What is the pathophysiology of disseminated cryptococcosis (fungal infection)?

Pathophysiology of Disseminated Cryptococcosis

Disseminated cryptococcosis begins with inhalation of Cryptococcus neoformans or C. gattii into the lungs, followed by failure of pulmonary containment, hematogenous spread through the bloodstream, and invasion of distant organs—most critically the central nervous system—driven by the organism's polysaccharide capsule and secreted virulence factors that enable immune evasion and blood-brain barrier penetration. 1

Initial Pulmonary Infection and Containment Failure

• Primary infection occurs via inhalation of infectious propagules (basidiospores or desiccated yeast cells) from environmental sources, which initially colonize the lungs 1, 2
• In immunocompetent hosts, cell-mediated immunity (particularly CD4+ T lymphocytes) and antibody responses typically contain the organism within pulmonary granulomas, where it may remain dormant 3, 1
• Dissemination occurs when immune defenses fail, most commonly in patients with impaired cell-mediated immunity including HIV/AIDS (especially CD4+ counts <200 cells/μL), solid organ transplant recipients, those on chronic corticosteroids, or patients with hematologic malignancies 3, 2
• Reactivation of dormant infection is believed to be the mechanism in most cases, though acute symptomatic disease can follow recent inhalation 3

Mechanisms of Pulmonary Escape and Hematogenous Dissemination

• The polysaccharide capsule is the primary virulence factor that promotes dissemination at every step by inhibiting phagocytosis, suppressing inflammatory responses, and protecting against oxidative killing 1, 4
• Cryptococcus can escape the lungs via two routes: extracellular traversal across the respiratory epithelium or intracellular transport within phagocytic cells (macrophages, monocytes) that fail to kill the organism and instead serve as a "Trojan horse" for dissemination 1, 2, 4
• Secreted enzymes facilitate pulmonary escape, including laccase (promotes melanin production and oxidative stress resistance) and phospholipase B (damages host cell membranes and promotes tissue invasion) 1, 4
• Once in the bloodstream (cryptococcemia), the organism can disseminate to virtually any organ, with particular tropism for the CNS, skin (up to 15% of disseminated cases), skeletal system (<10% of cases), and other sites including liver, spleen, kidneys, prostate, and eyes 3

Central Nervous System Invasion

• CNS invasion is the hallmark of disseminated cryptococcosis and the primary driver of mortality, resulting in meningoencephalitis that is fatal without treatment 2, 5
• Blood-brain barrier penetration is facilitated by urease (which increases local pH and damages endothelial tight junctions), direct transcellular migration, and transport within infected phagocytes 1, 2
• Once in the CNS, Cryptococcus encounters resident microglia and recruited immune cells, but the organism's virulence factors (capsule, melanin, regulatory proteins) enable it to modulate and evade these defenses 2
• Intracranial hypertension commonly develops due to impaired CSF reabsorption from capsular polysaccharide accumulation, fungal burden, and inflammatory responses—this is a critical determinant of mortality 3, 6

Host-Pathogen Interactions Determining Disease Progression

• The outcome depends on the balance between fungal virulence and host immunity: immunocompetent individuals may contain infection in the lungs or clear it entirely, while immunocompromised hosts develop progressive disseminated disease 2, 5
• High fungal burden (indicated by cryptococcal antigen titers ≥1:512 or positive blood cultures) correlates with dissemination and worse outcomes 3
• Immune reconstitution inflammatory syndrome (IRIS) can paradoxically worsen disease when immune function is restored (e.g., after starting antiretroviral therapy in HIV patients), as the inflammatory response to fungal antigens causes tissue damage including ARDS and worsening CNS inflammation 3
• Regulatory factors and metabolic adaptations allow Cryptococcus to survive and replicate in the nutrient-poor, high-pressure environment of the CNS, contributing to persistent infection 1, 2

Clinical Implications of Pathophysiology

• Non-meningeal, non-pulmonary cryptococcosis almost always represents disseminated disease, even when clinically confined to a single anatomical site, because hematogenous spread is required to reach these locations 3
• Cryptococcemia is frequent in HIV-infected patients with disseminated infection and indicates high fungal burden requiring aggressive treatment 3
• Even low antigen titers (e.g., 1:80) with positive blood cultures indicate disseminated infection requiring treatment as CNS disease, as recent case reports demonstrate that low titers do not exclude serious dissemination 7
• The strong CNS tropism mandates lumbar puncture to rule out meningitis in all immunosuppressed patients with pulmonary or other cryptococcal infections, as CNS involvement fundamentally alters treatment intensity and duration 3, 6, 8