turkey e-mail: [email protected]
A. Yildiz e-mail: [email protected]
S. Z. Sahin e-mail: [email protected]
G. Ocakoglu Department of Biostatistics, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
E. Kazak e-mail: [email protected] B. Ener e-mail: [email protected] A. Ersoy A. Yildiz O. S. Dizdar Division of Nephrology, Department of Internal Medicine, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
O. S. Dizdar e-mail: [email protected]
E. D. Cetinoglu Department of Chest Diseases, Uludag University Medical School, 16059 Bursa, Turkey e-mail: [email protected]
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Mycopathologia
Keywords Kidney transplantation Fungal infection Invasive aspergillosis Candida infections
Introduction Solid organ transplant recipients comprise a growing and increasingly important group of immunocompromised hosts. Despite considerable progress in immunosuppressive and supportive treatments, a number of factors still interfere with the complete success of kidney transplantation (KT) [1]. The incidence of fungal infections varies between 1 and 14 % in renal transplant recipients [2]. Opportunistic fungi, such as Aspergillus species, species in the Mucorales order, Candida species, and Cryptococcus neoformans, cause most infections. Symptoms of systemic fungal infections are non-specific, particularly in the early stages [3]. Invasive fungal infections following KT remain a major cause of morbidity and death [1]. Many studies have investigated the epidemiology of fungal infections in renal transplant recipients [4–6]. Determining the risk factors for the development of fungal infections in this population can provide early diagnosis and treatment that may reduce mortality. Therefore, the objective of this study is to identify the epidemiology of invasive fungal infections and the risk factors affecting the development of infections and their prognosis in renal transplant recipients.
Materials and Methods This study retrospectively evaluated the medical records of 367 recipients of kidney transplants from December 1988 to June 2010 at the transplant unit of a university hospital. The study protocol was approved by our Institutional Review Board and was conducted in accordance with the Declaration of Helsinki. Ten patients who were under the age of 18 years at the time of KT, 13 patients with missing data in their charts, 14 patients with superficial Candida spp. infections, and 17 patients with possible IPA were excluded from the study. In the remaining 313 kidney transplant recipients, the following variables were assessed: age; gender; cause of end-stage renal disease; serology for cytomegalovirus (CMV),
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hepatitis B, and hepatitis C virus (HCV) prior to transplantation; dialysis type and duration; donor type (cadaveric or living); acute or chronic rejection; comorbid diseases; a history of tuberculosis; and initial immunosuppressive regimens. We identified the patients who had been diagnosed with an invasive fungal infection and who were treated at least once since the KT. Retrospective chart reviews of clinical and microbiological data were performed. Diagnosis was based on clinical, radiological, and specific laboratory (appropriate culture and/or histopathological examination) findings. Fungal infections were classified according to the site from which they originated. Invasive (hematogenous) fungal infections were included. Cutaneous and mucosal infections were considered superficial infections and were excluded. In the patients diagnosed with invasive pulmonary aspergillosis (IPA), the IPA was classified as ‘‘proven,’’ ‘‘probable,’’ or ‘‘possible’’ according to the EORTC/MSG-2008 criteria for fungal infections. ‘‘Possible’’ cases were excluded [7]. After 2003, the galactomannan antigen test (Platelia aspergillus; BioRad, France) was included for the presumptive diagnosis of IPA. Serum (cutoff = 0.5) and, if obtained, bronchoalveolar specimens (cutoff = 1) were evaluated for the presence of antigen. The definitions of CMV infection and CMV disease were followed according to Canadian Transplantation Society Guidelines [8]. For the patients diagnosed with a fungal infection, note was made of the last immunosuppressive agent combination used as maintenance therapy before the diagnosis, the amount of immunosuppressive agents administered within the previous 1 month, elevated levels of drugs, hospitalization within the last 3 months before diagnosis, a history of antibiotic treatment within the last 3 months before diagnosis, and CMV infections that had developed within the previous 6 months. In the patients who did not develop a fungal infection, determination was made of the last immunosuppressive agent combinations used during the last visit, the last level of drug measured, hospitalization at any time after KT, and the history of bacterial infection. In all patients, CMV infection occurring at any time after KT, and the treatments administered, were recorded. We decided the death whether or not due to invasive fungal infection based on clinical, laboratory, and host findings.
Mycopathologia
In all patients, total transplant time (days) was calculated from the difference between the last visit or death and the date on which KT was performed. In the patients who developed fungal infections, transplantation time at the time of diagnosis (days) was calculated from the difference between the date of fungal infection diagnosis and the date on which KT was performed. All patients received initial immunosuppressive therapy with prednisolone (KS), antimetabolites [mycophenolate mofetil (MMF), sodium-MMF, or azathioprine (AZA)] combined with calcineurin inhibitors (CNIs) [cyclosporine (CsA) or tacrolimus (TAC)] or mTOR inhibitors [sirolimus (SRL) or everolimus (EVL)] with interleukin-2 receptor antagonists (IL2ra) or antithymocyte globulin (ATG) induction, if required. All patients received intra-operative methylprednisolone (500 mg intravenously) and maintenance prednisolone (1–2 mg/kg per day orally). Surgical prophylaxis consisted of a single dose of cefazoline. Antimicrobial prophylaxis also included trimethoprim/sulfamethoxazole for the first 6–9 months after KT. Antiviral prophylaxis was with acyclovir. Isoniazid prophylaxis was administered for 9 months in recipients with a history of tuberculosis or [5 mm positivity on tuberculin skin test. Statistical Analysis Statistical analysis of the data was performed using SPSS 13.0 software (Chicago, IL). Categorical variables were given as frequency and percentage, and continuous variables were given as median (minimum–maximum). For inter-group comparison of the categorical variables, Chi-square test was used. In the inter-group comparison of the continuous variables, Mann–Whitney U test was used. In order to determine the independent risk factors for the development of fungal infection and IPA development, forward stepwise logistic regression analysis was performed, and risk factors were reported with p values, odds ratio (OR), and 95 % confidence interval (CI). In the study, p \ 0.05 was considered to be statistically significant.
Results For all patients (n = 313), median age was 33 years (18–69), and of these, 200 (63.90 %) were men and
113 (36.10 %) were women. Before KT, 220 patients had received hemodialysis, 28 patients had received peritoneal dialysis, and 32 patients had received both dialysis therapies. In 32 patients (10.30 %), at least one fungal infection developed after the transplantation. Of these 32 patients, a total of 36 (11.50 %) fungal infection episodes developed: one episode in each of 28 patients and two episodes in each of four patients. Distribution of gender, type of dialysis, donor type, and human leukocyte antigen (HLA) tissue compatibility were similar in the patients who developed fungal infections and those who did not. The patients who developed fungal infections had significantly more advanced ages, higher diabetes mellitus (DM) rates, and a fewer days post-KT compared to the patients who did not develop fungal infections (p \ 0.001, p \ 0.001, and p \ 0.001, respectively) (Table 1). All patients received at least two immunosuppressive agents. In both groups, the most commonly used regimen was the combination of KS?TAC?MMF (Table 2). The rate of immunosuppressive regimen use was similar in both groups. In 32 patients diagnosed with a fungal infection, the blood level of the immunosuppressive agent was measured within the last month before the diagnosis and eight patients (25 %) were found to have elevated levels. On the last visit of 272 patients who did not develop a fungal infection, 33 patients (12.10 %) were found to have elevated blood levels of the immunosuppressive agent (p = 0.055). Cytomegalovirus infection was detected in 10 patients who developed fungal infections (31.30 %) and in 24 patients who did not develop fungal infections (8.50 %) (p \ 0.001). CMV disease was not diagnosed in these patients. Ten of 32 patients (31.30 %) who developed a fungal infection had experienced the development of a CMV infection within the last 6 months before the fungal infection, and of these, nine (28.10 %) were treated with ganciclovir. Twelve patients who did not develop fungal infections (4.30 %) were given ganciclovir after KT (p \ 0.001). Twenty-four patients who developed fungal infections (75 %) had a history of hospitalization within the last 3 months before the diagnosis. Ninety-two patients who did not develop fungal infections (32.70 %) were hospitalized at least once after KT (p \ 0.001). Twenty-five patients who
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Mycopathologia Table 1 Characteristics of recipients with and without fungal infection Variables
Fungal infection group (n = 32)
Non-fungal infection group (n = 281)
p value
Sex (male/female)
18/14
182/99
Age (years)
36 (18–69)
32 (18–69)
Donor type (cadaveric/living) Dialysis type [n (%)]
12/20
94/186
0.805 0.402
Preemptive
3 (9.4)
30 (10.6)
Hemodialysis
21 (65.6)
199 (70.8)
Peritoneal dialysis
2 (6.2)
26 (9.3)
Both dialysis
6 (18.8)
26 (9.3)
0.449 \0.001
Hemodialysis duration (months)
36 (2–228)
24 (1–204)
Transplant duration (days)
344 (23–4237)
1141 (7–6245)
0.064
HLA matching (n)
3 (1–6)
3 (1–6)
0.227
Acute rejection [n (%)]
8 (25)a
40 (14.2)
0.121
Glomerulonephritis
2
36
Hypertension
5
30
Reflux nephropathy
3
18
Urolithiasis
1
11
\0.001
Primary disease (n)
Polycystic kidney disease
1
6
Pyelonephritis Alport syndrome
3 1
8 7
Diabetes mellitus
4
2
Amyloidosis
1
5
Acute tubular necrosis
1
4
Lupus nephritis
1
2
Vasculitis
1
2
Unknown
8
150
16 (50)
51 (18.1)
Diabetes mellitus [n (%)] a
\0.001
Acute rejection episode within last 6 month before the diagnosis of fungal infection
developed fungal infections (78.10 %) had a history of antibiotic treatment that had developed within the last 3 months before the diagnosis. Eighty patients who did not develop fungal infections (28.50 %) had experienced antibiotic treatment at any time after KT (p \ 0.001). Features of Fungal Infections We found IPA in 13 patients, intra-abdominal infection in six patients, Candida pneumonia in four patients, symptomatic urinary tract infection in four patients, candidemia in three patients, central nervous system infection in two patients, rhinocerebral mucormycosis in two patients, and osteomyelitis in two patients.
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When the fungal infections were examined according to the transplantation period during which they developed, the numbers of episodes were four (11.10 %) within the first month after KT (first period), 17 (47.20 %) within 1–6 months after KT (second period), and 15 (41.70 %) beyond 6 months after KT (third period) (Table 3). The median time to onset of the infections due to Candida species after the transplantation was 105 days, whereas the median time to onset of infections due to Aspergillus species (IPA) was 121 days. According to the EORTC/MSG fungal infection criteria, of the IPA attacks, only one (7.70 %) was proved and 12 (92.30 %) were probable. Of 13 patients diagnosed with IPA, eight patients were
Mycopathologia Table 2 Comparison of immunosuppressive regimen ratios in recipients with and without fungal infection Immunosuppressive combination [n (%)]
Fungal infection group (n = 32)
Non-fungal infection group (n = 281)
p value
KS?TAC?MMF
12 (37.5)
116 (41.3)
0.824
KS?CsA?MMF
9 (28.1)
54 (19.2)
0.338
KS?CsA?AZA KS?TAC?AZA
4 (12.5) 2 (6.3)
61 (21.7) 10 (3.6)
0.324 0.352
KS?MMF?SRL/EVL
0
KS?TAC?SRL/EVL
4 (12.5)
KS?CsA?SRL/EVL
0
KS?AZA?SRL
1 (3.1)
15 (5.3)
0.380
12 (4.3)
0.068
5 (1.8)
1.00
1 (0.4)
0.194
KS?CsA/TAC
0
6 (2.0)
1.00
KS?AZA
0
1 (0.4)
1.00
KS corticosteroid, TAC tacrolimus, CsA cyclosporin, AZA azathioprine, MMF mycophenolate mofetil or sodium, SRL sirolimus, EVL everolimus
Table 3 Distribution of 36 fungal infection episodes according to posttransplant period Fungal infection localization [n (%)]
Transplant period 1 month
1–6 months [6 months
IPA
0
8
CNS infectiona
0
0
2
Candidemia
1
1
1
Symptomatic UTI
1
1
2
Candida pneumonia
0
1
3
Osteomyelitisb
0
1
1
Rhinocerebral mucormycosis
0
1
1
Intra-abdominal infection
2
4
0
5
IPA invasive pulmonary aspergillosis, CNS central nervous system, UTI urinary tract infection a
CNS infection: Aspergillus spp. Cryptococcus neoformans in one case b
in
one
case
and
Osteomyelitis: Aspergillus fumigatus in two cases
diagnosed within the second period and five within the third period after KT. In 11 of 13 patients diagnosed with IPA, serum galactomannan (GM) antigen was investigated, and of these patients, eight (72.70 %) had positive test results. In three patients, GM antigen was investigated by bronchoalveolar lavage (BAL) and all had positive test results. Of three patients who had positive test results for BAL GM antigen, blood GM antigen was positive in one patient and negative in the other two.
Of 13 patients diagnosed with IPA, seven were treated with liposomal amphotericin-B, four were treated with caspofungin, and one was treated with voriconazole. One patient was initially treated with caspofungin and was then switched to voriconazole. In the patients diagnosed with IPA, the median of days passed with amphotericin-B was 13 (2–60). Of the patients diagnosed with IPA, eight (61.50 %) died. In all four of the patients in whom a urinary tract infection was detected, the causal microorganisms were Candida species. From the urinary cultures, Candida glabrata was isolated in one patient, Candida krusei was isolated in two patients, and Candida kefyr was isolated in one patient. In three patients, a bloodstream infection was detected. While Candida glabrata was isolated from the blood cultures of two patients, the blood culture of the third patient showed the growth of Candida parapsilosis. Among 36 fungal infection episodes, the causal microorganism was determined by culture or pathologic examination in 32 cases (89 %). Four IPA episodes were diagnosed based on galactomannan positivity in addition to the clinical and host factors. The distribution of the causal microorganisms that could be isolated is shown in Table 4. Risk Factors for Fungal Infection All of the risk factors for development of fungal infection were evaluated with logistic regression analyses. The results of the logistic regression model were found to be statistically significant (p \ 0.001).
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Mycopathologia Table 4 Distribution of the isolated fungi during 32 fungal infection episodes Causative microorganism [n (%)] Candida albicans Aspergillus spp.
Frequency 6 12
Candida glabrata
5
Candida krusei
2
Candida kefyr
2
Mucorales spp.
2
Candida parapsilosis
1
Trichosporon asahii
1
Cryptococcus neoformans
1
The variables that remained as significant independent risk factors associated with fungal infection episodes in that analysis were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90–64.73, p \ 0.001), CMV infection (OR 18.54, 95 % CI 9.01–38.17, p \ 0.001), and the presence of DM (OR 6.01, 95 % CI 2.95–12.25, p \ 0.001). Graft Function Eight patients who developed fungal infections (25 %) developed graft loss following the fungal infection due to the infection itself or other reasons. In 93 patients who did not develop infection (33.10 %), graft loss was seen following KT due to several reasons (p = 0.466). Mortality Of 32 patients who developed fungal infections, 17 (53.10 %) died due to their infection. Of 281 patients who did not develop fungal infections, 50 died due to other reasons, with a mortality rate of 17.80 % (p \ 0.001).
Discussion It is known that renal transplant recipients have the lowest rate of fungal infection among all patients who undergo solid organ transplantation. The risk of invasive fungal infection depends on variables such as underlying disease, comorbid factors, surgical technique, and the facility at which the transplantation is performed [9, 10]. In studies that retrospectively
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investigated infectious complications, the incidence of systemic or invasive fungal infection was reported to range between 0.87 and 22 % [4–7, 10]. In our study, the percentage of at least one invasive fungal infection was 10.30 %. This rate was higher compared to most of the previous studies. In our study, the most commonly isolated causal microorganisms were Candida (n = 16, of which six were Candida albicans) and Aspergillus (n = 12) species. Similar findings were reported in the literature. However, cryptococcosis is more common in the USA cohort and mucormycosis is more common in China cohort [4, 5, 10–13]. The differences in invasive fungal infection rates and fungal agents might have been due to number of patients in the study population, underlying diseases, comorbid factors, types of solid organ transplantation, definition criteria for invasive fungal infection, design of study, follow-up duration of patients after transplantation, geographical differences, time for enrollment of the patients, antifungal prophylaxis protocols, and types of immunosuppressive treatment and combinations. Some studies show that TAC is a risk factor for the development of fungal infections [11, 14]. However, some publications suggest that CNIs decrease the development of fungal infections. Calcineurin was demonstrated to play an important role in the virulence and pathogenesis of at least three important opportunistic fungi (Candida, Cryptococcus, and Aspergillus spp.) [15–18]. In a study that prospectively investigated the development of mucormycosis in patients who underwent solid organ transplantation, the use of TAC in the immunosuppressive maintenance therapy decreased the development of mucormycosis fourfold [15]. In another study, it was demonstrated that in solid organ transplant receivers who were using CNI, the dissemination and the mortality of infections due to Cryptococcus species were lower [19]. The median time to onset of infection due to Candida species after transplantation was 105 days, whereas the median time to onset of infection due to Aspergillus species (IPA) was 121 days, consistent with the literature [4, 5, 10, 12–20]. The advanced age, re-transplantation, ATG induction therapy, use of broad-spectrum antibiotics, acute rejection episodes, CMV infection, leukopenia, use of TAC or MMF in the maintenance therapy, delayed
Mycopathologia
wound-healing, the presence of DM, a prolonged hospital stay, DM-related end-stage renal disease, and having received dialysis for at least 4 years before the transplantation were reported as independent risk factors for invasive fungal infections in the literature [4, 5, 11, 13]. In our study, we determined that the presence of antibiotic treatment within the previous 3 months increased the development of fungal infections 15.88fold, the presence of DM increased them 6.01-fold, and CMV infection increased them 18.54-fold. The usage of broad-spectrum antibiotic alters the gastrointestinal tract microbiota and causes the Candida spp. colonization and invasion [21]. The usage of broad-spectrum antibiotics was reported as an independent risk factor for Candida spp. infections [22]. We know that CMV infection indirectly caused immunosuppression [23]. It was reported that reduced leukocyte response and cell-mediated immunity in DM [24]. We believe that there is no key risk factor for invasive fungal infection in KT patients. On the other hand, CMV infection, DM, usage of broad-spectrum antibiotics, TAC, and rejection are most common risk factors in the literature. However, all of the risk factors above except usage of broad-spectrum antibiotics caused increasing immunosuppression. We believe that the cumulative of risk factors-related immunosuppression is major determinant of development of invasive fungal infection in KT patients. As seen in all solid organ transplant recipients, those who undergo KT have a high mortality rate from fungal infections. Mortality rates vary by the causal factor of the infection and are reported to be 23–71 % for infections caused by Candida species and 20–100 % for infections caused by Aspergillus species [14]. Especially in IPA and central nervous system aspergillosis, mortality rates are approximately 100 % [25–27]. Rosenhagen et al. [28] retrospectively examined the medical records of 170 patients who underwent liver transplantation between 2001 and 2004. They detected proven IPA in two patients (1.20 %), probable IPA in seven patients (4.10 %), and possible IPA in five patients (2.90 %). Of these 14 patients, 13 (92 %) died within the first month after diagnosis. In another study, for IPA that developed in solid organ transplant recipients, the mortality rate was reported to be 34.40 % [29]. Pappas et al. [10] reported that 12-month survival after fungal infection was
59 % for invasive aspergillosis, 66 % for invasive candidiasis, and 73 % for cryptococcosis. In our study, in renal transplant recipients, the mortality rate from fungal infections was 53.10 % (61.5 % for IPA), consistent with the previous studies. We believe that delayed diagnosis contributes to these high mortality rates. On the other hand, it is difficult to compare the mortality rates due to differences in the time of diagnosis, treatment protocols, and follow-up duration of the patients. Especially in neutropenic patients, the investigation of GM antigen in the serum and on BAL for early diagnosis of IPA is quite promising [30, 31]. It has been reported that in solid organ transplant recipients, BAL GM levels were diagnostically more valuable than serum GM levels [32]. In our study, of 13 patients diagnosed with IPA, eight had positive serum GM testing. In all 3 patients in whom GM was investigated by BAL, the results were positive. During the last several years, an increase has been observed in cases of mucormycosis [33, 34]. While the rhinocerebral form is more commonly seen in diabetic patients, solid organ transplant recipients more commonly exhibit the pulmonary form. Mortality rates range between 52 and 92 % [15, 35]. In our study, one of the two patients who had rhinocerebral form died. The limitations of our study are that it is retrospective, single-center, and small and that it includes a long-term cohort. However, the strength of our study is that all of the KT patients were under well-organized and regular follow-up by the transplant team. Consequently, despite their low incidence, fungal infections remain an important complication in renal transplant recipients. Despite new and strong antifungal agents, the mortality of invasive fungal infections is still high in all transplant recipients. In the surviving patients, serious complications, such as graft loss, may develop. Early diagnosis and treatment of fungal infections are not always possible. Invasive fungal infection should be considered in KT patients who had CMV infection or DM or antibiotic treatment history within the 3 months. Serum and BAL GM test should be done in these patients for diagnosis of invasive aspergillosis, especially those not responding to antibiotic treatment of pneumonia. Acknowledgments The authors declare that they have no conflict of interest. The authors alone are responsible for the content and the writing of the paper.
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References 1. Ersoy A, Yıldız A. Bo¨brek Transplantasyonunda Viral Olmayan Enfeksiyo¨z Hastalıklarda Medikal Tedavi. Tu¨rkiye Klinikleri J Nephrol (Special Topics). 2010;3:55–62. 2. Singh N. Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy. Clin Infect Dis. 2000;31:545–53. 3. Badiee P, Alborzi A. Invasive fungal infections in renal transplant recipients. Exp Clin Transpl. 2011;9:355–62. 4. Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transpl. 2006;20:401–9. 5. Altiparmak MR, Apaydin S, Trablus S, et al. Systemic fungal infections after renal transplantation. Scand J Infect Dis. 2002;34:284–8. 6. Veroux M, Giuffrida G, Corona D, et al. Infective complications in renal allograft recipients: epidemiology and outcome. Transpl Proc. 2008;40:1873–6. 7. De Pauw B, Walsh TJ, Donnelly JP, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) Consensus Group. 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;46:1813–21. 8. Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian Society of Transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transpl. 2005;5:218–27. 9. Patel R. Infections in recipients of kidney transplants. Infect Dis Clin N Am. 2001;15:901–51. 10. 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;50:1101–11. 11. Abbott KC, Hypolite I, Poropatich RK, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis. 2001;3:203–11. 12. Einollahi B, Lessan-Pezeshki M, Pourfarziani V, et al. Invasive fungal infections following renal transplantation: a review of 2410 recipients. Ann Transpl. 2008;13:55–8. 13. Chen G, Zhang Z, Gu J, et al. Incidence and Risk Factors For Pulmonary Mycosis in Kidney Transplantation. Transplant Proc. 2010;42:4094–8. 14. Lecompte T, Garzoni C, Mueller N, et al. Fungal infections in solid organ transplant recipients in the Swiss Transplant Cohort Study. 52nd ICAAC, 9–12 Sep 2012, T-343, San Francisco. 15. 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;200:1002–11. 16. Blankenship JR, Wormley FL, Boyce MK, et al. Calcineurin is essential for Candida albicans survival in serum and virulence. Eukaryot Cell. 2003;2:422–30.
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17. Odom A, Muir S, Lim E, et al. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997;16:2576–89. 18. Steinbach W, Cramer RA, Perfect BZ, et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell. 2006;5:1091–103. 19. 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;195:756–64. 20. Zhang XD, HU XP, Yin H, et al. Aspergillus pneumoniae in renal transplant recipients. Chin Med J. 2008;128:791–4. 21. Mason KL, Downward JRE, Mason KD, et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun. 2012;80:3371–80. 22. Yapar N. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014;10:95–105. 23. Roman A, Manito N, Campistol JM, et al. The impact of the prevention strategies on the direct effects of CMV infection in solid organ transplant recipients. Transpl Rev. 2014;28: 84–91. 24. Rajagopalan S. Serious infections in elderly patients with diabetes mellitus. Clin Infect Dis. 2005;40:990–6. 25. Chugh KS, Sakhuja V, Jain S, et al. High mortality in systemic fungal infections following renal transplantation in third-world countries. Nephrol Dial Transpl. 1993;8:168. 26. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality: systematic review of the literature. Clin Infect Dis. 2001; 32:358. 27. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine. 1999;78:123. 28. Rosenhagen M, Feldhues R, Schmidt J, et al. A risk profile for invasive aspergillosis in liver transplant recipients. Infection. 2009;37:313–9. 29. Baddley JW, Andes DR, Marr KA, et al. Factors associated with in transplant patients with invasive aspergillosis. Clin Infect Dis. 2010;50:1559–67. 30. Maertens J, Theunissen K, Verbeken E, et al. Prospective clinical evaluation of lower cut-offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients. Br J Haematol. 2004;126:852–60. 31. Guo YL, Chen YQ, Wang K, Qin SM, Wu C, Kong JL. Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review. Chest. 2010;138:817–24. 32. Tabarsi P, Soraghi A, Marjani M, et al. Comparison of serum and bronchoalveolar lavage galactomannan in diagnosing invasive aspergillosis in solid organ transplant recipients. Exp Clin Transpl. 2012;10:278–81. 33. Bitar D, Cauteren DV, Lanternier F, et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006. Emerg Infect Dis. 2009;15(9):1395–401. 34. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. 35. Einollahi B, Lessan-Pezeshki M, Aslani J, et al. Two decades of experience in mucormycosis after kidney transplantation. Ann Transpl. 2011;16:44–8.
