Cryptococcosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.
Overview
Infective cryptococcal species are ubiquitous and natural exposure by inhalation is very common. Cryptococci are intracellular pathogens. Once they are phagocytosed, they germinate and multiply within the macrophages. The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling. Microscopically, Cryptococci are characterized by a thick mucopolysaccharide capsule with a refractile center.
Pathophysiology
Transmission
- Infective cryptococcal species are ubiquitous and natural exposure is very common.[1]
- Infection occurs by inhalation of aerosolized, dessicated basidiospores.[2]
Virulence factors
- Cryptococcus polysaccharide capsule, phospholipase activity and extracellular vesicles play key roles in the survival of the organism within the host.[3]
Pathogenesis
- Once these spores reach the alveoli, they are phagocytosed by the alveolar macrophages without prior opsonization (usually required for yeast forms).
- Cryptococci are intracellular pathogens. Once they are phagocytosed, they germinate and multiply within the macrophages.[4]
- Activated macrophages are capable of destroying the yeast forms that develop; however, non-activated macrophages act as germination centers for cryptococci.[5]
- Cryptococci have the ability to form giant cells that resist phagocytosis and have been hypothesized to play a role in latent infections, and reactivation.[5]
- Cryptococci also have the ability to change the number of sets of chromosomes they have during infection; this has been associated with heteroresistance to certain antifungal agents.[6]
Host response
- After exposure to desiccated yeast cells or spores, patients may clear the infection, contain it within granulomata as a latent infection, or the infection may disseminate. This depends on the host's immune status or other, less well-understood mechanisms.
Dissemination
- Disseminated disease occurs among patients with compromised cell-mediated immunity.
- The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling.
- Granuloma formation can be seen and may also be responsible for reactivation in patients presenting with immunocompromised states.[7][8]
Microscopic Pathology
- Cryptococcus exists in yeast form.
- It is round/ovoid and approximately 5-15 μm (resembles Histoplasma or Candida, but often larger).
- It is characterized by a thick mucopolysaccharide capsule with a refractile center.
- India ink staining is used for easy visualization of the capsule in cerebrospinal fluid.[9]
- It has a tear drop-shaped budding pattern which is useful for differentiating Cryptococcus from Blastomyces and Histoplasma.
- Cryptococcal infections are usually accompanied by very little inflammation.
- Cryptococcus stain positive with methenamine silver, Alcian blue, and PAS (may be confused with corpora amylacea in the CNS).[10]
Cryptococcosis (PAS stain)
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References
- ↑ Wang CY, Wu HD, Hsueh PR (2005). "Nosocomial transmission of cryptococcosis". N. Engl. J. Med. 352 (12): 1271–2. doi:10.1056/NEJM200503243521225. PMID 15788512.
- ↑ Jarvis JN, Harrison TS (2008). "Pulmonary cryptococcosis". Semin Respir Crit Care Med. 29 (2): 141–50. doi:10.1055/s-2008-1063853. PMID 18365996.
- ↑ Alspaugh JA (2015). "Virulence mechanisms and Cryptococcus neoformans pathogenesis". Fungal Genet. Biol. 78: 55–8. doi:10.1016/j.fgb.2014.09.004. PMC 4370805. PMID 25256589.
- ↑ Goldman D, Lee SC, Casadevall A (1994). "Pathogenesis of pulmonary Cryptococcus neoformans infection in the rat". Infect. Immun. 62 (11): 4755–61. PMC 303183. PMID 7927751.
- ↑ 5.0 5.1 Mansour MK, Reedy JL, Tam JM, Vyas JM (2014). "Macrophage Cryptococcus interactions: an update". Curr Fungal Infect Rep. 8 (1): 109–115. doi:10.1007/s12281-013-0165-7. PMC 3958962. PMID 24660045.
- ↑ Sionov E, Chang YC, Kwon-Chung KJ (2013). "Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment". Antimicrob. Agents Chemother. 57 (10): 5127–30. doi:10.1128/AAC.00694-13. PMC 3811407. PMID 23836187.
- ↑ Brizendine KD, Baddley JW, Pappas PG (2011). "Pulmonary cryptococcosis". Semin Respir Crit Care Med. 32 (6): 727–34. doi:10.1055/s-0031-1295720. PMID 22167400.
- ↑ May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K (2015). "Cryptococcus: from environmental saprophyte to global pathogen". Nat Rev Microbiol. doi:10.1038/nrmicro.2015.6. PMID 26685750.
- ↑ Zerpa R, Huicho L, Guillén A (1996). "Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens". J Clin Microbiol. 34 (9): 2290–1. PMC 229234. PMID 8862601.
- ↑ Fungi. Libre Pathology (2015). http://librepathology.org/wiki/index.php/Fungi#Cryptococcosis. Accessed on December 31, 2015.