Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study

Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study

ORIGINAL ARTICLE PARASITOLOGY Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrosp...

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ORIGINAL ARTICLE

PARASITOLOGY

Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study W. Clemente1, E. Vidal2,6, E. Girão12, A. S. D. Ramos2,3, F. Govedic2,4, E. Merino13, P. Muñoz2,5, N. Sabé2,7, C. Cervera2,8, G. F. Cota1, E. Cordero2,9, A. Mena2,10, M. Montejo2,11, F. López-Medrano2,4, J. M. Aguado2,4, P. Fernandes12, M. Valerio2,5, J. Carratalá2,7, A. Moreno2,8, J. Oliveira1, P. H. O. Mourão1 and J. Torre-Cisneros6 1) Hospital das Clínicas da Universidade Federal de Minas Gerais (HC/UFMG), Belo Horizonte, Minas Gerais, Brazil, 2) Spanish Network for Research in Infectious Diseases (REIPI RD12/0015), Instituto de Salud Carlos III, 3) Department of Infectious Diseases, University Hospital Puerta de Hierro, 4) Infectious Diseases Unit, University Hospital “12 de Octubre”, 5) Department of Clinical Microbiology and Infectious Diseases, University General Hospital Gregorio Marañón, Madrid, 6) Infectious Disease Unit, Maimonides Institute for Research in Biomedicine of Córdoba (Reina Sofía University Hospital/University of Córdoba), Córdoba, Spain, 7) Infectious Diseases Service, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Universitari de Bellvitge, 8) Infectious Diseases Service, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 9) Infectious Diseases Service, University Hospital Virgen del Rocío, Sevilla, 10) Microbiology Service, University Hospital Son Espases, Palma de Mallorca, 11) Infectious Diseases Unit, University Hospital de Cruces, Bilbao, Spain, 12) Hospital Universitário Walter Cantidio (HUWC) da Universidade Federal do Ceará (HUWC/UFCE), Fortaleza, Ceará, Brazil and 13) Infectious Disease Unit, University General Hospital, Alicante, Spain

Abstract Visceral leishmaniasis (VL) is a rare disease in solid-organ transplant (SOT) recipients. Therefore, little is known about the risk factors and disease behavior in the transplant setting. This multicenter, matched case–control study (1:2 ratio) was designed to determine the risk factors, clinical features and outcomes of VL among this population. Control and case subjects were matched by center, transplant type and timing. Thirty-six VL cases were identified among 25 139 SOT recipients (0.1%). VL occurred 5.7-fold more frequently in Brazil than in Spain, presenting a median time of 11 months after transplantation. High-dose prednisone in the preceding 6 months was associated with VL. Patients were diagnosed over 1 month after symptom onset in 25% of cases. Thirty-one patients (86%) were febrile upon diagnosis, 81% exhibited visceromegaly and 47% showed pancytopenia. Concomitant infection was common. Parasites were identified in 89% of patients; the remaining patients were diagnosed by serology. The majority of the patients received amphotericin B. Relapses occurred in 25.7% of cases, and the crude mortality rate was 2.8%. VL after SOT is related to the VL prevalence in the general population. Delayed diagnosis frequently occurs. Liposomal amphotericin is the most commonly used therapy; mortality is low, although relapses are common. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Keywords: Parasitic infection, posttransplant infection, solid-organ transplant, tropical diseases, visceral leishmaniasis Original Submission: 5 March 2014; Revised Submission: 25 August 2014; Accepted: 5 September 2014 Editor: E. Bottieau Article published online: XXX

Corresponding author: W. T. Clemente, Liver and Pancreas Transplant Unit, Instituto Alfa de Gastroenterologia do Hospital das Clínicas da UFMG, Departamento de Propedêutica Complementar da Faculdade de Medicina da UFMG, Av, Prof, Alfredo Balena, 190, Belo Horizonte, MG, Brazil E-mail: [email protected]

Introduction Visceral leishmaniasis (VL) is an uncommon disease even in endemic zones. Solid-organ transplant (SOT) recipients have an increased risk of VL, but the effect of higher incidence rates on the frequency of VL in SOT is unknown. VL can occur after

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primary infection through a sandfly bite, via transplanted organs, blood products or reactivation of latent infections. Although more than 100 VL case reports have been described and reviewed in the literature [1–5], there is a lack of information regarding risk factors, the role of immunosuppression and disease outcome across different types of transplantation. The recognition and management of VL remains challenging even in transplant recipients from endemic regions [6–11]. The present study was designed to determine the frequency, risk factors, clinical characteristics and prognosis of VL in SOT in two countries, Spain and Brazil, in which leishmaniasis is endemic, although with different incidences in the general population.

Materials and methods Setting and study population This retrospective study was conducted at ten Spanish hospitals (included in the Spanish Network for Research in Infectious Diseases [REIPI]) and two centers in Brazil. All patients diagnosed with VL from January 1995 to June 2012 and January 1995 to December 2011 at the participating transplant centers in Spain and Brazil, respectively, were included. The patients were identified using transplantation program databases. The initial identification was followed by a detailed medical records review. The study was approved by the institutional review board of the IMIBIC (Instituto Maiomônides de Investigación Biomédica de Córdoba)-Hospital Universitario Reina Sofia. For risk factor analysis, a matched case–control study (1:2 ratio) was performed. The control subjects were matched by three factors: institution, type of transplantation and time of follow-up after transplantation. Recipients who underwent transplantation immediately before and after the index case patient and who survived at least as long as that patient’s elapsed time to the diagnosis of VL were eligible to be control subjects. Definitions A VL diagnosis was established on the basis of clinical manifestations combined with the demonstration of parasites using one of the following methods: microscopy, culture, polymerase chain reaction (PCR) and positive serology (indirect immunofluorescence 1/80 or direct agglutination test [DAT rK39] or enzyme immunoassay). The time of event was defined as the time of VL diagnosis after transplant. Pancytopenia was defined as haemoglobin <12 g/dL, leukocytes <4000/mm3 and platelets <150 000/mm3, and severe pancytopenia was established as haemoglobin <10 g/dL, leukocytes <1000/mm3 and platelets <100 000/mm3.

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VL was considered cured if a patient remained asymptomatic for 1 month after the end of treatment. For patients who survived longer than 1 month, recurrence or relapse was diagnosed when symptoms, signs or laboratory abnormalities reappeared at least one month after the end of treatment. Mortality was considered related to VL when the infection had not been cured by the time of death. The following variables were analysed as potential risk factors: sex, age, diabetes mellitus within the preceding 6 months, human immunodeficiency virus (HIV) serology, previous VL, prophylaxis with intravenous amphotericin B and cytomegalovirus disease or replication within the preceding 6 months. An immunosuppressive status at the time of the event was defined as follows: an elevated mean calcineurin inhibitor level within the preceding 30 days (>15 μg/mL for tacrolimus and >300 ng/mL for cyclosporin), prior use of everolimus and sirolimus, history of high-dose prednisone therapy within the preceding 6 months (20 mg of prednisone for >1 month or >2 pulses of 1 g of intravenous methylprednisolone), lymphocyte-depleting antibody treatment within the preceding 12 months and allograft rejection within the preceding 6 months. Microbiologic studies Leishmania serology, antigen detection, PCR and culture were performed at each center using routine tests, according to the manufacturers’ instructions. Statistical analysis To detect differences between groups, the χ2 test (or Fisher’s exact test, when indicated) was used with continuity correction for categorical variables, and the Student’s t test was used for continuous variables. The VL-free survival time was calculated by Kaplan-Meier curves and compared by the log-rank test. Univariate and multivariate analyses (binary logistic regression) were performed to identify potential risk factors. All reported p values are two-tailed.

Results Epidemiology The frequency of VL by country and transplanted organ is shown in Table 1. Thirty-six VL cases were identified among 25 139 SOT recipients at 12 participating hospitals, representing 0.1% of all transplant recipients. VL cases appeared in 25 (0.2%) of 12 895 kidney recipients, four (0.05%) of 8681 liver recipients, six (0.2%) of 2669 heart recipients and one (0.2%) of 894 lung recipients. The frequency of VL was 5.7-fold higher in Brazil (0.5%) than in Spain (0.1%).

Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, xxx 1–7

Please cite this article in press as: Clemente W, et al., Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study, Clinical Microbiology and Infection (2014), http://dx.doi.org/10.1016/j.cmi.2014.09.002

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TABLE 1. Frequency of VL in solid-organ transplant recipients at ten Spanish and two Brazilian hospitals Total

Spain

Brazil

Transplant

Cases per total transplants

% (95% CI)

Cases per total transplants

% (95% CI)

Cases per total transplants

% (95% CI)

RR (95% CI)a, p

Kidney Liver Heart Lung All

25/12 895 4/8681 6/2669 1/894 36/25 139

0.2% (0.2–0.3) 0.05% (0.01–0.1) 0.2% (0.1–0.5) 0.1% (0.00–0.5) 0.1% (0.1–0.2)

15/11 819 1/7360 5/2535 1/877 22/22 591

0.1% (0.1–0.2) 0.01% (0.0–0.1) 0.2% (0.1–0.4) 0.1% (0.0–0.6) 0.1% (0.1–0.2)

10/1076 3/1321 1/134 0/17 14/2548

0.9% (0.5–1.6) 0.2% (0.1–0.6) 0.7 (0.04–3.6) — 0.5% (0.3–0.9)

7.4 (3.1–17.4), <0.001 16.1 (1.57–99.9), 0.01 0.3 (0.03–6.0), 0.27 — 5.7 (2.7–11.6), <0.001

VL, visceral leishmaniasis; RR, relative risk; CI, confidence interval. Comparison of frequencies in Spain and Brazil.

a

The median time to the diagnosis of VL after transplantation was 11 months (range 2–150 months), 7 months in Brazil and 17 months in Spain. Twelve (33.3%) of the 36 patients were diagnosed with VL within the first 6 months after transplantation. Risk factors for VL Risk factors were analysed for the 36 case patients and 72 control subjects (Table 2). No patients or control subject received prophylaxis with amphotericin B. Treatment in the preceding 6 months with high-dose prednisone to prevent organ rejection was the only factor significantly associated with VL (Table 3). Clinical characteristics of VL Table 4 presents the clinical characteristics of the 36 SOT patients with VL. The average follow-up was 51 months. Thirtyone patients (86%) were febrile at the time of diagnosis. Visceromegaly (splenomegaly plus hepatomegaly) was observed in ~81% of patients, and adenomegaly was observed in two patients (5.6%). Pancytopenia was observed in 17 patients (47%), but none had severe pancytopenia. Three patients exhibited septic shock at the time of presentation. Thirteen VL patients (36.1%) had concomitant infections. Diagnosis The diagnosis was based on the clinical manifestations of VL and evidence of the parasite by microscopy (n = 29), culture

(n = 11) or PCR (n = 3) in 32 patients (88.9%). The VL diagnosis was established solely on the basis of positive serology in four patients (13.8%, 4/29). Leishmania amastigotes were observed in the peripheral blood in three of the four patients in whom this test was performed. Serology was positive in 22 (75.9%) of 29 patients: DAT rK39 in seven, indirect immunofluorescence in 11, enzyme immunoassay in two and urinary antigen in one. The method for diagnosis was not recorded in one case (Table 5). Treatment and outcomes N-methyl-glucamine (30 mg/kg per day for 20 days) was administered to nine patients (26%), although the treatment was changed to liposomal amphotericin B (LamB) in four cases because of intolerance. One patient was prescribed miltefosine and was cured after 28 days of treatment. This patient experienced recurrence 2 months after treatment and was successfully treated again with the same protocol. Amphotericin B, regardless of the formulation, was the most widely used treatment drug (n = 30/36); it was prescribed as a first, second or combined treatment option. LamB was well tolerated, and in no instance was treatment stopped because of adverse effects. The median duration of LamB treatment was 10 days (Table 6). One patient died on the third day of treatment. Among the patients who lived longer than 1 month (n = 35), two patients presented recrudescence of symptoms soon after treatment and were defined as not cured. Thirty-three patients (94.2%) were considered to be cured at the 1-month follow-up.

TABLE 2. Univariate analysis of risk factors for VL in SOT recipients Variable

Patients (n [ 36), n (%)

Control subjects (n [ 72), n (%)

OR (95% CI)

p

Male sex Age, years, median (range) Diabetes mellitus CMV disease within preceding 6 months CMV replication within preceding 6 months Receipt of lymphocyte-depleting antibody within preceding 12 months Use of cyclosporin vs. tacrolimus Use of mycophenolate Receipt of high-dose steroids within preceding 6 monthsa

27 (75.0) 46 (14–76) 7 (19.4) 5 (13.9) 7 (19.4) 5 (13.9) 31 (86.1) 21 (58.3) 15 (41.7)

54 (75.0) 45 (10–76) 18 (25.0) 5 (6.9) 6 (8.3) 7 (9.7) 65 (90.3) 42 (58.3) 16 (22.2)

1.0 0.8 1.4 0.5 0.4 0.7 1.5 1.0 2.5

1.00 0.50 0.52 0.30 0.12 0.53 0.53 1.00 0.03

(0.4–2.5) (0.4–1.9) (0.5–3.7) (0.1–1.7) (0.1–1.2) (0.2–2.3) (0.4–5.1) (0.4–2.2) (1.1–5.9)

VL, visceral leishmaniasis; SOT, solid-organ transplant; OR, odds ratio; CI, confidence interval; CMV, cytomegalovirus. High-dose prednisone was defined as >20 mg of prednisone for >1 month or >2 pulses of 1 g intravenous methylprednisolone.

a

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Please cite this article in press as: Clemente W, et al., Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study, Clinical Microbiology and Infection (2014), http://dx.doi.org/10.1016/j.cmi.2014.09.002

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TABLE 3. Independent risk factors for VL in SOT recipients as defined by multivariate logistic regression

TABLE 5. Diagnostic methods in transplant patients with VL Method

Predictor

Wald’s χ2

p

OR

95% CI

Constant Receipt of high-dose steroids within preceding 6 months

0.032 4.313

0.857 0.038

1.07 2.50

NA 1.05–5.94

For logistic regression analysis, we considered variables with p <0.20 (i.e., receipt of high-dose steroids or CMV replication) or possible contributing factors to the occurrence of VL according to the literature (e.g., eosinophils, albumin, kidney transplantation). The use of high-dose steroids within the preceding 6 months was identified as the only risk factor for LV and increased the risk of developing the disease by 2.5-fold. VL, visceral leishmaniasis; SOT, solid-organ transplant; OR, odds ratio; CI, confidence interval; NA, not applicable.

The patient who died within the first month after treatment was not included in the analysis of secondary prophylaxis and relapse. Secondary prophylaxis was provided to 12 patients (34.3%). As shown in Table 6, different prophylaxis schemes were used. Relapses occurred in nine (25.7%) of 35 patients. Relapse was observed in one (8.3%) of the 12 patients receiving prophylaxis and in eight (34.8%) of the 23 patients not receiving prophylaxis (p 0.19, Fisher’s exact test).

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Microscopy Bone marrow Blood PCRa Bone marrow Blood Culture Bone marrow Blood Serologyb

Total

Positive, n (%)

36 4

29 (80.6) 3 (75.0)

4 3

3 (75.0) 2 (66.7)

20 3 29

11 (56.0) 1 (33.3) 22 (75.9)

VL, visceral leishmaniasis; PCR, polymerase chain reaction. A variety of PCR-based methods were used according to the protocol of each institution. b Includes different methods: indirect immunofluorescence, enzyme immunoassay, DAT rK39 and urinary antigen. a

Discussion

transplantation and was associated with high-dose prednisone. Disease presentation can be atypical; and only one-third of the patients exhibited the triad of fever, visceromegaly and cytopenia. Concomitant infection was not infrequent: ~36% of patients presented primarily bacterial or cytomegalovirus infections. LamB was the most widely used treatment, and relapse was common, observed in about a quarter of the patients (~25.7%). This study presents limitations that are inherent to retrospective multicenter studies, and the quality of data depended

In this series, VL occurred in 0.1% of SOT recipients from endemic countries at a median time of 11 months after

VL

TABLE 4. Clinical and laboratory characteristics of 36 SOT recipients with VL Variable

Patients, no. (%)

Male sex Age, median years (range) Time from transplant to diagnosis, median months (range) Follow-up, median months (range) Previous symptomatic VL infection Positive HIV serology Amphotericin use Main signs and symptoms Temperature >38°C Visceromegaly Pancytopenia Coexisting infections Bacterial CMV Tuberculosis Influenza A H1N1 Severe disease Intensive care unit admission Shock at presentation Laboratory abnormalities at presentation Albumin, g/dL Serum creatinine, mg/dL Haemoglobin, g/dL Platelet count, cells/μL Leukocyte count, cells/μL Neutrophils, cells/μL Eosinophils, cells/μL

27 (75.0) 46 (14–76) 9 (1–150) 51 (2–237) 0 0 0 31 (86.1) 29 (80.6) 17 (47.2) 13 (36.1) 8 (22.2) 5 (13.9) 1 (2.8) 1 (2.8) 11 (30.6) 3 (8.3) 3.1 (1.6–4.4) 3.9 (0.5–11) 11.2 (7.5–15.0) 99 900 (18 500–300 000) 3320 (1000–14 000) 2160 (170–7840) 181 (0–1120)

Note: Data are presented as no. (%) of patients, unless otherwise indicated. CMV, cytomegalovirus; SOT, Solid Organ Transplant; VL Visceral Leishmaniasis.

TABLE 6. Treatment and outcomes of 36 SOT recipients with

Drug chosen as first treatment Amphotericin B deoxycholate Liposomal amphotericin B Pentavalent antimonials Miltefosine All treatment regimens a Amphotericin B Pentavalent antimonials Others Days of treatment, median (range) Cure within the first month of treatment b Secondary prophylaxis after cure (drug option) Amphotericin B Others Scheme of secondary prophylaxis Daily to every other week Monthly Disease after cure (recurrence) * With prophylaxis Without prophylaxis Number of episodes/patient 1 2 3 4 Time from the end of treatment to relapse 6 months 6-12 months >12 months Relapse treatment Liposomal amphotericin B Pentavalent antimonials Miltefosine Crude mortality at 30 days

(n = 36) 4 22 9 1 (n = 36) 30 9 2 10 33/35 12/35 9 3 (n = 35) 9 3 (n = 35) 1/12 8/23 (n = 9) 4 2 2 1 (n = 9) 4 3 2 (n = 9) 7 1 1 1/36

(11.1) (61.1) (25.0) (2.8) (83.3) (25.0) (5.5) (3 – 34) (94.2) (25.7) (8.6) (25.7) (8.6) (8.3) (34.8) (44.4) (22.2) (22.2) (11.1) (44.4) (33.3) (22.2) (77.7) (11.1) (11.1) (2.8)

Note: Data are presented as n. (%) of patients or median (range); SOT, Solid Organ Transplant; VL, Visceral Leishmaniasis; CMV, cytomegalovirus; a treatment option included first, sequential or combined treatment; b number of patients who survived more than 1 month after treatment (n=35); * p value = 0.19

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Please cite this article in press as: Clemente W, et al., Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study, Clinical Microbiology and Infection (2014), http://dx.doi.org/10.1016/j.cmi.2014.09.002

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on the clinical records. The patient enrollment occurred over a long period of time (16 years), with the possible consequences of missed VL cases and nonstandardized management across different hospitals. Also, during the time of recruitment, there was an improvement in diagnostic techniques and an increase in the availability of treatment options. The number of cases was nonetheless small (n = 36), despite the considerable number of SOT recipients assessed (n = 25 139). Nevertheless, we should also take into account that VL is a rare disease among transplant recipients, even in endemic regions [1]. In SOT recipients, VL frequency varies according to both the prevalence of VL in the general population and the organ transplant type [1]. In Brazil, which is a highly endemic country (1.8 cases per 100 000 inhabitants), VL among SOT recipients was 5.7-fold more frequent than in Spain (0.4 cases per 100 000 inhabitants). It is worth mentioning that the incidence of VL in Brazil ranges from low to high and from no transmission to intense transmission, depending on location [11]. The frequency of disease among SOT recipients from endemic zones may also depend on the socioeconomic level of the population, and in nonendemic countries, VL should be considered in immigrants arriving from endemic zones [12,13]. In this study, neither the socioeconomic category nor the degree of exposure of the recipient was evaluated. No patient was diagnosed with symptomatic leishmaniasis before transplantation, and patients were not routinely screened for VL infection. Donorderived transmission was not investigated by any method, and donor origin was not evaluated. Leishmaniasis is predominantly described in renal transplant recipients, which is probably related to the preeminence of kidney transplants as opposed to other types of organ transplants [1,4,14]. Nevertheless, it has been suggested that renal insufficiency and haemodialysis may be factors that contribute to increased risk [15,16]. Our study cannot provide clear evidence of an association between the type of transplant and risk. The use of high doses of steroids was identified as the sole risk factor for VL. Prior reports demonstrated that steroid use is related to the development of intracellular infections [17]. In our study, VL was not related to induction therapy with antilymphocyte globulins or to baseline immunosuppression. In the transplant scenario, VL is difficult to recognize even in endemic countries, where delayed diagnosis still occurs. Although most cases appear within the first year after transplantation, VL can develop at any time. In our series, disease developed more rapidly in Brazil than in Spain, possibly correlating with Brazil’s higher incidence. Overall, ~20% of VL cases (n = 6) were diagnosed within the first 3 months after transplantation, and two cases were diagnosed within the first 30 days. A recent report suggested that during early disease onset, transmission is related to the reactivation of a dormant

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infection, when immunosuppression is at its highest level [18]. Despite this risk, VL screening is not routinely performed because the value of serologic and molecular screening of asymptomatic donors and recipients remains unclear [19,20]. In our series, 14% of patients were afebrile, 19% did not exhibit visceromegaly and 53% had no pancytopenia. Overall, only one-third of the patients (n = 12) presented this classic triad when the diagnosis was established. Considering the high frequency of atypical VL in SOT [9,18,21–24], disease should not be ruled out even in the absence of typical signs, particularly when the recipient or donor has traveled from an endemic zone. The most widely used diagnostic method was bone marrow aspiration microscopy, which had a sensitivity of 80.6%, consistent with previous studies [1]. Peripheral blood microscopy was positive in three of four cases. Further investigation is necessary to evaluate whether this high sensitivity occurs in transplanted patient as described in HIV [4,25,26]. Microscopy combined with PCR and culture diagnosed VL in up to 89% of cases. In this series, Leishmania serology was the sole diagnostic method in four patients. It should be noted that serology is minimally invasive and could be routinely used for VL diagnosis in SOT recipients [1,4,20]; however, serology cannot distinguish between prior exposure and active infection and may presents a cross-reaction with other protozoa [20]. Additionally, serologic methods can exhibit a lack of agreement. Furthermore, the sensitivity is variable, and specificity can be unsatisfactory [4,12,19]. however, serology cannot distinguish between prior exposure and active infection and may presents a cross-reaction with other protozoa [20]. At the present time, the best approach for diagnosis remains the combination of methods [4]. Amphotericin was the drug of choice for the majority of patients, and the liposomal formulation was preferred [27,28]. Only one patient was treated with miltefosine, which is a new oral drug [29], but the patient required two treatment courses. Although our study was not designed to determine the efficacy and safety of a particular therapy, 10 patients switched from amphotericin B deoxycholate (n = 4) or N-methyl-glucamine therapy (n = 6) to LamB, possibly indicating a low tolerance in the context of SOT. Conversely, LamB was a safe and widely used drug. Nine patients experienced recurrence within the first year. Therefore, close monitoring of patients could be especially useful during the first year after treatment. However, it is not possible to definitively differentiate relapse from reinfection. There is no consensus regarding the most effective drug or whether secondary prophylaxis is beneficial, as demonstrated for HIV [4,20,30]. Our study was also not designed to examine the efficacy of secondary prophylaxis, although this strategy can

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Please cite this article in press as: Clemente W, et al., Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study, Clinical Microbiology and Infection (2014), http://dx.doi.org/10.1016/j.cmi.2014.09.002

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reduce the number of relapses, as suggested in other studies [20]. Such an analysis would require additional cases or a prospective design. In HIV patients, performing PCR on blood samples is considered a useful tool to monitor therapy and to identify relapses in treated patients to avoid invasive procedures [4], and it may be recommended to monitor response in high-risk patients with immunosuppression, in particular quantitative PCR. However, no clear information is available on the use of a positive PCR result to predict relapses in the transplant setting. The mortality rate was lower than that described in previous studies [1], likely as a result of accumulated experience. Despite the limitations, this study presents the largest series of cases of VL in SOT, allowing us to draw the following conclusions regarding the frequency of VL in SOT recipients from endemic zones: (a) endemicity may be related to early onset of the disease; (b) the disease can be atypical, thereby delaying the diagnosis; (c) the risk of VL increases with the use of high-dose steroids; (d) a combination of diagnostic methods may serve as the best approach; (e) LamB is the drug of choice and is typically well tolerated; and (f) in our view, secondary prophylaxis is recommended to prevent relapse, but this issue remains unresolved.

Transparency declaration Supported by Plan Nacional de I+D+i 2008–2011 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008 and RD12/0015). All authors report no conflicts of interest relevant to this article.

References [1] Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008;8: 191–9. [2] Antinori S, Schifanella L, Corbellino M. Leishmaniasis: new insights from an old and neglected disease. Eur J Clin Microbiol Infect Dis 2012;31:109–18. [3] Kotton CN, Lattes R, AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant 2009;9(suppl. 4):S234–51. [4] van Griensven J, Carrillo E, López-Vélez R, Lynen L, Moreno J. Leishmaniasis in immunosuppresed individuals. Clin Microbiol Infect 2014;20:286–99. [5] Postorino MC, Bellantoni M, Catalano C, Caridi G, De Rosa M, Seck S, et al. Visceral leishmaniasis reactivation in transplant patients: a minireview with report of a new case. J Nephrol 2011;24: 530–4.

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Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, xxx 1–7

Please cite this article in press as: Clemente W, et al., Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case–control study, Clinical Microbiology and Infection (2014), http://dx.doi.org/10.1016/j.cmi.2014.09.002