CHAPTER 115: CANDIDIASIS

The genus Candida encompasses more than 150 species, only a few of which cause disease in humans. With rare exceptions (although the exceptions are increasing in number), the human pathogens are C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, C. kefyr, C. lusitaniae, C. dubliniensis, and C. glabrata. Ubiquitous in nature, they inhabit the gastrointestinal tract (including the mouth and oropharynx), the female genital tract, and the skin. Although cases of candidiasis have been described since antiquity in debilitated patients, the advent of Candida species as common human pathogens dates to the introduction of modern therapeutic approaches that suppress normal host defense mechanisms. Of these relatively recent advances, the most important is the use of antibacterial agents that alter the normal human microbiota and allow nonbacterial species to become more prevalent in the commensal flora. With the introduction of antifungal agents, the causes of Candida infections shifted from an almost complete dominance of C. albicans to the common involvement of C. glabrata and the other species listed above. The non-albicans species now account for approximately half of all cases of candidemia and hematogenously disseminated candidiasis. Recognition of this change is clinically important, since the various species differ in susceptibility to the newer antifungal agents. In developed countries, where medical therapeutics are commonly used, Candida species are now among the most common nosocomial pathogens.

Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm in diameter and reproduces by budding. Organisms of this genus occur in three forms in tissue: blastospores, pseudohyphae, and hyphae. Candida grows readily on simple medium; lysis centrifugation enhances its recovery from blood. Species are identified by biochemical testing (currently with automated devices) or on special agar (e.g., CHROMagar).

Candida organisms are ubiquitous in nature; worldwide, these fungi are present in humans as commensals, in animals, in foods, and on inanimate objects. In developed countries, where advanced medical therapeutics are commonly used (see “Treatment,” below), Candida species are now among the most common health care–associated pathogens. In the United States, these species are the fourth most common isolates from the blood of hospitalized patients. In countries where advanced medical care is rarely available, mucocutaneous Candida infections, such as thrush, are more common than deep organ infections, which rarely occur; however, the incidence of deep organ candidiasis increases steadily as advances in health care—such as therapy with broad-spectrum antibiotics, more aggressive treatment of cancer, and the use of immunosuppression for sustaining organ transplants—are introduced and implemented. In recent decades, as a result of the HIV epidemic, the incidence of thrush and Candida esophagitis has increased substantially. In aggregate, the global incidence of infections due to Candida species has risen steadily over the past few decades.

In the most serious form of Candida infection, the organisms disseminate hematogenously and form microabscesses and small macroabscesses in major organs. Although the exact mechanism is not known, Candida probably enters the bloodstream from mucosal surfaces after growing to large numbers as a consequence of bacterial suppression by antibacterial drugs; alternatively, in some instances, the organism may enter from the skin. A change from the blastospore stage to the pseudohyphal and hyphal stages is generally considered integral to the organism’s penetration into tissue. However, C. glabrata can cause extensive infection even though it does not transform into pseudohyphae or hyphae. Adherence to both epithelial and endothelial cells, thought to be the first step in invasion and infection, has been studied extensively, and several adhesins have been identified. Biofilm formation also is considered important in pathogenesis. Numerous reviews of cases of hematogenously disseminated candidiasis have identified the predisposing factors or conditions associated with disseminated disease (Table 115-1). Women who receive antibacterial agents may develop vaginal candidiasis.

Innate immunity is the most important defense mechanism against hematogenously disseminated candidiasis, and the neutrophil is the most important component of this defense. Macrophages also play an important defensive role. STAT1, Dectin-1, CARD9, and T_H1 and T_H17 lymphocytes contribute significantly to innate defense (see “Clinical Manifestations,” below). Although many immunocompetent individuals have antibodies to Candida, the role of these antibodies in defense against the organism is not clear. Multiple genetic polymorphisms that predispose to disseminated candidiasis will most likely be identified in future studies.

Mucocutaneous candidiasis

Thrush is characterized by white, adherent, painless, discrete or confluent patches in the mouth, on the tongue, or in the esophagus, occasionally with fissuring at the corners of the mouth. This form of disease caused by Candida can also occur at points of contact with dentures. Organisms are identifiable in gram-stained scrapings from lesions. The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection. More commonly, thrush is seen as a nonspecific manifestation of severe debilitating illness. Vulvovaginal candidiasis is accompanied by pruritus, pain, and vaginal discharge which is usually thin but may contain whitish “curds” in severe cases. A subset of patients with recurrent vulvovaginitis have a deficiency in the surface expression of Dectin-1, a major recognition factor for β-glucan on Candida. This deficiency leads to suboptimal functioning of the CARD9 pathway, which ultimately increases the propensity for recurrent vaginal infections.

Other Candida skin infections include paronychia, a painful swelling at the nail-skin interface; onychomycosis, a fungal nail infection rarely caused by this genus; intertrigo, an erythematous irritation with redness and pustules in the skin folds; balanitis, an erythematous-pustular infection of the glans penis; erosio interdigitalis blastomycetica, an infection between the digits of the hands or toes; folliculitis, with pustules developing most frequently in the area of the beard; perianal candidiasis, a pruritic, erythematous, pustular infection surrounding the anus; and diaper rash, a common erythematous-pustular perineal infection in infants. Generalized disseminated cutaneous candidiasis, another form of infection that occurs primarily in infants, is characterized by widespread eruptions over the trunk, thorax, and extremities. The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 115-1) indicate a high probability of dissemination to multiple organs as well as the skin. While the lesions are seen predominantly in immunocompromised patients treated with cytotoxic drugs, they may also develop in patients without neutropenia.

Chronic mucocutaneous candidiasis is a heterogeneous infection of the hair, nails, skin, and mucous membranes that persists despite intermittent therapy. The onset of disease usually comes in infancy or within the first two decades of life but in rare cases comes in later life. The condition may be mild and limited to a specific area of the skin or nails, or it may take a severely disfiguring form (Candida granuloma) characterized by exophytic outgrowths on the skin. Chronic mucocutaneous candidiasis is usually associated with specific immunologic dysfunction; most frequently reported is a failure of T lymphocytes to proliferate or to excrete cytokines in response to stimulation by Candida antigens in vitro. A subset of the affected patients have mutations in the STAT1 gene resulting in an insufficiency of interferon γ, interleukin 17, and interleukin 22.

Approximately half of patients with chronic mucocutaneous candidiasis have associated endocrine abnormalities that together are designated the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. This syndrome is due to mutations in the autoimmune regulator (AIRE) gene and is most prevalent among Finns, Iranian Jews, Sardinians, northern Italians, and Swedes. Conditions that usually follow the onset of the disease include hypoparathyroidism, adrenal insufficiency, autoimmune thyroiditis, Graves’ disease, chronic active hepatitis, alopecia, juvenile-onset pernicious anemia, malabsorption, and primary hypogonadism. In addition, dental enamel dysplasia, vitiligo, pitted nail dystrophy, and calcification of the tympanic membranes may occur. Patients with chronic mucocutaneous candidiasis rarely develop hematogenously disseminated candidiasis, probably because their neutrophil function remains intact.

Deeply invasive candidiasis

Deeply invasive Candida infections may or may not be due to hematogenous seeding. Deep esophageal infection may result from penetration by organisms from superficial esophageal erosions; joint or deep wound infection from contiguous spread of organisms from the skin; kidney infection from catheter-initiated spread of organisms through the urinary tract; infection of intraabdominal organs and the peritoneum from perforation of the gastrointestinal tract; and gallbladder infection from retrograde migration of organisms from the gastrointestinal tract into the biliary drainage system.

However, far more commonly, deeply invasive candidiasis results from hematogenous seeding of various organs as a complication of candidemia. Once the organism gains access to the intravascular compartment (either from the gastrointestinal tract or, less often, from the skin through the site of an indwelling intravascular catheter), it may spread hematogenously to a variety of deep organs. The brain, chorioretina (Fig. 115-2), heart, and kidneys are most commonly infected and the liver and spleen less commonly so (most often in neutropenic patients). In fact, nearly any organ can become involved, including the endocrine glands, pancreas, heart valves (native or prosthetic), skeletal muscle, joints (native or prosthetic), bone, and meninges. Candida organisms can also spread hematogenously to the skin and cause classic macronodular lesions (Fig. 115-1). Frequently, painful muscular involvement also is evident beneath the area of affected skin. Chorioretinal involvement and skin involvement are highly significant, since both findings are associated with a very high probability of abscess formation in multiple deep organs as a result of generalized hematogenous seeding. Ocular involvement (Fig. 115-2) may require specific treatment (e.g., partial vitrectomy or intraocular injection of antifungal agents) to prevent permanent blindness. An ocular examination is indicated for all patients with candidemia, whether or not they have ocular manifestations.

The diagnosis of Candida infection is established by visualization of pseudohyphae or hyphae on wet mount (saline and 10% KOH), tissue Gram’s stain, periodic acid–Schiff stain, or methenamine silver stain in the presence of inflammation. Absence of organisms on hematoxylin-eosin staining does not reliably exclude Candida infection. The most challenging aspect of diagnosis is determining which patients with Candida isolates have hematogenously disseminated candidiasis. For instance, recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection, and Candida isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter. Despite extensive research into both antigen and antibody detection systems, there is currently no widely available and validated diagnostic test to distinguish patients with inconsequential seeding of the blood from those whose positive blood cultures represent hematogenous dissemination to multiple organs. Many studies are under way to establish the utility of the β-glucan test; at present, its greatest utility is its negative predictive value (∼90%). Meanwhile, the presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs. Although extensive research is being conducted on other tests for infection, such as PCR, none of these tests is fully validated or widely available at present.

The use of antifungal agents to prevent Candida infections has been controversial, but some general principles have emerged. Most centers administer prophylactic fluconazole (400 mg/d) to recipients of allogeneic stem cell transplants. High-risk liver transplant recipients also are given fluconazole prophylaxis in most centers. The use of prophylaxis for neutropenic patients has varied considerably from center to center; many centers that elect to give prophylaxis to this population use either fluconazole (200–400 mg/d) or a lipid formulation of amphotericin B (AmBiSome, 1–2 mg/d). Caspofungin (50 mg/d) also has been recommended. Some centers have used itraconazole suspension (200 mg/d). Posaconazole (200 mg three times daily) also has been approved by the FDA for prophylaxis in neutropenic patients and is gaining in popularity.

Prophylaxis is sometimes given to surgical patients at very high risk. The widespread use of prophylaxis for nearly all patients in general surgical or medical intensive care units is not—and should not be—a common practice for three reasons: (1) the incidence of disseminated candidiasis is relatively low, (2) the cost-benefit ratio is suboptimal, and (3) increased resistance with widespread prophylaxis is a valid concern.

Prophylaxis for oropharyngeal or esophageal candidiasis in HIV-infected patients is not recommended unless there are frequent recurrences.