Cryptococcus neoformans: Difference between revisions

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__NOTOC__
{{Cryptococcosis}}
{{Taxobox
{{Taxobox
| color = lightblue
| image = Cryptococcus_neoformans2.jpg
| width = 150px
| image_caption = ''Cryptococcus neoformans''
| name = ''Cryptococcus neoformans''
| name = ''Cryptococcus neoformans''
| regnum = [[Fungi]]
| regnum = Fungi
| phylum = [[Basidiomycota]]
| phylum = Basidiomycota
| subphylum = [[Basidiomycotina]]
| classis = Tremellomycetes
| ordo = [[Sporidiales]]
| ordo = Tremellales
| familia = [[Sporidiobolaceae]]
| familia = Tremellaceae
| genus = Filobasidiella (''[[Cryptococcus]]'')
| genus = ''Cryptococcus''
| species = '''''Filobasidiella neoformans <br>(Cryptococcus neoformans)'''''
| species = '''''Cryptococcus neoformans'''''
}}
}}
__NOTOC__
{{Cryptococcosis}}
{{About0|Cryptococcosis}}
{{About0|Cryptococcosis}}
{{CMG}}
{{CMG}}


==Overview==
==Overview==
'''''Cryptococcus neoformans''''' is an encapsulated yeast-like [[fungus]] that can live in both [[plant]]s and [[animal]]s.This species, also known by its [[teleomorph]] name, ''Filobasidiella neoformans'', belongs to the broad class of organisms called "club fungi" or [[Basidiomycota|Division Basidiomycota]], which is one the five major types of fungi.  ''C. neoformans'' usually grows as a [[yeast]] (unicellular) and replicates by [[budding]].  Under certain conditions, both in nature and in the laboratory, ''C. neoformans'' can grow as a filamentous fungus as pictured here: [http://tolweb.org/tree/ToLimages/Filobasidiella_neoformans.jpg picture of the organism]<ref>[[Photomicrograph]] hosted by the [http://tolweb.org/tree/phylogeny.html Tree of Life project] and specifically contributed by the [http://www.dumru.mc.duke.edu/ Duke University Mycology Research Unit]; the picture is part of the [http://tolweb.org/tree?group=Hymenomycetes&contgroup=Basidiomycota Hymenomycetes article].  Retrieved 2005-03-15</ref>.  When grown as a yeast, ''C. neoformans'' has a prominent capsule composed mostly of [[polysaccharides]].  Microscopically, the [[India ink]] stain is used for easy visualization of the capsule.  The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells.
'''''Cryptococcus neoformans''''' is an encapsulated [[yeast]] and an [[obligate aerobe]] that can live in both [[plant]]s and animals.<ref>{{Cite web|url=http://wwwnc.cdc.gov/eid/article/4/1/98-0109_article|title=What Makes Cryptococcus neoformans a Pathogen? - Volume 4, Number 1—March 1998 - Emerging Infectious Disease journal - CDC|website=wwwnc.cdc.gov|accessdate=2015-11-18}}</ref> <ref>{{Cite journal|last=Ingavale|first=Susham S.|last2=Chang|first2=Yun C.|last3=Lee|first3=Hyeseung|last4=McClelland|first4=Carol M.|last5=Leong|first5=Madeline L.|last6=Kwon-Chung|first6=Kyung J.|date=2008-09-01|title=Importance of Mitochondria in Survival of Cryptococcus neoformans Under Low Oxygen Conditions and Tolerance to Cobalt Chloride|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528940/|journal=PLoS Pathogens|volume=4|issue=9|pages=e1000155|doi=10.1371/journal.ppat.1000155|issn=1553-7366|pmc=2528940|pmid=18802457}}</ref>It is often found in bird excrement. It is the causative agent of [[cryptococcosis]] (cryptococcal [[pneumonia]] and [[meningitis]]).
[[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|right|250px|'''Cryptococcus neoformans''' seen in the lung of a patient with AIDS. The inner capsule of the organism stains red in this photomicrograph]]
The species ''C. neoformans'' is composed of three variants (v.): ''C. neoformans v. gattii'', ''v. grubii'', and ''v. neoformans''.  ''C. neoformans v. gattii'' is found mostly in the [[tropics]], but has also been confirmed on southern [[Vancouver Island]] on the southwestern [[coast]] of [[Canada]]. ''Cryptococcus gattii'' has recently been shown to be different enough from other subspecies to be elevated to its own species level. ''C. neoformans v. grubii'' and ''v. neoformans'' have a worldwide distribution and are often found in soil which has been contaminated by bird excrement.  The genome sequence of ''C. neoformans v. neoformans'' was published in 2005.<ref>{{cite journal | author=Loftus BJ, et al. | title=The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans | journal=Science | volume=307 | issue=5713 | pages=1321&ndash;24 | id=PMID 15653466 }}</ref> Recent studies made on [[Chernobyl Nuclear Power Plant]] have shown that colonies of ''Cryptococcus neoformans'' developed on the ruins of [[nuclear meltdown|melted down]] reactor harvest energy of [[particle radiation|radiation]] (primary [[beta radiation]] from [[caesium-137]]) itself.<ref>{{cite journal | author=Dadachova E, ''et al.'' | title=Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi | journal=PLoS One | volume=2(5)| doi=10.1371/journal.pone.0000457 | id=PMID 17520016 }}</ref>  
 
Infection with ''C. neoformans'' is termed [[cryptococcosis]].
 
==Treatment==
Cryptococcosis that does not affect the central nervous system can be treated with [[fluconazole]] alone.
 
Cryptococcal meningitis should be treated for two weeks with [[intravenous]] [[Amphotericin B]] 0.7&ndash;1.0 (mg/kg)/day and oral [[flucytosine]] 100 (mg/kg)/day (or [[intravenous]] flucytosine 75 (mg/kg)/day if the patient is unable to swallow).  This should then be followed by oral fluconazole 200mg daily for ten weeks<ref>{{cite journal | author=Saag MS, Graybill RJ, Larsen RA, ''et al.'' | title=Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. |journal=Clin Infect Dis | year=2000 | volume=30 | issue=4 | pages=710&ndash;8 | id=PMID 10770733 }}</ref> and then 200 mg daily until the patient's [[CD4]] count is above 100 for three months and his HIV [[viral load]] is undetectable.<ref>{{cite journal | title=Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy
| journal=AIDS | volume=14 | issue=16 | year=2000 | pages=2615&ndash;26 | author=Martínez E, García-Viejo MA, Marcos MA, ''et al.''|id=PMID 11101078 }}</ref><ref>{{cite journal | title=Discontinuation of secondary prophylaxis for Cryptococcal meningitis in Human Immunodeficiency Virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study | author=Vibhagool A, Sungkanuparph S, Mootsikapun P, ''et al.'' | journal=Clin Infect Dis | volume=36 | year=2003 | pages=1329&ndash;31 |
doi=10.1086/374849 | id=PMID 12746781 }}</ref>
 
Intravenous [[Ambisome]] 4 (mg/kg)/day may be used but is not superior: its main use is in patients who do not tolerate Amphotericin B. The 200 (mg/kg)/day dose for flucytosine is not more effective, is associated with more side-effects and should not be used.
 
In Africa, oral fluconazole at a rate of 200 mg daily is used. However, this does not result in cure because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from [[cerebrospinal fluid|CSF]] of patients who have taken fluconazole for many months. An increased dose of 400 mg daily does not improve outcomes,<ref>{{cite journal | title=Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole | author=CF Schaars, Meintjes GA, Morroni C, ''et al.'' | journal=BMC Infect Dis | year=2006 | volume=6 | pages=118 | doi=10.1186/1471-2334-6-118 }}</ref> but preliminary data from [[Uganda]] shows that very high doses of 1200 mg or more per day may be effective. The duration of this treatment and the post-treatment maintenance dose is not known.
 
===Antimicrobial Regimen===
*'''Cryptococcus'''
:* '''1. Cryptococcus neoformans'''
::* '''1.1. Cryptococcus neoformans meningitis in HIV infected patients'''<ref name="pmid20047480">{{cite journal| author=Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ et al.| title=Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 3 | pages= 291-322 | pmid=20047480 | doi=10.1086/649858 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20047480  }} </ref>
:::* '''1.1.1. Induction and consolidation'''
::::*Preferred regimen : ([[Amphotericin B]] deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) {{or}} [[Liposomal AmB]] 3-4mg/kg IV qd {{or}} [[Amphotericin B]] lipid complex (ABLC) 5mg/kg IV qd) {{plus}} [[Flucytosine]] 100mg/kg/day PO or IV qid for at least 2 weeks followed by [[Fluconazole]] 400mg (6mg/kg) PO qd for at least 8 weeks.
::::*Alternative regimen (1): [[Amphotericin B]] deoxycholate 0.7-1.0 mg/kg IV qd {{or}} [[Liposomal AmB]] 3-4 mg/kg IV qd {{or}} AmB lipid complex 5mg/kg IV qd for 4-6 weeks
::::*Alternative regimen (2): [[Amphotericin B]] deoxycholate 0.7 mg/kg IV qd {{and}} [[Fluconazole]] 800mg PO qd for 2 weeks, followed by [[Fluconazole]] 800mg PO qd for at least 8 weeks
::::*Alternative regimen (3): [[Fluconazole]] (>800 mg PO qd, 1200mg PO qd is favored) {{and}} [[Flucytosine]] 100mg/kg/day PO qid for 6 weeks
::::*Alternative regimen (4): [[Fluconazole]] PO 800-2000mg qd for 10-12 weeks
:::* '''1.1.2. Maintenance and prophylactic therapy'''
::::*Preferred regimen for : Initiate HAART 2-10 weeks after commencing initial antifungal therapy {{and}} [[Fluconazole]] 200mg PO qd
::::*Alternative regimen : [[Itraconazole]] 200mg PO bid - monitor drug-level {{or}} [[Amphotericin B]] deoxycholate (1 mg/kg) per week IV (should be used in azole-intolerant patients).
::::* Note (1): Consider discontinuing supressive therapy if CD4 count is higher than 100 cells/uL {{and}} undetectable {{or}} very low HIV RNA level for more than 3 months. Consider reinstitution of maintenance therapy if CD4 count <100 cels/uL.
::::* Note (2): Do not use [[acetazolamide]] {{or}} [[mannitol]] {{or}} [[corticosteroids]] to treat increased intracranial pressure, instead it should be used lombar puncture in the absence of focal neurologic signs or impaired mentation (which, if present, patient must be submitted to CT or MRI scan first).
 
::*'''1.2. Cerebral cryptococcomas'''
:::*Preferred regimen for induction and consolidation: ([[Amphotericin B]] deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) {{or}} [[Liposomal AmB]] 3-4mg/kg IV qd {{or}} [[Amphotericin B]] lipid complex (ABLC) 5mg/kg IV qd) {{plus}} [[Flucytosine]] 100mg/kg/day PO or IV qid for at least 2 weeks followed by [[Fluconazole]] 400mg (6mg/kg) PO qd for at least 8 weeks
:::*Note: Consider surgery if lesions are larger than 3cm, accessible lesions with mass effect or lesions that are enlarging and not explained by IRIS.
 
::*'''1.3. Cryptococcus neoformans meningitis in HIV negative patients'''
:::*Preferred regimen: [[Amphotericin B deoxycholate]] 0.7-1.0 mg/kg IV qd {{plus}} [[Flucytosine]] 100mg/kg/day PO or IV qid for at least 4 weeks (which may be extended to 6 weeks if there is any neurological complication) followed by [[Fluconazole]] 400mg PO qd for 8 weeks. If there's toxicity to AmBd, consider changing to LFAmB in the second 2 weeks.
:::*Note (1): After induction and consolidation therapy, start Fluconazole 200mg (3mg/kg) PO qd for 6-12 months.
:::*Note (2): If Flucytosine is not given, consider lengthening the induction therapy for at least 2 weeks.


::*'''1.4. Cryptococcus neoformans pulmonary disease - immunosupressed'''
== Classification ==
:::*Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:
''[[Cryptococcus neoformans]]'' is composed of two varieties (v.): ''C. neoformans ''v.'' neoformans'' and ''C. n. '' v.'' grubii''. A third variety, ''C. n. ''v.'' gattii'', is now considered a distinct species, ''[[Cryptococcus gattii]]''. ''C. n.'' v.'' grubii'' and ''C. n. ''v.'' neoformans'' have a worldwide distribution and are often found in soil [[Contamination|contaminated]] by bird excrement. The [[genome]] sequence of ''C. neoformans v. neoformans'' was published in 2005.<ref>{{cite journal | author=Loftus BJ | title=The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans | journal=Science | volume=307 | issue=5713 | pages=1321&ndash;24 | pmid=15653466 | doi=10.1126/science.1103773 | year=2005 | pmc=3520129|display-authors=etal}}</ref> Recent studies suggest colonies of ''[[C. neoformans]]'' and related fungi growing on the ruins of the melted down reactor of the chernobyl nuclear power plant may be able to use the energy of [[particle radiation|radiation]] (primary beta radiation) for "[[Radiotrophic fungus|radiotrophic]]" growth.<ref>{{cite journal | author=Dadachova E | title=Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi | journal=PLoS ONE | volume=2| doi=10.1371/journal.pone.0000457 | pmid=17520016  | year=2007 | pages=e457 | issue=5 | pmc=1866175 | editor1-last=Rutherford | editor1-first=Julian|display-authors=etal}}</ref>
::::*Preferred regimen: [[Fluconazole]] 400mg PO qd for 6-12 months
:::*Severe pneumonia or disseminated disease or CNS infection:
::::*Preferred regimen: treat like CNS cryptococcosis.
:::*Note (1): In HIV- infected patients, treatment should be stopped after 1 year if CD4 count is >100 and a cryptococcal antigen titer is <1:512 and not increasing.
:::*Note (2): Consider [[corticosteroid]] if [[ARDS]] is present in a context which it might be attributed to [[IRIS]].


::*'''1.5 Cryptococcus neoformans pulmonary disease - non-immunosupressed'''
==Characteristics==
:::*Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:
[[File:Cryptococcus1.jpg|thumb|200px|left|''[[C. neoformans]]'' on [[Gram stain]]]]
::::*Preferred regimen: [[Fluconazole]] 400mg PO qd for 6-12 months
''[[C. neoformans]]'' grows as a [[yeast]] ([[Unicellular organism|unicellular]]) and replicates by [[budding]]. It makes [[hyphae]] during mating, and eventually creates basidiospores at the end of the [[hyphae]] before producing [[spores]]. Under host-relevant conditions, including low [[glucose]], [[serum]], 5% [[carbon dioxide]], and low [[iron]], among others, the cells produce a characteristic [[polysaccharide]] [[Capsule (anatomy)|capsule]].<ref name="Cryptococcus: From Human Pathogen to Model Yeast, Editors: Joseph Heitman, Thomas R. Kozel, Kyung J. Kwon-Chung, John R Perfect, and Arturo Casadevall">[http://estore.asm.org/viewItemDetails.asp?ItemID=920]</ref> The recognition of ''[[C. neoformans]]'' in [[Gram stain|Gram-stained]] smears of [[purulent]] [[Exudate|exudates]] may be hampered by the presence of the large gelatinous [[Capsule (anatomy)|capsule]] which apparently prevents definitive [[staining]] of the [[yeast]]-like cells. In such [[stained]] preparations, it may appear either as round cells with [[Gram-positive]] granular [[inclusions]] impressed upon a pale lavender [[cytoplasmic]] background or as [[Gram-negative]] lipoid bodies.<ref name="JCM Article">{{cite web|last1=Bottone|first1=E J|title=Cryptococcus neoformans: pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates.|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC273699/|website=National Center for Biotechnology Information|publisher=Journal of Clinical Microbiology|accessdate=2014-11-19}}</ref>
::::*Alternative regimen: if [[Fluconazole]] is unavailable or contraindicated, [[Itraconazole]] 200mg PO bid, [[Voriconazole]] 200 mg PO bid, and [[Posaconazole]] 400mg PO bid
When grown as a [[yeast]], ''[[C. neoformans]]'' has a prominent [[Capsule (anatomy)|capsule]] composed mostly of [[polysaccharides]]. Under the microscope, the India ink [[stain]] is used for easy visualization of the [[capsule]] in [[cerebrospinal fluid]].<ref name="pmid8862601">{{cite journal|last=Zerpa|first=R|author2=Huicho, L |author3=Guillén, A |title=Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens.|journal=Journal of clinical microbiology|date=September 1996|volume=34|issue=9|pages=2290–1|pmid=8862601|url=http://jcm.asm.org/content/34/9/2290.full.pdf}}</ref> The particles of ink pigment do not enter the [[Capsule (anatomy)|capsule]] that surrounds the spherical [[yeast]] cell, resulting in a zone of clearance or "halo" around the cells. This allows for quick and easy identification of ''[[C. neoformans]]''. Unusual morphological forms are rarely seen.<ref name="pmid17642731">{{cite journal|last=Shashikala|author2=Kanungo, R |author3=Srinivasan, S |author4=Mathew, R |author5= Kannan, M |title=Unusual morphological forms of Cryptococcus neoformans in cerebrospinal fluid.|journal=Indian journal of medical microbiology|date=Jul–Sep 2004|volume=22|issue=3|pages=188–90|pmid=17642731|url=http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=3;spage=188;epage=190;aulast=Shashikala}}</ref> For identification in tissue, [[mucicarmine]] [[stain]] provides specific [[staining]] of [[polysaccharide]] cell wall in ''[[C. neoformans]]''. [[Cryptococcal infection|Cryptococcal]] [[antigen]] from [[cerebrospinal fluid]] is thought to be the best test for diagnosis of [[Cryptococcal Meningitis|cryptococcal meningitis]] in terms of sensitivity, though it might be unreliable in [[Human Immunodeficiency Virus (HIV)|HIV-positive]] patients.<ref name="pmid16272534">{{cite journal|last=Antinori|first=Spinello|author2=Radice, Anna |author3=Galimberti, Laura |author4=Magni, Carlo |author5=Fasan, Marco |author6= Parravicini, Carlo |title=The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis.|journal=Journal of clinical microbiology|date=November 2005|volume=43|issue=11|pages=5828–9|pmid=16272534|pmc=1287839|doi=10.1128/JCM.43.11.5828-5829.2005}}</ref>
:::*If there's severe pneumonia, disseminated disease or CNS infection:
::::*Preferred regimen: treat like CNS cryptococcosis for 6-12 months.


::*'''1.6 Cryptococcus neoformans non-lung, non-CNS infection'''
== Pathology ==
:::*Cryptococcemia or disseminated cryptococcic disease  (involvement of at least 2 noncontiguous sites or cryptococcal antigen titer >1:512):
[[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|left|250px|''[[C. neoformans]]'' seen in the lung of a patient with AIDS: The inner capsule of the organism stains red in this photomicrograph.]]
::::*Preferred regimen: treat like CNS infection.  
[[Infection]] with ''[[C. neoformans]]'' is termed [[cryptococcosis]]. Most [[Infection|infections]] with ''[[C. neoformans]]'' occur in the [[lungs]].<ref>Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012).[http://www.ncbi.nlm.nih.gov/pubmed/22783238 "Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."]</ref> However, [[fungal meningitis]] and [[encephalitis]], especially as a secondary [[infection]] for [[AIDS]] patients, are often caused by ''[[C. neoformans]]'', making it a particularly dangerous fungus.  [[Infection|Infections]] with this [[fungus]] are rare in those with fully functioning [[immune systems]].<ref name="cdcpathogen">[http://www.cdc.gov/ncidod/eid/vol4no1/buchanan.htm What Makes Cryptococcus neoformans a Pathogen?], Kent L. Buchanan and Juneann W. Murphy University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA</ref> So, ''[[C. neoformans]]'' is sometimes referred to as an [[Opportunistic infection|opportunistic]] fungus.<ref name="cdcpathogen" /> It is a facultative [[intracellular]] [[pathogen]].<ref>{{cite doi|10.1186/1471-2180-9-51}}</ref>  ''Cryptococcus neoformans'' was the first [[intracellular]] [[pathogen]] for which the non-lytic escape process termed vomocytosis was observed.<ref>{{cite journal|last1=Alvarez|first1=M|last2=Casadevall|first2=A|title=Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages.|journal=Current biology : CB|date=7 November 2006|volume=16|issue=21|pages=2161–5|pmid=17084702}}</ref><ref>{{cite journal|last1=Ma|first1=H|last2=Croudace|first2=JE|last3=Lammas|first3=DA|last4=May|first4=RC|title=Expulsion of live pathogenic yeast by macrophages.|journal=Current biology : CB|date=7 November 2006|volume=16|issue=21|pages=2156–60|pmid=17084701}}</ref>
:::*If infection occurs at a single site and no immunosupressive risk factors
::::*Preferred regimen: [[Fluconazole]] 400mg PO qd for 6-12 months


::*'''1.7. Cryptococcosis in Children'''
In human infection, ''[[C. neoformans]]'' is spread by [[inhalation]] of [[Aerosol|aerosolized]] basidiospores, and can [[Disseminated disease|disseminate]] to the [[central nervous system]], where it can cause [[meningoencephalitis]].<ref>Velagapudi R, Hsueh YP, Geunes-Boyer S, Wright JR, Heitman J (2009). Spores as infectious propagules of ''Cryptococcus neoformans''" ''Infect Immun'' 77(10) 4345-55. doi: 10.1128/IAI.00542-09. PMID 19620339</ref> In the [[lungs]], ''[[C. neoformans]]'' cells are [[phagocytosed]] by [[alveolar]] [[macrophages]].<ref name="Fan">Fan W, Kraus PR, Boily MJ, Heitman J (2005).'' Cryptococcus neoformans'' gene expression during murine macrophage infection. Eukaryot Cell 4(8) 1420-1433. PMID 16087747</ref> [[Macrophages]] produce [[oxidative]] and nitrosative agents, creating a hostile environment, to kill invading [[pathogens]].<ref>Alspaugh JA, Granger DL (1991). Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis" ''Infect Immun'' 59(7) 2291-2296. PMID 2050398</ref> However, some ''[[C. neoformans]]'' cells  can survive [[Intracellular|intracellularly]] in [[macrophages]].<ref name="Fan" /> [[Intracellular]] survival appears to be the basis for latency, [[disseminated disease]], and [[Drug resistance|resistance]] to eradication by [[Antifungal agent|antifungal agents]].  One mechanism by which ''[[C. neoformans]]'' survives the hostile [[intracellular]] environment of the [[macrophage]] involves [[upregulation]] of [[Gene expression|expression of genes]] involved in responses to [[oxidative stress]].<ref name="Fan" />
::::*Preferred regimen for induction and consolidation: [[Amphotericin B]] deoxycholate 1.0 mg/kg qd IV {{plus}} [[Flucytosine]] 100mg/kg PO or IV qid for 2 weeks followed by [[Fluconazole]] 10-12mg/kg PO qd for 8 weeks
::::*Alternative regimen: patients with renal dysfunction: change [[Amphotericin B]] deoxycholate by [[Liposomal AmB]] 5mg/kg IV qd or [[Amphotericin B]] lipid complex (ABLC) 5mg/kg IV qd
::::*Preferred regimen for maintenance: Fluconazole 6mg/kg PO qd. Discontinuation of maintenance therapy is poorly studied and should be individualized.
:::*Cryptococcal pneumonia:
::::*Preferred regimen Fluconazole 6-12mg/kg PO qd for 6-12 months


::*'''1.8. Cryptococcosis in Pregnant Women'''
Traversal of the [[blood–brain barrier]] by ''[[C. neoformans]]'' plays a key role in [[meningitis]] pathogenesis.<ref name="pmid = 22460646">{{cite journal | author = Liu TB | title = Molecular mechanisms of cryptococcal meningitis. | journal = Virulence |pmid = 22460646 | doi=10.4161/viru.18685 | pmc=3396696 | volume=3 | issue=2 | year=2012 | pages=173–81}}</ref> However, precise mechanisms by which it passes the [[blood-brain barrier]] are still unknown; one recent study in rats suggested an important role of [[Secretion|secreted]] [[serine]] [[proteases]].<ref name="pmid = 24398759">{{cite journal | author = Xu CY | title = permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis. | journal = J Int Med Res | volume = 42 | issue = 1|date=Feb 2014 | pmid = 24398759 | url = http://imr.sagepub.com/content/42/1/85.full  | pages = 85–92 | doi=10.1177/0300060513504365}}</ref>  The [[metalloprotease]] Mpr1 has been demonstrated to be critical in [[blood-brain barrier]] penetration.<ref>http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html</ref>
:::*Preferred regimen for induction and consolidation: [[Amphotericin B]] deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction - [[Liposomal AmB]] 3-4mg/kg IV qd {{or}} [[Amphotericin B]] lipid complex (ABLC) 5mg/kg IV qd. Consider using [[Flucytosine]] in relationship to benefit risk basis, since it is a Category C drug for pregnancy. Start [[Fluconazole]] after delivery. Avoid use during first trimester and consider use in the last 2 trimesters with the need for continuous antifungal therapy during pregnancy.  
:::*Note: If pulmonary cryptococcosis: perform close follow-up and administer fluconazole after delivery.


:*'''2. Cryptococcus gatti'''
The vast majority of environmental and clinical isolates of ''[[C. neoformans]]'' are mating type a.  Filaments of mating type a have [[haploid]] [[nuclei]] ordinarily, but these can undergo a process of [[Diploid|diploidization]] (perhaps by endoduplication or stimulated nuclear fusion) to form [[diploid]] cells termed blastospores.  The [[diploid]] [[nuclei]] of blastospores are able to undergo [[meiosis]], including [[recombination]], to form [[haploid]] basidiospores that can then be dispersed.<ref name="Lin">Lin X, Hull CM, Heitman J (2005). Sexual reproduction between partners of the same mating type in ''Cryptococcus neoformans''" ''Nature'' 434(7036) 1017-1021. PMID 15846346</ref> This process is referred to as monokaryotic fruiting. Required for this process is a [[gene]] designated ''dmc1'', a conserved [[Homolog|homologue]] of [[Gene|genes]] ''[[recA]]'' in [[bacteria]], and ''rad51'' in [[eukaryotes]] (see articles [[recA]] and rad51).  ''Dmc1'' mediates [[homologous chromosome]] pairing during [[meiosis]] and repair of [[Double-stranded DNA helix|double-strand]] breaks in [[DNA]].<ref>Michod RE, Bernstein H, Nedelcu AM Adaptive value of sex in microbial pathogens" ''Infect Genet Evol'' 8(3) 267-285. Review. {{DOI|10.1016/j.meegid.2008.01.002}} PMID 18295550 http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf</ref> One benefit of [[meiosis]] in ''[[C. neoformans]]'' could be to promote [[DNA repair]] in the DNA-damaging environment caused by the [[oxidative]] and nitrosative agents produced in [[macrophages]].<ref name="Lin" />  Thus, ''[[C. neoformans]]'' can undergo a [[Meiosis|meiotic]] process, monokaryotic fruiting, that may promote recombinational repair in the [[oxidative]], DNA-damaging environment of the host [[macrophage]], and this may contribute to its [[virulence]].
::*Disseminated cryptococcosis or CNS disease:
:::*Preferred regimen: treatment is the same as C. neoformans.
::*Pulmonary disease: single and small cryptococcoma:
:::*Preferred regimen: [[Fluconazole]] 400mg per day PO for 6-18months
::*Pulmonary disease: Very large or multiple cryptococcomas:
:::*Preferred regimen: administer [[Flucytosine]] {{and}} [[AmB deocycholate]] for 4-6 weeks, followed by fluconazole for 6-18 months.
:::*Note: Surgery should be considered if there is compression of vital structures {{or}} failure to reduce the size of the cryptococcoma after 4 weeks of therapy


==References==
== References ==
{{Reflist|2}}
{{Reflist|2}}


==External links==
*[http://www.scq.ubc.ca/?p=525 A good overview of Cryptococcus neoformans biology from the Science Creative Quarterly]


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style="background:#Template:Taxobox colour;"|Cryptococcus neoformans
Cryptococcus neoformans
Cryptococcus neoformans
style="background:#Template:Taxobox colour;" | Scientific classification
Kingdom: Fungi
Phylum: Basidiomycota
Class: Tremellomycetes
Order: Tremellales
Family: Tremellaceae
Genus: Cryptococcus
Species: Cryptococcus neoformans
This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Cryptococcosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Cryptococcus neoformans is an encapsulated yeast and an obligate aerobe that can live in both plants and animals.[1] [2]It is often found in bird excrement. It is the causative agent of cryptococcosis (cryptococcal pneumonia and meningitis).

Classification

Cryptococcus neoformans is composed of two varieties (v.): C. neoformans v. neoformans and C. n. v. grubii. A third variety, C. n. v. gattii, is now considered a distinct species, Cryptococcus gattii. C. n. v. grubii and C. n. v. neoformans have a worldwide distribution and are often found in soil contaminated by bird excrement. The genome sequence of C. neoformans v. neoformans was published in 2005.[3] Recent studies suggest colonies of C. neoformans and related fungi growing on the ruins of the melted down reactor of the chernobyl nuclear power plant may be able to use the energy of radiation (primary beta radiation) for "radiotrophic" growth.[4]

Characteristics

C. neoformans on Gram stain

C. neoformans grows as a yeast (unicellular) and replicates by budding. It makes hyphae during mating, and eventually creates basidiospores at the end of the hyphae before producing spores. Under host-relevant conditions, including low glucose, serum, 5% carbon dioxide, and low iron, among others, the cells produce a characteristic polysaccharide capsule.[5] The recognition of C. neoformans in Gram-stained smears of purulent exudates may be hampered by the presence of the large gelatinous capsule which apparently prevents definitive staining of the yeast-like cells. In such stained preparations, it may appear either as round cells with Gram-positive granular inclusions impressed upon a pale lavender cytoplasmic background or as Gram-negative lipoid bodies.[6] When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides. Under the microscope, the India ink stain is used for easy visualization of the capsule in cerebrospinal fluid.[7] The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells. This allows for quick and easy identification of C. neoformans. Unusual morphological forms are rarely seen.[8] For identification in tissue, mucicarmine stain provides specific staining of polysaccharide cell wall in C. neoformans. Cryptococcal antigen from cerebrospinal fluid is thought to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, though it might be unreliable in HIV-positive patients.[9]

Pathology

C. neoformans seen in the lung of a patient with AIDS: The inner capsule of the organism stains red in this photomicrograph.

Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans occur in the lungs.[10] However, fungal meningitis and encephalitis, especially as a secondary infection for AIDS patients, are often caused by C. neoformans, making it a particularly dangerous fungus. Infections with this fungus are rare in those with fully functioning immune systems.[11] So, C. neoformans is sometimes referred to as an opportunistic fungus.[11] It is a facultative intracellular pathogen.[12] Cryptococcus neoformans was the first intracellular pathogen for which the non-lytic escape process termed vomocytosis was observed.[13][14]

In human infection, C. neoformans is spread by inhalation of aerosolized basidiospores, and can disseminate to the central nervous system, where it can cause meningoencephalitis.[15] In the lungs, C. neoformans cells are phagocytosed by alveolar macrophages.[16] Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.[17] However, some C. neoformans cells can survive intracellularly in macrophages.[16] Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents. One mechanism by which C. neoformans survives the hostile intracellular environment of the macrophage involves upregulation of expression of genes involved in responses to oxidative stress.[16]

Traversal of the blood–brain barrier by C. neoformans plays a key role in meningitis pathogenesis.[18] However, precise mechanisms by which it passes the blood-brain barrier are still unknown; one recent study in rats suggested an important role of secreted serine proteases.[19] The metalloprotease Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.[20]

The vast majority of environmental and clinical isolates of C. neoformans are mating type a. Filaments of mating type a have haploid nuclei ordinarily, but these can undergo a process of diploidization (perhaps by endoduplication or stimulated nuclear fusion) to form diploid cells termed blastospores. The diploid nuclei of blastospores are able to undergo meiosis, including recombination, to form haploid basidiospores that can then be dispersed.[21] This process is referred to as monokaryotic fruiting. Required for this process is a gene designated dmc1, a conserved homologue of genes recA in bacteria, and rad51 in eukaryotes (see articles recA and rad51). Dmc1 mediates homologous chromosome pairing during meiosis and repair of double-strand breaks in DNA.[22] One benefit of meiosis in C. neoformans could be to promote DNA repair in the DNA-damaging environment caused by the oxidative and nitrosative agents produced in macrophages.[21] Thus, C. neoformans can undergo a meiotic process, monokaryotic fruiting, that may promote recombinational repair in the oxidative, DNA-damaging environment of the host macrophage, and this may contribute to its virulence.

References

  1. ↑ "What Makes Cryptococcus neoformans a Pathogen? - Volume 4, Number 1—March 1998 - Emerging Infectious Disease journal - CDC". wwwnc.cdc.gov. Retrieved 2015-11-18.
  2. ↑ Ingavale, Susham S.; Chang, Yun C.; Lee, Hyeseung; McClelland, Carol M.; Leong, Madeline L.; Kwon-Chung, Kyung J. (2008-09-01). "Importance of Mitochondria in Survival of Cryptococcus neoformans Under Low Oxygen Conditions and Tolerance to Cobalt Chloride". PLoS Pathogens. 4 (9): e1000155. doi:10.1371/journal.ppat.1000155. ISSN 1553-7366. PMC 2528940. PMID 18802457.
  3. ↑ Loftus BJ; et al. (2005). "The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans". Science. 307 (5713): 1321&ndash, 24. doi:10.1126/science.1103773. PMC 3520129. PMID 15653466.
  4. ↑ Dadachova E; et al. (2007). Rutherford, Julian, ed. "Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi". PLoS ONE. 2 (5): e457. doi:10.1371/journal.pone.0000457. PMC 1866175. PMID 17520016.
  5. ↑ [1]
  6. ↑ Bottone, E J. "Cryptococcus neoformans: pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates". National Center for Biotechnology Information. Journal of Clinical Microbiology. Retrieved 2014-11-19.
  7. ↑ Zerpa, R; Huicho, L; Guillén, A (September 1996). "Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens" (PDF). Journal of clinical microbiology. 34 (9): 2290–1. PMID 8862601.
  8. ↑ Shashikala; Kanungo, R; Srinivasan, S; Mathew, R; Kannan, M (Jul–Sep 2004). "Unusual morphological forms of Cryptococcus neoformans in cerebrospinal fluid". Indian journal of medical microbiology. 22 (3): 188–90. PMID 17642731.
  9. ↑ Antinori, Spinello; Radice, Anna; Galimberti, Laura; Magni, Carlo; Fasan, Marco; Parravicini, Carlo (November 2005). "The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis". Journal of clinical microbiology. 43 (11): 5828–9. doi:10.1128/JCM.43.11.5828-5829.2005. PMC 1287839. PMID 16272534.
  10. ↑ Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012)."Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."
  11. ↑ 11.0 11.1 What Makes Cryptococcus neoformans a Pathogen?, Kent L. Buchanan and Juneann W. Murphy University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  12. ↑ Template:Cite doi
  13. ↑ Alvarez, M; Casadevall, A (7 November 2006). "Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages". Current biology : CB. 16 (21): 2161–5. PMID 17084702.
  14. ↑ Ma, H; Croudace, JE; Lammas, DA; May, RC (7 November 2006). "Expulsion of live pathogenic yeast by macrophages". Current biology : CB. 16 (21): 2156–60. PMID 17084701.
  15. ↑ Velagapudi R, Hsueh YP, Geunes-Boyer S, Wright JR, Heitman J (2009). Spores as infectious propagules of Cryptococcus neoformans" Infect Immun 77(10) 4345-55. doi: 10.1128/IAI.00542-09. PMID 19620339
  16. ↑ 16.0 16.1 16.2 Fan W, Kraus PR, Boily MJ, Heitman J (2005). Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryot Cell 4(8) 1420-1433. PMID 16087747
  17. ↑ Alspaugh JA, Granger DL (1991). Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis" Infect Immun 59(7) 2291-2296. PMID 2050398
  18. ↑ Liu TB (2012). "Molecular mechanisms of cryptococcal meningitis". Virulence. 3 (2): 173–81. doi:10.4161/viru.18685. PMC 3396696. PMID 22460646.
  19. ↑ Xu CY (Feb 2014). "permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis". J Int Med Res. 42 (1): 85–92. doi:10.1177/0300060513504365. PMID 24398759.
  20. ↑ http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html
  21. ↑ 21.0 21.1 Lin X, Hull CM, Heitman J (2005). Sexual reproduction between partners of the same mating type in Cryptococcus neoformans" Nature 434(7036) 1017-1021. PMID 15846346
  22. ↑ Michod RE, Bernstein H, Nedelcu AM Adaptive value of sex in microbial pathogens" Infect Genet Evol 8(3) 267-285. Review. doi:10.1016/j.meegid.2008.01.002 PMID 18295550 http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf
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