Equipe ATIP/AVENIR, INSERM, UMR 738, Paris, France.
PLoS One. 2013 Jun 14;8(6):e65776. doi: 10.1371/journal.pone.0065776. Print 2013.
The performance of serum biomarkers for the early detection of invasive aspergillosis expectedly depends on the timing of test results relative to the empirical administration of antifungal therapy during neutropenia, although a dynamic evaluation framework is lacking.
We developed a multi-state model describing simultaneously the likelihood of empirical antifungal therapy and the risk of invasive aspergillosis during neutropenia. We evaluated whether the first positive test result with a biomarker is an independent predictor of invasive aspergillosis when both diagnostic information used to treat and risk factors of developing invasive aspergillosis are taken into account over time. We applied the multi-state model to a homogeneous cohort of 185 high-risk patients with acute myeloid leukemia. Patients were prospectively screened for galactomannan antigenemia twice a week for immediate treatment decision; 2,214 serum samples were collected on the same days and blindly assessed for (1->3)- β-D-glucan antigenemia and a quantitative PCR assay targeting a mitochondrial locus.
The usual evaluation framework of biomarker performance was unable to distinguish clinical benefits of β-glucan or PCR assays. The multi-state model evidenced that the risk of invasive aspergillosis is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of invasive aspergillosis (P = .010), independently of other diagnostic information used to treat, while β-glucan assay did not (P = .53).
The performance of serum biomarkers for the early detection of invasive aspergillosis is better apprehended by the evaluation of time-varying predictors in a multi-state model. Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with galactomannan antigenemia and a standardized quantitative PCR assay.
血清生物标志物在中性粒细胞减少症期间进行经验性抗真菌治疗时，对侵袭性曲霉病的早期检测的性能预计取决于测试结果与经验性抗真菌治疗之间的时间关系，但缺乏动态评估框架。
我们开发了一种多状态模型，该模型同时描述了中性粒细胞减少期间经验性抗真菌治疗的可能性和侵袭性曲霉病的风险。我们评估了当考虑到诊断信息和侵袭性曲霉病的发展危险因素时，生物标志物的首次阳性测试结果是否是侵袭性曲霉病的独立预测指标。我们将多状态模型应用于 185 例高危急性髓细胞白血病患者的同质队列。前瞻性地每周两次对患者进行半乳甘露聚糖抗原血症筛查，以便及时进行治疗决策；在相同的日子收集了 2214 份血清样本，并对其进行（1->3）-β-D-葡聚糖抗原血症和针对线粒体基因座的定量 PCR 检测进行了盲法评估。
生物标志物性能的常用评估框架无法区分β-葡聚糖或 PCR 检测的临床益处。多状态模型证明，侵袭性曲霉病的风险是中性粒细胞减少持续时间和风险管理的复杂时间函数。定量 PCR 检测可加速侵袭性曲霉病的早期检测（P = .010），而与其他用于治疗的诊断信息无关，而β-葡聚糖检测则无（P = .53）。
通过在多状态模型中评估时间变化的预测因子，可以更好地理解血清生物标志物对侵袭性曲霉病的早期检测的性能。我们的结果为前瞻性研究提供了有力的依据，这些研究通过临床，影像学和每两周一次的半乳甘露聚糖抗原血症和标准化定量 PCR 检测来指导经验性抗真菌治疗，以实现抢先治疗。
