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Timely intervention for invasive fungal disease: should the road now lead to the laboratory instead of the pharmacy?

Received 31 December 2008; accepted 5 January 2009; electronically published 12 March 2009. Reprints or correspondence: Dr. J. Peter Donnelly, Dept. of Haematology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands (p.donnelly@usa.net). Clinical Infectious Diseases 2009; 48:1052–4 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4808-0004$15.00 DOI: 10.1086/597396 When Pizzo et al. [1] reported the results of their landmark study on the empirical use of amphotericin B for treatment of neutropenic patients with persistent, antibiotics-refractory fever, they did not need statistics. The results perfectly reflected the prevailing perception enunciated by DeGregorio et al. [2] and seemed to provide a rational basis for what became clinical habit. As usual, the things that appear absolutely logical are seldom true. However, it took a considerable length of time before this concept of empirical antifungal treatment showed the first cracks and doubts emerged. The need for empirical antifungal therapy was distilled into a definition— namely, any fever persisting for 3 or more days despite broad-spectrum antibiotic therapy while the patient was neutropenic. In the meantime, we were presented with 4 large studies that compared the potential of various new antifungal drugs for empirical treatment [3–6]. Each drug vied to attain the label for empirical use, although, in fact, no substantial differences between them were found [7]. Liposomal amphotericin B and caspofungin won their spurs, but voriconazole did not [5]. Thanks to the quirks of statistics, we discovered that the drug with the highest clinical anti-Aspergillus activity could not be used for empirical purposes because it did not fulfill the criteria of “noninferiority” [8]. This situation has changed considerably in the past 30 years. High-resolution CT of the chest is known to be superior to the traditional chest radiograph for detection of pulmonary fungal disease [9]. It has also been shown that systematic use of this technique permits earlier diagnosis and treatment and thus better rates of survival [10]. The search for metabolites or cell components of a given fungus, such as specific antigens and DNA, led to some crucial developments, the most important of which was the ELISA test for galactomannan, an antigen present in the Aspergillus cell wall [11]. Molecular techniques based on PCR have not yet been validated to a similar extent, but an overview of the developments in the diagnostic field indicates that timely discovery of an incipient invasive fungal infection is becoming feasible [12]. The newer diagnostics offered the potential for an alternative to empirical therapy, one that is commonly referred to as the “preemptive” approach. The seminal article of Maertens et al. [13] showed that, by incorporating these new diagnostic tools into their practice, it was possible to reduce the rates of antifungal therapy use by almost one-half, proving that the principle was feasible. They also proposed a randomized trial of preemptive therapy versus empirical therapy to confirm their findings, which one of us (B.E.d.P.) found not to be a particularly attractive idea [14]. In this issue, Cordonnier et al. [15] report the results of their attempt to address the question of whether a preemptive approach is equally effective as an empirical approach in terms of overall survival. The group chose patients they considered to be at high risk of developing invasive fungal disease but excluded allogeneic stem cell transplant recipients. They anticipated a survival rate of 90% for patients given empirical therapy, and their hypothesis was that preemptive therapy would not prove to be inferior to empirical therapy by 110%. Thus, 228 patients would need to be assigned to each arm to achieve a power of 80% with use of a 1-sided 95% CI. The criteria adopted for starting empirical therapy were persistent fever (13 days of fever and antibacterial therapy) or recurrent fever. The criteria defined for starting preemptive therapy included clin-