candidiases

Residing normally in the skin, mouth, gastrointestinal tract, and vagina, Candida species are versatile microorganisms. In healthy people, Candida species usually live as benign commensals and produce no disease. However, Candida species, most often C. albicans, are the most frequent cause of human fungal infections. These infections range from superficial lesions in healthy persons to disseminated infections in immunocompromised patients.

C. albicans grows best on warm, moist surfaces and so frequently causes oral thrush, vaginitis, and diaper rash. Diabetics and burn patients are particularly susceptible to superficial candidiasis. Candida can be directly introduced into the blood by intravenous lines, catheters, peritoneal dialysis, cardiac surgery, or intravenous drug abuse. Severe disseminated candidiasis is associated with neutropenia secondary to leukemia or anticancer therapy, immunosuppression after transplantation, and neutrophil disorders such as chronic granulomatous disease. Although the course of candidal sepsis is less rampant than that of bacterial sepsis, disseminated Candida eventually may cause shock and DIC.

Pathogenesis. A single strain of Candida can be successful as a commensal or a pathogen. Candida species have highly developed mechanisms to adapt rapidly to changes in the host environment (produced by antibiotic therapy, the immune response, or altered host physiology). Candida can shift between different phenotypes in a reversible and apparently random fashion. Phenotypic switching involves coordinated regulation of phase-specific genes and provides a way for Candida to adapt to changes in the host environment. C. albicans produces genetically altered variants at a high rate. These variants can exhibit altered colony morphology, cell shape, antigenicity, and virulence.

Candida produce a large number of functionally distinct adhesins that mediate adherence to host cells, and some of them also function in Candida morphogenesis or signaling.128,129 These adhesins include (1) an integrin-like protein, which binds arginine-glycine-aspartic acid (RGD) groups on fibrinogen, fibronectin, and laminin; (2) a protein that resembles transglutaminase substrates and binds to epithelial cells; and (3) several agglutinins that bind to endothelial cells or fibronectin. Adhesion is an important determinant of virulence, since strains with reduced adherence to cells in vitro are avirulent in experimental models in vivo. Differential expression of adhesins by yeast and hyphae leads to recognition of distinct receptors on host cells. Candida yeast mainly bind mannose receptors, while Candida hyphae primarily bind complement receptor 3 (CR3) and Fcγ receptor.

The immune response to Candida is complex. Innate immunity and T-cell responses are important for protection against mucosal and cutaneous Candida infection, while neutrophils and mononuclear phagocytes appear to be more important for resistance to systemic Candida infections. Dendritic cells phagocytose yeast and hyphal forms in different ways. Hyphae, but not yeast, can escape from phagosomes and enter the cytoplasm.

The differential interactions of yeast and hyphae with dendritic cells lead to the production of distinct cytokines and activation of distinct subsets of T cells. TH1 responses are needed for protective antifungal immunity. It has been speculated that the interaction of Candida adhesins with distinct recognition receptors on dendritic cells may determine commensalism of Candida on mucosal surfaces.

Candida produce a number of enzymes that contribute to invasiveness, including at least nine secreted aspartyl proteinases, which may be involved in tissue invasion by degrading extracellular matrix proteins, and catalases, which may aid intracellular survival and resist oxidative killing by phagocytic cells.128,130 Candida also secrete adenosine, which blocks neutrophil oxygen radical production and degranulation.

Morphology

In tissue sections, C. albicans can appear as yeastlike forms (blastoconidia), pseudohyphae, and, less commonly, true hyphae, defined by the presence of septae (Fig. 8-47). Pseudohyphae are an important diagnostic clue for C. albicans and represent budding yeast cells joined end to end at constrictions, thus simulating true fungal hyphae. All forms may be present together in the same tissue. The organisms may be visible with routine hematoxylin and eosin stains, but a variety of special "fungal" stains (Gomori methenamine-silver, periodic acid-Schiff) are commonly used to better visualize them.

Most commonly candidiasis takes the form of a superficial infection on mucosal surfaces of the oral cavity (thrush). Florid proliferation of the fungi creates gray-white, dirty-looking pseudomembranes composed of matted organisms and inflammatory debris. Deep to the surface, there is mucosal hyperemia and inflammation. This form of candidiasis is seen in newborns, debilitated patients, and children receiving oral steroids for asthma and following a course of broad-spectrum antibiotics that destroy competing normal bacterial flora. The other major risk group includes HIV-positive patients; patients with oral thrush for no obvious reason should be evaluated for HIV infection.

Candida esophagitis is commonly seen in AIDS patients and in those with hematolymphoid malignancies. These patients present with dysphagia (painful swallowing) and retrosternal pain; endoscopy demonstrates white plaques and pseudomembranes resembling oral thrush on the esophageal mucosa.

Candida vaginitis is a common form of vaginal infection in women, especially those who are diabetic or pregnant or on oral contraceptive pills. It is usually associated with intense itching and a thick, curdlike discharge.

Cutaneous candidiasis can present in many different forms, including infection of the nail proper ("onychomycosis"), nail folds ("paronychia"), hair follicles ("folliculitis"), moist, intertriginous skin such as armpits or webs of the fingers and toes ("intertrigo"), and penile skin ("balanitis"). "Diaper rash" is a cutaneous candidial infection seen in the perineum of infants, in the region of contact of wet diapers.

Chronic mucocutaneous candidiasis is a chronic refractory disease afflicting the mucous membranes, skin, hair, and nails; it is associated with underlying T-cell defects. Predisposing conditions include endocrinopathies (most commonly hypoparathyroidism and Addison’s disease). Disseminated candidiasis is rare in this disease.

Invasive candidiasis is caused by blood-borne dissemination of organisms to various tissues or organs.

Common patterns include (1) renal abscesses, (2) myocardial abscesses and endocarditis, (3) brain involvement (most commonly meningitis, but parenchymal microabscesses occur), (4) endophthalmitis (virtually any eye structure can be involved), (5) hepatic abscesses, and (6) Candida pneumonia, usually presenting as bilateral nodular infiltrates, resembling Pneumocystis pneumonia.

In any of these locations, the fungus may evoke little or no inflammatory reaction, cause the usual suppurative response, or occasionally produce granulomas. Patients with acute leukemias who are profoundly neutropenic post-chemotherapy are particularly prone to developing systemic disease.

Candida endocarditis is the most common fungal endocarditis, usually occurring in the setting of prosthetic heart valves or in intravenous drug abusers.