Pathophysiology

Of the 19 species that comprise the genus Cryptococcus, human disease is associated with only C neoformans. Animal models provide much of the understanding of the pathogenesis and the host defense mechanisms involved in C neoformans infections. The organism is primarily transmitted via the respiratory route and not directly from human to human.

Following inhalation, the yeast are deposited into the pulmonary alveoli, where they must survive the neutral-to-alkaline pH and physiologic concentrations of carbon dioxide before they are phagocytized by alveolar macrophages. Glucosylceramide synthase (GCS) has recently been identified as an essential factor in the survival of C neoformans in this extracellular environment. Although GCS is a critical factor in extracellular survival of the yeast, the yeast no longer requires GCS to survive the intracellular, more acidic, environment of within the macrophage once it is phagocytized by alveolar macrophages.

Unencapsulated yeast are readily phagocytosed and destroyed, whereas encapsulated organisms are more resistant to phagocytosis. A cryptococcal polysaccharide capsule has antiphagocytic properties and may be immunosuppressive. The antiphagocytic properties of the capsule block recognition of the yeast by phagocytes and inhibit leukocyte migration into the area of fungal replication.

The host response to cryptococcal infection includes both cellular and humoral components. Animal models demonstrate that natural killer cells participate in the early killing of cryptococci and, possibly, antibody-dependent cell-mediated killing. In vitro monocyte-derived macrophages, natural killer cells, and T lymphocytes can inhibit or kill cryptococci. A successful host response includes an increase in helper T-cell activity, skin test conversion, and a reduction in the number of viable organisms in the tissues. In addition to cellular mechanisms, anticryptococcal antibodies and soluble anticryptococcal factors have been described. Antibodies to a cryptococcal antigen and its complement play a critical role in enhancing the macrophage- and lymphocyte-mediated immune response to the organism. Researchers use monoclonal antibodies to capsular polysaccharide to passively immunize mice against C neoformans.

C neoformans infection is usually characterized by little or no necrosis or organ dysfunction until late in the disease. Organ damage may accelerate in persons with heavy infections. The lack of identifiable endotoxins or exotoxins partly causes the absence of extensive necrosis early in cryptococcal infections. Organ damage is primarily due to tissue distortion secondary to the expanding fungal burden. Extensive inflammation or fibrosis is rare. The characteristic lesion of C neoformans consists of a cystic cluster of yeast with no well-defined inflammatory response. Well-formed granulomas are generally absent.

C neoformans can cause an asymptomatic pulmonary infection followed later by the development of meningitis, which is often the first indication of disease. If limited to the lungs, C neoformans infection may cause pneumonia, poorly defined mass lesions, pulmonary nodules, and, rarely, pleural effusion. Although immune defects are common in patients with meningitis or disseminated infection, patients with disease that is confined to the lungs are usually immunocompetent.