BACKGROUND: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated.
OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people.
SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12).
SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis.
DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity.
MAIN RESULTS: We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results.
AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.
La aspergilosis invasiva es una infección difícil de diagnosticar con una alta tasa de mortalidad que afecta a grupos de alto riesgo, como pacientes con neutropenia y hematológicos tumores malignos. Se realizó un meta-análisis bivariado de los datos de diagnóstico para un Aspergillus sp. Ensayo de PCR con muestras de sangre de pacientes hematológicos de alto riesgo. Se incluyeron todos los estudios en seres humanos que evaluaron el desempeño de cualquier ensayo de PCR para la aspergilosis invasiva en la sangre entera o suero y que utilizan la Organización Europea para el tratamiento de cáncer de criterios / Micosis Grupo de Estudio como patrón de referencia. Tres investigadores buscaron de forma independiente la literatura para los estudios elegibles y extrajeron los datos. De un total de 37 estudios, 25 cumplieron con los criterios estrictos de calidad y se incluyeron en nuestra síntesis de la evidencia. Se analizaron los Veinticinco estudios con 2.595 pacientes. El rendimiento diagnóstico agrupado de los ensayos de PCR de sangre completa y suero fue moderada, con una sensibilidad y especificidad del 84% (95% intervalo de confianza [IC] del 75 al 91%) y 76% (IC 95%, 65-84%) , respectivamente, lo que sugiere que un resultado positivo o negativo no puede, por sí solo, para confirmar o descartar una sospecha de infección. El rendimiento de un ensayo de PCR de suero no fue significativamente diferente de la de la sangre entera. En particular, se encontró que al menos dos resultados positivos de la prueba de PCR para tener una especificidad del 95% y una sensibilidad del 64% para la infección invasiva, logrando un alto cociente de probabilidad positivo de 12,8. Es importante destacar que la Iniciativa Europea Aspergillus PCR (EAPCRI) recomendaciones mejoró el rendimiento de la PCR aún más cuando se utilizaron al menos dos muestras positivas para definir la positividad de la PCR. En conclusión, dos resultados positivos de PCR deben considerarse altamente indicativo de un activo Aspergillus sp. infección. El uso de las recomendaciones EAPCRI por laboratorios clínicos puede mejorar aún más el rendimiento de la PCR.
Una revisión sistemática y meta-análisis se realizó sobre el uso de pruebas de PCR para el diagnóstico de la aspergilosis invasiva. Los datos de más de 10.000 muestras de sangre, suero o plasma obtenidas a partir de 1618 pacientes en riesgo de la aspergilosis invasiva fueron recuperados de 16 estudios. En general, las proporciones medias de las probabilidades de diagnóstico (DORS) de PCR para los casos probables y probadas fueron similares independientemente de dos muestras positivas consecutivas fueron necesarios para definir la positividad (DOR 15,97 [IC 95%: 6,83-37,34]) o una sola prueba PCR positiva se requiere ( DOR 16,41 [IC 95%: 6,43-41,88]). La sensibilidad y la especificidad de la PCR para dos muestras positivas consecutivas fueron de 0,75 (IC 95% 0.54-0.88) y 0.87 (IC 95% 0,78 a 0.93), respectivamente, y si sólo una muestra positiva se requiere, estos valores fueron de 0,88 (IC del 95% IC 0.75-0.94) y 0.75 (IC 95% 0.63-0.84), respectivamente. Mientras que la especificidad sobre la base de una sola prueba positiva fue significativamente menor (p = 0,027) de dos pruebas positivas, la sensibilidad y el DOR no difirió significativamente. Un solo resultado negativo de la PCR es, pues, suficiente para excluir el diagnóstico de la aspergilosis invasiva comprobada o probable. Sin embargo, dos pruebas positivas se requiere para confirmar el diagnóstico debido a la especificidad es mayor que la alcanzada a partir de una sola prueba positiva. Poblaciones en riesgo variado y había una falta de homogeneidad de los métodos de PCR utilizados. Se están realizando esfuerzos para elaborar una norma para Aspergillus sp PCR para la detección, lo que ayudará a que la validación formal de la PCR y estimar su uso en pacientes con más probabilidades de beneficiarse.
This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated.
OBJECTIVES:
To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people.
SEARCH METHODS:
We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12).
SELECTION CRITERIA:
We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis.
DATA COLLECTION AND ANALYSIS:
Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity.
MAIN RESULTS:
We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results.
AUTHORS' CONCLUSIONS:
PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.
