Review
Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis

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Summary

The availability of the Platelia Aspergillus, a sandwich ELISA kit that detects circulating galactomannan, has been a major advance for managing patients at risk for invasive aspergillosis because of the early detection of the antigen. The assay is now widely used throughout the world, including the USA. Although initial studies that assessed the performance characteristics of this assay reported high sensitivity and specificity, more recent studies show significant variation in performance. The causes of this variability are multifactorial and, in large part, cannot be explained because there is insufficient understanding of the kinetics of galactomannan in vivo. We explored some of the factors that affect the release of the aspergillus antigen that bears the epitope that reacts with the monoclonal antibody used in the ELISA, its leakage from the site of infection into the blood, and its binding to substances present in the blood. Factors that affect the detection of antigen in blood are also discussed, most notably the pretreatment procedure aimed at liberating the antigen from immune complexes. Understanding the biology of galactomannan release by aspergillus will greatly enhance our understanding of the kinetics of this and other surrogate markers and allow their optimum use in the management of invasive aspergillosis.

Section snippets

Causes of variability

There are several reasons that might explain the reported differences in performance, relating to (i) the fungus (strain, growth, release of antigen), (ii) the host (underlying condition, location and extent of fungal disease, antifungal treatment, age), and (iii) definition and method (ELISA, sampling and storage, definition of case, definition of results; table 1). At present the kinetics of galactomannan (release at the site of infection, leakage to the circulation, characteristics of

The galf-antigen

In-vivo studies to identify the molecules secreted by the fungus during invasive growth in host tissues have been confounded by the small amount of antigens present. Only one study deals with antigens secreted in vivo during infection of mouse kidney.18 This and earlier studies suggested that circulating Aspergillus sp antigens in patients with invasive aspergillosis varied in size from 35 to greater than 100 kDa, although the nature of the antigens was not characterised.19 The presence of

Exposure to antifungal agents

An important factor that affects the release of galf-antigens is antifungal drug therapy. Amphotericin B is known to suppress the expression of galactomannan antigenaemia in neutropenic rabbits with primary pulmonary aspergillosis.44 Rohrlich et al8 reported that in vitro this negative effect is caused by a reduction in mycelial growth and not by a direct effect of amphotericin B on the secretion of galactomannan, although the method used was not described. Exposure to amphotericin B resulted

Cut-off value

Other factors that have been under debate are the cut-off value of a positive result. When the ELISA kit was launched in Europe a decade ago, a cut-off serum ratio of 1·5 was recommended in the manufacturers manual. Although the course of the antigen titre is considered more important than the actual cut-off, several studies indicated that 1·5 was too high. Over the past years many investigators have used 1·0 as cut-off and a receiver operating characteristic analysis indicated that a cut-off

Conclusions

The sandwich ELISA allows detection of circulating galf-antigens (galactomannan) in the blood of patients with invasive aspergillosis with high sensitivity and specificity. There is, however, considerable variation in performance. This variability is multifactorial and is far from being understood. Some of the factors that might affect the release of the Aspergillus antigen bearing the epitope that reacts with the monoclonal antibody EB-A2 used in the ELISA include those relating to fungal

Recommendations for use of antigen detection in clinical practice

Despite many uncertainties with respect to the release and detection of galactomannan and the variable performance in clinical practice, the commercial ELISA test Platelia Aspergillus is routinely used worldwide in the management of patients at high risk of invasive aspergillosis. The fact that circulating antigen can be detected at an early stage of infection makes prospective monitoring of serum or plasma feasible. Patients that are at high risk include those with acute myeloid leukaemia,

Search strategy and selection criteria

Information was identified by searches in Medline, references of relevant articles, and of the extensive files of the authors. Views and concepts evolved from discussions with colleagues who are specialists in mycology. Search terms were “invasive aspergillosis”, “Aspergillus”, “fungal”, “diagnosis”, “management”, “antigen”, “antigenaemia”, “galactomannan”, “galactofur*”, “glycoprotein”, “carbohydrate”, “polysaccharide”, “oligosaccharide”, “(lipo)glycan”, “amphiphile”, and “(lipo)teichoic

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