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Paula Durante Andrade PAULA DURANTE ANDRADE DIAGNÓSTICO MOLECULAR DA INFECÇÃO ATIVA POR CITOMEGALOVÍRUS HUMANO (HCMV) EM PACIENTES SUBMETIDOS A TRANSPLANTE PELA REAÇÃO EM CADEIA DA POLIMERASE (tipo “NESTED PCR”): comparação entre leucócitos do sangue periférico e soro CAMPINAS Unicamp 2009 i PAULA DURANTE ANDRADE DIAGNÓSTICO MOLECULAR DA INFECÇÃO ATIVA POR CITOMEGALOVÍRUS HUMANO (HCMV) EM PACIENTES SUBMETIDOS A TRANSPLANTE PELA REAÇÃO EM CADEIA DA POLIMERASE (tipo “NESTED PCR”): comparação entre leucócitos do sangue periférico e soro Dissertação de Mestrado apresentada à Pós-Graduação da Faculdade de Ciências Médicas da Universidade Estadual de Campinas, para obtenção do título de Mestre em Farmacologia ORIENTADORA: PROFa. DRa. SANDRA CECÍLIA BOTELHO COSTA CAMPINAS Unicamp 2009 iii FICHA CATALOGRÁFICA ELABORADA PELA BIBLIOTECA DA FACULDADE DE CIÊNCIAS MÉDICAS DA UNICAMP Bibliotecário: Sandra Lúcia Pereira – CRB-8ª / 6044 Andrade, Paula Durante An24d Diagnóstico molecular da infecção ativa por citomegalovírus humano (HCMV) em pacientes submetidos a transplante pela reação em cadeia da polimerase (tipo “Nested PCR”): comparação entre leucócitos do sangue periférico e soro / Paula Durante Andrade. Campinas, SP: [s.n.], 2009. Orientador: Sandra Cecília Botelho Costa Dissertação (Mestrado) Universidade Estadual de Campinas. Faculdade de Ciências Médicas. 1. Citomegalovirus. 2. Herpesvirus humano. 3. Citomegalovirus humano. 4. Reação em cadeia da polimerase. 5. Biologia molecular. 6. Infecão. 7. Transplante de órgãos – Tecidos. I. Costa, Sandra Cecília Botelho. II. Universidade Estadual de Campinas. Faculdade de Ciências Médicas. III. Título. Título em inglês: Molecular diagnosis of active human cytomegalovirus infection in patient undergoing transplantation by nested polymerase chain reaction: comparison between peripheral blood leucocytes and serum Keywords: • Cytomegalovirus • Human cytomegalovirus • Polymerase chain reaction • Molecular biology • Infection • Transplant Titulação: Mestre em Farmacologia Banca examinadora: Profa. Dra. Sandra Cecília Botelho Costa Prof. Dr. Celso Francisco Hernandes Granato Profa. Dra. Maria de Lourdes Rios Barjas Castro Data da defesa: 19-02-2009 iv v DEDICATÓRIA Aos meus filhos Lucas e Luana, que, na inocência de sua infância, me forneceram a força para a conclusão deste estudo... Aos meus pais, que me ensinaram que nada se alcança sem esforço, e que lutar por um sonho sempre vale a pena! Ao meu pai, meu exemplo... em tudo! Ao meu avô (in memorian), que sempre esteve presente, em todos os momentos... Saudades! Ao meu marido, pela compreensão, companheirismo e, sobretudo, pela paciência... A Deus, Por estar presente em minha vida! vii AGRADECIMENTOS As pessoas que passam em nossas vidas “Há pessoas que nos falam e nem as escutamos. Há pessoas que nos ferem e nem cicatrizes deixam. Mas, há pessoas que, simplesmente, aparecem em nossa vida e que marcam para sempre...”. (Cecília Meireles) Ao Prof. Dr. Fernando Ferreira Costa, pela oportunidade de estar na Unicamp... Quem, simplesmente, possibilitou tudo! À Profa. Dra. Sandra Cecília Botelho Costa, pela confiança, amizade e infinita paciência. Obrigada! ix “Cada um tem de mim exatamente o que cativou, e cada um é responsável pelo que cativou, não suporto falsidade e mentira, a VERDADE pode machucar, mas é SEMPRE mais DIGNA. Bom mesmo é ir a luta com DETERMINAÇÃO, abraçar a VIDA e VIVER com PAIXÃO. Perder com Classe e Vencer com OUSADIA, pois o triunfo pertence a Quem SE ATREVE e a VIDA É MUITO para Ser Insignificante. Eu faço e abuso da FELICIDADE e não desisto dos meus sonhos. O mundo está nas mãos daqueles que tem coragem de sonhar, CORRER o RISCO de VIVER SEUS SONHOS." Coragem...Coragem...Coragem é não buscar desculpas para ser Feliz !!!!!!!!! (Charles Chaplin) A todos os alunos do Laboratório, meus amigos, e, a todos os colegas e amigos de trabalho, pelo incentivo para a finalização deste projeto! x “Procure ser um homem de valor em vez de procurar ser um homem de sucesso.” (Albert Einstein) xi RESUMO O Citomegalovírus Humano (HCMV) é o principal causador de complicações pós-transplante. Métodos específicos que permitam identificar, precocemente, os pacientes com risco de desenvolvimento de doença, para os quais tratamento é indicado, têm sido requeridos, a fim de que poucos pacientes sejam desnecessariamente tratados e para a efetiva instituição terapêutica. A “Nested-PCR”, dupla Reação em Cadeia da Polimerase, é um teste comumente utilizado no diagnóstico da infecção ativa por HCMV, contudo, quando realizada em leucócitos do sangue periférico, devido à sua alta sensibilidade, não apresenta boa correlação com o desenvolvimento de doença por HCMV. A detecção do DNA do HCMV no soro, pela PCR, tem sido associada com o desenvolvimento de doença por HCMV. Neste estudo, nós aplicamos a “Nested-PCR” em leucócitos do sangue periférico (denominada “L-PCR”), o método Convencional do Laboratório, e em soro (“sPCR”), para o diagnóstico da infecção ativa por HCMV, a fim de estabelecermos a correlação dos resultados obtidos, de ambos os métodos, com o desenvolvimento de infecção sintomática. Com este propósito, nós avaliamos, prospectivamente, amostras de 37 pacientes, 20 submetidos a transplante renal, e 17 submetidos a transplante de células tronco hematopoiéticas. Para excluir resultados falso negativos, na reação de amplificação pela “sPCR”, um controle interno foi construído e todas as reações foram realizadas utilizando-o. De acordo com os critérios estabelecidos neste estudo, 21 pacientes (21/37 - 57%) desenvolveram infecção ativa por HCMV. Todos os pacientes com infecção ativa por HCMV foram positivos para a “L-PCR” (p= 0,0003). A “sPCR” foi positiva para somente 10 pacientes (10/37 – 27%) (p= 0,01). Resultados discordantes foram observados em 11 pacientes que foram positivos para infecção ativa para a “L-PCR”, mas negativos para a “sPCR”, 5 dos quais desenvolveram sintomas clínicos para o HCMV. O coeficiente Kappa de concordância observado para ambos os métodos foi de 0,44 (acordo moderado). Em dezesseis pacientes (43%), dos 37 estudados, não foram observados resultados positivos por nenhum dos métodos empregados — não desenvolveram infecção ativa —, contudo, 2 destes desenvolveram sintomas clínicos de provável doença por HCMV e um apresentou, posteriormente, biópsia confirmativa para doença por HCMV. xiii Sintomas clínicos foram observados em 14 pacientes, em 12 deles infecção ativa foi diagnosticada através da “L-PCR” (p= 0,007) e, em 7, através da “sPCR” (p= 0,02). Ausência de sintomas clínicos foram observados em 9 pacientes nos quais a “L-PCR” detectou infecção ativa e em 3 pacientes nos quais a “sPCR” detectou (coeficiente Kappa 0,57, acordo moderado). De 14 pacientes sintomáticos, 2 pacientes soronegativos para o HCMV que receberam rins soropositivos desenvolveram infecção primária. Analizando os dois métodos para o diagnóstico da infecção ativa, nós observamos maior sensibilidade e valor preditivo negativo da “L-PCR” (“L-PCR” 100% vs. “sPCR” 62%), e maior especificidade e valor preditivo positivo da “sPCR” (“sPCR” 81% vs. “L-PCR” 50% e 72%). O valor dos testes positivos, “L-PCR” e “sPCR”, para predizer doença por HCMV foram, respectivamente, 57% e 70%, e o valor dos testes negativos para predizer que doença não desenvolveria foi 88% para “L-PCR” e 74% para a “sPCR”. A análise comparativa entre os primeiros resultados positivos para a presença de infecção ativa por HCMV e o aparecimento de sintomas mostrou que a “L-PCR” precedeu o inicio dos sintomas clínicos 19 dias (mediana) em 8 pacientes. Em 2 pacientes, a “sPCR” precedeu 7 dias (mediana) a “L-PCR” na detecção de infecção sintomática por HCMV. A “L-PCR” e a “sPCR” foram considerados métodos complementares para o diagnóstico e monitoramento da infecção sintomática por HCMV. xiv ABSTRACT The Human Cytomegalovirus (HCMV) is the main cause of post-transplant complications. Specific methods that allow to identify early patients with risk of developing disease for which treatment is indicated, have been required so that few patients are treated unnecessarily and for the effective therapeutic institution. The “Nested-PCR” has been commonly used in the diagnosis of HCMV infection, however, when performed in peripheral blood leukocytes, due to its high sensitivity does not present good correlation with the development of HCMV disease. Detection of HCMV DNA in serum by PCR has been associated with the development of HCMV disease. In this study, we apply the “Nested-PCR” in peripheral blood leukocytes (termed “L-PCR”), the conventional method of Laboratory, and in serum (“sPCR”), for the diagnosis of active HCMV infection, in order to establish the correlation of results obtained of both methods with the development of symptomatic infection. With this purpose, we evaluated prospectively samples of 37 patients, 20 undergoing kidney transplantation, and 17 submitted to haematopoietic stem cells transplantation. To exclude false negative results in the amplification reaction by “sPCR”, an internal control was constructed and all reactions were carried out by using it. According to the criteria established in this study, 21 patients (21/37 - 57%) developed active HCMV infection. All patients with active HCMV infection were positive by LPCR (p= 0,0003). The serum PCR were active HCMV infection positive for only 10 patients (10/37 - 27%) (p= 0,01). Discordant results were observed in 11 patients who had active HCMV infection positive for “L-PCR” but negative for “sPCR”, of which 5 developed clinical symptoms for HCMV.
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