Voriconazole or Amphotericin B as Primary Therapy Yields Distinct Early Serum Galactomannan Trends Related to Outcomes in Invasive Aspergillosis

Louis Yi Ann Chai,Alieke G Vonk,Bart Jan Kullberg,Raoul Herbrecht,Arul Earnest,Haran T Schlamm,Peter F Troke,Mihai G Netea,Steven Teerenstra,Elizabeth M Johnson

doi:10.1371/journal.pone.0090176

Abstract

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Highlights

Invasive aspergillosis (IA) is the most common opportunistic mold infection in immunocompromised patients and leads to significant morbidity and mortality
We explored the prognostic usefulness of serial galactomannan index (GMI) measurements and reported that early GMI trends at Week 1 and Week 2 of antifungal treatment were of value for predicting eventual clinical outcomes [5]
Our analysis was based on the well-characterized IA patient cohort in the landmark multicenter Global Aspergillosis Study, which compared the efficacy of voriconazole (VCZ) versus conventional amphotericin B deoxycholate (CAB) as primary therapy for IA [6]

Summary

Introduction

Invasive aspergillosis (IA) is the most common opportunistic mold infection in immunocompromised patients and leads to significant morbidity and mortality. The presence of neutropenia and the concurrent use immunomodulatory agents hinder the ability of the host to mount an efficient inflammatory response against the pathogen and make the monitoring of response to anti-fungal treatment difficult. The detection of galactomannan with the Platelia Aspergillus EIA, the galactomannan index (GMI) has been adopted as a criterion in the diagnosis of IA [2,3] and it has been suggested that serial determination of serum GMI may be useful for monitoring the response to treatment [4]. We explored the prognostic usefulness of serial GMI measurements and reported that early GMI trends at Week 1 and Week 2 of antifungal treatment were of value for predicting eventual clinical outcomes [5]. The influence of the respective antifungal agents on GMI trends was not delineated in the above study

Methods

Results

Conclusion