declaração de conflito de interesse - sbtmo...
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CISTITE HEMORRÁGICA
George Maurício Navarro Barros
Unidade de Transplante de Medula Óssea
Hospital de Câncer de Barretos
Rio de Janeiro-RJ
04/08/2018
Complicações imediatas não-infecciosas: profilaxia e tratamento
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Cistite hemorrágica
• Etiologia
• Incidência
• Fatores de risco
• Profilaxia
• Tratamento
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Cistite hemorrágica
• Definição:
– Complicação precoce
– Elevada morbidade
– Prolonga o tempo de hospitalização
– Eleva o consumo de hemocomponentes e os custos do transplante
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• Etiologia (não-infecciosas)
– Relacionada a quimioterapia e radioterapia
– Início precoce (primeiros 3 dias)
– Ciclofosfamida, ifosfamida, bussulfan, etoposide e thiotepa
– Acroleína (metabólito da ciclofosfamida)
Cistite hemorrágica
Manikandan R, Kumar S, Dorairajan LN
Hemorrhagic cystitis: A challenge to the urologist
Indian J Urol. 2010 Apr-Jun; 26(2): 159-166
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Cistite hemorrágica
Ciclofosfamida
Hidroxiciclofosfamida
Aldofosfamida
Mostarda fosforamida Acroleína+
Liberação de TNF-α IL-1-β e óxido nítrico
Edema da mucosa da bexiga, dilatação vascular e aumento
da fragilidade capilar
Hemorragia
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Cistite hemorrágica
• Incidência (relacionada ao uso da ciclofosfamida)
– 5-25% - conforme as medidas profiláticas
• Regimes de hiperidratação endovenosa
• Uso de Mesna (2-mercaptoetanossulfonato de sódio)
• Irrigação vesical contínua
Continuous bladder irrigation prevents hemorrhagic cystitis after allogeneic hematopoietic cell transplantation.
Urol Oncol. 2008 Jan-Feb;26(1):43-6
Mesna versus hyperhydration for the prevention of cyclophosphamide induced hemorrhagic cystitis in bone marrow transplantation
Shepard JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE, Phillips GLJ Clin Oncol 1991;9:2016-20
Hadjibabaie M, Alimoghaddam K, Shamshiri AR, Iravani M, Bahar B, Mousavi A, et al
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Cistite hemorrágica
• Mesna (2-mercaptoetanossulfonato de sódio)Excretada rapidamente pela urina (50%) em 4 horas
Metabólito único: Dimesna (dissulfeto)
Reage com o grupo metil da acroleína
Thioéter não-tóxico
Ifosfamide and mesna
Schoenike SE, Dana WJ
Clin Pharm 1990;9:179-91
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Cistite hemorrágica
DrugsIfosfamideCyclophosphamideBusulphanThiotepaTemozolomide9-nitrocamptothecinPencillin and its derivatives like methicillin, carbenicillin, ticarcillin, piperacillinDanazolTiaprofenic acidAllopurinolMethaqualoneMethenamine mandelateGentian violetAcetic acid Manikandan R, Kumar S, Dorairajan LN
Hemorrhagic cystitis: A challenge to the urologist
Indian J Urol. 2010 Apr-Jun; 26(2): 159-166
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Cateterismo vesical
Neoplasias de bexiga primárias ou metastáticas
Litíase renal
Distúrbios de coagulação com ou sem plaquetopenia
Cistite hemorrágica
Manikandan R, Kumar S, Dorairajan LN
Hemorrhagic cystitis: A challenge to the urologist
Indian J Urol. 2010 Apr-Jun; 26(2): 159-166
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Cistite hemorrágica
• Etiologia (infecciosas)
– Vírus
– Início nas primeiras 2-8 semanas (varia de 1 semana a 6 meses)
– Polyomavirus hominis 1 (BK-vírus)
– Reativação e replicação viral
– Relação com intensa imunossupressão
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Cistite hemorrágica
AdenovírusHerpes simplesJC (John Cunningham) - virusCitomegalovírus
Bactérias: Escherichia coli, Staphylococcus saprophyticus, Proteusmirabilis e espécies de Klebsiella spFungos: Candida albicans, Cryptococcus neoformans, Aspergillusfumigatus e Torulopsis glabrataParasitas: Schistosoma haematobium e Echinococcus granulosus
Manikandan R, Kumar S, Dorairajan LN
Hemorrhagic cystitis: A challenge to the urologist
Indian J Urol. 2010 Apr-Jun; 26(2): 159-166
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Cistite hemorrágica
Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.05.013
• Incidência (Vírus)
– Estudo retrospectivo
– 1992-2013
– 64 pacientes com cistite hemorrágica
– 56 (87,5%) de etiologia viral
– 54 (96%) BK-V, 7 ADV e 1 CMV
– Média de 39,5 dias após o TMO
Grupo da Bélgica e Líbano
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Cistite hemorrágica
• Incidência (Cistite hemorrágica por Adenovírus)
39 pacientes com CH24 pacientes ADV15 pacientes BK-vírus
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Cistite hemorrágica
• BK-vírus
DNA-vírusSão pequenos 40-45 nmNão-envelopadosCapsídeo: VP1, VP2 e VP3Estáveis no meio ambiente
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Cistite hemorrágica
• BK-vírus
• Adquirido na infância• Transmissão por via respiratória• Permanece latente nos rins
Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues.
J Infect Dis. 1983 Apr;147(4): 676-84
Chester PM, Heritage J, McCance DJ
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Cistite hemorrágica
• Incidência (Cistite hemorrágica por BK-vírus)
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Cistite hemorrágica
• Incidência (BK-vírus)
– >80% dos pacientes submetidos ao TMO terão altos títulos de virúria
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Cistite hemorrágica
• Fatores de risco (CH por BK-vírus)
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Cistite hemorrágica
Estudo observacional prospectivo30 centros italianos participaram
• Fatores de risco (CH BK-vírus)
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Cistite hemorrágica
• Fatores de risco (CH por BK-vírus)
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Cistite hemorrágica
• Fatores de risco (BK-vírus)
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Cistite hemorrágica
• Apresentação clínica (classificação de Droller)
Grau 1: sangramento microscópico
Grau 2: sangramento macroscópico
Grau 3: formação de coágulos
Grau 4: quadros obstrutivos graves com necessidade de procedimentos invasivos e hemodiálise
Prevention of cyclophosphamide-induced hemorrhagic cystitis.Droller MJ, Saral R, Santos G.
Urology. 1982 Sep;20(3):256-8
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Cistite hemorrágica
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Cistite hemorrágica
• Manifestações clínicas• Dor abdominal baixa• Disúria• Polaciúria
• Diagnóstico• Urina rotina e urocultura
• USG de rins e vias urinárias
• PCR quantitativo para poliomavírus (BK e JC), herpes simples, citomegalovírus e adenovírus na urina (AII) e no sangue (BII)
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Cistite hemorrágica
• Profilaxia (fluorquinolonas)
– Inibição in vitro da replicação do BK-vírus
Ofloxacina e levofloxacina
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Análise retrospectiva2006-2010
Cistite hemorrágica• Profilaxia de CH por BK-vírus (fluorquinolonas) - DII
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Cistite hemorrágica
Estudo prospectivo
• Profilaxia de CH por BK-vírus (fluorquinolonas) - DII
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Cistite hemorrágica
• Tratamento
– Medidas de suporte
– Medidas específicas contra o agente etiológico (anti-virais)
– Medidas para controle de sangramento
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Cistite hemorrágica
• Tratamento (medidas de suporte)– Controle da dor - AII
– Suporte transfusional/ correção dos distúrbios de coagulação – AII
– Hidratação EV - AII
– Prevenção da formação de coágulos• Irrigação vesical contínua
• Cistoscopia higiênica
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Cistite hemorrágica
• Tratamento (antivirais)
– Cidofovir
– Leflunomid
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Cistite hemorrágica
• Tratamento de CH por BK-vírus (Cidofovir) - CII
Análise retrospectiva2011-201327 pacientesRC 81,5%
Biol Blood Marrow Transplant. 2016 Apr; 22(4): 723-730.
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Cistite hemorrágica
Taxas de RC da CH47-100%
• Tratamento de CH por BK-vírus (Cidofovir) - CII
Biol Blood Marrow Transplant. 2016 Apr; 22(4): 723-730.
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Cistite hemorrágica
• Tratamento da CH por BK-vírus (Cidofovir) - CII
– Cuidados:• Nefrotoxicidade
• Uso concomitante de probenecid (inibe a absorção pelas células epiteliais dos túbulos renais)
• Na ausência do probenecid reduzir a dose do cidofovir 3-5x
• Hidratação EV com solução salina
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Cistite hemorrágica
• Tratamento da CH por BK-vírus (Leflunomid)
Estudo retrospectivo2006-20097 (50%) RC5 (35%) RP
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Cistite hemorrágica
• Tratamento (terapia celular)PyVST cells – Células T Poliomavírus específicas
MVST cells – Células T multivírusespecíficas – BK-vírus, ADV, CMV e EBV
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Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell
TransplantationTzannou I et al. Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital; Meng-Fen Wu and Hao Liu, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.
Journal of Clinical Oncology 35, no. 31 (November 1 2017) 3547-3557.
Cistite hemorrágica
• Tratamento (terapia celular)Banco de VST (células T vírus específicas)EBV, ADV, CMV, BK-vírus e HHV-6Clinical trial phase 238 pacientes45 infecçõesInfusão única: taxa de RC ou RP: 92% (IC 95%: 78,1-98,3%)
100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3).
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Cistite hemorrágica
• Tratamento (controle de sangramento/ cicatrização) - CIII
Estudo retrospectivo16 pacientesHematúria macroscópica + infecção por BK-vírusOxigenioterapia 5x/semana – mediana de 13 sessões (4-84)94% RC
Oxigenioterapia hiperbárica
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Cistite hemorrágica
• Tratamento (controle de sangramento/ cicatrização) - CIII CII
7 centros em Roma35 pacientes tratados10 não tratados devido a CH muito grave
Cola de fibrina
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Cistite hemorrágica
• Tratamento (controle de sangramento/ cicatrização) - CIIICola de fibrina
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Cistite hemorrágica
• Tratamento (controle de sangramento/ cicatrização)