Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of cryptococcosis. There are two species, C. neoformans and C. gattii, each of which can cause cryptococcosis in humans. C. neoformans occurs in two varieties known as grubii and neoformans, which correlate with serotypes A and D, respectively. C. gattii has not been divided into varieties but is also antigenically diverse, consisting of serotypes B and C. Most clinical microbiology laboratories do not routinely distinguish between C. neoformans and C. gattii or among varieties, but rather identify and report all isolates simply as C. neoformans.
Cryptococcosis was first described in the 1890s but remained relatively rare until the mid-twentieth century, when advances in diagnosis and increases in the number of immunosuppressed individuals markedly raised its reported prevalence. The spectrum of disease caused by Cryptococcus species consists predominantly of meningoencephalitis and pneumonia, but skin and soft tissue infections also occur. Serologic studies have shown that, although evidence for cryptococcal infection is common among immunocompetent individuals, cryptococcal disease (cryptococcosis) is relatively rare in the absence of impaired immunity. Individuals at high risk for cryptococcosis include patients with hematologicmalignancies, recipients of solid organ transplants who require ongoing immunosuppressive therapy, persons whose medical conditions necessitate glucocorticoid therapy, and patients with advanced HIV infection and CD4+ T lymphocyte counts of <200/μL.
Since the onset of the HIVpandemic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS (Chap. 189). To understand the impact of HIV infection on the epidemiology of cryptococcosis, it is instructive to note that in the early 1990s there were >1000 cases of cryptococcal meningitis each year in New York City—a figure far exceeding that for all cases of bacterial meningitis. With the advent of effective antiretroviral therapy, the incidence of AIDS-related cryptococcosis has been sharply reduced among treated individuals; however, the disease remains distressingly common in regions where antiretroviral therapy is not readily available, such as Africa and Asia, where up to one-third of patients with AIDS have cryptococcosis. The global burden of cryptococcosis was recently estimated at ~1 million cases, with >600,000 deaths annually. Thus cryptococci are major human pathogens.
Cryptococcal infection is acquired from the environment. C. neoformans and C. gattii inhabit different ecologic niches. C. neoformans is frequently found in soils contaminated with avian excreta and can easily be recovered from shaded and humid soils contaminated with pigeon droppings. In contrast, C. gattii is not found in bird feces. Instead, it inhabits a variety of arboreal species, including several types of eucalyptus tree. C. neoformans strains are found throughout the world; however, var. grubii (serotype A) strains are far more common than var. neoformans (serotype D) strains among both clinical and environmental isolates. The geographic distribution of C. gattii was thought to be largely limited to tropical regions until an outbreak of cryptococcosis caused by a new serotype B strain began in Vancouver in 1999. This outbreak has extended into the United States, and C. gattii is now being encountered in several states in the Pacific Northwest. In addition to the different geographic distributions of the two cryptococcal species, individual susceptibility to these species affects epidemiology. Cryptococcosis caused by the C. neoformans varieties occurs mostly in individuals with AIDS (Chap. 189) and other forms of impaired immunity. In contrast, C. gattii–related disease is not associated with specific immune deficits and often occurs in immunocompetent individuals.
Cryptococcal infection is acquired by inhalation of aerosolized infectious particles. The exact nature of these particles is not known; the two leading candidate forms are small desiccated yeast cells and basidiospores. Little is known about the pathogenesis of initial infection. Serologic studies have shown that cryptococcal infection is acquired in childhood, but it is not known whether the initial infection is symptomatic. Given that cryptococcal infection is common while disease is rare, the consensus is that pulmonary defense mechanisms in immunologically intact individuals are highly effective at containing this fungus. It is not clear whether initial infection leads to a state of immunity or whether most individuals are subject throughout life to frequent and recurrent infections that resolve without clinical disease. However, evidence indicates that some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for prolonged periods, possibly in granulomas. Thus the inhalation of cryptococcal cells and/or spores can be followed by either clearance or establishment of the latent state. The consequences of prolonged harboring of cryptococcal cells in the lung are not known, but evidence from animal studies indicates that the organisms' prolonged presence could alter the immunologic milieu in the lung and predispose to allergic airway disease.
Cryptococcosis usually presents clinically as chronic meningoencephalitis. The mechanisms by which the fungus undergoes extrapulmonary dissemination and enters the central nervous system (CNS) remain poorly understood. The mechanism by which cryptococcal cells cross the blood-brain barrier is a subject of intensive study. Current evidence suggests either direct fungal-cell migration across the endothelium or fungal-cell carriage inside macrophages as "Trojan horse" invaders. Cryptococcus species have well-defined virulence factors that include the polysaccharide capsule, the ability to make melanin, and the elaboration of enzymes (e.g., phospholipase and urease) that enhance the survival of fungal cells in tissue. Among these virulence factors, the capsule and melanin production have been most extensively studied. The cryptococcal capsule is antiphagocytic, and the capsular polysaccharide has been associated with numerous deleterious effects on host immune function. Cryptococcal infections can elicit little or no tissue inflammatory response. The immune dysfunction seen in cryptococcosis has been attributed to the release of copious amounts of capsular polysaccharide into tissues, where it probably interferes with local immune responses (Fig. 202-1). In clinical practice, the capsular polysaccharide is the antigen that is measured as a diagnostic ...