ABSTRACT

Opportunistic fungal diseases occur most commonly in highly immunocompromised patients, such as those with prolonged neutropenia or transplant recipients treated with intensive immunosuppression. Significant advances have been made in antifungal agents, which have led to improved therapeutic outcomes as well as a greater emphasis on antifungal prophylaxis targeted to the highly immuncompromised. In addition, we are gaining more knowledge about how our immune system recognizes fungi and protects us from fungal disease, while limiting potentially injurious inflammation and allergy. This knowledge has led to novel experimental approaches for immunotherapy. Progress in paving the way from promising pre-clinical approaches and limited clinical experience to properly conducted clinical trials has been poor – a reflection of invasive fungal diseases being relatively uncommon and the heterogeneity of the patient populations at risk, and insufficient funding for multicenter clinical immunotherapeutic trials. We describe our approaches to immunotherapy for severe and refractory invasive fungal diseases, realizing that important gaps in knowledge exist regarding benefit and toxicity. Future perspectives on immunotherapy are discussed.

ABSTRACT

With improved laboratory techniques and the availability of new antifungal agents, complexity in the treatment of invasive fungal disease has rapidly increased over the past decade, stimulating a debate on the best management strategies.  In this chapter, we address four important areas of current uncertainty, including: 1) the role of therapeutic drug monitoring for voriconazole and posaconazole, 2) the utility of in vitro antifungal susceptibility testing of yeasts and moulds, 3) the optimal treatment of zygomycosis, and 4) the value of combination therapy for invasive aspergillosis.  For each topic, we examine the available evidence surrounding the ambiguity and then offer data-driven recommendations on how to proceed with management.

ABSTRACT

Invasive mold infections (IMIs) are a major cause of morbidity and mortality in severely immunocompromised hematologic malignancy patients and hematopoietic stem cell transplantations recipients. Invasive aspergillosis caused by Aspergillus fumigatus is the most common cause of IMI, but recent advances in the pharmacotherapy of fungal infections and an increase in the number of patients at risk has caused an epidemiologic shift towards infections with resistant non-fumigatus Aspergillus species and non-Aspergillus molds such as Zygomycetes. Patient outcome is a function of immune function recovery, early diagnosis, and multiple interventions, such as with broad-spectrum antifungal therapy and adjunct immunotherapy and surgery in select patients. In this chapter, we review the utility of new diagnostic modalities such as the galactomannan test, the 1,3-beta-D-glucan test, and fungal DNA tests in diagnosing IMIs early. We focus on modern antifungal agents (the lipid formulations of amphotericin B, the broad-spectrum azoles, and the echinocandins) and evaluate them in the context of evolving prophylactic, pre-emptive, and targeted therapies for IMIs.

ABSTRACT

The diagnosis of invasive fungal infections (IFI) relies on the critical assessment of clinical presentation, associated risk factors, and careful interpretation of the appropriate diagnostic tests.  Frequently, clinicians have to initiate antifungal therapy based on their clinical suspicion and without having made a definitive diagnosis, particularly in cancer or other critically ill patients.  To complicate diagnosis, isolation of fungal organisms does not imply pathogenicity, especially from non-sterile sites, and may not necessitate treatment.  Hence, making the diagnosis of an IFI in clinical practice requires suspicion of disease, depends mostly on the acuity and severity of clinical signs and symptoms, and necessitates careful consideration of findings.  In this chapter we will review the traditional diagnostic modalities (culture, histopathology, and imaging) and recently developed diagnostic tools (BG, PCR, and GM EIA) for the diagnosis of IFIs.  This review will focus on the diagnosis of the most commonly identified IFIs in cancer patients, specifically invasive candidiasis (IC), invasive aspergillosis (IA), and zygomycosis.