Page 433 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Host Defenses to Fungal Pathogens

Allison K. Lord, Jatin M. Vyas

Advances in modern medicine have significantly improved the is an urgent need to define the mechanisms of host defense
prognosis and quality of life for patients with a wide spectrum against fungal pathogens with the goal of developing novel
of diseases, including many forms of cancer. However, oppor- therapeutics as well as improving diagnostic and preventative
tunistic fungal pathogens have exploited these modern immu- procedures.
nosuppressive and invasive medical interventions. Invasive fungal One of the greatest limiting factors in the treatment of IFIs
infections (IFIs) represent a significant cause of morbidity and is lack of effective and prompt diagnostic tools. Although Candida
mortality among immunocompromised patients. Patients at is capable of growing in conventional blood cultures, most other
highest risk for IFIs include solid organ or hematopoietic stem invasive fungal organisms, including Cryptococcus, Aspergillus,
cell transplant (HSCT) recipients on intensive immunosuppressive and Histoplasma, are typically not recovered by adding blood
regimens, patients with hematological malignancies, and other to growth media. There has been a heavy reliance on clinical
patients that are immunocompromised as a result of various diagnosis and a few biomarkers. Fungal cell wall carbohydrates
clinical conditions and treatments (e.g., human immunodeficiency can be detected in the bloodstream of some patients. β-1,3 glucan,
virus/acquired immunodeficiency syndrome [HIV/AIDS], galactomannan, and glucuronoxylomannan (GXM) are three
1,2
advanced age, recent surgery, etc.) (Fig. 29.1). The clinical carbohydrates that can be analyzed clinically. β-1,3 glucan is a
consequences of these pathogenic fungi include superficial disease, common fungal cell wall carbohydrate found in Candida albicans
allergic disease, and IFIs. and many other fungi (with the notable exception of Cryptococcus
neoformans). Galactomannan is typically associated with Aspergil-
lus fumigatus. This fungal biomarker can be measured in blood
KEY CONCEPTS and bronchoalveolar lavage fluid. GXM is an abundant fungal-
Invasive Fungal Infections derived carbohydrate produced by C. neoformans. GXM can also
be found on the surface of Candida gattii, a closely related fungal
• Invasive fungal infections are systemic life-threatening infections that organism that can cause disease in immunocompetent individuals.
are estimated to cause 1.5 million deaths annually. Although GXM appears to be a useful biomarker for Cryptococcus,
• Aspergillus, Candida, Cryptococcus, and Pneumocystis are opportunistic
fungi that cause the majority of invasive fungal infections. its widespread use is limited by technical and economic issues.
• Risk factors for invasive fungal infections include bone marrow or solid Finally, a urine test for histoplasmosis has been established. Again,
organ transplantation, intensive immunosuppressive regimens, hema- the antigen for this test is a polysaccharide derived from the cell
tological malignancies, HIV/AIDS, advanced age, recent surgery, and wall of this fungal organism. Many of these biomarkers suffer
other clinical conditions and treatments that cause immunosuppression. from poor sensitivity (galactomannan) and, in some cases, poor
specificity (e.g., testing urine for Histoplasma antigen).
Current therapeutic approaches for IFIs include the prompt
Superficial fungal infections of the skin and nails affect 25% institution of antifungal agents (including polyenes, azoles, and
of the global population (≈1.7 billion people) and give rise to echinocandins) and even more important, the reversal of underly-
various conditions, including athlete’s foot and ringworm of the ing host immune defects, such as neutropenia or high doses of
scalp. Fungi also commonly cause mucosal infections of the oral immunosuppressive therapy. The first-line therapy for the
and genital tracts; vulvovaginal candidiasis occurs at least once treatment of invasive aspergillosis (IA) is voriconazole, an
3,4
in 50–75% of women in their childbearing years. Superficial extended-spectrum azole. Despite its in vitro efficacy, voriconazole
fungal infections of the skin and mucosa can become chronic, only demonstrated a survival rate at 12 weeks of 70.8% compared
5
but they are rarely life threatening. with 57.9% in the amphotericin B group. Although voriconazole
IFIs occur when fungal pathogens invade the bloodstream, has become the gold standard for treatment, its high mortality
resulting in a systemic life-threatening infection that affects rate indicates that the host immune response plays a critical role
multiple organs. IFIs are estimated to cause 1.5 million deaths in determining host outcome. Despite clinical vigilance, preven-
annually, with four genera accounting for most of the infections: tion, diagnosis, and treatment of IFIs remain a significant
Cryptococcus, Candida, Aspergillus, and Pneumocystis. Mortality challenge because of lack of rapid and reliable diagnostic methods
resulting from infections with these fungal organisms exceeds and limited treatment options. Discovery of novel diagnostic
4
that caused by tuberculosis or malaria. As a result, IFIs have tools and antifungal therapies is crucial to ameliorating this
emerged as an escalating and worrisome clinical problem. There public health burden.
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