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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Cryptococcus, Histoplasma, Coccidioides, and Other Systemic Fungal Pathogens

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Cryptococcosis

The primary disease caused by cryptococci is a chronic meningitis.

CRYPTOCOCCOSIS

The primary disease caused by cryptococci is a chronic meningitis. The onset is slow, even insidious, with low-grade fever and headache progressing to altered mental state and seizures. In the cerebrospinal fluid (CSF) and in tissues, the inflammatory response is often remarkably muted. Most patients have some obvi-ous form of immune compromise, although some show no demonstrable immune defect.

EPIDEMIOLOGY

C. neoformans is found throughout the world, particularly in soil contaminated with pigeonor other bird droppings. The birds themselves are not ill. The cryptococci in the soil produce few or no capsules, which makes them more readily aerosolized. Inhalation of yeast cells stirred up from these sites is the presumed mode of transmission. Cases appear sporadically, with no particular occupational predisposition, including pigeon fanciers or in those who work with the organism in the laboratory. Cryptococcosis in immunocompromised patients occurs primarily in those with defects in T-lymphocyte function, particularly acquired im-munodeficiency syndrome (AIDS), or in those treated with immunosuppressive agents (eg, steroids). Cryptococcal disease is the most common fungal infection seen in AIDS. Case-to-case transmission has not been documented.

PATHOGENESIS

Following inhalation, the yeast begins to overproduce the polysaccharide capsule, which determines virulence. The capsule is antiphagocytic and has a number of other im-munomodulating effects. The GXM is able to bind complement components while at the same time reducing the ability of polymorphonuclear neutrophils (PMNs) and macrophages to phagocytose and kill cryptococci. This may be due to the combination of the massive size of the capsule and the way in which it binds C3. There is also evidence that the capsule can interfere with antigen presentation and the development of T cell–mediated immune processes. This muting of the first lines of defense allows the or-ganisms to multiply and eventually spread outside the lung. At this stage the organism has a strong affinity for the central nervous system (CNS), possibly due to its C3 binding and the relatively low levels of complement found there.

Cryptococci produce enough capsule that the GXM can be readily detected in the blood and other body fluids. This circulating polysaccharide is able to downregulate immune responses, particularly the development of protective TH1-type mediators and suppression of the specific antibody response. These modulations may be either antigen specific or cause a general suppression of key immune functions, such as leukocyte mi-gration. Cryptococci are also able to oxidize exogenous catecholamines to produce melanin, a process that may protect them from the oxidative injury of phagocytes.

Tissue reaction to C. neoformans varies from little or none to purulent or granuloma-tous. Many cases of pulmonary, cutaneous, and even meningeal cryptococcal infection show a remarkable paucity of inflammatory cells. This certainly fits for a fungus that not only blocks its own phagocytosis but is able to downregulate multiple aspects of the im-mune response.

IMMUNITY

In immunocompetent persons, alternate pathway binding of complement by the capsule is probably sufficient for opsonophagocytosis. The capsule is not particularly antigenic, and anticryptococcal antibodies are not usually detected in the course of infection. When formed, the classical pathway can play a role in opsonization, but this mecha-nism is not believed to play a strong role in immunity. Anticryptococcal antibody and complement do not directly damage the organism but may be a key component in the development of cellular host defense mechanisms and the clearance of circulating antigen.

Animal studies and the strong clinical association of cryptococcosis with T-cell defects indicate that T lymphocyte–mediated immune responses are crucial to the outcome of infection. Cryptococci phagocytosed by macrophages may not be killed, and cytokine activation is needed to complete the clearing of the organisms. Patients with cryptococcosis who have no known immune defects often have subnormal cellular im-mune functions as measured by their lymphocyte-mediated responses to cryptococcal and other antigens. Clinical recovery in such cases is associated with return of cellular immune functions.


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