Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model

Michaël Schwarzinger et al. PLoS One. .

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: This work was supported in part by the French Ministry of Health (research grant PHRC 2002 AOR02028) and Translational Health Economics Network, a for-profit organization led by Michaël Schwarzinger. Stéphane Bretagne is consultant for Gilead Sciences, and has received speaking honoraria from Pfizer and Gilead Sciences and travel grants from Astellas, Pfizer and Schering-Plough. Catherine Cordonnier has received travel grants and research supports from Pfizer, Gilead, and Merck Sharp & Dohme-Chibret, and has been a consultant for Pfizer, Schering-Plough, Gilead, Merck Sharp & Dohme-Chibret, Astellas Pharma, and Zeneus Pharma. All other authors: no conflict of interest. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Multi-State Model of Invasive Aspergillosis and Antifungal Therapy in Febrile, Neutropenic Patients with Acute Myeloid Leukemia.
See this image and copyright information in PMC

References

    1. Segal BH (2009) Aspergillosis. N Engl J Med 360: 1870–1884. - PubMed
    1. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, et al. (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34: 7–14. - PubMed
    1. de Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, et al. (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46: 1813–1821. - PMC - PubMed
    1. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, et al. (1984) Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 100: 345–351. - PubMed
    1. Muhlemann K, Wenger C, Zenhausern R, Tauber MG (2005) Risk factors for invasive aspergillosis in neutropenic patients with hematologic malignancies. Leukemia 19: 545–550. - PubMed

Publication types

MeSH terms