Performance of Serum Biomarkers for the Early Detection of Invasive Aspergillosis in Febrile, Neutropenic Patients: A Multi-State Model

• Published in: PloS one Vol. 8; no. 6; p. e65776
• Main Authors: Schwarzinger, Michaël, Sagaon-Teyssier, Luis, Cabaret, Odile, Bretagne, Stéphane, Cordonnier, Catherine
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.06.2013; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Adult; Aged; Analysis; Antifungal agents; Antifungal Agents - administration & dosage; Antigenemia; Antigens; Antigens, Fungal - blood; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Aspergillosis; Aspergillus; Assaying; beta-Glucans - blood; Biological markers; Biomarkers; Biomarkers - blood; Bone marrow; Chemotherapy; Chemotherapy-Induced Febrile Neutropenia - blood; Chemotherapy-Induced Febrile Neutropenia - immunology; Clinical trials; Diagnostic systems; DNA, Fungal - blood; DNA, Fungal - genetics; Early Diagnosis; Enzymes; Female; Fungal infections; Fungal Polysaccharides - blood; Fungicides; Genes, Fungal; Glucan; Human health and pathology; Humans; Infectious diseases; Invasive Pulmonary Aspergillosis - blood; Invasive Pulmonary Aspergillosis - diagnosis; Invasive Pulmonary Aspergillosis - drug therapy; Invasiveness; Leukemia; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - drug therapy; Life Sciences; Male; Mannans - blood; Markov Chains; Mathematical models; Medical diagnosis; Medical prognosis; Medicine; Middle Aged; Mitochondria; Models, Biological; Myeloid leukemia; Neutropenia; Parasitology; Patients; Performance evaluation; Preempting; Prospective Studies; Randomized Controlled Trials as Topic; Real-Time Polymerase Chain Reaction; Risk analysis; Risk factors; Risk groups; Risk management; Studies; Therapy; Time functions; β-Glucan; France; Antifungals; Fevers; Diagnostic medicine; Aspergillosis; Biomarkers; Acute myeloid leukemia; Blood; Neutropenia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065776

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.