Fungal Infections in Neutropenic Patients
Authors: Gea-Banacloche Juan , Groll Andreas H , Walsh Thomas J 
Published: October 2023

Abstract
Invasive fungal infections (IFIs) are a significant problem in neutropenic patients. They are common, difficult to diagnose, and associated with high mortality. This chapter is organized according to the clinical, diagnostic, and therapeutic approaches that are recommended for the management of neutropenic patients at risk for IFIs. Although any fungal pathogen may potentially cause infection in neutropenic patients (Walsh and Groll, 1999a), here the focus is on more common fungal infections with special emphasis on Candida spp., Aspergillus spp., Fusarium spp., Scedosporium spp., Trichosporon spp., and the Zygomycetes. The epirical treatment of persistent fever in the neutropenic patient is also reviewed. The initial description of fungal infections in neutropenic patients was published more than 30 years ago (Bodey, 1966a). Bodey reviewed the records of all 454 patients with acute leukemia who died at the National Institutes of Health between 1954 and 1964 and found that 107 patients (24%) had a major fungal infection (excluding focal candidiasis). Despite the changes in clinical practice during the last 4 decades, more recent autopsy studies continue to show high frequencies of IFIs in leukemic patients: 25% overall in a study that included 12 hospitals in Europe, Canada, and Japan (Bodey et al, 1992), and a striking 58% in a more recent European report (Jandrlic et al, 1995). The frequencies are much lower for patients with solid tumors (1%–8%). These numbers must be interpreted with caution because of the selection bias inherent to autopsy studies, and the various definitions used in these series (Krick and Remington, 1976; Fraser et al, 1979; Wingard et al, 1979). The recent large trials of empirical antifungal therapy in neutropenic fever have documented relatively low frequencies of IFI (at the initiation of empirical therapy), ranging between 1.5% and 5.9% (Winston et al, 2000; Boogaerts et al, 2001) and similarly low frequencies of breakthrough infections during treatment, ranging between 2.6% and 5.5% (Boogaerts et al, 2001; Walsh et al, 2002). This broad range of rates reflects in part methodological and definition issues, but also underscores that not all neutropenic patients are at the same risk (Walsh et al, 1994; Prentice et al, 2000). The autopsy studies are also consistent on other points. A large percentage of fungal infections go undiagnosed during life. The general frequencies of pathogens are also fairly similar, with Candida comprising roughly 50% of all cases, Aspergillus 40% and the Zygomycetes, Cryptococcus and other pathogens accounting for the remainder. The current widespread use of azole prophylaxis is probably changing the epidemiology of IFI: Candida albicans is becoming less common, and other more resistant species (C. glabrata, C. krusei) are becoming more prevalent (Abbas et al, 2000; Bodey et al, 2002). At the same time, Aspergillus is emerging as the more common pathogen in some institutions, particularly in the setting of hematopoietic stem cell transplantation, where Aspergillus has replaced Candida as the most common fungal pathogen in a recent series (Martino et al, 2002).