Recent advances in early diagnosis and preemptive therapy

Early diagnosis and rapid initiation of effective antifungal chemotherapy is paramount to the successful management of invasive mycoses. The microbiological diagnosis should be attempted if feasible in all cases of suspected invasive fungal infection, and the organism identified at the species level. Because of the lack of its predictive value in other settings, the performance of in vitro susceptibility testing is currently reserved to Candida species vs. fluconazole and flucytosine, respectively. Additional in vitro testing of other organism/drug combinations may be indicated in refractory infections and within surveillance programs [170].

Improved blood culture detection techniques, such as the lysis-cen-trifugation and the BacTec Alert system, are able to detect candidemia earlier and more frequently than conventional systems [171]. However, it must be emphasized that candidemia is only one manifestation of invasive candidiasis, and that single organ or early disseminated candidiasis are not reliably detected by blood culture techniques and may therefore require more invasive diagnostic procedures [172]. For such tissue-invasive Candida infections, ultrasound, high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) have become indispensable tools for detection, monitoring and as guidance of diagnostic procedures [173-176]. In the future, nonculture techniques, particularly nucleic acid amplification based systems, may complement existing blood culture systems not only for early detection purposes but also for determining resistance patterns to antifungal agents [177].

Apart from improved detection of invasive mould infections of the paranasal sinuses [178], the advent of modern imaging techniques has also permitted earlier detection of pulmonary infiltrates consistent with invasive pulmonary aspergillosis and early preemptive treatment [179-181]. However, although peripheral nodules, the halo-sign and cavitation are all characteristic of pulmonary aspergillosis, these radiological criteria are not entirely specific, and nonspecific air space consolidation is common in early phases [181]. As previously rare filamentous fungi are becoming more common, a microbiological diagnosis by fiberoptic bronchoscopy with bron-choalveolar lavage or transcutaneous bioptic measures is greatly encouraged. Indeed, amplification of fungal DNA from biopsy specimens allows for rapid identification of the causative organism of invasive aspergillosis and mucormycosis and may allow guided antifungal treatment in patients with invasive mold infections [182].

Serial monitoring of galactomannan antigen and Aspergillus-specific nucleic acid sequences in blood [183-186] may contribute substantially to the detection of invasive pulmonary aspergillosis, particularly in the neutropenic host. The feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutrope-nic patients, while avoiding empirical therapy, has been demonstrated in a single-center study: Preemptive therapy based on serial galactomannan testing and high-resolution CT scans reduced the exposure to antifungal drugs and offered effective antifungal control, but it failed to detect non-Aspergillus invasive mycoses [187]. However, both galactomannan ELISA and PCR protocols appear to be less useful in children than in adults, and reliance on invasive procedures such as bronchoalveolar lavage or lung biopsy coupled with molecular diagnostics has been advocated [188]. Carefully designed clinical trials are now needed to determine the value of preemptive strategies at the dawn of more effective chemoprophylaxis in high-risk populations.

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