Early serum galactomannan trend as a predictor of outcome of invasive aspergillosis

Abstract

The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of ≥ 0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.

Fig. 1

Galactomannan index (GMI) of patients with a positive GMI of ≥0.5 at baseline plotted against predefined clinical outcome parameters at week 12: treatment response (a) or survival (b). #p is the P value for the difference in the absolute GMI values between W12 responders and nonresponders. This was 0.003 by univariate analysis. After multivariate correction for age, sex, underlying hematological condition, neutropenia, and receipt of the primary trial drug (amphotericin B or voriconazole), #p was 0.035. The numbers of distinct specimens analyzed at each time point are as follows: 71 specimens at baseline, 60 at week 1, 53 at week 2, and 42 at week 4. Statistical analysis was performed by the generalized estimation equation (GEE) approach. The table below each graph depicts positive likelihood ratios (LHR) and 95% confidence intervals (95% C.I.) of the respective adverse outcomes (poor clinical response or mortality at week 12) should the GM index remain higher than the cutoff value, as indicated.

Fig. 2

Galactomannan index (GMI) of patients with a GMI of <0.5 at baseline plotted against predefined clinical outcome parameters at week 12: treatment response (a) or survival (b). The values enclosed by horizontal brackets represent the multivariate P value for the difference in the ΔGMIs of both groups between the indicated study intervals, incorporating correction for age, sex, underlying hematological condition, neutropenia, and receipt of primary trial drug (amphotericin B or voriconazole). The numbers of distinct specimens analyzed at each time point are as follows: 131 specimens at baseline, 119 at week 1, 112 at week 2, and 102 at week 4. Statistical analysis was performed by the generalized estimation equation (GEE) approach. The table below each graph depicts the positive likelihood ratios (LHR) and 95% confidence intervals (95% C.I.) of the respective adverse outcomes (poor clinical response or mortality at week 12) should the GM index remain higher than the cutoff value, as indicated.