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Leishmaniasis Transplant in the Tropics
First, of all I would like to thank the organizers for the invitation. Leishmaniasis in transplant setting is the topic of my talk today. Wanessa Clemente Digestive Transplant Service University of Minas Gerais - Brazil
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No conflicts of interest to disclose
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Epidemiology Protozoan disease transmitted through the bite of infected female sandflies Broad range of clinical presentation CL: single or multiple lesions, associated with multiple species MCL: metastasis to mucosal tissues (L braziliensis) VL: internal organs (liver, spleen and BM) - Macrophage system In SOT presentation and response to treatment can be altered, with dissemination and visceralization of dermatotropic species Remains a rare complication even in tropical settings Antinori LID 2008, de Vries Am J Clin Dermatol 2015, Schwartz & Mawhorter AJT 2013, van Griesven CMI 2014.
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Leishmania Taxonomy and Leishmaniasis Distribution
Different species are circulating worldwide 350 million people at risk ~2 million new cases/year True prevalence: understimated Therapy depends on Leishmania species WHO, 2010 Kevric, Dermatol Clin 2015
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Leishmania Taxonomy and Leishmaniasis Distribution
Visceral Leishmaniasis Cutaneous and MC Leishmaniasis/ PKDL General population million/y million/y SOT Several cases, % endemic area Few cases Greater susceptibility to VL, fewer transplants performed in highly endemic areas (CL/MCL) or publication bias. WHO, 2010 Kevric, Dermatol Clin 2015
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WHO 2010, Vries Am J Clin Dermatol 2015, Antinori LID 2008
Risk Factors Exposure: outdoor activities (timber harvesting or mining, agriculture, military operations and road construction). But... Urban spread is common in some areas. Clinical disease: parasite virulence, nutricional status, age and host genetic. SOT: poorly studied. Disease prevalence in SOT x general population. Transplanted organ: renal recipients (bias, related to renal failure or dialysis). IS: High-dose steroids WHO 2010, Vries Am J Clin Dermatol 2015, Antinori LID 2008
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Reactivation or de novo infection
Acquisition Reactivation or de novo infection Primary infection Reactivation of latent infection DD transmission Antinori, LID 2008
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Clinical and Laboratory findings
Fever is the most common sympton Organomegaly SOT < IC Can be atypical and secondary infections are common Cutaneous manifestations (before, during or after VL) Serology: good performance N: 79 cases, >75%: KT Median: 18 mo after Tx. Mortality: 22% Antinori, LID 2008
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Diagnosis Visceral Leishmaniasis Method Direct examination Serology
Comments Direct examination Sensitivity: BMA 53 to 86%. Spleen: > 95% Serology Should be supported by clinical correlation IFAT; ELISA; ICT; DAT Sensitivity and specificity varies Ag: rK39; rKLO8 Methods lack of agreement Exposure x active infection Cross-reaction Molecular diagnosis Choice of target: rDNA – ITS-1 (identification) kDNA Mini-exon Non-invasive sampling Enable species identification Allows monitoring, PCR + is not disease Ag detection Ag serum/urine, usefulness remains unclear Ideally: combination of methods! WHO 2010, van Griesven CMI 2014, de Vries Am J Clin Dermatol 2015
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Older lesions lower number of parasites
Diagnosis Cutaneous and MC Leishmaniasis/ PKDL Method Comments Direct examination Gold-standard. Culture Enable species identification Histopathology Immunohistochemical Depends on stage, species, host response and cellular immunity. Molecular diagnosis Useful if parasite burden is low Immunological and serological tests Skin test (Montenegro) Epidemiological studies If DE is negative, PCR should be employed. Older lesions lower number of parasites WHO 2010, de Vries Am J Clin Dermatol 2015
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Treatment and secondary prophylaxis
Overall, decision is based on an individual basis age immune status renal/liver function Leishmania species extend of disease drug availability concomitant infections previous treatment CL/MCL: depends also on the number and size of skin lesions. Topical treatment (cryotherapy, thermotherapy, intralesional antimonals or surgical excision) as sole therapy has not yet been reported. Systemic treatment is the preferred approach.
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Treatment recommendations in immunosuppressed individuals
LAmb: preferred drug in different squemes Cure rate: ~ 80% (immunocompetent patients: >90%) Relapses episodes ≈ 30% van Griensven, CMI, 2014 Kotton et al. AJT Schwartz et al AJT 2013
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Is Miltefosine an option ?
Evidence-Based recommendations Old World VL AI Combined therapy LAmB or Paramomycin L donovani BI Alone New World CIII L infantum CL BI or CIII Alone (28d) Depending on species CL, MCL BI or BII Alone (varies) Mong lo & Lopéz-Vélez CID, 2015
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Value of screening both donors and candidates
International Guidelines: Donors: screening not recommended Recipients: screening if previous epidemiological exposure Serologic, skin testing or PCR If screening is positive: Close monitoring (clinical and laboratory) Primary prophylaxis/ pre-emptive therapy is not recommended Martín-Dávila P et al. Clin Microbiol Rev 2008 Schwartz B et al. Am J Transplant 2013 Johan van Griensven, et al. Clin Microbiol Infect 2014
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Screening limitations
VL screening in LT recipients and donors Laboratory test LT Recipients (N = 50) Matched-Liver Donors (N = 17) Positive IFA (≥ 1:80) 1 (2%) Anti-Leish rK39 rapid test Any PCR detection 4 (8%) 4 (23.5%) Blood 1 4 Liver 3 Spleen NA None of the LT recipients developed VL over 24 mo follow-up Clemente et al, AJT 2014. No concordance between serology and PCR Serology should not be used for screening because of the lack of sensitivity PCR presented higher sensitivity and specificity, but the role of PCR pre-tx needs to be determined 3 VL cases ~ 830 LT; 2% asymptomatic infection Persistence of parasite in tissue after treatment does not necessarily represent development to relapse. Silva LA et al. Rev Inst Med Trop São Paulo 2013 Moreno EC et al. PloS Negl Trop Dis 2009
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Worldwide asymptomatic carriers of L infantum
Up to 70% depending on the method and studied endemic area Michel, Acta Tropica 2011
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Exposure prevention When visiting endemic areas, minimize outdoors ativities (especially during late afternoon) Protective clothing Insect repellent Bed nets Ahead of print. Recommendations on Travel Medicine and Management of Endemic Diseases in SOT recipients: Latin America
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Case Presentation – Visceral Leishmaniasis
17 yo male, LT due to Autoimmune cirrhosis (3 y before) IS regimen: Steroid + FK. Admission: 3 months: weight loss (3kg), bloody diarrhea, visceromegaly, but no fever. Pancytopenia (Hg 8.1g/dL; WBC 1,300/mm3; Platelets 79,000/ mm3). Negative Anti-Leishmania serology IFAT Colonoscopy: Gross nodularity hyperemia and friability. Intestinal biopsy and Bone Marrow aspirate: Leishmania amastigotes. COLONIC LEISHMANIASIS Treatment: LamB 3 mg for 7 days. Resolution of diarrhea, weight gain and spleen size normalization. Normal blood count. Relapse 5 mo after treatment. Mantained with secondary prophylaxis 3 mg/kg/monthly (18 months) Araujo et al Am J Trop Med Hyg 2010 Clemente et al Transplantation 2011
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No previous symptomatic infection or treatment
Visceral Leishmaniasis after SOT Multicenter study, ( 10 Spanish and 2 Brazilian centers) 36 VL cases:/ Tx (0.1%) Treatment option % Amphotericin B 83% Days of LamB 10 d Secondary prophylaxis after cure 34% 75% Relapse after cure 26% With NO secondary prophylaxis 35% With secondary prophylaxis 8% Mortality at 30 days 2.8% 5.7 fold more frequent in Brazil compared to Spain Brazil - ~ 2 cases/ 100,000 (0.5%) Spain cases/100,000 (0.1%) Median time post-transplant 11 months Clinical manifestations Temperature > 38ºC 86% Visceromegaly 81% Cytopenia 47% Diagnostic methods Bone marrow microscopy PCR 75% Culture 59% Serology (IFA + rK39) 76% No previous symptomatic infection or treatment Clemente et al REIPI Network. CMI 2015 19
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Case Presentation – Simultaneous Mucosal and Cutaneous Leishmaniasis
67 yo woman from Igassu falls (endemic), living in Curitiba/BR One-year post-KT: Edema in nose, nasal obstruction and persistent rhinorrhea 2 cutaneous lesions (2 wk before admission) Lesions biopsies: Amastigotes Positive culture Positive PCR: Leishmania (Viannia) braziliensis. Treated with LamB 3 mg/kg/day with improvement after 14 days SOT: Self-limiting lesion to severe anddisfiguring lesions. Atypical features include dissemination polymorphism and visceralization Tuon et al. Am J Trop Med Hyg 2014.
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Leishmaniasis Distribution in Latin America
MCL: L braziliensis and L panamensis CL: L amazonensis VL: L infantum ~ L chagasi
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Summary: Leishmaniasis in SOT
Is an unusual disease (even in endemic areas), the frequency varies according to prevalence in the GP. Occur any time after transplantation, mostly during the first year. Endemicity can be related to early disease. VL most common manifestations: fever, spleen enlargement and pancytopenia. Only one-third of the patients exhibited this classical triad (Clemente et al, CMI 2015) Diagnosis: combination of different methods (microscopy, serology, culture and PCR) is the best approach. The current recommendation of recipient screening should be reconsidered. The preferred therapy is LAmB. Secondary prophylaxis after treatment may reduce the risk of relapse. Mortality rate: ~30, if not promptly recognized and treated. Antinori et al., LID 2008, de Vries Am J Clin Dermatol 2015, Schwartz & Mawhorter AJT 2013, van Griesven CMI 2014
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