Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis

Abstract

Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or β-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.

Conflict of interest statement

Competing Interests: R. Railkar, R. Fox, C. Douglas, R. Iannone, E. Kauh, and N. Shire are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, which provided funding towards this study. D. Neofytos, D. Fredricks, B. Granwehr and N. Almyroudis report grant from Merck & Co., Inc. K. Mullane reports grant from Merck & Co., Inc., outside the submitted work. K. Marr reports grant from Astellas, Merck & Co., Inc., and Pfizer, and received personal fees from Astellas, Merck, and Pfizer, outside the submitted work. K. Marr reports a US patent: Lateral Flow Device for Diagnosing Microbial Infections, US2013/0017561. D. Neofytos reports grants from Pfizer and personal fees from Roche and Astellas, outside the submitted work. D. Kontoyiannis reports grants from Merck & Co., Inc. and Pfizer; he received personal fees from Pfizer, Gilead, and Schering-Plough, outside the submitted work. J. Maertens reports no conflict of interest. There are no further 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

Fig 1. Kaplan-Meier survival curves among: (A) patients with hematologic malignancies and stem cell transplant recipients compared to patients with other underlying diseases, and (B) patients with positive vs negative baseline galactomannan enzyme immunoassay optical density index.

In Fig 1A, 0 (solid line) represents “other populations” and 1 (dashed line) represents patients with “HSCT/BMT patients”. In Fig 1B, 0 (solid line) represents patients with negative GMI at baseline, and 1 (dashed line) represents patients with positive GMI at baseline.