O papel da pentraxina 3 como biomarcador para diagnóstico de fusariose invasiva em pacientes onco-hematológicos e receptores de transplante de células-tronco hematopoiéticas
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Data
2024-02-27
Autores
Gandolpho, Larissa Simão [UNIFESP]
Orientadores
Colombo, Arnaldo Lopes [UNIFESP]
Tipo
Dissertação de mestrado
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Introdução: A Doença fúngica invasiva ainda representa grandes desafios diagnósticos e terapêuticos, que implicam em piores desfechos para os pacientes onco-hematológicos. Embora Aspergillus seja o principal fungo filamentoso isolado na maior parte dos centros ao redor do mundo, observa-se um aumento progressivo na ocorrência de fungos filamentosos não-Aspergillus, especialmente aquelas causadas por espécies de Fusarium. Esses achados epidemiológicos são particularmente relevantes considerando a dificuldade no diagnóstico precoce, a refratariedade ao tratamento antifúngico e a alta mortalidade frequentemente observadas nessas infecções. Portanto, torna-se evidente a importância de estudos que investiguem diferentes aspectos da história natural dessas micoses, e principalmente, estratégias terapêuticas e diagnósticas precoces. Neste contexto, a pentraxina 3 tem sido reconhecida por desempenhar um papel significativo como adjuvante no diagnóstico de aspergilose invasiva. Portanto, é relevante investigar o potencial uso desse biomarcador para o diagnóstico de outros fungos filamentosos. Objetivos: Detectar e quantificar a presença de pentraxina 3 em amostras de soro de pacientes com fusariose provada e de grupos controles, assim como avaliar o potencial de uso da dosagem de pentraxina 3 como um biomarcador diagnóstico complementar para casos de suspeita de fusariose invasiva. Pacientes e Métodos: Foi realizado seleção retrospectiva de amostras armazenadas no biorepossitório do Laboratório Especial de Micologia-UNIFESP de casos provados de fusariose invasiva e dos seguintes grupos controles de pacientes: (I) Com aspergilose invasiva provada/provável, (II) Saudáveis (III) Com leucemia mieloide aguda e (IV) Receptores de Transplante de Células-Tronco Hematopoéticas (TCTH). Ainda, foi selecionado de maneira prospectiva, (V) pacientes onco-hematológicos com bacteremia. Após, foram realizadas dosagens duplicadas das concentrações de pentraxina 3 nas amostras de soro selecionadas. Resultados: Após exclusão de oito casos que apresentaram níveis de detecção abaixo do limiar mínimo do teste, 55 soros de 54 pacientes foram analisados. Inicialmente, testou-se a hipótese nula de que as concentrações seriam iguais nos 6 grupos avaliados através da análise de variância. Observou-se que os níveis de pentraxina 3 variaram entre 5532,8 pg/mL e 299,5 pg/mL, sendo maiores no grupo aspergilose invasiva (5532,8 pg/mL), seguido pelo grupo fusariose invasiva (3718,1 pg/mL). Por outro lado, os indivíduos saudáveis apresentaram as menores concentrações séricas desta proteína (máxima de 385,7 pg/mL e mínima de 109.9 pg/mL). Após, os grupos foram comparados dois a dois, pelo teste post hoc de Dunn. A concentração sérica média de pentraxina3 em pacientes com fusariose invasiva (mediana= 2548,9 pg/mL) foi significativamente maior em relação aos controles saudáveis, com Leucemia Miolóide Aguda, receptores de TCTH ou bacteremia. No entanto, quando comparada ao grupo de aspergilose invasiva, não houve diferença estatística nos níveis observados entre pacientes com as duas infecções fúngicas. Após aplicação de correção de Bonferroni, observou-se que o teste perdeu nível de significância quando se comparou pacientes com doença fúngica versus bacteremia, provavelmente pelo pequeno tamanho amostral. Entretanto, observou-se que apenas amostras que representavam alguma infecção fúngica (fusariose ou aspergilose) apresentaram valores de pentraxina3 que ultrapassavam 1000 pg/mL. Além disso, todas as amostras obtidas de pacientes com doença fúngica apresentaram valores entre 1000 e 4000 pg/mL, enquanto nenhuma amostra de grupo controle apresentou valores superiores a 1000 pg/mL. Conclusão: O perfil de resposta da pentraxina3 em pacientes com fusariose invasiva é possivelmente análogo ao da aspergilose invasiva, sugerindo que quando associada a outros marcadores, como a galactomanana, pode desempenhar um papel crucial no diagnóstico precoce da aspergilose invasiva e, potencialmente, de outras infecções causadas por Fusarium e outros fungos filamentosos.
Introduction: Invasive fungal disease still poses significant diagnostic and therapeutic challenges, leading to worse outcomes for onco-hematological patients. While Aspergillus is the primary filamentous fungus isolated in most centers around the world, there is a progressive increase in the occurrence of non-Aspergillus filamentous fungi, especially those caused by Fusarium species. These epidemiological findings are particularly relevant considering the difficulty in early diagnosis, refractoriness to antifungal treatment, and high mortality often observed in these infections. Therefore, the importance of studies investigating different aspects of the natural history of these mycoses, particularly therapeutic and early diagnostic strategies, becomes evident. In this scenario, pentraxin 3 has been shown to play a relevant role as an adjunct in the diagnosis of invasive aspergillosis, making it important to investigate the potential use of this biomarker for the diagnosis of other filamentous fungi. Objectives: To detect and quantify the presence of pentraxin 3 in serum samples from patients with proven fusariosis and control groups, as well as to evaluate the potential use of pentraxin 3 levels as a complementary diagnostic biomarker for suspected invasive fusariosis cases. Patients and Methods: A retrospective selection of stored samples from the Special Laboratory of Mycology-UNIFESP biorepository was performed, including cases of proven invasive fusariosis and the following control groups: (I) Proven/probable invasive aspergillosis, (II) Healthy individuals, (III) Acute myeloid leukemia patients, and (IV) Hematopoietic stem cell transplant recipients. Additionally, a prospective selection of (V) onco-hematological patients with bacteremia was conducted. Duplicate measurements of pentraxin 3 concentrations were then performed on the selected serum samples. Results: After excluding eight cases with detection levels below the test's minimum threshold, 55 sera from 54 patients were analyzed. Initially, the null hypothesis of equal concentrations in the six evaluated groups was tested through analysis of variance. Pentraxin 3 levels ranged from 5532.8 pg/mL to 299.5 pg/mL, with the highest levels observed in the invasive aspergillosis group (5532.8 pg/mL), followed by the invasive fusariosis group (3718.1 pg/mL). Conversely, healthy individuals showed the lowest serum concentrations of this protein (maximum 385.7 pg/mL, minimum 109.9 pg/mL). Subsequently, pairwise comparisons between groups were conducted using the Dunn post hoc test. The mean serum concentration of pentraxin 3 in patients with invasive fusariosis (median = 2548.9 pg/mL) was significantly higher than in healthy controls, acute myeloid leukemia patients, hematopoietic stem cell transplant recipients, or those with bacteremia. However, when compared to the invasive aspergillosis group, no statistical difference was observed in the levels between patients with these two fungal infections. After Bonferroni correction, the test lost significance when comparing patients with fungal disease versus bacteremia, likely due to the small sample size. Nevertheless, samples representing fungal infections (fusariosis or aspergillosis) consistently had pentraxin 3 values exceeding 1000 pg/mL. Furthermore, all samples from patients with fungal disease had values between 1000 and 4000 pg/mL, while no control group samples surpassed 1000 pg/mL. Conclusion: The pentraxin 3 response profile in patients with invasive fusariosis is possibly analogous to that of invasive aspergillosis, suggesting that, when combined with other markers like galactomannan, it may play a crucial role in the early diagnosis of invasive aspergillosis and potentially other infections caused by Fusarium and other filamentous fungi.
Introduction: Invasive fungal disease still poses significant diagnostic and therapeutic challenges, leading to worse outcomes for onco-hematological patients. While Aspergillus is the primary filamentous fungus isolated in most centers around the world, there is a progressive increase in the occurrence of non-Aspergillus filamentous fungi, especially those caused by Fusarium species. These epidemiological findings are particularly relevant considering the difficulty in early diagnosis, refractoriness to antifungal treatment, and high mortality often observed in these infections. Therefore, the importance of studies investigating different aspects of the natural history of these mycoses, particularly therapeutic and early diagnostic strategies, becomes evident. In this scenario, pentraxin 3 has been shown to play a relevant role as an adjunct in the diagnosis of invasive aspergillosis, making it important to investigate the potential use of this biomarker for the diagnosis of other filamentous fungi. Objectives: To detect and quantify the presence of pentraxin 3 in serum samples from patients with proven fusariosis and control groups, as well as to evaluate the potential use of pentraxin 3 levels as a complementary diagnostic biomarker for suspected invasive fusariosis cases. Patients and Methods: A retrospective selection of stored samples from the Special Laboratory of Mycology-UNIFESP biorepository was performed, including cases of proven invasive fusariosis and the following control groups: (I) Proven/probable invasive aspergillosis, (II) Healthy individuals, (III) Acute myeloid leukemia patients, and (IV) Hematopoietic stem cell transplant recipients. Additionally, a prospective selection of (V) onco-hematological patients with bacteremia was conducted. Duplicate measurements of pentraxin 3 concentrations were then performed on the selected serum samples. Results: After excluding eight cases with detection levels below the test's minimum threshold, 55 sera from 54 patients were analyzed. Initially, the null hypothesis of equal concentrations in the six evaluated groups was tested through analysis of variance. Pentraxin 3 levels ranged from 5532.8 pg/mL to 299.5 pg/mL, with the highest levels observed in the invasive aspergillosis group (5532.8 pg/mL), followed by the invasive fusariosis group (3718.1 pg/mL). Conversely, healthy individuals showed the lowest serum concentrations of this protein (maximum 385.7 pg/mL, minimum 109.9 pg/mL). Subsequently, pairwise comparisons between groups were conducted using the Dunn post hoc test. The mean serum concentration of pentraxin 3 in patients with invasive fusariosis (median = 2548.9 pg/mL) was significantly higher than in healthy controls, acute myeloid leukemia patients, hematopoietic stem cell transplant recipients, or those with bacteremia. However, when compared to the invasive aspergillosis group, no statistical difference was observed in the levels between patients with these two fungal infections. After Bonferroni correction, the test lost significance when comparing patients with fungal disease versus bacteremia, likely due to the small sample size. Nevertheless, samples representing fungal infections (fusariosis or aspergillosis) consistently had pentraxin 3 values exceeding 1000 pg/mL. Furthermore, all samples from patients with fungal disease had values between 1000 and 4000 pg/mL, while no control group samples surpassed 1000 pg/mL. Conclusion: The pentraxin 3 response profile in patients with invasive fusariosis is possibly analogous to that of invasive aspergillosis, suggesting that, when combined with other markers like galactomannan, it may play a crucial role in the early diagnosis of invasive aspergillosis and potentially other infections caused by Fusarium and other filamentous fungi.
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Citação
GANDOLPHO, Larissa Simão. O papel da pentraxina 3 como biomarcador para diagnóstico de fusariose invasiva em pacientes onco-hematológicos e receptores de transplante de células-tronco hematopoiéticas. 2024. 117 f. Dissertação (Mestrado em Infectologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2024.