Yeasts Are Beasts

Dear Colleagues,

Invasive yeast infections remain deadly complications in modern medicine. These fungi particularly attack weakened hosts and their victims; complications can range from the immune devastation of HIV infection to the circumstances of the Intensive Care Unit patient, who can suffer from a combination of foreign bodies, antibacterial exposure, and septic physiology to become a high risk host. Within the landscape of these compromised hosts, cryptococcosis and candidiasis can wreak havoc with patient health.

There have been three major outbreaks of cryptococcosis: (1) the outbreak in the late 1960’s, with the introduction of immunosuppressive agents and transplantation; (2) the outbreak during the mid-1980s through the early turn of the century, in which the outbreak followed the pandemic of HIV infections; (3) the outbreak around 2000, in Vancouver and in the Pacific North West, which was identified as a C. gattii outbreak. These three outbreaks continue. In cryptococcal infections, the principles of fungal disease pathobiology and management abound. First, mortality for cryptococcal meningoencephalitis continues to be 20-30% in resource-available environments; in resource-limited environments, mortality can reach over 50%. Clearly, our institution of optimal antifungal therapy and its delivery have substantial room for improvements. Second, cryptococcosis separates itself into three groups, including in those with underlying diseases, such as HIV or transplant recipients; the final group consists of a heterogeneous patient population with a myriad of apparent and non-apparent risks. In many respects, this latter group is the hardest to manage. Third, the lethal cryptococcal meningoencephalitis patient precisely defines the impact of immune reconstitution inflammatory syndrome (IRIS) on disease outcome. IRIS is a major clinical feature in the era of host immune modulations. Its impact on clinical disease, from increased intracranial pressure to symptomatic headaches and worsening radiographs, has become a major clinical conundrum for clinicians. Fourth, although new antifungal agents for treating cryptococcosis are not yet in the clinic, there has been an explosion of molecular pathogenesis studies on this yeast, which has allowed it to become a major fungal pathogenic model system for understanding mycologic pathobiology. Fifth, on the host side, we continue to pull back the mysteries of immune suppression, including the recent identification of anti GM-CSF antibodies as a risk factor that contributes to C. gattii infections.

Candidiasis, in all its local and invasive forms, remains the most common fungal problem to cause widespread disease in the human host.  From our antibiotic usage, with selective pressure on the microbiome, to our genetic susceptibility to neutropenia/mucositis, to the placement of a variety of catheters/foreign bodies, this relatively benign fungal colonizer can become a life-threatening infection. There are multiple species, such as C. albicans, C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei, which we lump under the term candidiasis, but they all have their own unique features. In the study of candidiasis, we have excellent and mature molecular tools to help understand the disease. The disease covers certain territories, such as foreign bodies and biofilms, the switching of forms from commensal to pathogen, and the development of direct drug resistance. There has now been extensive therapeutic experience with three classes of antifungal agents (polyenes, azoles, and echinocandins) in candidiasis. In fact, the echinocandins have been gaining favor as the safe and most effective class of agents for invasive candidiasis; however, with frequent use, drug resistance has again raised its ugly consequences. It is important that we develop new antifungal classes against candidiasis, but immediately, we need to strengthen our antifungal stewardships to wisely utilize our present armamentarium in prophylactic, empirical, and pre-emptive uses, and in therapy. Early diagnostic strategies and targeted treatments are essential to care for these candida superinfections, which critically modulate patient outcome.

Cryptococcosis and candidiasis are different in multiple aspects, but they critically define the immune compromised hosts today, and they represent a major stumbling block in the return to health of seriously ill patients. They are defined sentinel markers linked to the immunocompromised individual. The articles presented in this Special Issue concern various aspects of these diseases; the Special Issue will dial down into the understandings of the yeasts and the diseases they produce. It is simply important to understand the “enemy” if we want to control it.

Here is a list of topics I would suggest (including but not limited to):

Cryptococcosis

•Understanding the molecular aspect of cryptococcosis: What makes the yeast produce disease
•The outbreaks of cryptococcosis (From the rise of transplantation to the HIV pandemic and capped by the environmental resurgence in Vancouver)
•The clash of titans in cryptococcal meningitis: IRIS vs. the burden of yeasts.
•Cryptococcosis: One of the best-studied fungal diseases for treatment but what do we really know and what we need to know?

Candidiasis

•Candidiasis: From commensal to invasive disease, what does the yeast really do?
•Multiple host risk groups and how does that impact management of candidiasis.
•Foreign bodies, biofilms, antifungal susceptibility testing, and diagnostic strategies, in candidiasis: What is important and why?
•In candidiasis treatment: What are the principles and how do the treatment guidelines help or hinder management?

Prof. Dr. John R. Perfect
Guest Editor

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