Abstract
BackgroundThe 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.MethodsWe 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.ResultsThe 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).ConclusionsThe 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.
Highlights
The evaluation of biomarker performance to detect invasive aspergillosis is often limited by the absence of the gold standard for diagnosis and the empirical administration of antifungal therapy for a persistent or recurrent fever
We evaluated biomarker performance overall with use of all samples collected during study enrollement, and according to two restrictive approaches with selection of serum samples to underline the importance of the timing of test results on biomarker performance: 1) an early detection approach with selection of samples collected after neutropenia or fever onset, and before treatment, invasive fungal disease, or neutropenia recovery; 2) a confirmatory diagnosis approach of a positive galactomannan antigenemia with selection of samples collected on the same sample or the consecutive sample of a Aspergillus galactomannan antigenemia (GM) index $0.5
We checked whether the first positive galactomannan antigenemia available to clinicians increased the likelihood to start antifungal therapy, and we evaluated whether the first positive test result with b-glucan or quantitative PCR (qPCR) may accelerate the early detection of invasive aspergillosis, i.e., the biomarker was independently associated with an increased risk of invasive aspergillosis before antifungal therapy was started
Summary
The evaluation of biomarker performance to detect invasive aspergillosis is often limited by the absence of the gold standard for diagnosis and the empirical administration of antifungal therapy for a persistent or recurrent fever. The performance of biomarkers to detect invasive aspergillosis depends on the timing of test results during neutropenia [7]. The need to evaluate biomarker performance is important in untreated patients because serial blood screening may accelerate the early detection of invasive aspergillosis, independently of other diagnostic information [8,9,10,11]. 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, a dynamic evaluation framework is lacking
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